User login
IBS Meta-Analysis Offers Some Support for Mesalamine
Certain patients with irritable bowel syndrome (IBS) may benefit from treatment with mesalamine, although the quality of evidence supporting this strategy remains low, according to a recent systematic literature review and meta-analysis.
Global IBS symptoms improved significantly across the entire population, however, a subgroup analysis suggested that mesalamine may be most beneficial for patients who present with diarrhea, providing support for a large clinical trial in this patient population, reported lead author Vivek C. Goodoory, MBChB, of St. James’s University Hospital, Leeds, United Kingdom, and colleagues.
Some patients with IBS may present with low-grade inflammation in the intestine, offering theoretical grounds for prescribing mesalamine, which is typically used for treating ulcerative colitis, the investigators wrote in Clinical Gastroenterology and Hepatology. Yet previous randomized controlled trials (RCTs) evaluating mesalamine for IBS have yielded mixed results, and a meta-analysis showed that mesalamine offered no benefit.
According to Dr. Goodoory and colleagues, however, that meta-analysis fell short since it “only pooled mean symptom scores, rather than the proportion of patients in each trial experiencing an improvement in symptoms, and did not appear to include data from all available RCTs.” Furthermore, they noted that this prior study lacked subgroup analyses conducted based on IBS subtype or postinfection status.
“We, therefore, conducted a contemporaneous meta-analysis to examine the efficacy and safety of mesalamine in IBS addressing these deficits in knowledge,” the investigators wrote.
Their meta-analysis included 820 patients from 8 RCTs published between 2009 and 2022. Efficacy and safety were evaluated via dichotomous assessments of global IBS symptoms, bowel habit or stool frequency, abdominal pain, and adverse events. Two subgroup analyses were planned to evaluate responses based on post-infection status and predominant stool pattern.
Unlike the previous meta-analysis, Dr. Goodoory and colleagues detected a potential signal for efficacy.
Across all patients, mesalamine was associated with significant improvement in global IBS symptoms, compared with placebo (relative risk [RR], 0.86; 95% CI, 0.79-0.95). However, no significant improvements were detected for abdominal pain or bowel habit/stool frequency.
A subgroup analysis of patients exhibiting IBS with diarrhea showed significantly greater improvements in global IBS symptoms for mesalamine versus placebo (RR, 0.88; 95% CI, 0.79-0.99). This subgroup showed no improvements in abdominal pain or bowel habit/stool frequency.
Subgroup analyses for patients with constipation or mixed bowel habits, or based on postinfection status, revealed no significant differences, although the investigators noted that relevant data were limited.
Mesalamine appeared to be well tolerated. Across five studies reporting adverse events, 43.5% of patients receiving mesalamine reported any adverse event, compared with 41.4% of patients on placebo. The RR of experiencing an adverse event in those taking mesalamine was 1.20 (95% CI, 0.89-1.63), which was not statistically significant.
“There was no evidence of heterogeneity between studies in most of our analyses, but only one trial was at low risk of bias across all domains, and there were insufficient studies to assess for funnel plot asymmetry,” Dr. Goodoory and colleagues wrote. “Based on these limitations of the evidence,” they continued, “our confidence in the results of the meta-analysis would be low, and further large trials at low risk of bias would be informative.”
Specifically, the investigators suggested an RCT recruiting only patients with IBS with diarrhea, and reporting efficacy according to postinfection status.
One coauthor reported research funding from Tillotts Pharma and Dr Falk Pharma UK. The remaining authors reported no conflicts.
Advancements in the understanding of irritable bowel syndrome (IBS) pathophysiology have led to new pharmacological agents and guidelines on the delivery of patient-specific IBS care. However, treatments targeting specific IBS mechanisms including altered immune responses, barrier dysfunction, and low-grade inflammation are lacking.
In a systematic review and meta-analysis, Goodoory et al. find that pooled results from six randomized controlled trials suggest efficacy with mesalamine, an anti-inflammatory agent, for global IBS symptoms with subgroup analyses further suggesting efficacy in IBS with diarrhea. However, results are tempered by the overall low quality of evidence and lack of benefit for abdominal pain or bowel habits. Notably, the only study rated as low risk of bias did not find mesalamine to be effective. Thus, these findings cannot yet be used to inform clinical decision-makers.
Still, further study is warranted. Such future work will benefit from including well-phenotyped patients and novel biomarkers with the ability to identify individuals in whom inflammatory mechanisms contribute to IBS symptoms.
Dr. Andrea Shin is based in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California Los Angeles. She is a member of the editorial boards of Clinical Gastroenterology and Hepatology, and Alimentary Pharmacology & Therapeutics. She is associate clinical editor of Neurogastroenterology & Motility, and a member of the Scientific Communications Advisory Board for IBS-C. As an AGA member, she sits on the Research Awards Panel, and is a section councilor for neurogastroenterology & motility, as well as a patient education advisor. Dr. Shin has received funding from the NIH R03 Limited Competiation Small Grant Program, an ANMS Diversity Development Award, and is an NIH Loan Repayment Program Awardee. She has no other relevant disclosures.
Advancements in the understanding of irritable bowel syndrome (IBS) pathophysiology have led to new pharmacological agents and guidelines on the delivery of patient-specific IBS care. However, treatments targeting specific IBS mechanisms including altered immune responses, barrier dysfunction, and low-grade inflammation are lacking.
In a systematic review and meta-analysis, Goodoory et al. find that pooled results from six randomized controlled trials suggest efficacy with mesalamine, an anti-inflammatory agent, for global IBS symptoms with subgroup analyses further suggesting efficacy in IBS with diarrhea. However, results are tempered by the overall low quality of evidence and lack of benefit for abdominal pain or bowel habits. Notably, the only study rated as low risk of bias did not find mesalamine to be effective. Thus, these findings cannot yet be used to inform clinical decision-makers.
Still, further study is warranted. Such future work will benefit from including well-phenotyped patients and novel biomarkers with the ability to identify individuals in whom inflammatory mechanisms contribute to IBS symptoms.
Dr. Andrea Shin is based in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California Los Angeles. She is a member of the editorial boards of Clinical Gastroenterology and Hepatology, and Alimentary Pharmacology & Therapeutics. She is associate clinical editor of Neurogastroenterology & Motility, and a member of the Scientific Communications Advisory Board for IBS-C. As an AGA member, she sits on the Research Awards Panel, and is a section councilor for neurogastroenterology & motility, as well as a patient education advisor. Dr. Shin has received funding from the NIH R03 Limited Competiation Small Grant Program, an ANMS Diversity Development Award, and is an NIH Loan Repayment Program Awardee. She has no other relevant disclosures.
Advancements in the understanding of irritable bowel syndrome (IBS) pathophysiology have led to new pharmacological agents and guidelines on the delivery of patient-specific IBS care. However, treatments targeting specific IBS mechanisms including altered immune responses, barrier dysfunction, and low-grade inflammation are lacking.
In a systematic review and meta-analysis, Goodoory et al. find that pooled results from six randomized controlled trials suggest efficacy with mesalamine, an anti-inflammatory agent, for global IBS symptoms with subgroup analyses further suggesting efficacy in IBS with diarrhea. However, results are tempered by the overall low quality of evidence and lack of benefit for abdominal pain or bowel habits. Notably, the only study rated as low risk of bias did not find mesalamine to be effective. Thus, these findings cannot yet be used to inform clinical decision-makers.
Still, further study is warranted. Such future work will benefit from including well-phenotyped patients and novel biomarkers with the ability to identify individuals in whom inflammatory mechanisms contribute to IBS symptoms.
Dr. Andrea Shin is based in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California Los Angeles. She is a member of the editorial boards of Clinical Gastroenterology and Hepatology, and Alimentary Pharmacology & Therapeutics. She is associate clinical editor of Neurogastroenterology & Motility, and a member of the Scientific Communications Advisory Board for IBS-C. As an AGA member, she sits on the Research Awards Panel, and is a section councilor for neurogastroenterology & motility, as well as a patient education advisor. Dr. Shin has received funding from the NIH R03 Limited Competiation Small Grant Program, an ANMS Diversity Development Award, and is an NIH Loan Repayment Program Awardee. She has no other relevant disclosures.
Certain patients with irritable bowel syndrome (IBS) may benefit from treatment with mesalamine, although the quality of evidence supporting this strategy remains low, according to a recent systematic literature review and meta-analysis.
Global IBS symptoms improved significantly across the entire population, however, a subgroup analysis suggested that mesalamine may be most beneficial for patients who present with diarrhea, providing support for a large clinical trial in this patient population, reported lead author Vivek C. Goodoory, MBChB, of St. James’s University Hospital, Leeds, United Kingdom, and colleagues.
Some patients with IBS may present with low-grade inflammation in the intestine, offering theoretical grounds for prescribing mesalamine, which is typically used for treating ulcerative colitis, the investigators wrote in Clinical Gastroenterology and Hepatology. Yet previous randomized controlled trials (RCTs) evaluating mesalamine for IBS have yielded mixed results, and a meta-analysis showed that mesalamine offered no benefit.
According to Dr. Goodoory and colleagues, however, that meta-analysis fell short since it “only pooled mean symptom scores, rather than the proportion of patients in each trial experiencing an improvement in symptoms, and did not appear to include data from all available RCTs.” Furthermore, they noted that this prior study lacked subgroup analyses conducted based on IBS subtype or postinfection status.
