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A pill for C. difficile works by increasing microbiome diversity
CP101, under development by Finch Therapeutics, proved more effective than a placebo in preventing recurrent infections for up to 24 weeks.
The CP101 capsules contain a powder of freeze-dried human stools from screened donors. They restore natural diversity that has been disrupted by antibiotics, said Jessica Allegretti, MD, MPH a gastroenterologist at Brigham and Women’s Hospital in Boston.
The treatment offers an alternative to fecal microbiota transplant, which can effectively treat antibiotic-resistant C. difficile infections but is difficult to standardize and administer – and doesn’t have full approval from the U.S. Food and Drug Administration, she added.
“I think this marks a moment in this space where we’re going to have better, safer, and more available options for patients,” she said in an interview. “It’s exciting.”
Dr. Allegretti is an author on three presentations of results from PRISM3, a phase 2 trial of CP101. They will be presented this week at the annual meeting of the American College of Gastroenterology. These results extend out to 24 weeks, whereas the 8-week results of this trial were presented a year ago at the same meeting.
Study details
The study enrolled 198 people who received antibiotics for recurrent C. difficile infections. Some patients had two or more recurrences, while others had only one recurrence but were 65 years of age or older.
“That was a unique aspect of this study, to see the effect of bringing a therapy like CP101 earlier in the treatment paradigm,” said Dr. Allegretti. “You can imagine for an older, frail, or more fragile patient that you would want to get rid of this [infection] earlier.”
After waiting 2-6 days for the antibiotics to wash out, the researchers randomly assigned 102 of these patients to take the CP101 pills orally and 96 to take placebo pills, both without bowel preparation.
The two groups were not significantly different in age, gender, comorbidities, the number of C. difficile recurrences, or the type of test used to diagnose the infection (PCR-based vs. toxin EIA-based).
After 8 weeks, 74.5% of those given the CP101 pills had not had a recurrence, compared with 61.5% of those given the placebo. The difference was just barely statistically significant (P = .0488).
Sixteen weeks later, the effect endured, with 73.5% of the CP101 group and 59.4% of the placebo group still free of recurrence. The statistical significance of the difference improved slightly (P = .0347).
Drug-related emergent adverse events were similar between the two groups: 16.3% for the CP101 group vs. 19.2% for the placebo group. These were mostly gastrointestinal symptoms, and none were serious.
Some of the patients received vancomycin as a first-line treatment for C. difficile infections, and the researchers wondered if the washout period was not sufficient to purge that antibiotic, leaving enough to interfere with the effectiveness of CP101.
Therefore, they separately analyzed 40 patients treated with fidaxomicin, which they expected to wash out more quickly. Among these patients, 81% who received CP101 were free of recurrences, at 8 weeks and 24 weeks. This compared with 42.1% of those who received the placebo, at both time points. This difference was more statistically significant (P = .0211).
Understanding how it works
To understand better how CP101 achieves its effects, the researchers collected stool samples from the patients and counted the number of different kinds organisms in each sample.
At baseline, the patients had about the same number, but after a week the diversity was greater in the patients treated with CP101, and that difference had increased at week 8. The researchers also found much less diversity of organisms in the stools of those patients who had recurrences of C. difficile infection.
The diversity of microbes in the successfully treated patients appeared to have been introduced by CP101. Dr. Allegretti and colleagues measured the number of organisms in the stool samples that came from CP101. They found that 96% of patients colonized by the CP101 organisms had avoided recurrence of the C. difficile infections, compared with 54.2% of those patients not colonized by these microbes.
“We now have some microbiome-based markers that show us as early as week 1 that the patient is going to be cured or not,” Dr. Allegretti said.
Based on these results, Finch plans to launch a phase 3 trial soon, she said.
The data on colonization is interesting because it has not been found with fecal microbiota transplants, said Purna Kashyap, MBBS, codirector of the Microbiome Program at the Mayo Clinic College of Medicine in Rochester, Minn., who was not involved in the study.
But to better interpret the data, it would be helpful to know more about how the placebo and CP101 groups compared at baseline with regard to medications, immunosuppression, and antibiotics used to treat the C. difficile infections, Dr. Kashyap said. He was struck by the lower cure rate in the portion of the placebo group treated with fidaxomicin.
“Overall, I think these are exciting observations based on the data but require careful review of the entire data to make sense of [them], which will happen when it goes through peer review,” he told this news organization in an email.
Several other standardized microbiota restoration products are under development, including at least two other capsules. In contrast to CP101, which is made up of whole stool, VE303 (Vedanta Biosciences) is a “rationally defined bacterial consortium,” and SER-109 (Seres Therapeutics) is a “consortium of highly purified Firmicutes spores.” VE303 has completed a phase 2 trial, and SER-109 has completed a phase 3 trial.
Dr. Allegretti is a consultant for Finch Therapeutics, which funded the trial. Dr. Kashyap has disclosed no relevant financial relationships.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff.
A version of this article first appeared on Medscape.com.
CP101, under development by Finch Therapeutics, proved more effective than a placebo in preventing recurrent infections for up to 24 weeks.
The CP101 capsules contain a powder of freeze-dried human stools from screened donors. They restore natural diversity that has been disrupted by antibiotics, said Jessica Allegretti, MD, MPH a gastroenterologist at Brigham and Women’s Hospital in Boston.
The treatment offers an alternative to fecal microbiota transplant, which can effectively treat antibiotic-resistant C. difficile infections but is difficult to standardize and administer – and doesn’t have full approval from the U.S. Food and Drug Administration, she added.
“I think this marks a moment in this space where we’re going to have better, safer, and more available options for patients,” she said in an interview. “It’s exciting.”
Dr. Allegretti is an author on three presentations of results from PRISM3, a phase 2 trial of CP101. They will be presented this week at the annual meeting of the American College of Gastroenterology. These results extend out to 24 weeks, whereas the 8-week results of this trial were presented a year ago at the same meeting.
Study details
The study enrolled 198 people who received antibiotics for recurrent C. difficile infections. Some patients had two or more recurrences, while others had only one recurrence but were 65 years of age or older.
“That was a unique aspect of this study, to see the effect of bringing a therapy like CP101 earlier in the treatment paradigm,” said Dr. Allegretti. “You can imagine for an older, frail, or more fragile patient that you would want to get rid of this [infection] earlier.”
After waiting 2-6 days for the antibiotics to wash out, the researchers randomly assigned 102 of these patients to take the CP101 pills orally and 96 to take placebo pills, both without bowel preparation.
The two groups were not significantly different in age, gender, comorbidities, the number of C. difficile recurrences, or the type of test used to diagnose the infection (PCR-based vs. toxin EIA-based).
After 8 weeks, 74.5% of those given the CP101 pills had not had a recurrence, compared with 61.5% of those given the placebo. The difference was just barely statistically significant (P = .0488).
Sixteen weeks later, the effect endured, with 73.5% of the CP101 group and 59.4% of the placebo group still free of recurrence. The statistical significance of the difference improved slightly (P = .0347).
Drug-related emergent adverse events were similar between the two groups: 16.3% for the CP101 group vs. 19.2% for the placebo group. These were mostly gastrointestinal symptoms, and none were serious.
Some of the patients received vancomycin as a first-line treatment for C. difficile infections, and the researchers wondered if the washout period was not sufficient to purge that antibiotic, leaving enough to interfere with the effectiveness of CP101.
Therefore, they separately analyzed 40 patients treated with fidaxomicin, which they expected to wash out more quickly. Among these patients, 81% who received CP101 were free of recurrences, at 8 weeks and 24 weeks. This compared with 42.1% of those who received the placebo, at both time points. This difference was more statistically significant (P = .0211).
Understanding how it works
To understand better how CP101 achieves its effects, the researchers collected stool samples from the patients and counted the number of different kinds organisms in each sample.
At baseline, the patients had about the same number, but after a week the diversity was greater in the patients treated with CP101, and that difference had increased at week 8. The researchers also found much less diversity of organisms in the stools of those patients who had recurrences of C. difficile infection.
The diversity of microbes in the successfully treated patients appeared to have been introduced by CP101. Dr. Allegretti and colleagues measured the number of organisms in the stool samples that came from CP101. They found that 96% of patients colonized by the CP101 organisms had avoided recurrence of the C. difficile infections, compared with 54.2% of those patients not colonized by these microbes.
“We now have some microbiome-based markers that show us as early as week 1 that the patient is going to be cured or not,” Dr. Allegretti said.
Based on these results, Finch plans to launch a phase 3 trial soon, she said.
The data on colonization is interesting because it has not been found with fecal microbiota transplants, said Purna Kashyap, MBBS, codirector of the Microbiome Program at the Mayo Clinic College of Medicine in Rochester, Minn., who was not involved in the study.
But to better interpret the data, it would be helpful to know more about how the placebo and CP101 groups compared at baseline with regard to medications, immunosuppression, and antibiotics used to treat the C. difficile infections, Dr. Kashyap said. He was struck by the lower cure rate in the portion of the placebo group treated with fidaxomicin.
“Overall, I think these are exciting observations based on the data but require careful review of the entire data to make sense of [them], which will happen when it goes through peer review,” he told this news organization in an email.
Several other standardized microbiota restoration products are under development, including at least two other capsules. In contrast to CP101, which is made up of whole stool, VE303 (Vedanta Biosciences) is a “rationally defined bacterial consortium,” and SER-109 (Seres Therapeutics) is a “consortium of highly purified Firmicutes spores.” VE303 has completed a phase 2 trial, and SER-109 has completed a phase 3 trial.
Dr. Allegretti is a consultant for Finch Therapeutics, which funded the trial. Dr. Kashyap has disclosed no relevant financial relationships.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff.
A version of this article first appeared on Medscape.com.
CP101, under development by Finch Therapeutics, proved more effective than a placebo in preventing recurrent infections for up to 24 weeks.
The CP101 capsules contain a powder of freeze-dried human stools from screened donors. They restore natural diversity that has been disrupted by antibiotics, said Jessica Allegretti, MD, MPH a gastroenterologist at Brigham and Women’s Hospital in Boston.
The treatment offers an alternative to fecal microbiota transplant, which can effectively treat antibiotic-resistant C. difficile infections but is difficult to standardize and administer – and doesn’t have full approval from the U.S. Food and Drug Administration, she added.
“I think this marks a moment in this space where we’re going to have better, safer, and more available options for patients,” she said in an interview. “It’s exciting.”
Dr. Allegretti is an author on three presentations of results from PRISM3, a phase 2 trial of CP101. They will be presented this week at the annual meeting of the American College of Gastroenterology. These results extend out to 24 weeks, whereas the 8-week results of this trial were presented a year ago at the same meeting.
Study details
The study enrolled 198 people who received antibiotics for recurrent C. difficile infections. Some patients had two or more recurrences, while others had only one recurrence but were 65 years of age or older.
“That was a unique aspect of this study, to see the effect of bringing a therapy like CP101 earlier in the treatment paradigm,” said Dr. Allegretti. “You can imagine for an older, frail, or more fragile patient that you would want to get rid of this [infection] earlier.”
After waiting 2-6 days for the antibiotics to wash out, the researchers randomly assigned 102 of these patients to take the CP101 pills orally and 96 to take placebo pills, both without bowel preparation.
The two groups were not significantly different in age, gender, comorbidities, the number of C. difficile recurrences, or the type of test used to diagnose the infection (PCR-based vs. toxin EIA-based).
After 8 weeks, 74.5% of those given the CP101 pills had not had a recurrence, compared with 61.5% of those given the placebo. The difference was just barely statistically significant (P = .0488).
Sixteen weeks later, the effect endured, with 73.5% of the CP101 group and 59.4% of the placebo group still free of recurrence. The statistical significance of the difference improved slightly (P = .0347).
Drug-related emergent adverse events were similar between the two groups: 16.3% for the CP101 group vs. 19.2% for the placebo group. These were mostly gastrointestinal symptoms, and none were serious.
Some of the patients received vancomycin as a first-line treatment for C. difficile infections, and the researchers wondered if the washout period was not sufficient to purge that antibiotic, leaving enough to interfere with the effectiveness of CP101.
Therefore, they separately analyzed 40 patients treated with fidaxomicin, which they expected to wash out more quickly. Among these patients, 81% who received CP101 were free of recurrences, at 8 weeks and 24 weeks. This compared with 42.1% of those who received the placebo, at both time points. This difference was more statistically significant (P = .0211).
Understanding how it works
To understand better how CP101 achieves its effects, the researchers collected stool samples from the patients and counted the number of different kinds organisms in each sample.
At baseline, the patients had about the same number, but after a week the diversity was greater in the patients treated with CP101, and that difference had increased at week 8. The researchers also found much less diversity of organisms in the stools of those patients who had recurrences of C. difficile infection.
The diversity of microbes in the successfully treated patients appeared to have been introduced by CP101. Dr. Allegretti and colleagues measured the number of organisms in the stool samples that came from CP101. They found that 96% of patients colonized by the CP101 organisms had avoided recurrence of the C. difficile infections, compared with 54.2% of those patients not colonized by these microbes.
“We now have some microbiome-based markers that show us as early as week 1 that the patient is going to be cured or not,” Dr. Allegretti said.
Based on these results, Finch plans to launch a phase 3 trial soon, she said.
The data on colonization is interesting because it has not been found with fecal microbiota transplants, said Purna Kashyap, MBBS, codirector of the Microbiome Program at the Mayo Clinic College of Medicine in Rochester, Minn., who was not involved in the study.
But to better interpret the data, it would be helpful to know more about how the placebo and CP101 groups compared at baseline with regard to medications, immunosuppression, and antibiotics used to treat the C. difficile infections, Dr. Kashyap said. He was struck by the lower cure rate in the portion of the placebo group treated with fidaxomicin.
“Overall, I think these are exciting observations based on the data but require careful review of the entire data to make sense of [them], which will happen when it goes through peer review,” he told this news organization in an email.
Several other standardized microbiota restoration products are under development, including at least two other capsules. In contrast to CP101, which is made up of whole stool, VE303 (Vedanta Biosciences) is a “rationally defined bacterial consortium,” and SER-109 (Seres Therapeutics) is a “consortium of highly purified Firmicutes spores.” VE303 has completed a phase 2 trial, and SER-109 has completed a phase 3 trial.
Dr. Allegretti is a consultant for Finch Therapeutics, which funded the trial. Dr. Kashyap has disclosed no relevant financial relationships.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff.
A version of this article first appeared on Medscape.com.
FROM ACG 2021
UC relapse associated with impaired luminal control of macrophage maturation
Patients with ulcerative colitis (UC) who are in remission from their disease lack luminal signals capable of inducing macrophage hyporesponsiveness, which may contribute to a patient’s persistent vulnerability to relapse, according to a new study.
“Together with the distinct fecal metabolomic profile of UC patients in remission, our data suggest that UC patients may lack the signals required for proper macrophage education, rendering them vulnerable to relapse,” wrote study authors Lujain Maasfeh, PhD, of the University of Gothenburg (Sweden) and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
Macrophages found in the lamina propria play a role in sustaining intestinal homeostasis. Through education by local signals, intestinal macrophages adopt a hyporesponsive phenotype and tolerogenic nature and are replenished constantly from monocytes. In patients with UC who are in remission, however, the lack of proper macrophage maturation may result in gut inflammation.
Current evidence has yet to define fully the immunomodulating determinants in the education of intestinal macrophages; however, Dr. Maasfeh and associates wrote that “intestinal microbiota and microbiota-derived metabolites increasingly are recognized for their role in imprinting tissue-specific features of intestinal macrophages.”
The researchers added that previous evidence has established that patients with UC demonstrate dysbiosis, which may impact maturation of intestinal macrophages. As such, the hyporesponsive state of intestinal lamina propria macrophages induced by the microbiota may be lost in patients with UC who are in remission, ultimately resulting in disease relapse.
To gauge the effects of fecal luminal factors on macrophage phenotype and function, the researchers extracted fecal supernatants (FS) from the fecal samples of 10 healthy volunteers and 17 patients with UC who were in remission. Following maturation of monocytes to macrophages in the presence of granulocyte-macrophage colony-stimulating factor without and with FS, the researchers assessed macrophage phenotype and function. The investigators also used gas chromatography and mass spectrometry to analyze fecal metabolomic profiles.
In healthy donors, fecal luminal factors effectively downregulated Toll-like receptor signaling, cytokine signaling, as well as antigen presentation in macrophages. In contrast, the fecal luminal factors in patients with UC demonstrated less potency in their ability to induce lipopolysaccharide hyporesponsiveness. An immune pathway scoring analysis also showed a consistently higher reaction potential among UC remission FS-treated macrophages vs. healthy FS-treated macrophages.
While FS treatment did not seem to affect the phagocytic and bactericidal abilities of macrophages, the researchers observed that the healthy FS-treated macrophages better suppressed a cluster of differentiation 4+ T-cell activation as well as interferon gamma secretion vs. FS-treated macrophages from patients with UC in remission. The FS-treated macrophages in the UC remission population also featured less potency in their ability to suppress CD4+ T-cell activation and cytokine secretion.