“We, therefore, conducted a contemporaneous meta-analysis to examine the efficacy and safety of mesalamine in IBS addressing these deficits in knowledge,” the investigators wrote.
Their meta-analysis included 820 patients from 8 RCTs published between 2009 and 2022. Efficacy and safety were evaluated via dichotomous assessments of global IBS symptoms, bowel habit or stool frequency, abdominal pain, and adverse events. Two subgroup analyses were planned to evaluate responses based on post-infection status and predominant stool pattern.
Unlike the previous meta-analysis, Dr. Goodoory and colleagues detected a potential signal for efficacy.
Across all patients, mesalamine was associated with significant improvement in global IBS symptoms, compared with placebo (relative risk [RR], 0.86; 95% CI, 0.79-0.95). However, no significant improvements were detected for abdominal pain or bowel habit/stool frequency.
A subgroup analysis of patients exhibiting IBS with diarrhea showed significantly greater improvements in global IBS symptoms for mesalamine versus placebo (RR, 0.88; 95% CI, 0.79-0.99). This subgroup showed no improvements in abdominal pain or bowel habit/stool frequency.
Subgroup analyses for patients with constipation or mixed bowel habits, or based on postinfection status, revealed no significant differences, although the investigators noted that relevant data were limited.
Mesalamine appeared to be well tolerated. Across five studies reporting adverse events, 43.5% of patients receiving mesalamine reported any adverse event, compared with 41.4% of patients on placebo. The RR of experiencing an adverse event in those taking mesalamine was 1.20 (95% CI, 0.89-1.63), which was not statistically significant.
“There was no evidence of heterogeneity between studies in most of our analyses, but only one trial was at low risk of bias across all domains, and there were insufficient studies to assess for funnel plot asymmetry,” Dr. Goodoory and colleagues wrote. “Based on these limitations of the evidence,” they continued, “our confidence in the results of the meta-analysis would be low, and further large trials at low risk of bias would be informative.”
Specifically, the investigators suggested an RCT recruiting only patients with IBS with diarrhea, and reporting efficacy according to postinfection status.
One coauthor reported research funding from Tillotts Pharma and Dr Falk Pharma UK. The remaining authors reported no conflicts.
Certain patients with irritable bowel syndrome (IBS) may benefit from treatment with mesalamine, although the quality of evidence supporting this strategy remains low, according to a recent systematic literature review and meta-analysis.
Global IBS symptoms improved significantly across the entire population, however, a subgroup analysis suggested that mesalamine may be most beneficial for patients who present with diarrhea, providing support for a large clinical trial in this patient population, reported lead author Vivek C. Goodoory, MBChB, of St. James’s University Hospital, Leeds, United Kingdom, and colleagues.
Some patients with IBS may present with low-grade inflammation in the intestine, offering theoretical grounds for prescribing mesalamine, which is typically used for treating ulcerative colitis, the investigators wrote in Clinical Gastroenterology and Hepatology. Yet previous randomized controlled trials (RCTs) evaluating mesalamine for IBS have yielded mixed results, and a meta-analysis showed that mesalamine offered no benefit.
According to Dr. Goodoory and colleagues, however, that meta-analysis fell short since it “only pooled mean symptom scores, rather than the proportion of patients in each trial experiencing an improvement in symptoms, and did not appear to include data from all available RCTs.” Furthermore, they noted that this prior study lacked subgroup analyses conducted based on IBS subtype or postinfection status.
“We, therefore, conducted a contemporaneous meta-analysis to examine the efficacy and safety of mesalamine in IBS addressing these deficits in knowledge,” the investigators wrote.
Their meta-analysis included 820 patients from 8 RCTs published between 2009 and 2022. Efficacy and safety were evaluated via dichotomous assessments of global IBS symptoms, bowel habit or stool frequency, abdominal pain, and adverse events. Two subgroup analyses were planned to evaluate responses based on post-infection status and predominant stool pattern.
Unlike the previous meta-analysis, Dr. Goodoory and colleagues detected a potential signal for efficacy.
Across all patients, mesalamine was associated with significant improvement in global IBS symptoms, compared with placebo (relative risk [RR], 0.86; 95% CI, 0.79-0.95). However, no significant improvements were detected for abdominal pain or bowel habit/stool frequency.
A subgroup analysis of patients exhibiting IBS with diarrhea showed significantly greater improvements in global IBS symptoms for mesalamine versus placebo (RR, 0.88; 95% CI, 0.79-0.99). This subgroup showed no improvements in abdominal pain or bowel habit/stool frequency.
Subgroup analyses for patients with constipation or mixed bowel habits, or based on postinfection status, revealed no significant differences, although the investigators noted that relevant data were limited.
Mesalamine appeared to be well tolerated. Across five studies reporting adverse events, 43.5% of patients receiving mesalamine reported any adverse event, compared with 41.4% of patients on placebo. The RR of experiencing an adverse event in those taking mesalamine was 1.20 (95% CI, 0.89-1.63), which was not statistically significant.
“There was no evidence of heterogeneity between studies in most of our analyses, but only one trial was at low risk of bias across all domains, and there were insufficient studies to assess for funnel plot asymmetry,” Dr. Goodoory and colleagues wrote. “Based on these limitations of the evidence,” they continued, “our confidence in the results of the meta-analysis would be low, and further large trials at low risk of bias would be informative.”
Specifically, the investigators suggested an RCT recruiting only patients with IBS with diarrhea, and reporting efficacy according to postinfection status.
One coauthor reported research funding from Tillotts Pharma and Dr Falk Pharma UK. The remaining authors reported no conflicts.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Publishes New Pouchitis Management Guideline
The American Gastroenterological Association (AGA) has published a new clinical practice guideline on the management of pouchitis and inflammatory pouch disorders.
The guidance document, authored by Edward L. Barnes, MD, of the University of North Carolina at Chapel Hill and colleagues, includes eleven conditional recommendations that steer usage of probiotics, antibiotics, and immunosuppressive therapies in patients with these conditions, which occur most often after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC).
“Multiple strategies have been utilized in the treatment and prevention of pouchitis and inflammatory pouch conditions, including antibiotics, probiotics, corticosteroids, and advanced immunosuppressive therapies including biologics and oral small-molecule drugs,” the guideline panelists wrote on the AGA website. “However, most of the evidence base is primarily derived from retrospective observational studies or comparisons of small cohorts. Data on patients’ values and preferences for specific management decisions and treatment choices are also limited. This results in substantial practice variability.”
Still, the area is advancing. Dr. Barnes and colleagues highlighted new scoring systems for characterizing endoscopic findings and patient-reported outcomes, as well as the recent EARNEST trial (N Engl J Med. 2023 Mar 30;388(13):1191-1200), which compared vedolizumab with placebo in patients with chronic refractory pouchitis, and should be considered a “landmark study in the field,” as it could shape future trial design.
Based on all available evidence and clinical experience, the panelists issued the following recommendations, which were approved by the AGA Governing Board.
Probiotics
Because of a knowledge gap, the guideline makes no recommendation for or against use of probiotics for either the primary prevention or treatment of pouchitis.
They offered a similar explanation for the lack of guidance on using probiotics to treat pouchitis, and noted that antibiotics have demonstrated effectiveness where probiotics have not, making them the preferred treatment choice.
“There is potential that delaying therapy or using probiotics when they are not as effective as antibiotics may have significant impact on an individual patient’s quality of life,” Dr. Barnes and colleagues noted.
In contrast with the above statements, the guideline recommends usage of probiotics to prevent recurrent pouchitis in patients with recurrent, antibiotic-responsive pouchitis.
The De Simone formulation of multistrain probiotics is best supported in this scenario, the guideline notes, as this product was used in clinical trials, which collectively showed an 87% reduced risk of relapse over 12 months.
Antibiotics
Although the guideline supports antibiotics for prevention of pouchitis, the panelists noted that only one randomized controlled trial supports this recommendation, and negative effects of long-term usage need to be considered, including promotion of drug-resistant organisms and risk of Clostridioides difficile infection.
Dr. Barnes and colleagues cited more data supporting antibiotics for treatment of pouchitis, and noted that metronidazole and/or ciprofloxacin remain the preferred choices, with a typical duration of 2-4 weeks.
“An approach using a combination of antibiotics may be more effective in patients who do not respond to single-antibiotic therapy,” the panelists wrote, noting that oral vancomycin may also be considered when a patient does not respond to initial therapy.
For patients with recurrent pouchitis that relapses shortly after discontinuing antibiotics, chronic antibiotics should be considered, according to the guideline.
Immunosuppressive therapies
Advanced immunosuppressive therapies are recommended for patients with chronic antibiotic-dependent pouchitis, including those approved for treatment of UC or Crohn’s disease.
“Advanced immunosuppressive therapies may be used in lieu of chronic, continuous antibiotic therapy, particularly in patients who are intolerant to antibiotics or where patients and/or providers are concerned about risks of long-term antibiotic therapy,” the panelists wrote.
For patients with chronic antibiotic-refractory pouchitis, the guideline makes a general recommendation for advanced immunosuppressive therapies while specifically noting that vedolizumab has a greater strength of evidence in this scenario, citing the EARNEST trial.
A separate recommendation for corticosteroids is made for the same patient group, with ileal-release budesonide remaining the preferred formulation. In contrast, mesalamine is not recommended, based on a lack of supporting evidence.
Finally, the panelists recommend using corticosteroids in patients with Crohn’s-like disease of the pouch.