The authors acknowledged a few limitations, including the small sample size and the effects from using in vitro system.
“Identification of the factors involved in intestinal macrophage education is important to maintain/reestablish gut homeostasis in patients with UC,” they concluded.
The study received financial support from Swedish Research Council-Medicine, in addition to funding from a Region Västra Götaland ALF-agreement, the Knut och Alice Wallenberg Foundation Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Ruth and Richard Julin’s foundation, Adlerbertska Foundation, Wilhelm and Martina Lundgren Foundation, and Apotekare Hedberg’s Foundation. The authors disclose no conflicts.
Current therapies for ulcerative colitis, including anti-inflammatory drugs and biologics such as anti–tumor necrosis factor therapies and anti-interleukin-12/23 antibodies, are aimed at inducing and maintaining remission. However, approximately 20%-40% of patients are primary nonresponders and about 23%-46% patients lose response within 12 months of treatment, which suggests an unmet need to look for new therapeutic targets.
Intestinal macrophages are essential in the maintenance of intestinal immune homeostasis by acquiring a hyporesponsive state in response to microbial stimuli. This study by Maasfeh and colleagues highlights the role of luminal factors in shaping the macrophage response. The authors show that human monocyte-derived macrophage treated with fecal luminal factors derived from patients with ulcerative colitis in remission are less hyporesponsive to lipopolysaccharide stimulation. They are also less efficient in modulating cytokine and Toll-like receptor signaling pathway genes and have a dampened ability to suppress CD4+ T-cell activation and interferon gamma secretion compared to controls.
Luminal factors derived from gut microbiota (short-chain fatty acids, indole derivatives, polyamines, and bile acids) can shape macrophage differentiation and antibacterial response. This study points toward key luminal factors, which might be playing pivotal roles in maintaining homeostasis. However, the current study needs further validation in a larger cohort of patients and in the lamina propria macrophages. In addition, it will be important to know the physiologically relevant concentration to achieve functional effect. The identification of specific metabolites responsible for inducing hyporesponsiveness in macrophages could be an approach for mining potential therapeutic targets.
Dr. Sumeet Pandey is in the Translational Gastroenterology Unit at John Radcliffe Hospital at the University of Oxford (England). He has no conflicts of interest.
Current therapies for ulcerative colitis, including anti-inflammatory drugs and biologics such as anti–tumor necrosis factor therapies and anti-interleukin-12/23 antibodies, are aimed at inducing and maintaining remission. However, approximately 20%-40% of patients are primary nonresponders and about 23%-46% patients lose response within 12 months of treatment, which suggests an unmet need to look for new therapeutic targets.
Intestinal macrophages are essential in the maintenance of intestinal immune homeostasis by acquiring a hyporesponsive state in response to microbial stimuli. This study by Maasfeh and colleagues highlights the role of luminal factors in shaping the macrophage response. The authors show that human monocyte-derived macrophage treated with fecal luminal factors derived from patients with ulcerative colitis in remission are less hyporesponsive to lipopolysaccharide stimulation. They are also less efficient in modulating cytokine and Toll-like receptor signaling pathway genes and have a dampened ability to suppress CD4+ T-cell activation and interferon gamma secretion compared to controls.
Luminal factors derived from gut microbiota (short-chain fatty acids, indole derivatives, polyamines, and bile acids) can shape macrophage differentiation and antibacterial response. This study points toward key luminal factors, which might be playing pivotal roles in maintaining homeostasis. However, the current study needs further validation in a larger cohort of patients and in the lamina propria macrophages. In addition, it will be important to know the physiologically relevant concentration to achieve functional effect. The identification of specific metabolites responsible for inducing hyporesponsiveness in macrophages could be an approach for mining potential therapeutic targets.
Dr. Sumeet Pandey is in the Translational Gastroenterology Unit at John Radcliffe Hospital at the University of Oxford (England). He has no conflicts of interest.
Current therapies for ulcerative colitis, including anti-inflammatory drugs and biologics such as anti–tumor necrosis factor therapies and anti-interleukin-12/23 antibodies, are aimed at inducing and maintaining remission. However, approximately 20%-40% of patients are primary nonresponders and about 23%-46% patients lose response within 12 months of treatment, which suggests an unmet need to look for new therapeutic targets.
Intestinal macrophages are essential in the maintenance of intestinal immune homeostasis by acquiring a hyporesponsive state in response to microbial stimuli. This study by Maasfeh and colleagues highlights the role of luminal factors in shaping the macrophage response. The authors show that human monocyte-derived macrophage treated with fecal luminal factors derived from patients with ulcerative colitis in remission are less hyporesponsive to lipopolysaccharide stimulation. They are also less efficient in modulating cytokine and Toll-like receptor signaling pathway genes and have a dampened ability to suppress CD4+ T-cell activation and interferon gamma secretion compared to controls.
Luminal factors derived from gut microbiota (short-chain fatty acids, indole derivatives, polyamines, and bile acids) can shape macrophage differentiation and antibacterial response. This study points toward key luminal factors, which might be playing pivotal roles in maintaining homeostasis. However, the current study needs further validation in a larger cohort of patients and in the lamina propria macrophages. In addition, it will be important to know the physiologically relevant concentration to achieve functional effect. The identification of specific metabolites responsible for inducing hyporesponsiveness in macrophages could be an approach for mining potential therapeutic targets.
Dr. Sumeet Pandey is in the Translational Gastroenterology Unit at John Radcliffe Hospital at the University of Oxford (England). He has no conflicts of interest.
Patients with ulcerative colitis (UC) who are in remission from their disease lack luminal signals capable of inducing macrophage hyporesponsiveness, which may contribute to a patient’s persistent vulnerability to relapse, according to a new study.
“Together with the distinct fecal metabolomic profile of UC patients in remission, our data suggest that UC patients may lack the signals required for proper macrophage education, rendering them vulnerable to relapse,” wrote study authors Lujain Maasfeh, PhD, of the University of Gothenburg (Sweden) and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
Macrophages found in the lamina propria play a role in sustaining intestinal homeostasis. Through education by local signals, intestinal macrophages adopt a hyporesponsive phenotype and tolerogenic nature and are replenished constantly from monocytes. In patients with UC who are in remission, however, the lack of proper macrophage maturation may result in gut inflammation.
Current evidence has yet to define fully the immunomodulating determinants in the education of intestinal macrophages; however, Dr. Maasfeh and associates wrote that “intestinal microbiota and microbiota-derived metabolites increasingly are recognized for their role in imprinting tissue-specific features of intestinal macrophages.”
The researchers added that previous evidence has established that patients with UC demonstrate dysbiosis, which may impact maturation of intestinal macrophages. As such, the hyporesponsive state of intestinal lamina propria macrophages induced by the microbiota may be lost in patients with UC who are in remission, ultimately resulting in disease relapse.
To gauge the effects of fecal luminal factors on macrophage phenotype and function, the researchers extracted fecal supernatants (FS) from the fecal samples of 10 healthy volunteers and 17 patients with UC who were in remission. Following maturation of monocytes to macrophages in the presence of granulocyte-macrophage colony-stimulating factor without and with FS, the researchers assessed macrophage phenotype and function. The investigators also used gas chromatography and mass spectrometry to analyze fecal metabolomic profiles.
In healthy donors, fecal luminal factors effectively downregulated Toll-like receptor signaling, cytokine signaling, as well as antigen presentation in macrophages. In contrast, the fecal luminal factors in patients with UC demonstrated less potency in their ability to induce lipopolysaccharide hyporesponsiveness. An immune pathway scoring analysis also showed a consistently higher reaction potential among UC remission FS-treated macrophages vs. healthy FS-treated macrophages.
While FS treatment did not seem to affect the phagocytic and bactericidal abilities of macrophages, the researchers observed that the healthy FS-treated macrophages better suppressed a cluster of differentiation 4+ T-cell activation as well as interferon gamma secretion vs. FS-treated macrophages from patients with UC in remission. The FS-treated macrophages in the UC remission population also featured less potency in their ability to suppress CD4+ T-cell activation and cytokine secretion.
The authors acknowledged a few limitations, including the small sample size and the effects from using in vitro system.
“Identification of the factors involved in intestinal macrophage education is important to maintain/reestablish gut homeostasis in patients with UC,” they concluded.
The study received financial support from Swedish Research Council-Medicine, in addition to funding from a Region Västra Götaland ALF-agreement, the Knut och Alice Wallenberg Foundation Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Ruth and Richard Julin’s foundation, Adlerbertska Foundation, Wilhelm and Martina Lundgren Foundation, and Apotekare Hedberg’s Foundation. The authors disclose no conflicts.
Patients with ulcerative colitis (UC) who are in remission from their disease lack luminal signals capable of inducing macrophage hyporesponsiveness, which may contribute to a patient’s persistent vulnerability to relapse, according to a new study.
“Together with the distinct fecal metabolomic profile of UC patients in remission, our data suggest that UC patients may lack the signals required for proper macrophage education, rendering them vulnerable to relapse,” wrote study authors Lujain Maasfeh, PhD, of the University of Gothenburg (Sweden) and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
Macrophages found in the lamina propria play a role in sustaining intestinal homeostasis. Through education by local signals, intestinal macrophages adopt a hyporesponsive phenotype and tolerogenic nature and are replenished constantly from monocytes. In patients with UC who are in remission, however, the lack of proper macrophage maturation may result in gut inflammation.
Current evidence has yet to define fully the immunomodulating determinants in the education of intestinal macrophages; however, Dr. Maasfeh and associates wrote that “intestinal microbiota and microbiota-derived metabolites increasingly are recognized for their role in imprinting tissue-specific features of intestinal macrophages.”
The researchers added that previous evidence has established that patients with UC demonstrate dysbiosis, which may impact maturation of intestinal macrophages. As such, the hyporesponsive state of intestinal lamina propria macrophages induced by the microbiota may be lost in patients with UC who are in remission, ultimately resulting in disease relapse.
To gauge the effects of fecal luminal factors on macrophage phenotype and function, the researchers extracted fecal supernatants (FS) from the fecal samples of 10 healthy volunteers and 17 patients with UC who were in remission. Following maturation of monocytes to macrophages in the presence of granulocyte-macrophage colony-stimulating factor without and with FS, the researchers assessed macrophage phenotype and function. The investigators also used gas chromatography and mass spectrometry to analyze fecal metabolomic profiles.
In healthy donors, fecal luminal factors effectively downregulated Toll-like receptor signaling, cytokine signaling, as well as antigen presentation in macrophages. In contrast, the fecal luminal factors in patients with UC demonstrated less potency in their ability to induce lipopolysaccharide hyporesponsiveness. An immune pathway scoring analysis also showed a consistently higher reaction potential among UC remission FS-treated macrophages vs. healthy FS-treated macrophages.
While FS treatment did not seem to affect the phagocytic and bactericidal abilities of macrophages, the researchers observed that the healthy FS-treated macrophages better suppressed a cluster of differentiation 4+ T-cell activation as well as interferon gamma secretion vs. FS-treated macrophages from patients with UC in remission. The FS-treated macrophages in the UC remission population also featured less potency in their ability to suppress CD4+ T-cell activation and cytokine secretion.
The authors acknowledged a few limitations, including the small sample size and the effects from using in vitro system.
“Identification of the factors involved in intestinal macrophage education is important to maintain/reestablish gut homeostasis in patients with UC,” they concluded.
The study received financial support from Swedish Research Council-Medicine, in addition to funding from a Region Västra Götaland ALF-agreement, the Knut och Alice Wallenberg Foundation Wallenberg Centre for Molecular and Translational Medicine at the University of Gothenburg, Ruth and Richard Julin’s foundation, Adlerbertska Foundation, Wilhelm and Martina Lundgren Foundation, and Apotekare Hedberg’s Foundation. The authors disclose no conflicts.
In Crohn’s disease, no decline in stomas despite increasing use of anti-TNF
Despite increasing use of anti–tumor necrosis factor (TNF) medications in recent years and a lower rate of proctectomy, there has been no decline in stoma incidence among Crohn’s disease (CD) patients, according to a new retrospective analysis of a Swedish population database.
The overall 5-year stoma incidence was 2.5%, and there was no significant difference between calendar periods, wrote Åsa H Everhov, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues. Their report is in Inflammatory Bowel Diseases. Previous population studies looking at temporal trends have found mixed results with respect to stoma formation. However, many previous studies analyzed cohorts from referral centers that included patients with more severe disease. Others had small sample sizes.
“This is somewhat surprising as the rate of overall surgery for Crohn’s has decreased with the advent of biologic therapies,” said Miguel Regueiro, MD, who was asked to comment on the study. He is chair of the Digestive Disease and Surgery Institute, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.
Dr. Regueiro pointed out that the rate of stoma creation was quite low, and characteristics of the disease may explain the lack of a trend. For example, anorectal disease, especially when accompanied by fistula and strictures, is often medication refractory. “Although the study could not delineate this, it is my clinical practice experience that some patients present with destructive anorectal disease early, and that despite medications the ‘damage is too far gone’ to reverse,” said Dr. Regueiro. Also, the anorectum does not allow for an anastomosis since there is no region to connect to that isn’t damaged, he added.
The findings shouldn’t affect patient management or counseling, according to Stephen Hanauer, MD, professor of medicine at Northwestern University, Chicago, who was not involved in the study. “The indications for surgery in Crohn’s disease have not changed with the advent of newer therapies. Complications such as strictures and abscesses are still treated with similar surgeries. It is hopeful that the future course after surgery can be modified by effective biologic therapies,” he said.
The study authors noted that the findings are consistent with previous studies suggesting that the rate of abdominal surgery had begun to decline before anti-TNF drugs were introduced. The Swedish National Patient Register used in the current work includes only inpatient data before 2001, preventing a broader analysis prior to 1999, when infliximab gained approval in Sweden. But the researchers looked at time from first surgery to stoma, and found a decline in stoma formation between 1994 and 1997. A similar analysis found no decrease in the 2000s.
The researchers pointed out that anti-TNF inhibitor use would be expected to reduce the rate of stomas by inducing remission, although temporary stomas may be created to relieve symptoms while waiting for the medication to take effect. But anti-TNF agents could also encourage patients and physicians to postpone surgery. The delay could raise the chance of surgical complications, which in turn could lead to creation of a temporary stoma. Permanent stomas are typically created in cases of severe perianal CD.
The study could come as a disappointment to some patients and physicians, according to the authors. “The more active and early use of anti-TNF (therapeutics), in combination with the decreasing incidence of abdominal surgery in general for CD, has raised hopes of decreased incidence of stoma formation, but this was not observed in the present study,” the authors wrote.
But the news wasn’t all bad. The study found a lower cumulative stoma incidence than had previous studies, and the incidence of permanent stoma was just 0.8% at 5 years, “which should be reassuring for patients,” according to the authors.
CD patients often fear that a stoma will become necessary, but a stoma can be quite beneficial, allowing patients to regain some control over their lives. That can lead to more work participation and social activity. Qualitative studies showed that both patients and clinicians described outcomes of stoma placement as exceeding expectations, with a key factor being support from other inflammatory bowel disease patients with stomas. The authors encouraged clinicians to discuss the possibility of a stoma early on in the treatment process, and to avoid referring to it as a “last resort.”
The study also suggests that patients with anal and anorectal Crohn’s disease should receive biologics early, and a multidisciplinary approach involving both the gastroenterologist and surgeon is important. And patients should be counseled on the impact of disease on diet and psychological health, according to Dr. Regueiro.
The new study analyzed data between 2003 and 2014, from 18,815 Crohn’s disease patients who had not undergone previous surgery. The median age was 39 years, 53% were women, and 12% were pediatric patients.
After a median follow-up of 9.6 years, 9.5% of patients had perianal disease. Overall, 36% of patients had been treated with immunomodulators, and 17% with anti-TNF agents; 3.5% had stoma surgery, and just 0.05% underwent proctectomy.
Among those who had a stoma placed, the median age at diagnosis was 47 years, and 53% were men. In all, 12.6% had perianal disease at diagnosis, and 24.5% had perianal disease by the end of follow-up; 43% had received immunomodulators, and 26% anti-TNF agents. Among stomas, 64% were ileostomies, and 44% were temporary, with 88% of removals performed within 2 years of surgery.
The calendar periods of CD onset (2003-2006, 2007-2010, and 2011-2014) had similar rates of cumulative stoma placement (log rank test, P = .61). Overall, the 1-year cumulative incidence of stoma was 1.3%, the 3-year incidence was 1.9%, and the 5-year incidence was 2.5%.
The cumulative incidence of ever-use of anti-TNF agents increased with each successive calendar period (P < .001), but there was no significant difference in cumulative stoma incidence (P = .07).
One limitation of the study is the lack of detailed patient characteristics, and another is the short follow-up for patients diagnosed during 2011-2014. Another is that the results may not be generalizable to a U.S. population.
The study authors have received funding and consulted for various pharmaceutical companies. Dr. Regueiro has received grants from and has consulted or been on a scientific advisory board for Abbvie, UCB, and Janssen. Dr. Hanauer has no relevant financial disclosures.
This article was updated Oct. 13, 2021.
Despite increasing use of anti–tumor necrosis factor (TNF) medications in recent years and a lower rate of proctectomy, there has been no decline in stoma incidence among Crohn’s disease (CD) patients, according to a new retrospective analysis of a Swedish population database.
The overall 5-year stoma incidence was 2.5%, and there was no significant difference between calendar periods, wrote Åsa H Everhov, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues. Their report is in Inflammatory Bowel Diseases. Previous population studies looking at temporal trends have found mixed results with respect to stoma formation. However, many previous studies analyzed cohorts from referral centers that included patients with more severe disease. Others had small sample sizes.
“This is somewhat surprising as the rate of overall surgery for Crohn’s has decreased with the advent of biologic therapies,” said Miguel Regueiro, MD, who was asked to comment on the study. He is chair of the Digestive Disease and Surgery Institute, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.
Dr. Regueiro pointed out that the rate of stoma creation was quite low, and characteristics of the disease may explain the lack of a trend. For example, anorectal disease, especially when accompanied by fistula and strictures, is often medication refractory. “Although the study could not delineate this, it is my clinical practice experience that some patients present with destructive anorectal disease early, and that despite medications the ‘damage is too far gone’ to reverse,” said Dr. Regueiro. Also, the anorectum does not allow for an anastomosis since there is no region to connect to that isn’t damaged, he added.
The findings shouldn’t affect patient management or counseling, according to Stephen Hanauer, MD, professor of medicine at Northwestern University, Chicago, who was not involved in the study. “The indications for surgery in Crohn’s disease have not changed with the advent of newer therapies. Complications such as strictures and abscesses are still treated with similar surgeries. It is hopeful that the future course after surgery can be modified by effective biologic therapies,” he said.
The study authors noted that the findings are consistent with previous studies suggesting that the rate of abdominal surgery had begun to decline before anti-TNF drugs were introduced. The Swedish National Patient Register used in the current work includes only inpatient data before 2001, preventing a broader analysis prior to 1999, when infliximab gained approval in Sweden. But the researchers looked at time from first surgery to stoma, and found a decline in stoma formation between 1994 and 1997. A similar analysis found no decrease in the 2000s.
The researchers pointed out that anti-TNF inhibitor use would be expected to reduce the rate of stomas by inducing remission, although temporary stomas may be created to relieve symptoms while waiting for the medication to take effect. But anti-TNF agents could also encourage patients and physicians to postpone surgery. The delay could raise the chance of surgical complications, which in turn could lead to creation of a temporary stoma. Permanent stomas are typically created in cases of severe perianal CD.
The study could come as a disappointment to some patients and physicians, according to the authors. “The more active and early use of anti-TNF (therapeutics), in combination with the decreasing incidence of abdominal surgery in general for CD, has raised hopes of decreased incidence of stoma formation, but this was not observed in the present study,” the authors wrote.
But the news wasn’t all bad. The study found a lower cumulative stoma incidence than had previous studies, and the incidence of permanent stoma was just 0.8% at 5 years, “which should be reassuring for patients,” according to the authors.
CD patients often fear that a stoma will become necessary, but a stoma can be quite beneficial, allowing patients to regain some control over their lives. That can lead to more work participation and social activity. Qualitative studies showed that both patients and clinicians described outcomes of stoma placement as exceeding expectations, with a key factor being support from other inflammatory bowel disease patients with stomas. The authors encouraged clinicians to discuss the possibility of a stoma early on in the treatment process, and to avoid referring to it as a “last resort.”
The study also suggests that patients with anal and anorectal Crohn’s disease should receive biologics early, and a multidisciplinary approach involving both the gastroenterologist and surgeon is important. And patients should be counseled on the impact of disease on diet and psychological health, according to Dr. Regueiro.
The new study analyzed data between 2003 and 2014, from 18,815 Crohn’s disease patients who had not undergone previous surgery. The median age was 39 years, 53% were women, and 12% were pediatric patients.
After a median follow-up of 9.6 years, 9.5% of patients had perianal disease. Overall, 36% of patients had been treated with immunomodulators, and 17% with anti-TNF agents; 3.5% had stoma surgery, and just 0.05% underwent proctectomy.
Among those who had a stoma placed, the median age at diagnosis was 47 years, and 53% were men. In all, 12.6% had perianal disease at diagnosis, and 24.5% had perianal disease by the end of follow-up; 43% had received immunomodulators, and 26% anti-TNF agents. Among stomas, 64% were ileostomies, and 44% were temporary, with 88% of removals performed within 2 years of surgery.
The calendar periods of CD onset (2003-2006, 2007-2010, and 2011-2014) had similar rates of cumulative stoma placement (log rank test, P = .61). Overall, the 1-year cumulative incidence of stoma was 1.3%, the 3-year incidence was 1.9%, and the 5-year incidence was 2.5%.
The cumulative incidence of ever-use of anti-TNF agents increased with each successive calendar period (P < .001), but there was no significant difference in cumulative stoma incidence (P = .07).
One limitation of the study is the lack of detailed patient characteristics, and another is the short follow-up for patients diagnosed during 2011-2014. Another is that the results may not be generalizable to a U.S. population.
The study authors have received funding and consulted for various pharmaceutical companies. Dr. Regueiro has received grants from and has consulted or been on a scientific advisory board for Abbvie, UCB, and Janssen. Dr. Hanauer has no relevant financial disclosures.
This article was updated Oct. 13, 2021.
Despite increasing use of anti–tumor necrosis factor (TNF) medications in recent years and a lower rate of proctectomy, there has been no decline in stoma incidence among Crohn’s disease (CD) patients, according to a new retrospective analysis of a Swedish population database.
The overall 5-year stoma incidence was 2.5%, and there was no significant difference between calendar periods, wrote Åsa H Everhov, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues. Their report is in Inflammatory Bowel Diseases. Previous population studies looking at temporal trends have found mixed results with respect to stoma formation. However, many previous studies analyzed cohorts from referral centers that included patients with more severe disease. Others had small sample sizes.
“This is somewhat surprising as the rate of overall surgery for Crohn’s has decreased with the advent of biologic therapies,” said Miguel Regueiro, MD, who was asked to comment on the study. He is chair of the Digestive Disease and Surgery Institute, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.
Dr. Regueiro pointed out that the rate of stoma creation was quite low, and characteristics of the disease may explain the lack of a trend. For example, anorectal disease, especially when accompanied by fistula and strictures, is often medication refractory. “Although the study could not delineate this, it is my clinical practice experience that some patients present with destructive anorectal disease early, and that despite medications the ‘damage is too far gone’ to reverse,” said Dr. Regueiro. Also, the anorectum does not allow for an anastomosis since there is no region to connect to that isn’t damaged, he added.
The findings shouldn’t affect patient management or counseling, according to Stephen Hanauer, MD, professor of medicine at Northwestern University, Chicago, who was not involved in the study. “The indications for surgery in Crohn’s disease have not changed with the advent of newer therapies. Complications such as strictures and abscesses are still treated with similar surgeries. It is hopeful that the future course after surgery can be modified by effective biologic therapies,” he said.
The study authors noted that the findings are consistent with previous studies suggesting that the rate of abdominal surgery had begun to decline before anti-TNF drugs were introduced. The Swedish National Patient Register used in the current work includes only inpatient data before 2001, preventing a broader analysis prior to 1999, when infliximab gained approval in Sweden. But the researchers looked at time from first surgery to stoma, and found a decline in stoma formation between 1994 and 1997. A similar analysis found no decrease in the 2000s.
The researchers pointed out that anti-TNF inhibitor use would be expected to reduce the rate of stomas by inducing remission, although temporary stomas may be created to relieve symptoms while waiting for the medication to take effect. But anti-TNF agents could also encourage patients and physicians to postpone surgery. The delay could raise the chance of surgical complications, which in turn could lead to creation of a temporary stoma. Permanent stomas are typically created in cases of severe perianal CD.
The study could come as a disappointment to some patients and physicians, according to the authors. “The more active and early use of anti-TNF (therapeutics), in combination with the decreasing incidence of abdominal surgery in general for CD, has raised hopes of decreased incidence of stoma formation, but this was not observed in the present study,” the authors wrote.
But the news wasn’t all bad. The study found a lower cumulative stoma incidence than had previous studies, and the incidence of permanent stoma was just 0.8% at 5 years, “which should be reassuring for patients,” according to the authors.
CD patients often fear that a stoma will become necessary, but a stoma can be quite beneficial, allowing patients to regain some control over their lives. That can lead to more work participation and social activity. Qualitative studies showed that both patients and clinicians described outcomes of stoma placement as exceeding expectations, with a key factor being support from other inflammatory bowel disease patients with stomas. The authors encouraged clinicians to discuss the possibility of a stoma early on in the treatment process, and to avoid referring to it as a “last resort.”
The study also suggests that patients with anal and anorectal Crohn’s disease should receive biologics early, and a multidisciplinary approach involving both the gastroenterologist and surgeon is important. And patients should be counseled on the impact of disease on diet and psychological health, according to Dr. Regueiro.
The new study analyzed data between 2003 and 2014, from 18,815 Crohn’s disease patients who had not undergone previous surgery. The median age was 39 years, 53% were women, and 12% were pediatric patients.
After a median follow-up of 9.6 years, 9.5% of patients had perianal disease. Overall, 36% of patients had been treated with immunomodulators, and 17% with anti-TNF agents; 3.5% had stoma surgery, and just 0.05% underwent proctectomy.
Among those who had a stoma placed, the median age at diagnosis was 47 years, and 53% were men. In all, 12.6% had perianal disease at diagnosis, and 24.5% had perianal disease by the end of follow-up; 43% had received immunomodulators, and 26% anti-TNF agents. Among stomas, 64% were ileostomies, and 44% were temporary, with 88% of removals performed within 2 years of surgery.
The calendar periods of CD onset (2003-2006, 2007-2010, and 2011-2014) had similar rates of cumulative stoma placement (log rank test, P = .61). Overall, the 1-year cumulative incidence of stoma was 1.3%, the 3-year incidence was 1.9%, and the 5-year incidence was 2.5%.
The cumulative incidence of ever-use of anti-TNF agents increased with each successive calendar period (P < .001), but there was no significant difference in cumulative stoma incidence (P = .07).
One limitation of the study is the lack of detailed patient characteristics, and another is the short follow-up for patients diagnosed during 2011-2014. Another is that the results may not be generalizable to a U.S. population.
The study authors have received funding and consulted for various pharmaceutical companies. Dr. Regueiro has received grants from and has consulted or been on a scientific advisory board for Abbvie, UCB, and Janssen. Dr. Hanauer has no relevant financial disclosures.
This article was updated Oct. 13, 2021.
FROM INFLAMMATORY BOWEL DISEASES
Rivaroxaban’s single daily dose may lead to higher bleeding risk than other DOACs
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
The results, which were published in the Annals of Internal Medicine, could help guide DOAC selection for high-risk groups with a prior history of peptic ulcer disease or major GI bleeding, said lead study authors Arnar Bragi Ingason, MD and Einar S. Björnsson, MD, PhD, in an email.
DOACs treat conditions such as atrial fibrillation, venous thromboembolism, and ischemic stroke and are known to cause GI bleeding. Previous studies have suggested that rivaroxaban poses a higher GI-bleeding risk than other DOACs.
These studies, which used large administrative databases, “had an inherent risk of selection bias due to insurance status, age, and comorbidities due to their origin from insurance/administrative databases. In addition, they lacked phenotypic details on GI bleeding events,” said Dr. Björnsson and Dr. Ingason, who are both of Landspitali University Hospital, Reykjavik, Iceland,
Daily dosage may exacerbate risk
Rivaroxaban is administered as a single daily dose, compared with apixaban’s and dabigatran’s twice-daily regimens. “We hypothesized that this may lead to a greater variance in drug plasma concentration, making these patients more susceptible to GI bleeding,” the lead authors said.
Using data from the Icelandic Medicine Registry, a national database of outpatient prescription information, they compared rates of GI bleeding among new users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019. Overall, 5,868 patients receiving one of the DOACs took part in the study. Among these participants, 3,217 received rivaroxaban, 2,157 received apixaban, and 494 received dabigatran. The researchers used inverse probability weighting, Kaplan–Meier survival estimates, and Cox regression to compare GI bleeding.
Compared with dabigatran, rivaroxaban was associated with a 63%-104% higher overall risk for GI bleeding and 39%-95% higher risk for major GI bleeding. Rivaroxaban also had a 40%-42% higher overall risk for GI bleeding and 49%-50% higher risk for major GI bleeding, compared with apixaban.
The investigators were surprised by the low rate of upper GI bleeding for dabigatran, compared with the other two drugs. “However, these results must be interpreted in the context that the dabigatran group was relatively small,” said Dr. Björnsson and Dr. Ingason via email.
Overall, the study cohort was small, compared with previous registry studies.
Investigators also did not account for account for socioeconomic status or lifestyle factors, such as alcohol consumption or smoking. “However, because the cost of all DOACs is similar in Iceland, selection bias due to socioeconomic status is unlikely,” the investigators reported in their paper. “We are currently working on comparing the rates of thromboembolisms and overall major bleeding events between the drugs,” the lead authors said.
Clinicians should consider location of bleeding
Though retrospective, the study by Ingason et. al. “is likely as close as is feasible to a randomized trial as is possible,” said Don C. Rockey, MD, a professor of medicine at the Medical University of South Carolina, Charleston, in an interview.
“From the clinician’s perspective, it is important to take away that there may be differences among the DOACs in terms of where in the GI tract the bleeding occurs,” said Dr. Rockey. In the study, the greatest differences appeared to be in the upper GI tract, with rivaroxaban outpacing apixaban and dabigatran. In patients who are at risk for upper GI bleeding, it may be reasonable to consider use of dabigatran or apixaban, he suggested.
“A limitation of the study is that it is likely underpowered overall,” said Dr. Rockey. It also wasn’t clear how many deaths occurred either directly from GI bleeding or as a complication of GI bleeding, he said.The study also didn’t differentiate major bleeding among DOACs specifically in the upper or lower GI tract, Dr. Rockey added.
Other studies yield similar results
Dr. Ingason and Dr. Björnsson said their work complements previous studies, and Neena S. Abraham, MD, MSc , who has conducted a similar investigation to the new study, agreed with that statement.
Data from the last 4 years overwhelmingly show that rivaroxaban is most likely to cause GI bleeding, said Dr. Abraham, professor of medicine and a consultant with Mayo Clinic’s division of gastroenterology and hepatology, in an interview.
A comparative safety study Dr. Abraham coauthored in 2017 of rivaroxaban, apixaban, and dabigatran in a much larger U.S. cohort of 372,380 patients revealed that rivaroxaban had the worst GI bleeding profile. Apixaban was 66% safer than rivaroxaban and 64% safer than dabigatran to prevent gastrointestinal bleeding.
“I believe our group was the first to conduct this study and show clinically significant differences in GI safety of the available direct oral anticoagulants,” she said. Other investigators have since published similar results, and the topic of the new study needs no further investigation, according to Dr. Abraham.
“It is time for physicians to choose a better choice when prescribing a direct oral anticoagulant to their atrial fibrillation patients, and that choice is not rivaroxaban,” she said.
The Icelandic Centre for Research and the Landspítali University Hospital Research Fund provided funds for this study. Dr. Ingason, Dr. Björnsson, Dr. Rockey, and Dr. Abraham reported no disclosures.
FROM ANNALS OF INTERNAL MEDICINE
What’s the best approach for dysplasia surveillance in IBD?
Chromoendoscopy
Chromoendoscopy is superior in both the detection and long-term management of dysplasia in IBD when compared to high-definition white-light examination. Chromoendoscopy not only enhances dysplasia detection but further improves the definition of these lesions which then facilitates endoscopic management.
Human beings have an innate visual perception limitation due to our inability to perceive depth in the red/green wavelength of light compared to the blue wavelength. All of the improvements in scope magnification and resolution bump up against this fact of our biology. Blue dye enhances our ability to perceive depth in this milieu and therefore detect and define flat lesions.
The superiority of chromoendoscopy when using standard definition colonoscopes has been demonstrated repeatedly and set the stage for the 2015 SCENIC international consensus statement and a seismic shift in our endoscopic management of dysplasia in patients with colitis. This evidence base remains relevant because only 77% of colonoscopies performed in the United States are performed using high-definition equipment. Nearly one-quarter of our patients lack access to the newer equipment and therefore without chromoendoscopy are being surveyed outside of current guidelines.