Future directions
“Even though pouchitis is relatively common after IPAA for UC, we observed that most of the evidence informing these guidelines was low to very low quality, derived from case series or small cohort studies, and several knowledge gaps exist,” Dr. Barnes and colleagues wrote. “Several initiatives towards improving management of inflammatory pouch disorders are already underway. However, concerted efforts in key domains are central towards improving patient care.”
They suggested that research should focus on standardizing disease entities, characterizing natural history and risk factors for inflammatory disorders of the pouch, and improving clinical trial design.The guideline was funded by the AGA Institute. The panelists disclosed relationships with Bristol-Myers Squibb, Sandoz, AbbVie, and others.
The American Gastroenterological Association (AGA) has published a new clinical practice guideline on the management of pouchitis and inflammatory pouch disorders.
The guidance document, authored by Edward L. Barnes, MD, of the University of North Carolina at Chapel Hill and colleagues, includes eleven conditional recommendations that steer usage of probiotics, antibiotics, and immunosuppressive therapies in patients with these conditions, which occur most often after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC).
“Multiple strategies have been utilized in the treatment and prevention of pouchitis and inflammatory pouch conditions, including antibiotics, probiotics, corticosteroids, and advanced immunosuppressive therapies including biologics and oral small-molecule drugs,” the guideline panelists wrote on the AGA website. “However, most of the evidence base is primarily derived from retrospective observational studies or comparisons of small cohorts. Data on patients’ values and preferences for specific management decisions and treatment choices are also limited. This results in substantial practice variability.”
Still, the area is advancing. Dr. Barnes and colleagues highlighted new scoring systems for characterizing endoscopic findings and patient-reported outcomes, as well as the recent EARNEST trial (N Engl J Med. 2023 Mar 30;388(13):1191-1200), which compared vedolizumab with placebo in patients with chronic refractory pouchitis, and should be considered a “landmark study in the field,” as it could shape future trial design.
Based on all available evidence and clinical experience, the panelists issued the following recommendations, which were approved by the AGA Governing Board.
Probiotics
Because of a knowledge gap, the guideline makes no recommendation for or against use of probiotics for either the primary prevention or treatment of pouchitis.
They offered a similar explanation for the lack of guidance on using probiotics to treat pouchitis, and noted that antibiotics have demonstrated effectiveness where probiotics have not, making them the preferred treatment choice.
“There is potential that delaying therapy or using probiotics when they are not as effective as antibiotics may have significant impact on an individual patient’s quality of life,” Dr. Barnes and colleagues noted.
In contrast with the above statements, the guideline recommends usage of probiotics to prevent recurrent pouchitis in patients with recurrent, antibiotic-responsive pouchitis.
The De Simone formulation of multistrain probiotics is best supported in this scenario, the guideline notes, as this product was used in clinical trials, which collectively showed an 87% reduced risk of relapse over 12 months.
Antibiotics
Although the guideline supports antibiotics for prevention of pouchitis, the panelists noted that only one randomized controlled trial supports this recommendation, and negative effects of long-term usage need to be considered, including promotion of drug-resistant organisms and risk of Clostridioides difficile infection.
Dr. Barnes and colleagues cited more data supporting antibiotics for treatment of pouchitis, and noted that metronidazole and/or ciprofloxacin remain the preferred choices, with a typical duration of 2-4 weeks.
“An approach using a combination of antibiotics may be more effective in patients who do not respond to single-antibiotic therapy,” the panelists wrote, noting that oral vancomycin may also be considered when a patient does not respond to initial therapy.
For patients with recurrent pouchitis that relapses shortly after discontinuing antibiotics, chronic antibiotics should be considered, according to the guideline.
Immunosuppressive therapies
Advanced immunosuppressive therapies are recommended for patients with chronic antibiotic-dependent pouchitis, including those approved for treatment of UC or Crohn’s disease.
“Advanced immunosuppressive therapies may be used in lieu of chronic, continuous antibiotic therapy, particularly in patients who are intolerant to antibiotics or where patients and/or providers are concerned about risks of long-term antibiotic therapy,” the panelists wrote.
For patients with chronic antibiotic-refractory pouchitis, the guideline makes a general recommendation for advanced immunosuppressive therapies while specifically noting that vedolizumab has a greater strength of evidence in this scenario, citing the EARNEST trial.
A separate recommendation for corticosteroids is made for the same patient group, with ileal-release budesonide remaining the preferred formulation. In contrast, mesalamine is not recommended, based on a lack of supporting evidence.
Finally, the panelists recommend using corticosteroids in patients with Crohn’s-like disease of the pouch.
Future directions
“Even though pouchitis is relatively common after IPAA for UC, we observed that most of the evidence informing these guidelines was low to very low quality, derived from case series or small cohort studies, and several knowledge gaps exist,” Dr. Barnes and colleagues wrote. “Several initiatives towards improving management of inflammatory pouch disorders are already underway. However, concerted efforts in key domains are central towards improving patient care.”
They suggested that research should focus on standardizing disease entities, characterizing natural history and risk factors for inflammatory disorders of the pouch, and improving clinical trial design.The guideline was funded by the AGA Institute. The panelists disclosed relationships with Bristol-Myers Squibb, Sandoz, AbbVie, and others.
The American Gastroenterological Association (AGA) has published a new clinical practice guideline on the management of pouchitis and inflammatory pouch disorders.
The guidance document, authored by Edward L. Barnes, MD, of the University of North Carolina at Chapel Hill and colleagues, includes eleven conditional recommendations that steer usage of probiotics, antibiotics, and immunosuppressive therapies in patients with these conditions, which occur most often after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC).
“Multiple strategies have been utilized in the treatment and prevention of pouchitis and inflammatory pouch conditions, including antibiotics, probiotics, corticosteroids, and advanced immunosuppressive therapies including biologics and oral small-molecule drugs,” the guideline panelists wrote on the AGA website. “However, most of the evidence base is primarily derived from retrospective observational studies or comparisons of small cohorts. Data on patients’ values and preferences for specific management decisions and treatment choices are also limited. This results in substantial practice variability.”
Still, the area is advancing. Dr. Barnes and colleagues highlighted new scoring systems for characterizing endoscopic findings and patient-reported outcomes, as well as the recent EARNEST trial (N Engl J Med. 2023 Mar 30;388(13):1191-1200), which compared vedolizumab with placebo in patients with chronic refractory pouchitis, and should be considered a “landmark study in the field,” as it could shape future trial design.
Based on all available evidence and clinical experience, the panelists issued the following recommendations, which were approved by the AGA Governing Board.
Probiotics
Because of a knowledge gap, the guideline makes no recommendation for or against use of probiotics for either the primary prevention or treatment of pouchitis.
They offered a similar explanation for the lack of guidance on using probiotics to treat pouchitis, and noted that antibiotics have demonstrated effectiveness where probiotics have not, making them the preferred treatment choice.
“There is potential that delaying therapy or using probiotics when they are not as effective as antibiotics may have significant impact on an individual patient’s quality of life,” Dr. Barnes and colleagues noted.
In contrast with the above statements, the guideline recommends usage of probiotics to prevent recurrent pouchitis in patients with recurrent, antibiotic-responsive pouchitis.
The De Simone formulation of multistrain probiotics is best supported in this scenario, the guideline notes, as this product was used in clinical trials, which collectively showed an 87% reduced risk of relapse over 12 months.
Antibiotics
Although the guideline supports antibiotics for prevention of pouchitis, the panelists noted that only one randomized controlled trial supports this recommendation, and negative effects of long-term usage need to be considered, including promotion of drug-resistant organisms and risk of Clostridioides difficile infection.
Dr. Barnes and colleagues cited more data supporting antibiotics for treatment of pouchitis, and noted that metronidazole and/or ciprofloxacin remain the preferred choices, with a typical duration of 2-4 weeks.
“An approach using a combination of antibiotics may be more effective in patients who do not respond to single-antibiotic therapy,” the panelists wrote, noting that oral vancomycin may also be considered when a patient does not respond to initial therapy.
For patients with recurrent pouchitis that relapses shortly after discontinuing antibiotics, chronic antibiotics should be considered, according to the guideline.
Immunosuppressive therapies
Advanced immunosuppressive therapies are recommended for patients with chronic antibiotic-dependent pouchitis, including those approved for treatment of UC or Crohn’s disease.
“Advanced immunosuppressive therapies may be used in lieu of chronic, continuous antibiotic therapy, particularly in patients who are intolerant to antibiotics or where patients and/or providers are concerned about risks of long-term antibiotic therapy,” the panelists wrote.
For patients with chronic antibiotic-refractory pouchitis, the guideline makes a general recommendation for advanced immunosuppressive therapies while specifically noting that vedolizumab has a greater strength of evidence in this scenario, citing the EARNEST trial.
A separate recommendation for corticosteroids is made for the same patient group, with ileal-release budesonide remaining the preferred formulation. In contrast, mesalamine is not recommended, based on a lack of supporting evidence.
Finally, the panelists recommend using corticosteroids in patients with Crohn’s-like disease of the pouch.
Future directions
“Even though pouchitis is relatively common after IPAA for UC, we observed that most of the evidence informing these guidelines was low to very low quality, derived from case series or small cohort studies, and several knowledge gaps exist,” Dr. Barnes and colleagues wrote. “Several initiatives towards improving management of inflammatory pouch disorders are already underway. However, concerted efforts in key domains are central towards improving patient care.”
They suggested that research should focus on standardizing disease entities, characterizing natural history and risk factors for inflammatory disorders of the pouch, and improving clinical trial design.The guideline was funded by the AGA Institute. The panelists disclosed relationships with Bristol-Myers Squibb, Sandoz, AbbVie, and others.