Since the SCENIC statement multiple studies comparing chromoendoscopy with newer higher resolution colonoscopes have been performed. The vast preponderance of evidence has shown either a trend toward superiority or the outright superiority of chromoendoscopy when compared with high-definition white-light examination in detection and long-term management of dysplasia.
Chromoendoscopy has allowed us to increase our visual vocabulary in describing dysplasia in the setting of colitis and, thus, open the door to further innovation and perhaps adoption of artificial intelligence going forward. Our ability to classify lesions encountered in colitis mucosa has become more precise with the expanded terminology the dye-enhanced high-definition view affords, with the Frankfurt Advanced Chromoendoscopic IBD Lesion Classification being the best and most detailed example.
It is no accident that advanced endoscopists have universally adopted chromoendoscopy for the management of dysplastic lesions whether by mucosal resection or submucosal dissection techniques. Chromoendoscopy is recommended by all society guidelines because of these inherent advantages.
Is high-definition white-light “good enough” for surveilling our patients with colitis? The overall incidence of CRC in IBD has been declining which makes each colonoscopy count more. We are performing up to 88 colonoscopies in patients with colitis to find a single cancer (compared to 8 in non-IBD surveillance patients). We need to be performing fewer and more precise chromoendoscopic examinations. We are otherwise failing to serve our IBD patients by performing too many negative procedures at too high a cost. Our patients deserve more than merely “good enough.”
James F. Marion, MD, is professor of medicine at the Icahn School of Medicine at Mount Sinai and director of education and outreach at The Susan and Leonard Feinstein Inflammatory Bowel Disease Center of The Mount Sinai Hospital, both in New York. He is on the advisory board for Janssen.
High-definition white light endoscopy
Longstanding ulcerative colitis and Crohn’s colitis increase the risk for developing colorectal cancer. The majority of neoplastic lesions are visible endoscopically, and therefore, dye spraying chromoendoscopy (DCE) may not be necessary for all inflammatory bowel disease (IBD) patients undergoing a routine dysplasia surveillance colonoscopy.
High-definition white light (HDWL) endoscopes have higher magnification capacities and pixel density than the standard definition (SD) systems and provide sharper images with fewer artifacts. Although DCE has been proven to be superior to SD, there have been no differences in detection of dysplasia for routine surveillance with use of HDWL compared to DCE.
The SCENIC guidelines key recommendation for optimizing detection and management of dysplasia in IBD is to use a HD colonoscope. Further, based on the recent ACG Practice Guidelines for Dysplasia Screening and Surveillance in 2019, HD colonoscopes are also recommended.
In a network meta-analysis of eight parallel-group randomized controlled trials (RCT), there was very low quality of evidence to support the use of DCE over HDWL. This was contrary to prior, non-RCT studies which suggested that both SD and HDWL were inferior to DCE. More recently, Iacucci and colleagues conducted a randomized noninferiority trial to determine detection rates of neoplastic lesions in IBD patients with longstanding colitis who had inactive disease and enrolled in HDWL, DCE, or virtual chromoendoscopy (VCE) groups. The conclusion was that VCE and HDWL was not inferior to DCE, and HDWL was sufficient in detection of all neoplastic lesions including dysplasia and adenocarcinoma. In another large multicenter, prospective RCT of nine tertiary hospitals in South Korea, the detection rates of colitis-associated dysplasia or all colorectal neoplasia were comparable in HDWL versus high-definition chromoendoscopy. Lastly, a meta-analysis of six RCTs concluded that, although DCE is superior to SD in identification of dysplasia, there was no benefit of DCE compared to HDWL.
In summary, HDWL colonoscopy should be the standard of care for routine dysplasia surveillance in IBD. DCE should be considered in patients who are found to have a dysplastic lesion by HDWL in order to better delineate the lesion margins, endoscopically resect or remove, and for future dysplasia surveillance colonoscopies in the higher-risk IBD patient. Overall, a close and careful examination of the entire colon with use of HDWL is sufficient in detection of dysplasia and for routine surveillance in IBD patients.
Anita Afzali, MD, MPH, AGAF, is medical director of the Inflammatory Bowel Disease Center and program director of the Advanced Inflammatory Bowel Disease Fellowship at Ohio State University in Hilliard, Ohio. She has no relevant conflicts of interest.
These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.
Chromoendoscopy
Chromoendoscopy is superior in both the detection and long-term management of dysplasia in IBD when compared to high-definition white-light examination. Chromoendoscopy not only enhances dysplasia detection but further improves the definition of these lesions which then facilitates endoscopic management.
Human beings have an innate visual perception limitation due to our inability to perceive depth in the red/green wavelength of light compared to the blue wavelength. All of the improvements in scope magnification and resolution bump up against this fact of our biology. Blue dye enhances our ability to perceive depth in this milieu and therefore detect and define flat lesions.
The superiority of chromoendoscopy when using standard definition colonoscopes has been demonstrated repeatedly and set the stage for the 2015 SCENIC international consensus statement and a seismic shift in our endoscopic management of dysplasia in patients with colitis. This evidence base remains relevant because only 77% of colonoscopies performed in the United States are performed using high-definition equipment. Nearly one-quarter of our patients lack access to the newer equipment and therefore without chromoendoscopy are being surveyed outside of current guidelines.
Since the SCENIC statement multiple studies comparing chromoendoscopy with newer higher resolution colonoscopes have been performed. The vast preponderance of evidence has shown either a trend toward superiority or the outright superiority of chromoendoscopy when compared with high-definition white-light examination in detection and long-term management of dysplasia.
Chromoendoscopy has allowed us to increase our visual vocabulary in describing dysplasia in the setting of colitis and, thus, open the door to further innovation and perhaps adoption of artificial intelligence going forward. Our ability to classify lesions encountered in colitis mucosa has become more precise with the expanded terminology the dye-enhanced high-definition view affords, with the Frankfurt Advanced Chromoendoscopic IBD Lesion Classification being the best and most detailed example.
It is no accident that advanced endoscopists have universally adopted chromoendoscopy for the management of dysplastic lesions whether by mucosal resection or submucosal dissection techniques. Chromoendoscopy is recommended by all society guidelines because of these inherent advantages.
Is high-definition white-light “good enough” for surveilling our patients with colitis? The overall incidence of CRC in IBD has been declining which makes each colonoscopy count more. We are performing up to 88 colonoscopies in patients with colitis to find a single cancer (compared to 8 in non-IBD surveillance patients). We need to be performing fewer and more precise chromoendoscopic examinations. We are otherwise failing to serve our IBD patients by performing too many negative procedures at too high a cost. Our patients deserve more than merely “good enough.”
James F. Marion, MD, is professor of medicine at the Icahn School of Medicine at Mount Sinai and director of education and outreach at The Susan and Leonard Feinstein Inflammatory Bowel Disease Center of The Mount Sinai Hospital, both in New York. He is on the advisory board for Janssen.
High-definition white light endoscopy
Longstanding ulcerative colitis and Crohn’s colitis increase the risk for developing colorectal cancer. The majority of neoplastic lesions are visible endoscopically, and therefore, dye spraying chromoendoscopy (DCE) may not be necessary for all inflammatory bowel disease (IBD) patients undergoing a routine dysplasia surveillance colonoscopy.
High-definition white light (HDWL) endoscopes have higher magnification capacities and pixel density than the standard definition (SD) systems and provide sharper images with fewer artifacts. Although DCE has been proven to be superior to SD, there have been no differences in detection of dysplasia for routine surveillance with use of HDWL compared to DCE.
The SCENIC guidelines key recommendation for optimizing detection and management of dysplasia in IBD is to use a HD colonoscope. Further, based on the recent ACG Practice Guidelines for Dysplasia Screening and Surveillance in 2019, HD colonoscopes are also recommended.
In a network meta-analysis of eight parallel-group randomized controlled trials (RCT), there was very low quality of evidence to support the use of DCE over HDWL. This was contrary to prior, non-RCT studies which suggested that both SD and HDWL were inferior to DCE. More recently, Iacucci and colleagues conducted a randomized noninferiority trial to determine detection rates of neoplastic lesions in IBD patients with longstanding colitis who had inactive disease and enrolled in HDWL, DCE, or virtual chromoendoscopy (VCE) groups. The conclusion was that VCE and HDWL was not inferior to DCE, and HDWL was sufficient in detection of all neoplastic lesions including dysplasia and adenocarcinoma. In another large multicenter, prospective RCT of nine tertiary hospitals in South Korea, the detection rates of colitis-associated dysplasia or all colorectal neoplasia were comparable in HDWL versus high-definition chromoendoscopy. Lastly, a meta-analysis of six RCTs concluded that, although DCE is superior to SD in identification of dysplasia, there was no benefit of DCE compared to HDWL.
In summary, HDWL colonoscopy should be the standard of care for routine dysplasia surveillance in IBD. DCE should be considered in patients who are found to have a dysplastic lesion by HDWL in order to better delineate the lesion margins, endoscopically resect or remove, and for future dysplasia surveillance colonoscopies in the higher-risk IBD patient. Overall, a close and careful examination of the entire colon with use of HDWL is sufficient in detection of dysplasia and for routine surveillance in IBD patients.
Anita Afzali, MD, MPH, AGAF, is medical director of the Inflammatory Bowel Disease Center and program director of the Advanced Inflammatory Bowel Disease Fellowship at Ohio State University in Hilliard, Ohio. She has no relevant conflicts of interest.
These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.
Chromoendoscopy
Chromoendoscopy is superior in both the detection and long-term management of dysplasia in IBD when compared to high-definition white-light examination. Chromoendoscopy not only enhances dysplasia detection but further improves the definition of these lesions which then facilitates endoscopic management.
Human beings have an innate visual perception limitation due to our inability to perceive depth in the red/green wavelength of light compared to the blue wavelength. All of the improvements in scope magnification and resolution bump up against this fact of our biology. Blue dye enhances our ability to perceive depth in this milieu and therefore detect and define flat lesions.
The superiority of chromoendoscopy when using standard definition colonoscopes has been demonstrated repeatedly and set the stage for the 2015 SCENIC international consensus statement and a seismic shift in our endoscopic management of dysplasia in patients with colitis. This evidence base remains relevant because only 77% of colonoscopies performed in the United States are performed using high-definition equipment. Nearly one-quarter of our patients lack access to the newer equipment and therefore without chromoendoscopy are being surveyed outside of current guidelines.
Since the SCENIC statement multiple studies comparing chromoendoscopy with newer higher resolution colonoscopes have been performed. The vast preponderance of evidence has shown either a trend toward superiority or the outright superiority of chromoendoscopy when compared with high-definition white-light examination in detection and long-term management of dysplasia.
Chromoendoscopy has allowed us to increase our visual vocabulary in describing dysplasia in the setting of colitis and, thus, open the door to further innovation and perhaps adoption of artificial intelligence going forward. Our ability to classify lesions encountered in colitis mucosa has become more precise with the expanded terminology the dye-enhanced high-definition view affords, with the Frankfurt Advanced Chromoendoscopic IBD Lesion Classification being the best and most detailed example.
It is no accident that advanced endoscopists have universally adopted chromoendoscopy for the management of dysplastic lesions whether by mucosal resection or submucosal dissection techniques. Chromoendoscopy is recommended by all society guidelines because of these inherent advantages.
Is high-definition white-light “good enough” for surveilling our patients with colitis? The overall incidence of CRC in IBD has been declining which makes each colonoscopy count more. We are performing up to 88 colonoscopies in patients with colitis to find a single cancer (compared to 8 in non-IBD surveillance patients). We need to be performing fewer and more precise chromoendoscopic examinations. We are otherwise failing to serve our IBD patients by performing too many negative procedures at too high a cost. Our patients deserve more than merely “good enough.”
James F. Marion, MD, is professor of medicine at the Icahn School of Medicine at Mount Sinai and director of education and outreach at The Susan and Leonard Feinstein Inflammatory Bowel Disease Center of The Mount Sinai Hospital, both in New York. He is on the advisory board for Janssen.
High-definition white light endoscopy
Longstanding ulcerative colitis and Crohn’s colitis increase the risk for developing colorectal cancer. The majority of neoplastic lesions are visible endoscopically, and therefore, dye spraying chromoendoscopy (DCE) may not be necessary for all inflammatory bowel disease (IBD) patients undergoing a routine dysplasia surveillance colonoscopy.
High-definition white light (HDWL) endoscopes have higher magnification capacities and pixel density than the standard definition (SD) systems and provide sharper images with fewer artifacts. Although DCE has been proven to be superior to SD, there have been no differences in detection of dysplasia for routine surveillance with use of HDWL compared to DCE.
The SCENIC guidelines key recommendation for optimizing detection and management of dysplasia in IBD is to use a HD colonoscope. Further, based on the recent ACG Practice Guidelines for Dysplasia Screening and Surveillance in 2019, HD colonoscopes are also recommended.
In a network meta-analysis of eight parallel-group randomized controlled trials (RCT), there was very low quality of evidence to support the use of DCE over HDWL. This was contrary to prior, non-RCT studies which suggested that both SD and HDWL were inferior to DCE. More recently, Iacucci and colleagues conducted a randomized noninferiority trial to determine detection rates of neoplastic lesions in IBD patients with longstanding colitis who had inactive disease and enrolled in HDWL, DCE, or virtual chromoendoscopy (VCE) groups. The conclusion was that VCE and HDWL was not inferior to DCE, and HDWL was sufficient in detection of all neoplastic lesions including dysplasia and adenocarcinoma. In another large multicenter, prospective RCT of nine tertiary hospitals in South Korea, the detection rates of colitis-associated dysplasia or all colorectal neoplasia were comparable in HDWL versus high-definition chromoendoscopy. Lastly, a meta-analysis of six RCTs concluded that, although DCE is superior to SD in identification of dysplasia, there was no benefit of DCE compared to HDWL.
In summary, HDWL colonoscopy should be the standard of care for routine dysplasia surveillance in IBD. DCE should be considered in patients who are found to have a dysplastic lesion by HDWL in order to better delineate the lesion margins, endoscopically resect or remove, and for future dysplasia surveillance colonoscopies in the higher-risk IBD patient. Overall, a close and careful examination of the entire colon with use of HDWL is sufficient in detection of dysplasia and for routine surveillance in IBD patients.
Anita Afzali, MD, MPH, AGAF, is medical director of the Inflammatory Bowel Disease Center and program director of the Advanced Inflammatory Bowel Disease Fellowship at Ohio State University in Hilliard, Ohio. She has no relevant conflicts of interest.
These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.
Gastroenterology Data Trends 2021
Contents Include:
- Digital health in managing GI diseases
- Emergence of live biotherapeutic products for C. difficile and beyond
- AI and machine learning in GI practice
- Eosinophilic esophagitis: Addressing the rise in incidence and treatment options
- Racial and social diversity in GI practice
- The gut-brain connection in IBS
- Managing IBD in the backdrop of COVID-19
- Noncardia gastric cancer risk: Racial/ethnic disparity, gastric precancerous changes, and refractory H. pylori
- Rethinking management of alcohol-associated liver disease: The other fatty liver epidemic
- Endoscopic bariatric and metabolic therapies for weight loss
- The weight loss journey at University of Michigan
Contents Include:
- Digital health in managing GI diseases
- Emergence of live biotherapeutic products for C. difficile and beyond
- AI and machine learning in GI practice
- Eosinophilic esophagitis: Addressing the rise in incidence and treatment options
- Racial and social diversity in GI practice
- The gut-brain connection in IBS
- Managing IBD in the backdrop of COVID-19
- Noncardia gastric cancer risk: Racial/ethnic disparity, gastric precancerous changes, and refractory H. pylori
- Rethinking management of alcohol-associated liver disease: The other fatty liver epidemic
- Endoscopic bariatric and metabolic therapies for weight loss
- The weight loss journey at University of Michigan
Contents Include:
- Digital health in managing GI diseases
- Emergence of live biotherapeutic products for C. difficile and beyond
- AI and machine learning in GI practice
- Eosinophilic esophagitis: Addressing the rise in incidence and treatment options
- Racial and social diversity in GI practice
- The gut-brain connection in IBS
- Managing IBD in the backdrop of COVID-19
- Noncardia gastric cancer risk: Racial/ethnic disparity, gastric precancerous changes, and refractory H. pylori
- Rethinking management of alcohol-associated liver disease: The other fatty liver epidemic
- Endoscopic bariatric and metabolic therapies for weight loss
- The weight loss journey at University of Michigan
An update on COVID-19 vaccine recommendations for patients with IBD
In December 2019, cases of pulmonary infection secondary to a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2, were first identified in the city of Wuhan, China.
The clinical disease caused by the virus, COVID-19, has resulted in a worldwide pandemic that has portended significant morbidity and mortality throughout the United States. Three highly efficacious COVID-19 vaccines have received emergency use authorization (EUA) by the Food and Drug Administration to help prevent COVID-19, all of which are effective at preventing severe COVID-19.1-3 The Pfizer vaccine was given full FDA approval on Aug. 23, 2021.4
Patients with inflammatory bowel disease (IBD) are commonly treated with immune-modifying therapies that may increase their risk for serious and opportunistic infections. As such, there was concern at the beginning of the pandemic that patients with IBD may be at increased risk of contracting COVID-19 and/or developing severe disease (that is, ICU-level care, mechanical ventilation, and/or death). There is evidence that the incidence of COVID-19 in the IBD population is similar to that of the general population.5-7 Furthermore, most patients with IBD are not at increased risk of severe disease, including those on biologic therapies. Several studies demonstrated that those on corticosteroids are at increased risk of severe COVID-19, while those on other immune-modifying therapies such as tumor necrosis factor inhibitors (anti-TNFs) are not at increased risk.5,7-10 Patients with IBD with other well-known risk factors for severe disease include comorbidities such as diabetes and obesity.
It is known that patients with IBD on certain immune-modifying therapies such as anti-TNFs, especially those on combination therapy, may have a blunted immune response to certain vaccines.11 Neither patients with IBD nor patients on immunosuppressive therapy were included in phase 3 clinical trials for COVID-19 vaccine development, contributing to uncertainty regarding the safety and efficacy in our patient population. The risk of adverse events following COVID-19 vaccination in the IBD population has been found to be similar to that of the general population.12 It has also been reported that those who have had reactions to injectable therapies in the past may safely be vaccinated against COVID-19.13,14 With regard to vaccine efficacy, initial studies, including ICARUS, PREVENT-COVID, and CORALE-IBD, have demonstrated that patients with IBD do indeed mount a humoral immune response to the vaccine, including those on immune-modifying therapies.15-17 Nonhumoral aspects of immunity, such as cell-mediated immunity, have not yet been thoroughly evaluated. In addition, the risk of breakthrough COVID-19 infection after vaccination is low in patients with IBD, including those on immune-modifying therapy.14-18 While initial studies are reassuring that the vast majority of patients with IBD are able to mount a vaccine response, future studies are needed to determine the effects of immune-modifying therapy on sustained antibody concentrations and other correlates of immunity.
For those who received the Pfizer or Moderna vaccines, on Aug. 12, 2021, the FDA amended their EUA to allow for an additional dose in the initial vaccination series for certain immunocompromised individuals, specifically solid organ transplant recipients or those with conditions that make them equally immunocompromised.19 Based on evidence suggesting that certain solid organ transplant recipients do not mount an immune response after completing a two-dose series, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how to use vaccines, recommended that moderate to severely immunocompromised individuals should complete a three-dose series, with the third dose being given at least 28 days after the second dose.20 This recommendation included those on high-dose corticosteroids defined as oral prednisone at least 20 mg/day, anti-TNFs and biosimilars, and antimetabolites such as azathioprine, mercaptopurine, and methotrexate.
It is worth noting that the role of the ACIP here was to consider the available evidence supporting the use of an additional dose and then make recommendations on which conditions may qualify; the ACIP was not able to provide recommendations for every disease state. At the time of writing this article, no recommendations have been made with regards to an additional dose of the Janssen vaccine. Likewise, in response to the ACIP recommendations, the Crohn’s & Colitis Foundation recommended an additional dose for patients with IBD on immune-modifying therapies.21,22
Less than one week after the EUA amendment for an additional dose, the Department of Health & Human Services announced that booster shots would likely become available to the general population as early as the week of Sept. 20, 2021 and starting 8 months after an individual’s second dose.23 Here, it is worth noting that an additional dose is distinct from a booster. An additional dose (or third dose here) refers to the initial vaccination series and is given when the standard schedule is thought to be insufficient in a certain patient population. In contrast, a booster dose is administered when the initial and sufficient immunity gained from a primary vaccination series has likely dissipated. The HHS acknowledged that boosters would likely be needed for those who received the Janssen vaccine but noted that further data and recommendations would be forthcoming.
To summarize, COVID-19 vaccines are safe and effective in the IBD population, and patients should be vaccinated at the earliest opportunity regardless of concurrent therapies. For those that received the Pfizer or Moderna vaccine, the ACIP recommended an additional dose in the initial vaccination series to be given at least 28 days after the second dose for those that are immunosuppressed. This recommendation was largely based off of transplant data. Reassuringly, the available data demonstrates a humoral immune response to a two-dose vaccination series in patients with IBD, including those on immune-modifying therapies. The Crohn’s & Colitis Foundation recommends that patients with IBD on immune-modifying therapy receive an additional dose (i.e., a three-dose series), which should be from the same manufacturer as the first two doses. In addition, at press time, HHS indicated that there will be a movement toward a booster dose for the general population in late September, which would also apply to patients with IBD. The ACIP has yet to comment on this change at the time of preparing this article, but the announcement indicated that a booster could be given “8 months after an individual’s second dose.” It is unclear how those who may receive a three-dose vaccination series will factor in, but it is possible that they would be eligible for a booster 8 months after their most recent dose. Gastroenterologists should also be aware that there is no role for serologic testing in the clinical setting because it has not been validated for such purposes and is primarily used in the research setting. Finally, it is paramount to emphasize that patients with IBD have historically had lower vaccination rates than the general population,24 and we must take an active role in ensuring that our patients are immunized by addressing their concerns, communicating the risks of COVID-19 and the benefits of vaccination, providing information on how to get vaccinated, and strongly recommending vaccination.
The following list also summarizes the recommendations:
- Patients with IBD should be vaccinated against COVID-19 regardless of concurrent therapies.
- Patients with IBD are not at increased risk of severe COVID-19.
- Patients with IBD, including those on immune-modifying therapies, mount a humoral immune response to the vaccine.
- Patients with IBD on immune-modifying therapies, who received either the Pfizer or Moderna vaccine, should receive a three-dose vaccination series, with the third dose at least 28 days after the second dose.
- Patients with IBD on biologic therapy can receive the third dose of the vaccine at any time point and should not interrupt biologic therapy.
- Boosters are likely to become available to the general public in September and would be given at least 8 months after an individual’s second dose.
- Recommendations regarding boosters for those who received a three-dose vaccination series are forthcoming.
- Recommendations regarding boosters and additional doses for those that received the Janssen vaccine are forthcoming.
- Gastroenterologists should take an active role in ensuring that their patients are vaccinated.
Dr. Schell is a second-year graduate student in the division of internal medicine at the University of Wisconsin–Madison. Dr. Caldera is an associate professor of medicine in the division of gastroenterology & hepatology at the University of Wisconsin–Madison. Dr. Schell has no conflicts of interest to disclose. Dr. Caldera has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene.
References
1. Sadoff J et al. N Engl J Med. 2021;384(23):2187-201.
2. Baden LR et al. N Engl J Med. 2021;384(5):403-16.
3. Polack FP et al. N Engl J Med. 2020;383:2603-15.
4. Johnson K et al. U.S. FDA aims to give full approval to Pfizer vaccine on Monday – NYT. Reuters. 2021 Aug 20. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-aims-give-full-nod-pfizers-covid-19-vaccine-monday-new-york-times-2021-08-20/.
5. Allocca M et al. J Clin Med. 2020 Oct;9(11):3533.
6. Monteleone G and Ardizzone S. J Crohns Colitis. 2020 Sep;14(9):1334-6.
7. Papa A et al. Am J Gastroenterol. 2020;115(10):1722-4.
8. Derikx LAAP et al. J Crohn’s Colitis. 2021 Apr 6;15(4):529-39.
9. Brenner EJ et al. Gastroenterology. 2020;159(2):481-91.
10. Ungaro RC et al. Gut. 2021;70(4):725-32.
11. Caldera F et al. Inflamm Bowel Dis. 2020;26(4):593-602.
12. Botwin GJ et al. Am J Gastroenterol. 2021. doi: 10.14309/ajg.0000000000001342.
13. Squire JD et al. Inflamm Bowel Dis. 2021 Jul 27;27(8):1358-60.
14. Hadi YB et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.014.
15. Wong S-Y et al. Gastroenterology. 2021;161:715-8.
16. Kappelman MD et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.016.
17. Pozdnyakova V et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.014.
18. Ben-Tov A et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.076.
19. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. FDA News Release. 2021. Accessed 2021 Aug 18. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised.
20. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately to Severely Immunocompromised People. 2021. Accessed 2021 Aug 18. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.
21. Allocca M et al. J Clin Med. 2020 Oct 31;9(11):3533.
22. Crohn’s & Colitis Foundation. COVID-19 Vaccines: Position Statements. IBD & Coronavirus. 2021. Accessed 2021 Aug 20. https://www.crohnscolitisfoundation.org/coronavirus/vaccine-position-statements.
23. Centers for Disease Control and Prevention. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html.
24. Caldera F et al. Inflamm Bowel Dis. 2021;27(1):123-133.
In December 2019, cases of pulmonary infection secondary to a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2, were first identified in the city of Wuhan, China.
The clinical disease caused by the virus, COVID-19, has resulted in a worldwide pandemic that has portended significant morbidity and mortality throughout the United States. Three highly efficacious COVID-19 vaccines have received emergency use authorization (EUA) by the Food and Drug Administration to help prevent COVID-19, all of which are effective at preventing severe COVID-19.1-3 The Pfizer vaccine was given full FDA approval on Aug. 23, 2021.4
Patients with inflammatory bowel disease (IBD) are commonly treated with immune-modifying therapies that may increase their risk for serious and opportunistic infections. As such, there was concern at the beginning of the pandemic that patients with IBD may be at increased risk of contracting COVID-19 and/or developing severe disease (that is, ICU-level care, mechanical ventilation, and/or death). There is evidence that the incidence of COVID-19 in the IBD population is similar to that of the general population.5-7 Furthermore, most patients with IBD are not at increased risk of severe disease, including those on biologic therapies. Several studies demonstrated that those on corticosteroids are at increased risk of severe COVID-19, while those on other immune-modifying therapies such as tumor necrosis factor inhibitors (anti-TNFs) are not at increased risk.5,7-10 Patients with IBD with other well-known risk factors for severe disease include comorbidities such as diabetes and obesity.
It is known that patients with IBD on certain immune-modifying therapies such as anti-TNFs, especially those on combination therapy, may have a blunted immune response to certain vaccines.11 Neither patients with IBD nor patients on immunosuppressive therapy were included in phase 3 clinical trials for COVID-19 vaccine development, contributing to uncertainty regarding the safety and efficacy in our patient population. The risk of adverse events following COVID-19 vaccination in the IBD population has been found to be similar to that of the general population.12 It has also been reported that those who have had reactions to injectable therapies in the past may safely be vaccinated against COVID-19.13,14 With regard to vaccine efficacy, initial studies, including ICARUS, PREVENT-COVID, and CORALE-IBD, have demonstrated that patients with IBD do indeed mount a humoral immune response to the vaccine, including those on immune-modifying therapies.15-17 Nonhumoral aspects of immunity, such as cell-mediated immunity, have not yet been thoroughly evaluated. In addition, the risk of breakthrough COVID-19 infection after vaccination is low in patients with IBD, including those on immune-modifying therapy.14-18 While initial studies are reassuring that the vast majority of patients with IBD are able to mount a vaccine response, future studies are needed to determine the effects of immune-modifying therapy on sustained antibody concentrations and other correlates of immunity.
For those who received the Pfizer or Moderna vaccines, on Aug. 12, 2021, the FDA amended their EUA to allow for an additional dose in the initial vaccination series for certain immunocompromised individuals, specifically solid organ transplant recipients or those with conditions that make them equally immunocompromised.19 Based on evidence suggesting that certain solid organ transplant recipients do not mount an immune response after completing a two-dose series, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how to use vaccines, recommended that moderate to severely immunocompromised individuals should complete a three-dose series, with the third dose being given at least 28 days after the second dose.20 This recommendation included those on high-dose corticosteroids defined as oral prednisone at least 20 mg/day, anti-TNFs and biosimilars, and antimetabolites such as azathioprine, mercaptopurine, and methotrexate.
It is worth noting that the role of the ACIP here was to consider the available evidence supporting the use of an additional dose and then make recommendations on which conditions may qualify; the ACIP was not able to provide recommendations for every disease state. At the time of writing this article, no recommendations have been made with regards to an additional dose of the Janssen vaccine. Likewise, in response to the ACIP recommendations, the Crohn’s & Colitis Foundation recommended an additional dose for patients with IBD on immune-modifying therapies.21,22
Less than one week after the EUA amendment for an additional dose, the Department of Health & Human Services announced that booster shots would likely become available to the general population as early as the week of Sept. 20, 2021 and starting 8 months after an individual’s second dose.23 Here, it is worth noting that an additional dose is distinct from a booster. An additional dose (or third dose here) refers to the initial vaccination series and is given when the standard schedule is thought to be insufficient in a certain patient population. In contrast, a booster dose is administered when the initial and sufficient immunity gained from a primary vaccination series has likely dissipated. The HHS acknowledged that boosters would likely be needed for those who received the Janssen vaccine but noted that further data and recommendations would be forthcoming.
To summarize, COVID-19 vaccines are safe and effective in the IBD population, and patients should be vaccinated at the earliest opportunity regardless of concurrent therapies. For those that received the Pfizer or Moderna vaccine, the ACIP recommended an additional dose in the initial vaccination series to be given at least 28 days after the second dose for those that are immunosuppressed. This recommendation was largely based off of transplant data. Reassuringly, the available data demonstrates a humoral immune response to a two-dose vaccination series in patients with IBD, including those on immune-modifying therapies. The Crohn’s & Colitis Foundation recommends that patients with IBD on immune-modifying therapy receive an additional dose (i.e., a three-dose series), which should be from the same manufacturer as the first two doses. In addition, at press time, HHS indicated that there will be a movement toward a booster dose for the general population in late September, which would also apply to patients with IBD. The ACIP has yet to comment on this change at the time of preparing this article, but the announcement indicated that a booster could be given “8 months after an individual’s second dose.” It is unclear how those who may receive a three-dose vaccination series will factor in, but it is possible that they would be eligible for a booster 8 months after their most recent dose. Gastroenterologists should also be aware that there is no role for serologic testing in the clinical setting because it has not been validated for such purposes and is primarily used in the research setting. Finally, it is paramount to emphasize that patients with IBD have historically had lower vaccination rates than the general population,24 and we must take an active role in ensuring that our patients are immunized by addressing their concerns, communicating the risks of COVID-19 and the benefits of vaccination, providing information on how to get vaccinated, and strongly recommending vaccination.
The following list also summarizes the recommendations:
- Patients with IBD should be vaccinated against COVID-19 regardless of concurrent therapies.
- Patients with IBD are not at increased risk of severe COVID-19.
- Patients with IBD, including those on immune-modifying therapies, mount a humoral immune response to the vaccine.
- Patients with IBD on immune-modifying therapies, who received either the Pfizer or Moderna vaccine, should receive a three-dose vaccination series, with the third dose at least 28 days after the second dose.
- Patients with IBD on biologic therapy can receive the third dose of the vaccine at any time point and should not interrupt biologic therapy.
- Boosters are likely to become available to the general public in September and would be given at least 8 months after an individual’s second dose.
- Recommendations regarding boosters for those who received a three-dose vaccination series are forthcoming.
- Recommendations regarding boosters and additional doses for those that received the Janssen vaccine are forthcoming.
- Gastroenterologists should take an active role in ensuring that their patients are vaccinated.
Dr. Schell is a second-year graduate student in the division of internal medicine at the University of Wisconsin–Madison. Dr. Caldera is an associate professor of medicine in the division of gastroenterology & hepatology at the University of Wisconsin–Madison. Dr. Schell has no conflicts of interest to disclose. Dr. Caldera has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene.
References
1. Sadoff J et al. N Engl J Med. 2021;384(23):2187-201.
2. Baden LR et al. N Engl J Med. 2021;384(5):403-16.
3. Polack FP et al. N Engl J Med. 2020;383:2603-15.
4. Johnson K et al. U.S. FDA aims to give full approval to Pfizer vaccine on Monday – NYT. Reuters. 2021 Aug 20. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-aims-give-full-nod-pfizers-covid-19-vaccine-monday-new-york-times-2021-08-20/.
5. Allocca M et al. J Clin Med. 2020 Oct;9(11):3533.
6. Monteleone G and Ardizzone S. J Crohns Colitis. 2020 Sep;14(9):1334-6.
7. Papa A et al. Am J Gastroenterol. 2020;115(10):1722-4.
8. Derikx LAAP et al. J Crohn’s Colitis. 2021 Apr 6;15(4):529-39.
9. Brenner EJ et al. Gastroenterology. 2020;159(2):481-91.
10. Ungaro RC et al. Gut. 2021;70(4):725-32.
11. Caldera F et al. Inflamm Bowel Dis. 2020;26(4):593-602.
12. Botwin GJ et al. Am J Gastroenterol. 2021. doi: 10.14309/ajg.0000000000001342.
13. Squire JD et al. Inflamm Bowel Dis. 2021 Jul 27;27(8):1358-60.
14. Hadi YB et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.014.
15. Wong S-Y et al. Gastroenterology. 2021;161:715-8.
16. Kappelman MD et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.016.
17. Pozdnyakova V et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.014.
18. Ben-Tov A et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.076.
19. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. FDA News Release. 2021. Accessed 2021 Aug 18. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised.
20. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately to Severely Immunocompromised People. 2021. Accessed 2021 Aug 18. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.
21. Allocca M et al. J Clin Med. 2020 Oct 31;9(11):3533.
22. Crohn’s & Colitis Foundation. COVID-19 Vaccines: Position Statements. IBD & Coronavirus. 2021. Accessed 2021 Aug 20. https://www.crohnscolitisfoundation.org/coronavirus/vaccine-position-statements.
23. Centers for Disease Control and Prevention. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html.
24. Caldera F et al. Inflamm Bowel Dis. 2021;27(1):123-133.
In December 2019, cases of pulmonary infection secondary to a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2, were first identified in the city of Wuhan, China.
The clinical disease caused by the virus, COVID-19, has resulted in a worldwide pandemic that has portended significant morbidity and mortality throughout the United States. Three highly efficacious COVID-19 vaccines have received emergency use authorization (EUA) by the Food and Drug Administration to help prevent COVID-19, all of which are effective at preventing severe COVID-19.1-3 The Pfizer vaccine was given full FDA approval on Aug. 23, 2021.4
Patients with inflammatory bowel disease (IBD) are commonly treated with immune-modifying therapies that may increase their risk for serious and opportunistic infections. As such, there was concern at the beginning of the pandemic that patients with IBD may be at increased risk of contracting COVID-19 and/or developing severe disease (that is, ICU-level care, mechanical ventilation, and/or death). There is evidence that the incidence of COVID-19 in the IBD population is similar to that of the general population.5-7 Furthermore, most patients with IBD are not at increased risk of severe disease, including those on biologic therapies. Several studies demonstrated that those on corticosteroids are at increased risk of severe COVID-19, while those on other immune-modifying therapies such as tumor necrosis factor inhibitors (anti-TNFs) are not at increased risk.5,7-10 Patients with IBD with other well-known risk factors for severe disease include comorbidities such as diabetes and obesity.
It is known that patients with IBD on certain immune-modifying therapies such as anti-TNFs, especially those on combination therapy, may have a blunted immune response to certain vaccines.11 Neither patients with IBD nor patients on immunosuppressive therapy were included in phase 3 clinical trials for COVID-19 vaccine development, contributing to uncertainty regarding the safety and efficacy in our patient population. The risk of adverse events following COVID-19 vaccination in the IBD population has been found to be similar to that of the general population.12 It has also been reported that those who have had reactions to injectable therapies in the past may safely be vaccinated against COVID-19.13,14 With regard to vaccine efficacy, initial studies, including ICARUS, PREVENT-COVID, and CORALE-IBD, have demonstrated that patients with IBD do indeed mount a humoral immune response to the vaccine, including those on immune-modifying therapies.15-17 Nonhumoral aspects of immunity, such as cell-mediated immunity, have not yet been thoroughly evaluated. In addition, the risk of breakthrough COVID-19 infection after vaccination is low in patients with IBD, including those on immune-modifying therapy.14-18 While initial studies are reassuring that the vast majority of patients with IBD are able to mount a vaccine response, future studies are needed to determine the effects of immune-modifying therapy on sustained antibody concentrations and other correlates of immunity.
For those who received the Pfizer or Moderna vaccines, on Aug. 12, 2021, the FDA amended their EUA to allow for an additional dose in the initial vaccination series for certain immunocompromised individuals, specifically solid organ transplant recipients or those with conditions that make them equally immunocompromised.19 Based on evidence suggesting that certain solid organ transplant recipients do not mount an immune response after completing a two-dose series, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how to use vaccines, recommended that moderate to severely immunocompromised individuals should complete a three-dose series, with the third dose being given at least 28 days after the second dose.20 This recommendation included those on high-dose corticosteroids defined as oral prednisone at least 20 mg/day, anti-TNFs and biosimilars, and antimetabolites such as azathioprine, mercaptopurine, and methotrexate.
It is worth noting that the role of the ACIP here was to consider the available evidence supporting the use of an additional dose and then make recommendations on which conditions may qualify; the ACIP was not able to provide recommendations for every disease state. At the time of writing this article, no recommendations have been made with regards to an additional dose of the Janssen vaccine. Likewise, in response to the ACIP recommendations, the Crohn’s & Colitis Foundation recommended an additional dose for patients with IBD on immune-modifying therapies.21,22
Less than one week after the EUA amendment for an additional dose, the Department of Health & Human Services announced that booster shots would likely become available to the general population as early as the week of Sept. 20, 2021 and starting 8 months after an individual’s second dose.23 Here, it is worth noting that an additional dose is distinct from a booster. An additional dose (or third dose here) refers to the initial vaccination series and is given when the standard schedule is thought to be insufficient in a certain patient population. In contrast, a booster dose is administered when the initial and sufficient immunity gained from a primary vaccination series has likely dissipated. The HHS acknowledged that boosters would likely be needed for those who received the Janssen vaccine but noted that further data and recommendations would be forthcoming.
To summarize, COVID-19 vaccines are safe and effective in the IBD population, and patients should be vaccinated at the earliest opportunity regardless of concurrent therapies. For those that received the Pfizer or Moderna vaccine, the ACIP recommended an additional dose in the initial vaccination series to be given at least 28 days after the second dose for those that are immunosuppressed. This recommendation was largely based off of transplant data. Reassuringly, the available data demonstrates a humoral immune response to a two-dose vaccination series in patients with IBD, including those on immune-modifying therapies. The Crohn’s & Colitis Foundation recommends that patients with IBD on immune-modifying therapy receive an additional dose (i.e., a three-dose series), which should be from the same manufacturer as the first two doses. In addition, at press time, HHS indicated that there will be a movement toward a booster dose for the general population in late September, which would also apply to patients with IBD. The ACIP has yet to comment on this change at the time of preparing this article, but the announcement indicated that a booster could be given “8 months after an individual’s second dose.” It is unclear how those who may receive a three-dose vaccination series will factor in, but it is possible that they would be eligible for a booster 8 months after their most recent dose. Gastroenterologists should also be aware that there is no role for serologic testing in the clinical setting because it has not been validated for such purposes and is primarily used in the research setting. Finally, it is paramount to emphasize that patients with IBD have historically had lower vaccination rates than the general population,24 and we must take an active role in ensuring that our patients are immunized by addressing their concerns, communicating the risks of COVID-19 and the benefits of vaccination, providing information on how to get vaccinated, and strongly recommending vaccination.
The following list also summarizes the recommendations:
- Patients with IBD should be vaccinated against COVID-19 regardless of concurrent therapies.
- Patients with IBD are not at increased risk of severe COVID-19.
- Patients with IBD, including those on immune-modifying therapies, mount a humoral immune response to the vaccine.
- Patients with IBD on immune-modifying therapies, who received either the Pfizer or Moderna vaccine, should receive a three-dose vaccination series, with the third dose at least 28 days after the second dose.
- Patients with IBD on biologic therapy can receive the third dose of the vaccine at any time point and should not interrupt biologic therapy.
- Boosters are likely to become available to the general public in September and would be given at least 8 months after an individual’s second dose.
- Recommendations regarding boosters for those who received a three-dose vaccination series are forthcoming.
- Recommendations regarding boosters and additional doses for those that received the Janssen vaccine are forthcoming.
- Gastroenterologists should take an active role in ensuring that their patients are vaccinated.
Dr. Schell is a second-year graduate student in the division of internal medicine at the University of Wisconsin–Madison. Dr. Caldera is an associate professor of medicine in the division of gastroenterology & hepatology at the University of Wisconsin–Madison. Dr. Schell has no conflicts of interest to disclose. Dr. Caldera has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene.
References
1. Sadoff J et al. N Engl J Med. 2021;384(23):2187-201.
2. Baden LR et al. N Engl J Med. 2021;384(5):403-16.
3. Polack FP et al. N Engl J Med. 2020;383:2603-15.
4. Johnson K et al. U.S. FDA aims to give full approval to Pfizer vaccine on Monday – NYT. Reuters. 2021 Aug 20. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-aims-give-full-nod-pfizers-covid-19-vaccine-monday-new-york-times-2021-08-20/.
5. Allocca M et al. J Clin Med. 2020 Oct;9(11):3533.
6. Monteleone G and Ardizzone S. J Crohns Colitis. 2020 Sep;14(9):1334-6.
7. Papa A et al. Am J Gastroenterol. 2020;115(10):1722-4.
8. Derikx LAAP et al. J Crohn’s Colitis. 2021 Apr 6;15(4):529-39.
9. Brenner EJ et al. Gastroenterology. 2020;159(2):481-91.
10. Ungaro RC et al. Gut. 2021;70(4):725-32.
11. Caldera F et al. Inflamm Bowel Dis. 2020;26(4):593-602.
12. Botwin GJ et al. Am J Gastroenterol. 2021. doi: 10.14309/ajg.0000000000001342.
13. Squire JD et al. Inflamm Bowel Dis. 2021 Jul 27;27(8):1358-60.
14. Hadi YB et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.014.
15. Wong S-Y et al. Gastroenterology. 2021;161:715-8.
16. Kappelman MD et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.016.
17. Pozdnyakova V et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.014.
18. Ben-Tov A et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.076.
19. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. FDA News Release. 2021. Accessed 2021 Aug 18. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised.
20. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately to Severely Immunocompromised People. 2021. Accessed 2021 Aug 18. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.
21. Allocca M et al. J Clin Med. 2020 Oct 31;9(11):3533.
22. Crohn’s & Colitis Foundation. COVID-19 Vaccines: Position Statements. IBD & Coronavirus. 2021. Accessed 2021 Aug 20. https://www.crohnscolitisfoundation.org/coronavirus/vaccine-position-statements.
23. Centers for Disease Control and Prevention. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html.
24. Caldera F et al. Inflamm Bowel Dis. 2021;27(1):123-133.
Korean siblings face high familial IBD risk
Among Asian-Pacific populations, the first-degree relatives (FDRs) of individuals with inflammatory bowel disease (IBD) have a significantly increased risk for IBD themselves, according to a large analysis of data from South Korea. The greatest risk was found in siblings and for Crohn’s disease (CD).
The analysis of the South Korean Health Insurance Database included a cohort of 21,940,795 individuals from about 12 million families, with data collected between 2002 and 2017.
Previous studies have examined risk of IBD and familial relationships with existing IBD patients, but they have been subject to biases and have been heterogeneous in design, according to the authors, led by co–first authors Hyun Jung Kim, MD, of Korea University in Seoul, South Korea, and Shailja C. Shah, MD, of Vanderbilt University in Nashville, Tenn. There are few true population-based studies that quantify specific risks for family members of IBD patients, and none that were conducted in non-Western populations.
There are concerns about extrapolating familial IBD risk estimates from Western European populations to Asian populations because new data suggest that there are both genetic and nongenetic disease risk factors that reflect geography and ethnicity, the authors noted.
The researchers identified 45,717 individuals with ulcerative colitis (UC) and 17,848 with CD. Mean annual incidence rates were 4.6 cases of UC and 3.2 cases of CD per 100,000 person-years, which was relatively stable across the study period.
In all, 3.8% of UC and 3.1% of CD diagnoses occurred in FDR’s of existing patients. Among those with an FDR with IBD, the incidence of UC and CD was 54.5 and 99.2 per 100,000 person-years, respectively. When compared with individuals who had no FDRs with IBD, subjects who had an FDR with CD were at a more than 20-fold increased risk of CD (incident rate ratio, 22.2; 95% confidence interval, 20.5-24.5), whereas individuals with an FDR with UC were at a little more than a 10-fold risk for UC (IRR, 10.2; 95% CI, 9.39-11.1).
Subjects with an FDR with CD were at higher risk of UC (IRR, 3.56; 95% CI, 2.77-4.50), and those with an FDR with UC were at higher risk of CD (IRR, 2.94; 95% CI, 2.45-3.49). After adjustment for smoking, having an FDR with IBD was associated with an almost eightfold increased risk of UC (IRR, 7.94; 95% CI, 6.98-9.03) and a nearly 20-fold increased risk of CD (IRR, 19.03; 95% CI, 15.58-23.25).
The investigators also performed an analysis based on type of relative, with matching relations with unaffected relatives as the reference for each comparison. The highest risk for incident CD was with twin siblings (IRR, 336.2; 95% CI, 235.0-481.1) followed by nontwin siblings (IRR, 27.6; 95% CI, 24.6-30.9). The risk of CD among offspring of an affected father was 9.40 (95% CI, 6.81-13.0) and 6.54 (95% CI, 4.17-10.3) for offspring of affected mothers. There was a similar pattern for UC, although the magnitude was smaller: 163.7 for twin siblings (95% CI, 105.6-253.9), 13.1 for nontwin siblings (95% CI, 11.4-15.0), 7.11 for offspring of affected fathers (95% CI, 6.10-8.29), and 8.77 for offspring of affected mothers (95% CI, 7.46-10.3).
The researchers found no evidence of a birth cohort effect. Family history and IBD risk is a complicated relationship. Family history includes shared genetics as well as similar environmental exposures, and gene-environment interactions can add another layer of uncertainty. Previous studies have found that asymptomatic family members of IBD patients sometimes have preclinical signs such as changes in intestinal permeability, immune function, the microbiome, and biomarker levels.
IBD has emerged recently among Asian-Pacific populations as a serious health concern, with a recent rapid increase. This may reflect a shift in potentially modifiable environmental triggers. “Precisely quantifying familial risk and patterns might enable more accurate risk counseling and better-targeted clinical surveillance for earlier diagnosis and treatment among FDRs. Moreover, an accurate definition of familial IBD risk across populations also might inform subsequent investigations untangling the various shared environmental and genetic contributions,” the authors wrote.
Although genetic susceptibility is generally accepted as the predominant driver in familial trends for IBD, the authors noted their “study was not designed to determine the contribution of genetic vs. nongenetic determinants to familial IBD risk, and future well-designed dedicated investigations are needed to provide this clarity.”
The study is limited by the relatively short follow-up period, which may not have captured all IBD cases within patients’ families.
The authors have no relevant financial disclosures.
One of the hallmarks of effective IBD management is early disease intervention to modify the natural history. This work will be instrumental in counseling patients’ families on the need to monitor for subclinical red flag or early warning signs, and it will be important to recognize that male and female IBD patients will both need to be counseled equally on the risk of offspring developing IBD. Further work will be needed to understand whether modifiable risk factors can be identified to help prevent the development of IBD in these at-risk individuals and whether specific mutations are responsible for multilineage IBD syndromes affecting several generations or multiple first-degree relatives.
Parambir S. Dulai, MD, is an assistant professor in the division of gastroenterology and hepatology at University of California, San Diego. He has no relevant conflicts of interest.
One of the hallmarks of effective IBD management is early disease intervention to modify the natural history. This work will be instrumental in counseling patients’ families on the need to monitor for subclinical red flag or early warning signs, and it will be important to recognize that male and female IBD patients will both need to be counseled equally on the risk of offspring developing IBD. Further work will be needed to understand whether modifiable risk factors can be identified to help prevent the development of IBD in these at-risk individuals and whether specific mutations are responsible for multilineage IBD syndromes affecting several generations or multiple first-degree relatives.
Parambir S. Dulai, MD, is an assistant professor in the division of gastroenterology and hepatology at University of California, San Diego. He has no relevant conflicts of interest.
One of the hallmarks of effective IBD management is early disease intervention to modify the natural history. This work will be instrumental in counseling patients’ families on the need to monitor for subclinical red flag or early warning signs, and it will be important to recognize that male and female IBD patients will both need to be counseled equally on the risk of offspring developing IBD. Further work will be needed to understand whether modifiable risk factors can be identified to help prevent the development of IBD in these at-risk individuals and whether specific mutations are responsible for multilineage IBD syndromes affecting several generations or multiple first-degree relatives.
Parambir S. Dulai, MD, is an assistant professor in the division of gastroenterology and hepatology at University of California, San Diego. He has no relevant conflicts of interest.
Among Asian-Pacific populations, the first-degree relatives (FDRs) of individuals with inflammatory bowel disease (IBD) have a significantly increased risk for IBD themselves, according to a large analysis of data from South Korea. The greatest risk was found in siblings and for Crohn’s disease (CD).
The analysis of the South Korean Health Insurance Database included a cohort of 21,940,795 individuals from about 12 million families, with data collected between 2002 and 2017.
Previous studies have examined risk of IBD and familial relationships with existing IBD patients, but they have been subject to biases and have been heterogeneous in design, according to the authors, led by co–first authors Hyun Jung Kim, MD, of Korea University in Seoul, South Korea, and Shailja C. Shah, MD, of Vanderbilt University in Nashville, Tenn. There are few true population-based studies that quantify specific risks for family members of IBD patients, and none that were conducted in non-Western populations.