FROM THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Rebranding NAFLD: Correcting ‘Flawed’ Conventions
Nonalcoholic fatty liver disease (NAFLD) should now be referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), according to a recent commentary by leading hepatologists.
This update, which was determined by a panel of 236 panelists from 56 countries, is part of a broader effort to rebrand “fatty liver disease” as “steatotic liver disease” (SLD), reported lead author Alina M. Allen, MD, of Mayo Clinic, Rochester, Minnesota, and colleagues.
Writing in Gastroenterology, they described a range of reasons for the nomenclature changes, from the need for better characterization of disease subtypes, to the concern that the term “fatty” may be perceived as stigmatizing by some patients.
“The scientific community and stakeholder organizations associated with liver diseases determined there was a need for new terminology to cover liver disease related to alcohol alone, metabolic risk factors (until recently termed NAFLD/nonalcoholic steatohepatitis [NASH]) alone, the combination of alcohol and metabolic risk factors, and hepatic steatosis due to other specific etiologies,” the authors wrote.
Naming conventions in this area have been flawed since inception, Dr. Allen and colleagues wrote, noting that “nonalcoholic” is exclusionary rather than descriptive, and is particularly misplaced in the pediatric setting. These shortcomings could explain why the term “NASH” took more than a decade to enter common usage, they suggested, and why the present effort is not the first of its kind.
“There have been several movements to change the nomenclature [of NAFLD], including most recently to ‘metabolic dysfunction–associated fatty liver disease’ (MAFLD), a term that received limited traction,” the authors wrote.
Still, a change is needed, they added, as metabolic dysfunction is becoming increasingly common on a global scale, driving up rates of liver disease. Furthermore, in some patients, alcohol consumption and metabolic factors concurrently drive steatosis, suggesting an intermediate condition between alcohol-related liver disease (ALD) and NAFLD that is indescribable via current naming conventions.
SLD (determined by imaging or biopsy) now comprises five disease subtypes that can be determined via an algorithm provided in the present publication.
If at least one metabolic criterion is present, but no other causes of steatosis, then that patient has MASLD. The three other metabolic subtypes include MetALD (2-3 drinks per day for women and 3-4 drinks per day for men), ALD (more than 3 drinks per day for women and more than 4 drinks per day for men), and monogenic miscellaneous drug-induced liver injury (DILI).
Patients without metabolic criteria can also be classified with monogenic miscellaneous DILI with no caveat, whereas patients with metabolic criteria need only consume 2 or 3 drinks per day for women or 3-4 drinks per day for men, respectively, to be diagnosed with ALD.
Finally, patients with no metabolic criteria or other cause of steatosis should be characterized by cryptogenic SLD.
“While renaming and redefining the disease was needed, the implementation is not without challenges,” Dr. Allen and colleagues wrote. “A more complex classification may add confusion in the mind of nonhepatology providers when awareness and understanding of the implications of SLD are already suboptimal.”
Still, they predicted that the new naming system could lead to several positive outcomes, including improved SLD screening among individuals with metabolic risk factors, more accurate phenotyping of patients with moderate alcohol consumption, increased disease awareness in nonhepatology practices, and improved multidisciplinary collaboration.
Only time will tell whether these benefits come to fruition, Dr. Allen and colleagues noted, before closing with a quote: “In the words of Jean Piaget, the developmental psychologist of the 20th century, who coincidentally died the year the term NASH was coined, ‘Scientific knowledge is in perpetual evolution; it finds itself changed from one day to the next.’”
The authors disclosed no conflicts of interest.
Nonalcoholic fatty liver disease (NAFLD) should now be referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), according to a recent commentary by leading hepatologists.
This update, which was determined by a panel of 236 panelists from 56 countries, is part of a broader effort to rebrand “fatty liver disease” as “steatotic liver disease” (SLD), reported lead author Alina M. Allen, MD, of Mayo Clinic, Rochester, Minnesota, and colleagues.
Writing in Gastroenterology, they described a range of reasons for the nomenclature changes, from the need for better characterization of disease subtypes, to the concern that the term “fatty” may be perceived as stigmatizing by some patients.
“The scientific community and stakeholder organizations associated with liver diseases determined there was a need for new terminology to cover liver disease related to alcohol alone, metabolic risk factors (until recently termed NAFLD/nonalcoholic steatohepatitis [NASH]) alone, the combination of alcohol and metabolic risk factors, and hepatic steatosis due to other specific etiologies,” the authors wrote.
Naming conventions in this area have been flawed since inception, Dr. Allen and colleagues wrote, noting that “nonalcoholic” is exclusionary rather than descriptive, and is particularly misplaced in the pediatric setting. These shortcomings could explain why the term “NASH” took more than a decade to enter common usage, they suggested, and why the present effort is not the first of its kind.
“There have been several movements to change the nomenclature [of NAFLD], including most recently to ‘metabolic dysfunction–associated fatty liver disease’ (MAFLD), a term that received limited traction,” the authors wrote.
Still, a change is needed, they added, as metabolic dysfunction is becoming increasingly common on a global scale, driving up rates of liver disease. Furthermore, in some patients, alcohol consumption and metabolic factors concurrently drive steatosis, suggesting an intermediate condition between alcohol-related liver disease (ALD) and NAFLD that is indescribable via current naming conventions.
SLD (determined by imaging or biopsy) now comprises five disease subtypes that can be determined via an algorithm provided in the present publication.
If at least one metabolic criterion is present, but no other causes of steatosis, then that patient has MASLD. The three other metabolic subtypes include MetALD (2-3 drinks per day for women and 3-4 drinks per day for men), ALD (more than 3 drinks per day for women and more than 4 drinks per day for men), and monogenic miscellaneous drug-induced liver injury (DILI).
Patients without metabolic criteria can also be classified with monogenic miscellaneous DILI with no caveat, whereas patients with metabolic criteria need only consume 2 or 3 drinks per day for women or 3-4 drinks per day for men, respectively, to be diagnosed with ALD.
Finally, patients with no metabolic criteria or other cause of steatosis should be characterized by cryptogenic SLD.
“While renaming and redefining the disease was needed, the implementation is not without challenges,” Dr. Allen and colleagues wrote. “A more complex classification may add confusion in the mind of nonhepatology providers when awareness and understanding of the implications of SLD are already suboptimal.”
Still, they predicted that the new naming system could lead to several positive outcomes, including improved SLD screening among individuals with metabolic risk factors, more accurate phenotyping of patients with moderate alcohol consumption, increased disease awareness in nonhepatology practices, and improved multidisciplinary collaboration.
Only time will tell whether these benefits come to fruition, Dr. Allen and colleagues noted, before closing with a quote: “In the words of Jean Piaget, the developmental psychologist of the 20th century, who coincidentally died the year the term NASH was coined, ‘Scientific knowledge is in perpetual evolution; it finds itself changed from one day to the next.’”
The authors disclosed no conflicts of interest.
Nonalcoholic fatty liver disease (NAFLD) should now be referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), according to a recent commentary by leading hepatologists.
This update, which was determined by a panel of 236 panelists from 56 countries, is part of a broader effort to rebrand “fatty liver disease” as “steatotic liver disease” (SLD), reported lead author Alina M. Allen, MD, of Mayo Clinic, Rochester, Minnesota, and colleagues.
Writing in Gastroenterology, they described a range of reasons for the nomenclature changes, from the need for better characterization of disease subtypes, to the concern that the term “fatty” may be perceived as stigmatizing by some patients.
“The scientific community and stakeholder organizations associated with liver diseases determined there was a need for new terminology to cover liver disease related to alcohol alone, metabolic risk factors (until recently termed NAFLD/nonalcoholic steatohepatitis [NASH]) alone, the combination of alcohol and metabolic risk factors, and hepatic steatosis due to other specific etiologies,” the authors wrote.
Naming conventions in this area have been flawed since inception, Dr. Allen and colleagues wrote, noting that “nonalcoholic” is exclusionary rather than descriptive, and is particularly misplaced in the pediatric setting. These shortcomings could explain why the term “NASH” took more than a decade to enter common usage, they suggested, and why the present effort is not the first of its kind.
“There have been several movements to change the nomenclature [of NAFLD], including most recently to ‘metabolic dysfunction–associated fatty liver disease’ (MAFLD), a term that received limited traction,” the authors wrote.
Still, a change is needed, they added, as metabolic dysfunction is becoming increasingly common on a global scale, driving up rates of liver disease. Furthermore, in some patients, alcohol consumption and metabolic factors concurrently drive steatosis, suggesting an intermediate condition between alcohol-related liver disease (ALD) and NAFLD that is indescribable via current naming conventions.
SLD (determined by imaging or biopsy) now comprises five disease subtypes that can be determined via an algorithm provided in the present publication.
If at least one metabolic criterion is present, but no other causes of steatosis, then that patient has MASLD. The three other metabolic subtypes include MetALD (2-3 drinks per day for women and 3-4 drinks per day for men), ALD (more than 3 drinks per day for women and more than 4 drinks per day for men), and monogenic miscellaneous drug-induced liver injury (DILI).
Patients without metabolic criteria can also be classified with monogenic miscellaneous DILI with no caveat, whereas patients with metabolic criteria need only consume 2 or 3 drinks per day for women or 3-4 drinks per day for men, respectively, to be diagnosed with ALD.
Finally, patients with no metabolic criteria or other cause of steatosis should be characterized by cryptogenic SLD.
“While renaming and redefining the disease was needed, the implementation is not without challenges,” Dr. Allen and colleagues wrote. “A more complex classification may add confusion in the mind of nonhepatology providers when awareness and understanding of the implications of SLD are already suboptimal.”
Still, they predicted that the new naming system could lead to several positive outcomes, including improved SLD screening among individuals with metabolic risk factors, more accurate phenotyping of patients with moderate alcohol consumption, increased disease awareness in nonhepatology practices, and improved multidisciplinary collaboration.
Only time will tell whether these benefits come to fruition, Dr. Allen and colleagues noted, before closing with a quote: “In the words of Jean Piaget, the developmental psychologist of the 20th century, who coincidentally died the year the term NASH was coined, ‘Scientific knowledge is in perpetual evolution; it finds itself changed from one day to the next.’”
The authors disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
Inflammatory Responses to a Common Food Additive May Depend On the Microbiome
Inflammatory responses to the food additive carboxymethylcellulose (CMC) may depend on the unique characteristics of an individual’s microbiome, according to recent research.
These findings suggest that CMC, which is commonly used as a thickener and emulsifier to improve texture and shelf life of food, could potentially trigger chronic inflammation in genetically prone individuals, although more work is needed to pinpoint the exact microbiota involved, reported lead author Noëmie Daniel, PhD, of the French National Institute of Health and Medical Research (INSERM), Paris, and colleagues.“Preclinical work has shown that [CMC] consumption detrimentally impacts the intestinal microbiota in a way that promotes chronic inflammation,” the investigators wrote in a research letter in Cellular and Molecular Gastroenterology and Hepatology.
They published the results of a randomized, double-blind controlled trial that showed that the seven individuals exposed to a CMC-supplemented diet had “significant alterations in microbiota composition and metabolome” compared with the nine control subjects.
Yet responses to CMC varied widely. In the treatment group, some participants were relatively insensitive to CMC, while two participants had “stark alterations” in their microbiome.
“Such CMC sensitivity was not associated with overt signs of intestinal inflammation but nonetheless might mark proneness to chronic inflammation, compelling us to better understand mechanisms that mediate CMC sensitivity,” the investigators wrote.
To learn more, Dr. Daniel and colleagues conducted the present study, which involved a series of analyses and experiments.
They first compared inflammatory bowel disease-associated mutations and basal gene expression between CMC-sensitive and CMC-insensitive individuals from their previous trial. Neither were associated with CMC sensitivity, they found.
Evaluating microbiota was a more fruitful approach. Microbiome multivariable association with linear models analysis revealed 11 amplicon sequence variants (ASVs) that differed between groups.
“This algorithm did not detect differences between randomly selected subjects, arguing that ASVs that are associated with CMC sensitivity were not false discoveries but rather had marked, and perhaps contributed to, CMC sensitivity status,” the investigators wrote.
Next, they transplanted pre-CMC fecal samples from 2 CMC-sensitive and 2 CMC-insensitive individuals into germ-free, colitis-prone, interleukin 10-/- mice. Exposing these mice to CMC led to distinct changes in microbiota that was not clearly associated with the sensitivity status of the donor. However, mice that received transplants from CMC-sensitive individuals demonstrated increased microbiota-derived proinflammatory markers, increased microbiota encroachment, and “stark” intestinal inflammation after CMC consumption, suggesting that these responses were somehow mediated by the microbiome.
“These [results] indicate a role for basal microbiotas in influencing CMC impact on this cardinal feature of intestinal inflammation and suspected driver of chronic diseases,” the investigators wrote.
“Our findings suggest that the microbiota participate in the extent to which an individual harbors proneness to CMC-induced inflammatory diseases,” they added. “Accordingly, CMC consumption may be one trigger of chronic inflammation in genetically prone individuals colonized with a given microbial ecosystem.”
Research on a larger number of participants appears needed to substantiate their observations and determine the exact microbiota contributor(s) driving CMC sensitivity, the researchers concluded.
The investigators disclosed no conflicts of interest. Funding support came from a starting grant from the European Research Council under the European Union’s Horizon 2020 research and innovation program, a Chaire d’Excellence from IdEx Université de Paris, an award from the Fondation de l’Avenir, ANR grants EMULBIONT and DREAM, and the national program Microbiote from INSERM (B.C.). Supported also came from National Institutes of Health grants, the Penn Center for Nutritional Science and Medicine, and the Max Planck Society.
The consumption of highly processed foods, enriched with food additives, is associated with an increased risk of developing inflammatory bowel disease (IBD). Alteration of the intestinal barrier and microbiota encroachment on epithelial cells is thought to be one of the mechanisms leading to inappropriate mucosal immune activation in response to food additive intake. However, we still do not know why some exposed individuals develop IBD while others do not. The findings of Daniel and colleagues suggest that proinflammatory sensitivity to the food additive carboxymethylcellulose (CMC) is primarily dependent on the composition of the gut microbiota, and that this sensitivity can be, at least partially, transferable, using fecal microbiota transfers in a mouse model of IBD. In particular, they identified 11 taxa of the host basal microbiota associated with the development of intestinal inflammation in response to CMC.
Finally, this study also illustrates the relevance of systematically assessing the impact of food additives and emulsifiers on the gut microbiota and intestinal physiology in order to evaluate their safety using translational approaches similar to those applied by Daniel and colleagues.
Nicolas Benech, MD, PhD is an assistant professor at the Lyon 1 University and Gastroenterology department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, the director of the Lyon Fecal Microbiota transplantation Center, and cofounder of the Lyon GEM Microbiota Study Group. He has no conflicts.
The consumption of highly processed foods, enriched with food additives, is associated with an increased risk of developing inflammatory bowel disease (IBD). Alteration of the intestinal barrier and microbiota encroachment on epithelial cells is thought to be one of the mechanisms leading to inappropriate mucosal immune activation in response to food additive intake. However, we still do not know why some exposed individuals develop IBD while others do not. The findings of Daniel and colleagues suggest that proinflammatory sensitivity to the food additive carboxymethylcellulose (CMC) is primarily dependent on the composition of the gut microbiota, and that this sensitivity can be, at least partially, transferable, using fecal microbiota transfers in a mouse model of IBD. In particular, they identified 11 taxa of the host basal microbiota associated with the development of intestinal inflammation in response to CMC.
Finally, this study also illustrates the relevance of systematically assessing the impact of food additives and emulsifiers on the gut microbiota and intestinal physiology in order to evaluate their safety using translational approaches similar to those applied by Daniel and colleagues.
Nicolas Benech, MD, PhD is an assistant professor at the Lyon 1 University and Gastroenterology department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, the director of the Lyon Fecal Microbiota transplantation Center, and cofounder of the Lyon GEM Microbiota Study Group. He has no conflicts.
The consumption of highly processed foods, enriched with food additives, is associated with an increased risk of developing inflammatory bowel disease (IBD). Alteration of the intestinal barrier and microbiota encroachment on epithelial cells is thought to be one of the mechanisms leading to inappropriate mucosal immune activation in response to food additive intake. However, we still do not know why some exposed individuals develop IBD while others do not. The findings of Daniel and colleagues suggest that proinflammatory sensitivity to the food additive carboxymethylcellulose (CMC) is primarily dependent on the composition of the gut microbiota, and that this sensitivity can be, at least partially, transferable, using fecal microbiota transfers in a mouse model of IBD. In particular, they identified 11 taxa of the host basal microbiota associated with the development of intestinal inflammation in response to CMC.
Finally, this study also illustrates the relevance of systematically assessing the impact of food additives and emulsifiers on the gut microbiota and intestinal physiology in order to evaluate their safety using translational approaches similar to those applied by Daniel and colleagues.
Nicolas Benech, MD, PhD is an assistant professor at the Lyon 1 University and Gastroenterology department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, the director of the Lyon Fecal Microbiota transplantation Center, and cofounder of the Lyon GEM Microbiota Study Group. He has no conflicts.
Inflammatory responses to the food additive carboxymethylcellulose (CMC) may depend on the unique characteristics of an individual’s microbiome, according to recent research.
These findings suggest that CMC, which is commonly used as a thickener and emulsifier to improve texture and shelf life of food, could potentially trigger chronic inflammation in genetically prone individuals, although more work is needed to pinpoint the exact microbiota involved, reported lead author Noëmie Daniel, PhD, of the French National Institute of Health and Medical Research (INSERM), Paris, and colleagues.“Preclinical work has shown that [CMC] consumption detrimentally impacts the intestinal microbiota in a way that promotes chronic inflammation,” the investigators wrote in a research letter in Cellular and Molecular Gastroenterology and Hepatology.
They published the results of a randomized, double-blind controlled trial that showed that the seven individuals exposed to a CMC-supplemented diet had “significant alterations in microbiota composition and metabolome” compared with the nine control subjects.
Yet responses to CMC varied widely. In the treatment group, some participants were relatively insensitive to CMC, while two participants had “stark alterations” in their microbiome.
“Such CMC sensitivity was not associated with overt signs of intestinal inflammation but nonetheless might mark proneness to chronic inflammation, compelling us to better understand mechanisms that mediate CMC sensitivity,” the investigators wrote.
To learn more, Dr. Daniel and colleagues conducted the present study, which involved a series of analyses and experiments.
They first compared inflammatory bowel disease-associated mutations and basal gene expression between CMC-sensitive and CMC-insensitive individuals from their previous trial. Neither were associated with CMC sensitivity, they found.