There are concerns about extrapolating familial IBD risk estimates from Western European populations to Asian populations because new data suggest that there are both genetic and nongenetic disease risk factors that reflect geography and ethnicity, the authors noted.
The researchers identified 45,717 individuals with ulcerative colitis (UC) and 17,848 with CD. Mean annual incidence rates were 4.6 cases of UC and 3.2 cases of CD per 100,000 person-years, which was relatively stable across the study period.
In all, 3.8% of UC and 3.1% of CD diagnoses occurred in FDR’s of existing patients. Among those with an FDR with IBD, the incidence of UC and CD was 54.5 and 99.2 per 100,000 person-years, respectively. When compared with individuals who had no FDRs with IBD, subjects who had an FDR with CD were at a more than 20-fold increased risk of CD (incident rate ratio, 22.2; 95% confidence interval, 20.5-24.5), whereas individuals with an FDR with UC were at a little more than a 10-fold risk for UC (IRR, 10.2; 95% CI, 9.39-11.1).
Subjects with an FDR with CD were at higher risk of UC (IRR, 3.56; 95% CI, 2.77-4.50), and those with an FDR with UC were at higher risk of CD (IRR, 2.94; 95% CI, 2.45-3.49). After adjustment for smoking, having an FDR with IBD was associated with an almost eightfold increased risk of UC (IRR, 7.94; 95% CI, 6.98-9.03) and a nearly 20-fold increased risk of CD (IRR, 19.03; 95% CI, 15.58-23.25).
The investigators also performed an analysis based on type of relative, with matching relations with unaffected relatives as the reference for each comparison. The highest risk for incident CD was with twin siblings (IRR, 336.2; 95% CI, 235.0-481.1) followed by nontwin siblings (IRR, 27.6; 95% CI, 24.6-30.9). The risk of CD among offspring of an affected father was 9.40 (95% CI, 6.81-13.0) and 6.54 (95% CI, 4.17-10.3) for offspring of affected mothers. There was a similar pattern for UC, although the magnitude was smaller: 163.7 for twin siblings (95% CI, 105.6-253.9), 13.1 for nontwin siblings (95% CI, 11.4-15.0), 7.11 for offspring of affected fathers (95% CI, 6.10-8.29), and 8.77 for offspring of affected mothers (95% CI, 7.46-10.3).
The researchers found no evidence of a birth cohort effect. Family history and IBD risk is a complicated relationship. Family history includes shared genetics as well as similar environmental exposures, and gene-environment interactions can add another layer of uncertainty. Previous studies have found that asymptomatic family members of IBD patients sometimes have preclinical signs such as changes in intestinal permeability, immune function, the microbiome, and biomarker levels.
IBD has emerged recently among Asian-Pacific populations as a serious health concern, with a recent rapid increase. This may reflect a shift in potentially modifiable environmental triggers. “Precisely quantifying familial risk and patterns might enable more accurate risk counseling and better-targeted clinical surveillance for earlier diagnosis and treatment among FDRs. Moreover, an accurate definition of familial IBD risk across populations also might inform subsequent investigations untangling the various shared environmental and genetic contributions,” the authors wrote.
Although genetic susceptibility is generally accepted as the predominant driver in familial trends for IBD, the authors noted their “study was not designed to determine the contribution of genetic vs. nongenetic determinants to familial IBD risk, and future well-designed dedicated investigations are needed to provide this clarity.”
The study is limited by the relatively short follow-up period, which may not have captured all IBD cases within patients’ families.
The authors have no relevant financial disclosures.
Among Asian-Pacific populations, the first-degree relatives (FDRs) of individuals with inflammatory bowel disease (IBD) have a significantly increased risk for IBD themselves, according to a large analysis of data from South Korea. The greatest risk was found in siblings and for Crohn’s disease (CD).
The analysis of the South Korean Health Insurance Database included a cohort of 21,940,795 individuals from about 12 million families, with data collected between 2002 and 2017.
Previous studies have examined risk of IBD and familial relationships with existing IBD patients, but they have been subject to biases and have been heterogeneous in design, according to the authors, led by co–first authors Hyun Jung Kim, MD, of Korea University in Seoul, South Korea, and Shailja C. Shah, MD, of Vanderbilt University in Nashville, Tenn. There are few true population-based studies that quantify specific risks for family members of IBD patients, and none that were conducted in non-Western populations.
There are concerns about extrapolating familial IBD risk estimates from Western European populations to Asian populations because new data suggest that there are both genetic and nongenetic disease risk factors that reflect geography and ethnicity, the authors noted.
The researchers identified 45,717 individuals with ulcerative colitis (UC) and 17,848 with CD. Mean annual incidence rates were 4.6 cases of UC and 3.2 cases of CD per 100,000 person-years, which was relatively stable across the study period.
In all, 3.8% of UC and 3.1% of CD diagnoses occurred in FDR’s of existing patients. Among those with an FDR with IBD, the incidence of UC and CD was 54.5 and 99.2 per 100,000 person-years, respectively. When compared with individuals who had no FDRs with IBD, subjects who had an FDR with CD were at a more than 20-fold increased risk of CD (incident rate ratio, 22.2; 95% confidence interval, 20.5-24.5), whereas individuals with an FDR with UC were at a little more than a 10-fold risk for UC (IRR, 10.2; 95% CI, 9.39-11.1).
Subjects with an FDR with CD were at higher risk of UC (IRR, 3.56; 95% CI, 2.77-4.50), and those with an FDR with UC were at higher risk of CD (IRR, 2.94; 95% CI, 2.45-3.49). After adjustment for smoking, having an FDR with IBD was associated with an almost eightfold increased risk of UC (IRR, 7.94; 95% CI, 6.98-9.03) and a nearly 20-fold increased risk of CD (IRR, 19.03; 95% CI, 15.58-23.25).
The investigators also performed an analysis based on type of relative, with matching relations with unaffected relatives as the reference for each comparison. The highest risk for incident CD was with twin siblings (IRR, 336.2; 95% CI, 235.0-481.1) followed by nontwin siblings (IRR, 27.6; 95% CI, 24.6-30.9). The risk of CD among offspring of an affected father was 9.40 (95% CI, 6.81-13.0) and 6.54 (95% CI, 4.17-10.3) for offspring of affected mothers. There was a similar pattern for UC, although the magnitude was smaller: 163.7 for twin siblings (95% CI, 105.6-253.9), 13.1 for nontwin siblings (95% CI, 11.4-15.0), 7.11 for offspring of affected fathers (95% CI, 6.10-8.29), and 8.77 for offspring of affected mothers (95% CI, 7.46-10.3).
The researchers found no evidence of a birth cohort effect. Family history and IBD risk is a complicated relationship. Family history includes shared genetics as well as similar environmental exposures, and gene-environment interactions can add another layer of uncertainty. Previous studies have found that asymptomatic family members of IBD patients sometimes have preclinical signs such as changes in intestinal permeability, immune function, the microbiome, and biomarker levels.
IBD has emerged recently among Asian-Pacific populations as a serious health concern, with a recent rapid increase. This may reflect a shift in potentially modifiable environmental triggers. “Precisely quantifying familial risk and patterns might enable more accurate risk counseling and better-targeted clinical surveillance for earlier diagnosis and treatment among FDRs. Moreover, an accurate definition of familial IBD risk across populations also might inform subsequent investigations untangling the various shared environmental and genetic contributions,” the authors wrote.
Although genetic susceptibility is generally accepted as the predominant driver in familial trends for IBD, the authors noted their “study was not designed to determine the contribution of genetic vs. nongenetic determinants to familial IBD risk, and future well-designed dedicated investigations are needed to provide this clarity.”
The study is limited by the relatively short follow-up period, which may not have captured all IBD cases within patients’ families.
The authors have no relevant financial disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Clinical Practice Update: Expert Review on IBD dysplasia surveillance, management
The American Gastroenterological Association recently published an expert review and clinical practice update addressing endoscopic surveillance and management of colorectal dysplasia in patients with inflammatory bowel disease (IBD).
Because of practice-altering advances in therapy and surveillance over the past 2 decades, an updated approach is needed, according to authors led by Sanjay K. Murthy, MD, of Ottawa Hospital Research Institute and Fernando Velayos, MD, from Kaiser Permanente San Francisco Medical Center.
“Not long ago, notions of imperceptible CRC [colorectal cancer] development and urgent need for colectomy in the face of dysplasia dominated IBD practice,” the authors wrote in Gastroenterology. “However, improvements in disease management, as well as endoscopic technology and quality, have dramatically changed the way in which we conceptualize and manage IBD-related dysplasia over the past 20 years.”
Most notably, the authors called for a more conservative approach to sample collection and intervention.
“The practices of taking nontargeted biopsies and of referring patients for colectomy in the setting of low-grade or invisible dysplasia are being increasingly challenged in favor of ‘smart’ approaches that emphasize careful inspection and targeted sampling of visible and subtle lesions using newer technologies ... as well as endoscopic management of most lesions that appear endoscopically resectable,” the authors wrote. “Indeed, surgery is being increasingly reserved for lesions harboring strong risk factors for invasive cancer or when endoscopic clearance is not possible.”
The 14 best practice advice statements cover a variety of topics, including appropriate lesion terminology and characterization, endoscopy timing, and indications for biopsies, resection, and colectomy.
“The proposed conceptual model and best practice advice statements in this review are best used in conjunction with evolving literature and existing societal guidelines as part of a shared decision-making process,” the authors noted.
Lesion descriptions
First, the authors provided best practice advice for retirement of three older terms: “dysplasia-associated lesion or mass, adenoma-like mass, and flat dysplasia.” Instead, they advised sorting precancerous colorectal lesions into one of three categories: nonpolypoid (less than 2.5 mm tall), polypoid (at least 2.5 mm tall), or invisible (if detected by nontargeted biopsy).
According to the update, lesion descriptions should also include location, morphology, size, presence of ulceration, clarity of borders, presence within an area of past or current colitis, use of special visualization techniques, and perceived completeness of resection.
Surveillance timing
All patients with chronic IBD should undergo colonoscopy screening for dysplasia 8-10 years after diagnosis, the authors wrote. Subsequent colonoscopies should be performed every 1-5 years, depending on risk factors, such as family history of colorectal cancer and quality of prior surveillance exams.
Higher-risk patients may require colonoscopies earlier and more frequently, according to the update. Patients diagnosed with primary sclerosing cholangitis, for instance, should undergo immediate colonoscopy, while patients at high risk of dysplasia (such as those with prior CRC) should undergo annual pouch surveillance.
General principles and surveillance colonoscopy
“Conditions and practices for dysplasia detection should be optimized,” the authors wrote, “including control of inflammation, use of high-definition endoscopes, bowel preparation, careful washing and inspection of all colorectal mucosa, and targeted sampling of any suspicious mucosal irregularities.”
Endoscopists should consider use of dye spray chromoendoscopy, “particularly if a standard definition endoscope is used or if there is a history of dysplasia,” the authors wrote. Alternatively, virtual chromoendoscopy may be used in conjunction with high-definition endoscopy.
Biopsy, resection, and colectomy
According to the update, if chromoendoscopy is used, then biopsies should be targeted “where mucosal findings are suspicious for dysplasia or are inexplicably different from the surrounding mucosa.”
If chromoendoscopy isn’t used, then the authors advised clinicians to also perform nontargeted biopsies, ideally four per 10 cm of colon, in addition to targeted biopsies of suspicious areas.
When lesions are clearly demarcated and lack submucosal fibrosis or stigmata of invasive cancer, then endoscopic resection is preferred over biopsy. Following resection, mucosal biopsies are usually unnecessary, “unless there are concerns about resection completeness.”
“If the resectability of a lesion is in question, referral to a specialized endoscopist or inflammatory bowel disease center is suggested,” wrote the authors.
They noted that, if visible dysplasia is truly unresectable or if invisible multifocal/high-grade dysplasia is encountered, then colectomy should be performed.
IBD control
Finally, the authors emphasized the importance of adequately managing IBD activity to reduce dysplasia risk.
“Because CRC risk in IBD is primarily driven by inflammation, and available data do not demonstrate a clear independent chemopreventive effect of available agents, the focus of chemoprevention in IBD should be control of inflammation,” they wrote.
The expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board. The investigators disclosed no conflicts of interest.
The American Gastroenterological Association recently published an expert review and clinical practice update addressing endoscopic surveillance and management of colorectal dysplasia in patients with inflammatory bowel disease (IBD).
Because of practice-altering advances in therapy and surveillance over the past 2 decades, an updated approach is needed, according to authors led by Sanjay K. Murthy, MD, of Ottawa Hospital Research Institute and Fernando Velayos, MD, from Kaiser Permanente San Francisco Medical Center.
“Not long ago, notions of imperceptible CRC [colorectal cancer] development and urgent need for colectomy in the face of dysplasia dominated IBD practice,” the authors wrote in Gastroenterology. “However, improvements in disease management, as well as endoscopic technology and quality, have dramatically changed the way in which we conceptualize and manage IBD-related dysplasia over the past 20 years.”
Most notably, the authors called for a more conservative approach to sample collection and intervention.
“The practices of taking nontargeted biopsies and of referring patients for colectomy in the setting of low-grade or invisible dysplasia are being increasingly challenged in favor of ‘smart’ approaches that emphasize careful inspection and targeted sampling of visible and subtle lesions using newer technologies ... as well as endoscopic management of most lesions that appear endoscopically resectable,” the authors wrote. “Indeed, surgery is being increasingly reserved for lesions harboring strong risk factors for invasive cancer or when endoscopic clearance is not possible.”
The 14 best practice advice statements cover a variety of topics, including appropriate lesion terminology and characterization, endoscopy timing, and indications for biopsies, resection, and colectomy.
“The proposed conceptual model and best practice advice statements in this review are best used in conjunction with evolving literature and existing societal guidelines as part of a shared decision-making process,” the authors noted.
Lesion descriptions
First, the authors provided best practice advice for retirement of three older terms: “dysplasia-associated lesion or mass, adenoma-like mass, and flat dysplasia.” Instead, they advised sorting precancerous colorectal lesions into one of three categories: nonpolypoid (less than 2.5 mm tall), polypoid (at least 2.5 mm tall), or invisible (if detected by nontargeted biopsy).
According to the update, lesion descriptions should also include location, morphology, size, presence of ulceration, clarity of borders, presence within an area of past or current colitis, use of special visualization techniques, and perceived completeness of resection.
Surveillance timing
All patients with chronic IBD should undergo colonoscopy screening for dysplasia 8-10 years after diagnosis, the authors wrote. Subsequent colonoscopies should be performed every 1-5 years, depending on risk factors, such as family history of colorectal cancer and quality of prior surveillance exams.
Higher-risk patients may require colonoscopies earlier and more frequently, according to the update. Patients diagnosed with primary sclerosing cholangitis, for instance, should undergo immediate colonoscopy, while patients at high risk of dysplasia (such as those with prior CRC) should undergo annual pouch surveillance.
General principles and surveillance colonoscopy
“Conditions and practices for dysplasia detection should be optimized,” the authors wrote, “including control of inflammation, use of high-definition endoscopes, bowel preparation, careful washing and inspection of all colorectal mucosa, and targeted sampling of any suspicious mucosal irregularities.”
Endoscopists should consider use of dye spray chromoendoscopy, “particularly if a standard definition endoscope is used or if there is a history of dysplasia,” the authors wrote. Alternatively, virtual chromoendoscopy may be used in conjunction with high-definition endoscopy.
Biopsy, resection, and colectomy
According to the update, if chromoendoscopy is used, then biopsies should be targeted “where mucosal findings are suspicious for dysplasia or are inexplicably different from the surrounding mucosa.”
If chromoendoscopy isn’t used, then the authors advised clinicians to also perform nontargeted biopsies, ideally four per 10 cm of colon, in addition to targeted biopsies of suspicious areas.
When lesions are clearly demarcated and lack submucosal fibrosis or stigmata of invasive cancer, then endoscopic resection is preferred over biopsy. Following resection, mucosal biopsies are usually unnecessary, “unless there are concerns about resection completeness.”
“If the resectability of a lesion is in question, referral to a specialized endoscopist or inflammatory bowel disease center is suggested,” wrote the authors.
They noted that, if visible dysplasia is truly unresectable or if invisible multifocal/high-grade dysplasia is encountered, then colectomy should be performed.
IBD control
Finally, the authors emphasized the importance of adequately managing IBD activity to reduce dysplasia risk.
“Because CRC risk in IBD is primarily driven by inflammation, and available data do not demonstrate a clear independent chemopreventive effect of available agents, the focus of chemoprevention in IBD should be control of inflammation,” they wrote.
The expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board. The investigators disclosed no conflicts of interest.