Evaluating microbiota was a more fruitful approach. Microbiome multivariable association with linear models analysis revealed 11 amplicon sequence variants (ASVs) that differed between groups.
“This algorithm did not detect differences between randomly selected subjects, arguing that ASVs that are associated with CMC sensitivity were not false discoveries but rather had marked, and perhaps contributed to, CMC sensitivity status,” the investigators wrote.
Next, they transplanted pre-CMC fecal samples from 2 CMC-sensitive and 2 CMC-insensitive individuals into germ-free, colitis-prone, interleukin 10-/- mice. Exposing these mice to CMC led to distinct changes in microbiota that was not clearly associated with the sensitivity status of the donor. However, mice that received transplants from CMC-sensitive individuals demonstrated increased microbiota-derived proinflammatory markers, increased microbiota encroachment, and “stark” intestinal inflammation after CMC consumption, suggesting that these responses were somehow mediated by the microbiome.
“These [results] indicate a role for basal microbiotas in influencing CMC impact on this cardinal feature of intestinal inflammation and suspected driver of chronic diseases,” the investigators wrote.
“Our findings suggest that the microbiota participate in the extent to which an individual harbors proneness to CMC-induced inflammatory diseases,” they added. “Accordingly, CMC consumption may be one trigger of chronic inflammation in genetically prone individuals colonized with a given microbial ecosystem.”
Research on a larger number of participants appears needed to substantiate their observations and determine the exact microbiota contributor(s) driving CMC sensitivity, the researchers concluded.
The investigators disclosed no conflicts of interest. Funding support came from a starting grant from the European Research Council under the European Union’s Horizon 2020 research and innovation program, a Chaire d’Excellence from IdEx Université de Paris, an award from the Fondation de l’Avenir, ANR grants EMULBIONT and DREAM, and the national program Microbiote from INSERM (B.C.). Supported also came from National Institutes of Health grants, the Penn Center for Nutritional Science and Medicine, and the Max Planck Society.
Inflammatory responses to the food additive carboxymethylcellulose (CMC) may depend on the unique characteristics of an individual’s microbiome, according to recent research.
These findings suggest that CMC, which is commonly used as a thickener and emulsifier to improve texture and shelf life of food, could potentially trigger chronic inflammation in genetically prone individuals, although more work is needed to pinpoint the exact microbiota involved, reported lead author Noëmie Daniel, PhD, of the French National Institute of Health and Medical Research (INSERM), Paris, and colleagues.“Preclinical work has shown that [CMC] consumption detrimentally impacts the intestinal microbiota in a way that promotes chronic inflammation,” the investigators wrote in a research letter in Cellular and Molecular Gastroenterology and Hepatology.
They published the results of a randomized, double-blind controlled trial that showed that the seven individuals exposed to a CMC-supplemented diet had “significant alterations in microbiota composition and metabolome” compared with the nine control subjects.
Yet responses to CMC varied widely. In the treatment group, some participants were relatively insensitive to CMC, while two participants had “stark alterations” in their microbiome.
“Such CMC sensitivity was not associated with overt signs of intestinal inflammation but nonetheless might mark proneness to chronic inflammation, compelling us to better understand mechanisms that mediate CMC sensitivity,” the investigators wrote.
To learn more, Dr. Daniel and colleagues conducted the present study, which involved a series of analyses and experiments.
They first compared inflammatory bowel disease-associated mutations and basal gene expression between CMC-sensitive and CMC-insensitive individuals from their previous trial. Neither were associated with CMC sensitivity, they found.
Evaluating microbiota was a more fruitful approach. Microbiome multivariable association with linear models analysis revealed 11 amplicon sequence variants (ASVs) that differed between groups.
“This algorithm did not detect differences between randomly selected subjects, arguing that ASVs that are associated with CMC sensitivity were not false discoveries but rather had marked, and perhaps contributed to, CMC sensitivity status,” the investigators wrote.
Next, they transplanted pre-CMC fecal samples from 2 CMC-sensitive and 2 CMC-insensitive individuals into germ-free, colitis-prone, interleukin 10-/- mice. Exposing these mice to CMC led to distinct changes in microbiota that was not clearly associated with the sensitivity status of the donor. However, mice that received transplants from CMC-sensitive individuals demonstrated increased microbiota-derived proinflammatory markers, increased microbiota encroachment, and “stark” intestinal inflammation after CMC consumption, suggesting that these responses were somehow mediated by the microbiome.
“These [results] indicate a role for basal microbiotas in influencing CMC impact on this cardinal feature of intestinal inflammation and suspected driver of chronic diseases,” the investigators wrote.
“Our findings suggest that the microbiota participate in the extent to which an individual harbors proneness to CMC-induced inflammatory diseases,” they added. “Accordingly, CMC consumption may be one trigger of chronic inflammation in genetically prone individuals colonized with a given microbial ecosystem.”
Research on a larger number of participants appears needed to substantiate their observations and determine the exact microbiota contributor(s) driving CMC sensitivity, the researchers concluded.
The investigators disclosed no conflicts of interest. Funding support came from a starting grant from the European Research Council under the European Union’s Horizon 2020 research and innovation program, a Chaire d’Excellence from IdEx Université de Paris, an award from the Fondation de l’Avenir, ANR grants EMULBIONT and DREAM, and the national program Microbiote from INSERM (B.C.). Supported also came from National Institutes of Health grants, the Penn Center for Nutritional Science and Medicine, and the Max Planck Society.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
More comprehensive testing needed to characterize esophageal dysphagia
The current approach to esophageal function testing is insufficient to characterize esophageal motility disorders, as many patients with esophageal dysphagia have abnormalities that are undetectable with routine tests, according to investigators.
More nuanced assessments of esophageal motility disorders could potentially lead to more accurate diagnoses, and more effective treatments, reported Ravinder K. Mittal, MD, and Ali Zifan, PhD, of the University of California San Diego.
Esophageal motility disorders are currently divided into major and minor variants based on the contraction phase of peristalsis, Dr. Mittal and Dr. Zifan wrote in their report in Gastro Hep Advances. Yet the reason for dysphagia in many of these patients remains a puzzle, particularly in patients with supernormal contraction during peristalsis, like those with nutcracker esophagus. What’s more, up to half of patients with dysphagia have normal findings on high-resolution manometry impedance (HRMZ), the typical diagnostic modality, leaving many with the broad label of functional dysphagia.
This lack of clarity “suggests that the etiology in many patients remains unknown,” according to the investigators, which prompted them to publish the present review article.
After describing the shortcomings of current test methods, the investigators provided an overview of the physiology of esophageal peristalsis, then dove deeper into available data concerning luminal cross section measurements, esophageal distension during peristalsis, bolus flow, and distension contraction patterns in normal patients versus those with various kinds of dysphagia.
They highlighted two key findings.
First, in patients with functional dysphagia, esophagogastric junction outflow obstruction (EGJOO), and high amplitude esophageal peristaltic contractions (HAEC), the bolus must travel through a narrow esophageal lumen. Second, in patients with nonobstructive dysphagia and type 3 achalasia, the bolus moves against distal luminal occlusion.
“These findings indicate a relative dynamic obstruction to bolus flow and reduced distensibility of the esophageal wall in patients with several primary esophageal motility disorders,” the investigators wrote. “We speculate that the dysphagia sensation experienced by many patients may result from a normal or supernormal contraction wave pushing the bolus against resistance.”
Yet routine esophageal function testing fails to capture these abnormalities, Dr. Mittal and Dr. Zifan noted.
“[C]urrent techniques used to measure esophageal distension during peristalsis are not adequate,” they wrote. “The high-resolution manometry and current scheme of classifying esophageal motor disorders in the current format emphasize only half of the story of peristalsis, probably the less important of the two halves, i.e., the contraction phase of peristalsis.”
More focus is needed on esophageal distension, they suggested, noting that relaxation is first needed to accommodate a bolus before contraction, no matter how powerful, can push it down the esophagus.
“A simple analogy is that of a car — it cannot get through a roadway that is smaller than its own width, irrespective of the horsepower of its engine,” they wrote.
The solution may lie in a more comprehensive approach to esophageal function testing.
“Integrating representations of distension and contraction, along with objective assessments of flow timing and distensibility, complements the current classification of esophageal motility disorders that are based on the contraction characteristics,” the investigators wrote, predicting that these efforts could improve diagnostic accuracy.
What to do about those diagnoses is another mystery.
“The question though remains regarding the optimal treatment for the impaired distension function of the esophagus, and whether improvement in the distension function will lead to improvement in dysphagia symptoms,” the investigators concluded.
The review was supported by the National Institutes of Health. The investigators reported copyright/patent protection for the computer software (Dplots) used to evaluate the distension contraction plots.
Medicine is strewn with diseases first labeled as functional or psychologically induced that have been recategorized into clear non-sensory disorders of which functional dysphagia is one.
In this review article, Dr. Mittal and Dr. Zifan discuss a summary and new paradigm for esophageal motility disorders and the origin of functional dysphagia (FD). As with other functional disorders, the predominance of research has suggested that functional dysphagia is in large part a sensory disorder in which patient are sensing normally sub-threshold events of normal bolus transit interpreted as dysphagia.
Will this lead to recategorization of all functional dysphagia as a perturbation in motor function and the discovery of new therapies? Certainly, to some degree, though sensory dysfunction will likely remain a prominent mechanism in some patients. Nevertheless, it is always exciting when a new approach to an old disorder emerges. With the work from Dr. Mittal’s laboratory and many others, functional dysphagia may soon drop the functional!
David A. Katzka, MD, is a gastroenterologist at New York–Presbyterian/Columbia University Irving Medical Center, New York, where he leads the Esophagology and Swallowing Center. He has performed research for Medtronic, but has no other relevant disclosures.
Medicine is strewn with diseases first labeled as functional or psychologically induced that have been recategorized into clear non-sensory disorders of which functional dysphagia is one.
In this review article, Dr. Mittal and Dr. Zifan discuss a summary and new paradigm for esophageal motility disorders and the origin of functional dysphagia (FD). As with other functional disorders, the predominance of research has suggested that functional dysphagia is in large part a sensory disorder in which patient are sensing normally sub-threshold events of normal bolus transit interpreted as dysphagia.
Will this lead to recategorization of all functional dysphagia as a perturbation in motor function and the discovery of new therapies? Certainly, to some degree, though sensory dysfunction will likely remain a prominent mechanism in some patients. Nevertheless, it is always exciting when a new approach to an old disorder emerges. With the work from Dr. Mittal’s laboratory and many others, functional dysphagia may soon drop the functional!
David A. Katzka, MD, is a gastroenterologist at New York–Presbyterian/Columbia University Irving Medical Center, New York, where he leads the Esophagology and Swallowing Center. He has performed research for Medtronic, but has no other relevant disclosures.
Medicine is strewn with diseases first labeled as functional or psychologically induced that have been recategorized into clear non-sensory disorders of which functional dysphagia is one.
In this review article, Dr. Mittal and Dr. Zifan discuss a summary and new paradigm for esophageal motility disorders and the origin of functional dysphagia (FD). As with other functional disorders, the predominance of research has suggested that functional dysphagia is in large part a sensory disorder in which patient are sensing normally sub-threshold events of normal bolus transit interpreted as dysphagia.
Will this lead to recategorization of all functional dysphagia as a perturbation in motor function and the discovery of new therapies? Certainly, to some degree, though sensory dysfunction will likely remain a prominent mechanism in some patients. Nevertheless, it is always exciting when a new approach to an old disorder emerges. With the work from Dr. Mittal’s laboratory and many others, functional dysphagia may soon drop the functional!
David A. Katzka, MD, is a gastroenterologist at New York–Presbyterian/Columbia University Irving Medical Center, New York, where he leads the Esophagology and Swallowing Center. He has performed research for Medtronic, but has no other relevant disclosures.
The current approach to esophageal function testing is insufficient to characterize esophageal motility disorders, as many patients with esophageal dysphagia have abnormalities that are undetectable with routine tests, according to investigators.
More nuanced assessments of esophageal motility disorders could potentially lead to more accurate diagnoses, and more effective treatments, reported Ravinder K. Mittal, MD, and Ali Zifan, PhD, of the University of California San Diego.
Esophageal motility disorders are currently divided into major and minor variants based on the contraction phase of peristalsis, Dr. Mittal and Dr. Zifan wrote in their report in Gastro Hep Advances. Yet the reason for dysphagia in many of these patients remains a puzzle, particularly in patients with supernormal contraction during peristalsis, like those with nutcracker esophagus. What’s more, up to half of patients with dysphagia have normal findings on high-resolution manometry impedance (HRMZ), the typical diagnostic modality, leaving many with the broad label of functional dysphagia.
This lack of clarity “suggests that the etiology in many patients remains unknown,” according to the investigators, which prompted them to publish the present review article.
After describing the shortcomings of current test methods, the investigators provided an overview of the physiology of esophageal peristalsis, then dove deeper into available data concerning luminal cross section measurements, esophageal distension during peristalsis, bolus flow, and distension contraction patterns in normal patients versus those with various kinds of dysphagia.
They highlighted two key findings.
First, in patients with functional dysphagia, esophagogastric junction outflow obstruction (EGJOO), and high amplitude esophageal peristaltic contractions (HAEC), the bolus must travel through a narrow esophageal lumen. Second, in patients with nonobstructive dysphagia and type 3 achalasia, the bolus moves against distal luminal occlusion.
“These findings indicate a relative dynamic obstruction to bolus flow and reduced distensibility of the esophageal wall in patients with several primary esophageal motility disorders,” the investigators wrote. “We speculate that the dysphagia sensation experienced by many patients may result from a normal or supernormal contraction wave pushing the bolus against resistance.”
Yet routine esophageal function testing fails to capture these abnormalities, Dr. Mittal and Dr. Zifan noted.
“[C]urrent techniques used to measure esophageal distension during peristalsis are not adequate,” they wrote. “The high-resolution manometry and current scheme of classifying esophageal motor disorders in the current format emphasize only half of the story of peristalsis, probably the less important of the two halves, i.e., the contraction phase of peristalsis.”
More focus is needed on esophageal distension, they suggested, noting that relaxation is first needed to accommodate a bolus before contraction, no matter how powerful, can push it down the esophagus.
“A simple analogy is that of a car — it cannot get through a roadway that is smaller than its own width, irrespective of the horsepower of its engine,” they wrote.
The solution may lie in a more comprehensive approach to esophageal function testing.
“Integrating representations of distension and contraction, along with objective assessments of flow timing and distensibility, complements the current classification of esophageal motility disorders that are based on the contraction characteristics,” the investigators wrote, predicting that these efforts could improve diagnostic accuracy.
What to do about those diagnoses is another mystery.
“The question though remains regarding the optimal treatment for the impaired distension function of the esophagus, and whether improvement in the distension function will lead to improvement in dysphagia symptoms,” the investigators concluded.
The review was supported by the National Institutes of Health. The investigators reported copyright/patent protection for the computer software (Dplots) used to evaluate the distension contraction plots.
The current approach to esophageal function testing is insufficient to characterize esophageal motility disorders, as many patients with esophageal dysphagia have abnormalities that are undetectable with routine tests, according to investigators.
More nuanced assessments of esophageal motility disorders could potentially lead to more accurate diagnoses, and more effective treatments, reported Ravinder K. Mittal, MD, and Ali Zifan, PhD, of the University of California San Diego.
Esophageal motility disorders are currently divided into major and minor variants based on the contraction phase of peristalsis, Dr. Mittal and Dr. Zifan wrote in their report in Gastro Hep Advances. Yet the reason for dysphagia in many of these patients remains a puzzle, particularly in patients with supernormal contraction during peristalsis, like those with nutcracker esophagus. What’s more, up to half of patients with dysphagia have normal findings on high-resolution manometry impedance (HRMZ), the typical diagnostic modality, leaving many with the broad label of functional dysphagia.
This lack of clarity “suggests that the etiology in many patients remains unknown,” according to the investigators, which prompted them to publish the present review article.
After describing the shortcomings of current test methods, the investigators provided an overview of the physiology of esophageal peristalsis, then dove deeper into available data concerning luminal cross section measurements, esophageal distension during peristalsis, bolus flow, and distension contraction patterns in normal patients versus those with various kinds of dysphagia.
They highlighted two key findings.
First, in patients with functional dysphagia, esophagogastric junction outflow obstruction (EGJOO), and high amplitude esophageal peristaltic contractions (HAEC), the bolus must travel through a narrow esophageal lumen. Second, in patients with nonobstructive dysphagia and type 3 achalasia, the bolus moves against distal luminal occlusion.
“These findings indicate a relative dynamic obstruction to bolus flow and reduced distensibility of the esophageal wall in patients with several primary esophageal motility disorders,” the investigators wrote. “We speculate that the dysphagia sensation experienced by many patients may result from a normal or supernormal contraction wave pushing the bolus against resistance.”
Yet routine esophageal function testing fails to capture these abnormalities, Dr. Mittal and Dr. Zifan noted.
“[C]urrent techniques used to measure esophageal distension during peristalsis are not adequate,” they wrote. “The high-resolution manometry and current scheme of classifying esophageal motor disorders in the current format emphasize only half of the story of peristalsis, probably the less important of the two halves, i.e., the contraction phase of peristalsis.”
More focus is needed on esophageal distension, they suggested, noting that relaxation is first needed to accommodate a bolus before contraction, no matter how powerful, can push it down the esophagus.
“A simple analogy is that of a car — it cannot get through a roadway that is smaller than its own width, irrespective of the horsepower of its engine,” they wrote.
The solution may lie in a more comprehensive approach to esophageal function testing.
“Integrating representations of distension and contraction, along with objective assessments of flow timing and distensibility, complements the current classification of esophageal motility disorders that are based on the contraction characteristics,” the investigators wrote, predicting that these efforts could improve diagnostic accuracy.
What to do about those diagnoses is another mystery.
“The question though remains regarding the optimal treatment for the impaired distension function of the esophagus, and whether improvement in the distension function will lead to improvement in dysphagia symptoms,” the investigators concluded.
The review was supported by the National Institutes of Health. The investigators reported copyright/patent protection for the computer software (Dplots) used to evaluate the distension contraction plots.
FROM GASTRO HEP ADVANCES
Real-world evidence: Early ileocecal resection outperforms anti-TNF therapy for Crohn’s disease
These findings add weight to previously reported data from the LIR!C trial, suggesting that ileocecal resection should be considered a first-line treatment option for CD, reported principal investigator Kristine H. Allin, MD, PhD, of Aalborg University, Copenhagen.