The American Gastroenterological Association recently published an expert review and clinical practice update addressing endoscopic surveillance and management of colorectal dysplasia in patients with inflammatory bowel disease (IBD).
Because of practice-altering advances in therapy and surveillance over the past 2 decades, an updated approach is needed, according to authors led by Sanjay K. Murthy, MD, of Ottawa Hospital Research Institute and Fernando Velayos, MD, from Kaiser Permanente San Francisco Medical Center.
“Not long ago, notions of imperceptible CRC [colorectal cancer] development and urgent need for colectomy in the face of dysplasia dominated IBD practice,” the authors wrote in Gastroenterology. “However, improvements in disease management, as well as endoscopic technology and quality, have dramatically changed the way in which we conceptualize and manage IBD-related dysplasia over the past 20 years.”
Most notably, the authors called for a more conservative approach to sample collection and intervention.
“The practices of taking nontargeted biopsies and of referring patients for colectomy in the setting of low-grade or invisible dysplasia are being increasingly challenged in favor of ‘smart’ approaches that emphasize careful inspection and targeted sampling of visible and subtle lesions using newer technologies ... as well as endoscopic management of most lesions that appear endoscopically resectable,” the authors wrote. “Indeed, surgery is being increasingly reserved for lesions harboring strong risk factors for invasive cancer or when endoscopic clearance is not possible.”
The 14 best practice advice statements cover a variety of topics, including appropriate lesion terminology and characterization, endoscopy timing, and indications for biopsies, resection, and colectomy.
“The proposed conceptual model and best practice advice statements in this review are best used in conjunction with evolving literature and existing societal guidelines as part of a shared decision-making process,” the authors noted.
Lesion descriptions
First, the authors provided best practice advice for retirement of three older terms: “dysplasia-associated lesion or mass, adenoma-like mass, and flat dysplasia.” Instead, they advised sorting precancerous colorectal lesions into one of three categories: nonpolypoid (less than 2.5 mm tall), polypoid (at least 2.5 mm tall), or invisible (if detected by nontargeted biopsy).
According to the update, lesion descriptions should also include location, morphology, size, presence of ulceration, clarity of borders, presence within an area of past or current colitis, use of special visualization techniques, and perceived completeness of resection.
Surveillance timing
All patients with chronic IBD should undergo colonoscopy screening for dysplasia 8-10 years after diagnosis, the authors wrote. Subsequent colonoscopies should be performed every 1-5 years, depending on risk factors, such as family history of colorectal cancer and quality of prior surveillance exams.
Higher-risk patients may require colonoscopies earlier and more frequently, according to the update. Patients diagnosed with primary sclerosing cholangitis, for instance, should undergo immediate colonoscopy, while patients at high risk of dysplasia (such as those with prior CRC) should undergo annual pouch surveillance.
General principles and surveillance colonoscopy
“Conditions and practices for dysplasia detection should be optimized,” the authors wrote, “including control of inflammation, use of high-definition endoscopes, bowel preparation, careful washing and inspection of all colorectal mucosa, and targeted sampling of any suspicious mucosal irregularities.”
Endoscopists should consider use of dye spray chromoendoscopy, “particularly if a standard definition endoscope is used or if there is a history of dysplasia,” the authors wrote. Alternatively, virtual chromoendoscopy may be used in conjunction with high-definition endoscopy.
Biopsy, resection, and colectomy
According to the update, if chromoendoscopy is used, then biopsies should be targeted “where mucosal findings are suspicious for dysplasia or are inexplicably different from the surrounding mucosa.”
If chromoendoscopy isn’t used, then the authors advised clinicians to also perform nontargeted biopsies, ideally four per 10 cm of colon, in addition to targeted biopsies of suspicious areas.
When lesions are clearly demarcated and lack submucosal fibrosis or stigmata of invasive cancer, then endoscopic resection is preferred over biopsy. Following resection, mucosal biopsies are usually unnecessary, “unless there are concerns about resection completeness.”
“If the resectability of a lesion is in question, referral to a specialized endoscopist or inflammatory bowel disease center is suggested,” wrote the authors.
They noted that, if visible dysplasia is truly unresectable or if invisible multifocal/high-grade dysplasia is encountered, then colectomy should be performed.
IBD control
Finally, the authors emphasized the importance of adequately managing IBD activity to reduce dysplasia risk.
“Because CRC risk in IBD is primarily driven by inflammation, and available data do not demonstrate a clear independent chemopreventive effect of available agents, the focus of chemoprevention in IBD should be control of inflammation,” they wrote.
The expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board. The investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
VARSITY: Better histologic outcomes with vedolizumab than adalimumab in UC
In patients with moderate to severe ulcerative colitis (UC), treatment with vedolizumab leads to better histologic outcomes than treatment with adalimumab, according to findings from the VARSITY trial.
The findings come from an analysis in Gastroenterology of prespecified histologic exploratory endpoints from the phase 3, multicenter, randomized, controlled VARSITY trial, which was the first head-to-head comparison of two biologics in the treatment of UC. VARSITY demonstrated improved rates of clinical remission and endoscopic improvement at week 52 with vedolizumab.
The authors, led by Laurent Peyrin-Biroulet of the department of gastroenterology at Nancy (France) University Hospital, noted that there is general consensus that endoscopic improvement is considered the best endpoint for demonstrating effective maintenance therapy in UC. However, they added that “endoscopic changes do not necessarily reflect quiescent microscopic disease, and complete resolution of mucosal inflammation can only be confirmed by histologic assessment.” Still, histologic outcomes are not currently recommended as a goal of therapy in clinical practice, possibly due to a lack of standardized and validated scoring systems suitable for routine clinical use. Nevertheless, histologic outcomes have been shown to predict hospitalization, corticosteroid use, exacerbation, and the risk of advanced colorectal neoplasia.
To assess histologic outcomes in the two treatment regimens, the researchers included the Geboes Index score and the Robarts Histopathology Index (RHI) as two validated scoring systems.
During the 52-week study, 769 patients were assigned to vedolizumab (300 mg IV) or adalimumab (40 mg subcutaneously).
At week 14 and week 52, more patients in the vedolizumab group achieved histologic remission as determined by Geboes Index score less than 2 (week 52, 29.2% vs. 8.3%; difference, 20.9%; 95% confidence interval, 15.6%-26.2%; P < .0001) and RHI score of 2 or less (week 52, 37.6% vs. 19.9%; difference, 17.6%; 95% CI, 11.3%-23.8%; P < .0001).
At week 52, more patients in the vedolizumab group than in the adalimumab group achieved minimum histologic disease activity as determined by Geboes Index score of 3.1 or less (45.7% vs. 30.8%; difference, 14.8%; 95% CI, 8.0%-21.5%; P < .0001) and RHI score of 4 or less(42.3% vs. 25.6%; difference, 16.6%; 95% CI, 10.0%-23.1%; P < .0001).
The investigators performed post hoc analyses of mucosal healing, defined as a composite of the histologic and endoscopic outcomes, with the latter defined as Mayo endoscopic subscore of 1 or less. A greater proportion of patients treated with vedolizumab than with adalimumab met the composite of histologic remission on each score plus endoscopic improvement (Geboes, 35.0% vs. 20.2%; RHI, 33.7% vs. 18.1%), with similar findings for minimal histologic disease activity plus endoscopic improvement (Geboes, 35.0% vs. 20.2%; RHI, 33.7% vs. 18.1%).
The authors noted that the RHI scoring system revealed greater associations between histologic outcomes and endoscopic improvement than did the Geboes Index score, which is an important finding considering the European Crohn’s and Colitis Organisation’s stance recommending consideration of mucosal healing based on findings from endoscopy and histology.
Some study limitations included how the study design precluded dose escalation and a lack of long-term follow-up among these patients.
The researchers believe that the RHI score may be a better choice than the Geboes score for comparing efficacy in clinical trials because RHI is more reproducible, more sensitive to change, and is comparatively easy to interpret.
The study was funded by Takeda, which makes vedolizumab. The authors disclosed several relationships with industry, including some having stock options with or being employed by Takeda.
Another important element of this study was the exploration of association between endoscopic and histologic outcomes using two validated histologic indices (the Geboes Index score and the Robarts Histopathology Index). While both indices showed moderate agreement overall between histologic activity and endoscopic improvement, the Robarts score correlated better with endoscopic improvement. Therefore, the authors propose that the Robarts scoring system may be the better index for assessing histologic outcomes. This is important because standardized scoring systems would be needed to translate histologic outcomes as a goal in real clinical practice.
The landscape continues to evolve for treatment goals in UC. Symptom control is the tip of the iceberg and endoscopic along with histologic control may lead to a more durable remission.
Robin Dalal, MD, is an assistant professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn. She has nothing to disclose.
Another important element of this study was the exploration of association between endoscopic and histologic outcomes using two validated histologic indices (the Geboes Index score and the Robarts Histopathology Index). While both indices showed moderate agreement overall between histologic activity and endoscopic improvement, the Robarts score correlated better with endoscopic improvement. Therefore, the authors propose that the Robarts scoring system may be the better index for assessing histologic outcomes. This is important because standardized scoring systems would be needed to translate histologic outcomes as a goal in real clinical practice.
The landscape continues to evolve for treatment goals in UC. Symptom control is the tip of the iceberg and endoscopic along with histologic control may lead to a more durable remission.
Robin Dalal, MD, is an assistant professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn. She has nothing to disclose.
Another important element of this study was the exploration of association between endoscopic and histologic outcomes using two validated histologic indices (the Geboes Index score and the Robarts Histopathology Index). While both indices showed moderate agreement overall between histologic activity and endoscopic improvement, the Robarts score correlated better with endoscopic improvement. Therefore, the authors propose that the Robarts scoring system may be the better index for assessing histologic outcomes. This is important because standardized scoring systems would be needed to translate histologic outcomes as a goal in real clinical practice.
The landscape continues to evolve for treatment goals in UC. Symptom control is the tip of the iceberg and endoscopic along with histologic control may lead to a more durable remission.
Robin Dalal, MD, is an assistant professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn. She has nothing to disclose.
In patients with moderate to severe ulcerative colitis (UC), treatment with vedolizumab leads to better histologic outcomes than treatment with adalimumab, according to findings from the VARSITY trial.
The findings come from an analysis in Gastroenterology of prespecified histologic exploratory endpoints from the phase 3, multicenter, randomized, controlled VARSITY trial, which was the first head-to-head comparison of two biologics in the treatment of UC. VARSITY demonstrated improved rates of clinical remission and endoscopic improvement at week 52 with vedolizumab.
The authors, led by Laurent Peyrin-Biroulet of the department of gastroenterology at Nancy (France) University Hospital, noted that there is general consensus that endoscopic improvement is considered the best endpoint for demonstrating effective maintenance therapy in UC. However, they added that “endoscopic changes do not necessarily reflect quiescent microscopic disease, and complete resolution of mucosal inflammation can only be confirmed by histologic assessment.” Still, histologic outcomes are not currently recommended as a goal of therapy in clinical practice, possibly due to a lack of standardized and validated scoring systems suitable for routine clinical use. Nevertheless, histologic outcomes have been shown to predict hospitalization, corticosteroid use, exacerbation, and the risk of advanced colorectal neoplasia.
To assess histologic outcomes in the two treatment regimens, the researchers included the Geboes Index score and the Robarts Histopathology Index (RHI) as two validated scoring systems.
During the 52-week study, 769 patients were assigned to vedolizumab (300 mg IV) or adalimumab (40 mg subcutaneously).
At week 14 and week 52, more patients in the vedolizumab group achieved histologic remission as determined by Geboes Index score less than 2 (week 52, 29.2% vs. 8.3%; difference, 20.9%; 95% confidence interval, 15.6%-26.2%; P < .0001) and RHI score of 2 or less (week 52, 37.6% vs. 19.9%; difference, 17.6%; 95% CI, 11.3%-23.8%; P < .0001).
At week 52, more patients in the vedolizumab group than in the adalimumab group achieved minimum histologic disease activity as determined by Geboes Index score of 3.1 or less (45.7% vs. 30.8%; difference, 14.8%; 95% CI, 8.0%-21.5%; P < .0001) and RHI score of 4 or less(42.3% vs. 25.6%; difference, 16.6%; 95% CI, 10.0%-23.1%; P < .0001).
The investigators performed post hoc analyses of mucosal healing, defined as a composite of the histologic and endoscopic outcomes, with the latter defined as Mayo endoscopic subscore of 1 or less. A greater proportion of patients treated with vedolizumab than with adalimumab met the composite of histologic remission on each score plus endoscopic improvement (Geboes, 35.0% vs. 20.2%; RHI, 33.7% vs. 18.1%), with similar findings for minimal histologic disease activity plus endoscopic improvement (Geboes, 35.0% vs. 20.2%; RHI, 33.7% vs. 18.1%).
The authors noted that the RHI scoring system revealed greater associations between histologic outcomes and endoscopic improvement than did the Geboes Index score, which is an important finding considering the European Crohn’s and Colitis Organisation’s stance recommending consideration of mucosal healing based on findings from endoscopy and histology.
Some study limitations included how the study design precluded dose escalation and a lack of long-term follow-up among these patients.
The researchers believe that the RHI score may be a better choice than the Geboes score for comparing efficacy in clinical trials because RHI is more reproducible, more sensitive to change, and is comparatively easy to interpret.
The study was funded by Takeda, which makes vedolizumab. The authors disclosed several relationships with industry, including some having stock options with or being employed by Takeda.
In patients with moderate to severe ulcerative colitis (UC), treatment with vedolizumab leads to better histologic outcomes than treatment with adalimumab, according to findings from the VARSITY trial.
The findings come from an analysis in Gastroenterology of prespecified histologic exploratory endpoints from the phase 3, multicenter, randomized, controlled VARSITY trial, which was the first head-to-head comparison of two biologics in the treatment of UC. VARSITY demonstrated improved rates of clinical remission and endoscopic improvement at week 52 with vedolizumab.
The authors, led by Laurent Peyrin-Biroulet of the department of gastroenterology at Nancy (France) University Hospital, noted that there is general consensus that endoscopic improvement is considered the best endpoint for demonstrating effective maintenance therapy in UC. However, they added that “endoscopic changes do not necessarily reflect quiescent microscopic disease, and complete resolution of mucosal inflammation can only be confirmed by histologic assessment.” Still, histologic outcomes are not currently recommended as a goal of therapy in clinical practice, possibly due to a lack of standardized and validated scoring systems suitable for routine clinical use. Nevertheless, histologic outcomes have been shown to predict hospitalization, corticosteroid use, exacerbation, and the risk of advanced colorectal neoplasia.
To assess histologic outcomes in the two treatment regimens, the researchers included the Geboes Index score and the Robarts Histopathology Index (RHI) as two validated scoring systems.
During the 52-week study, 769 patients were assigned to vedolizumab (300 mg IV) or adalimumab (40 mg subcutaneously).
At week 14 and week 52, more patients in the vedolizumab group achieved histologic remission as determined by Geboes Index score less than 2 (week 52, 29.2% vs. 8.3%; difference, 20.9%; 95% confidence interval, 15.6%-26.2%; P < .0001) and RHI score of 2 or less (week 52, 37.6% vs. 19.9%; difference, 17.6%; 95% CI, 11.3%-23.8%; P < .0001).
At week 52, more patients in the vedolizumab group than in the adalimumab group achieved minimum histologic disease activity as determined by Geboes Index score of 3.1 or less (45.7% vs. 30.8%; difference, 14.8%; 95% CI, 8.0%-21.5%; P < .0001) and RHI score of 4 or less(42.3% vs. 25.6%; difference, 16.6%; 95% CI, 10.0%-23.1%; P < .0001).
The investigators performed post hoc analyses of mucosal healing, defined as a composite of the histologic and endoscopic outcomes, with the latter defined as Mayo endoscopic subscore of 1 or less. A greater proportion of patients treated with vedolizumab than with adalimumab met the composite of histologic remission on each score plus endoscopic improvement (Geboes, 35.0% vs. 20.2%; RHI, 33.7% vs. 18.1%), with similar findings for minimal histologic disease activity plus endoscopic improvement (Geboes, 35.0% vs. 20.2%; RHI, 33.7% vs. 18.1%).
The authors noted that the RHI scoring system revealed greater associations between histologic outcomes and endoscopic improvement than did the Geboes Index score, which is an important finding considering the European Crohn’s and Colitis Organisation’s stance recommending consideration of mucosal healing based on findings from endoscopy and histology.
Some study limitations included how the study design precluded dose escalation and a lack of long-term follow-up among these patients.
The researchers believe that the RHI score may be a better choice than the Geboes score for comparing efficacy in clinical trials because RHI is more reproducible, more sensitive to change, and is comparatively easy to interpret.
The study was funded by Takeda, which makes vedolizumab. The authors disclosed several relationships with industry, including some having stock options with or being employed by Takeda.
FROM GASTROENTEROLOGY