“The LIR!C randomized clinical trial has demonstrated comparable quality of life with ileocecal resection and infliximab as a first-line treatment for limited, nonstricturing ileocecal CD at 1 year of follow-up, and improved outcomes with ileocecal resection on retrospective analysis of long-term follow-up data,” the investigators wrote in Gastroenterology. “However, in the real world, the long-term impact of early ileocecal resection for CD, compared with medical therapy, remains largely unexplored.”
To gather these real-world data, the investigators turned to the Danish National Patient Registry and the Danish National Prescription Registry, which included 1,279 individuals diagnosed with CD between 2003 and 2018 who received anti-TNF therapy or underwent ileocecal resection within 1 year of diagnosis. Within this group, slightly less than half underwent ileocecal resection (45.4%) while the remainder (54.6%) received anti-TNF therapy.
The primary outcome was a composite of one or more events: perianal CD, CD-related surgery, systemic corticosteroid exposure, and CD-related hospitalization. Secondary analyses evaluated the relative risks of these same four events as independent entities.
Multifactor-adjusted Cox proportional hazards regression analysis revealed that patients who underwent ileocecal resection had a 33% lower risk of the composite outcome compared with those who received anti-TNF therapy (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.54-0.83).
In the secondary analyses, which examined risks for each component of the composite outcome, the surgery group had a significantly lower risk of CD-related surgery (aHR, 0.56; 95% CI, 0.39-0.80) and corticosteroid exposure (aHR, 0.71; 95% CI, 0.54-0.92), but not perianal CD or CD-related hospitalization.
After 5 years, half of the patients (49.7%) who underwent ileocecal resection were not receiving any treatment for CD. At the same timepoint, a slightly lower percentage of this group (46.3%) had started immunomodulator therapy, while 16.8% started anti-TNF therapy. Just 1.8% of these patients required a second intestinal resection.
“To our knowledge, these are the first real-world data in a population-based cohort with long-term follow-up of early ileocecal resection compared with anti-TNF therapy for newly diagnosed ileal and ileocecal CD,” the investigators wrote. “These data suggest that ileocecal resection may have a role as first-line therapy in Crohn’s disease management and challenge the current paradigm of reserving surgery for complicated Crohn’s disease refractory or intolerant to medications.”
Corresponding author Manasi Agrawal, MD, of Icahn School of Medicine at Mount Sinai, New York, suggested that “validation of our findings in external cohorts [is needed], and understanding of factors associated with improved outcomes following ileocecal resection.”
For clinicians and patients choosing between first-line anti-TNF therapy versus ileocecal resection using currently available evidence, Dr. Agrawal suggested that a variety of factors need to be considered, including disease location, extent of terminal ileum involved, presence of complications such as stricture, fistula, comorbid conditions, access to biologics, financial considerations, and patient preferences.
Benjamin Cohen, MD, staff physician and co-section head and clinical director for inflammatory bowel diseases in the department of gastroenterology, hepatology, and nutrition at Cleveland Clinic, called this “an important study” because it offers the first real-world evidence to support the findings from the LIR!C trial.
Dr. Cohen agreed with Dr. Agrawal that more work is needed to determine which patients benefit most from early ileocecal resection, although he suggested that known risk factors for worse outcomes — such as early age at diagnosis, penetrating features of disease, or perianal disease — may increase strength of surgical candidacy.
Still, based on the “fairly strong” body of data now available, he suggested that all patients should be educated about first-line ileocecal resection, as it is “reasonable” approach.
“It’s always important to present surgery as a treatment option,” Dr. Cohen said in an interview. “We don’t want to think of surgery as a last resort, or a failure, because that really colors it in a negative light, and then that ultimately impacts patients’ quality of life, and their perception of outcomes.”
The study was supported by the Danish National Research Foundation. The investigators disclosed no conflicts of interest. Dr. Cohen disclosed consulting and speaking honoraria from AbbVie.
These findings add weight to previously reported data from the LIR!C trial, suggesting that ileocecal resection should be considered a first-line treatment option for CD, reported principal investigator Kristine H. Allin, MD, PhD, of Aalborg University, Copenhagen.
“The LIR!C randomized clinical trial has demonstrated comparable quality of life with ileocecal resection and infliximab as a first-line treatment for limited, nonstricturing ileocecal CD at 1 year of follow-up, and improved outcomes with ileocecal resection on retrospective analysis of long-term follow-up data,” the investigators wrote in Gastroenterology. “However, in the real world, the long-term impact of early ileocecal resection for CD, compared with medical therapy, remains largely unexplored.”
To gather these real-world data, the investigators turned to the Danish National Patient Registry and the Danish National Prescription Registry, which included 1,279 individuals diagnosed with CD between 2003 and 2018 who received anti-TNF therapy or underwent ileocecal resection within 1 year of diagnosis. Within this group, slightly less than half underwent ileocecal resection (45.4%) while the remainder (54.6%) received anti-TNF therapy.
The primary outcome was a composite of one or more events: perianal CD, CD-related surgery, systemic corticosteroid exposure, and CD-related hospitalization. Secondary analyses evaluated the relative risks of these same four events as independent entities.
Multifactor-adjusted Cox proportional hazards regression analysis revealed that patients who underwent ileocecal resection had a 33% lower risk of the composite outcome compared with those who received anti-TNF therapy (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.54-0.83).
In the secondary analyses, which examined risks for each component of the composite outcome, the surgery group had a significantly lower risk of CD-related surgery (aHR, 0.56; 95% CI, 0.39-0.80) and corticosteroid exposure (aHR, 0.71; 95% CI, 0.54-0.92), but not perianal CD or CD-related hospitalization.
After 5 years, half of the patients (49.7%) who underwent ileocecal resection were not receiving any treatment for CD. At the same timepoint, a slightly lower percentage of this group (46.3%) had started immunomodulator therapy, while 16.8% started anti-TNF therapy. Just 1.8% of these patients required a second intestinal resection.
“To our knowledge, these are the first real-world data in a population-based cohort with long-term follow-up of early ileocecal resection compared with anti-TNF therapy for newly diagnosed ileal and ileocecal CD,” the investigators wrote. “These data suggest that ileocecal resection may have a role as first-line therapy in Crohn’s disease management and challenge the current paradigm of reserving surgery for complicated Crohn’s disease refractory or intolerant to medications.”
Corresponding author Manasi Agrawal, MD, of Icahn School of Medicine at Mount Sinai, New York, suggested that “validation of our findings in external cohorts [is needed], and understanding of factors associated with improved outcomes following ileocecal resection.”
For clinicians and patients choosing between first-line anti-TNF therapy versus ileocecal resection using currently available evidence, Dr. Agrawal suggested that a variety of factors need to be considered, including disease location, extent of terminal ileum involved, presence of complications such as stricture, fistula, comorbid conditions, access to biologics, financial considerations, and patient preferences.
Benjamin Cohen, MD, staff physician and co-section head and clinical director for inflammatory bowel diseases in the department of gastroenterology, hepatology, and nutrition at Cleveland Clinic, called this “an important study” because it offers the first real-world evidence to support the findings from the LIR!C trial.
Dr. Cohen agreed with Dr. Agrawal that more work is needed to determine which patients benefit most from early ileocecal resection, although he suggested that known risk factors for worse outcomes — such as early age at diagnosis, penetrating features of disease, or perianal disease — may increase strength of surgical candidacy.
Still, based on the “fairly strong” body of data now available, he suggested that all patients should be educated about first-line ileocecal resection, as it is “reasonable” approach.
“It’s always important to present surgery as a treatment option,” Dr. Cohen said in an interview. “We don’t want to think of surgery as a last resort, or a failure, because that really colors it in a negative light, and then that ultimately impacts patients’ quality of life, and their perception of outcomes.”
The study was supported by the Danish National Research Foundation. The investigators disclosed no conflicts of interest. Dr. Cohen disclosed consulting and speaking honoraria from AbbVie.
These findings add weight to previously reported data from the LIR!C trial, suggesting that ileocecal resection should be considered a first-line treatment option for CD, reported principal investigator Kristine H. Allin, MD, PhD, of Aalborg University, Copenhagen.
“The LIR!C randomized clinical trial has demonstrated comparable quality of life with ileocecal resection and infliximab as a first-line treatment for limited, nonstricturing ileocecal CD at 1 year of follow-up, and improved outcomes with ileocecal resection on retrospective analysis of long-term follow-up data,” the investigators wrote in Gastroenterology. “However, in the real world, the long-term impact of early ileocecal resection for CD, compared with medical therapy, remains largely unexplored.”
To gather these real-world data, the investigators turned to the Danish National Patient Registry and the Danish National Prescription Registry, which included 1,279 individuals diagnosed with CD between 2003 and 2018 who received anti-TNF therapy or underwent ileocecal resection within 1 year of diagnosis. Within this group, slightly less than half underwent ileocecal resection (45.4%) while the remainder (54.6%) received anti-TNF therapy.
The primary outcome was a composite of one or more events: perianal CD, CD-related surgery, systemic corticosteroid exposure, and CD-related hospitalization. Secondary analyses evaluated the relative risks of these same four events as independent entities.
Multifactor-adjusted Cox proportional hazards regression analysis revealed that patients who underwent ileocecal resection had a 33% lower risk of the composite outcome compared with those who received anti-TNF therapy (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.54-0.83).
In the secondary analyses, which examined risks for each component of the composite outcome, the surgery group had a significantly lower risk of CD-related surgery (aHR, 0.56; 95% CI, 0.39-0.80) and corticosteroid exposure (aHR, 0.71; 95% CI, 0.54-0.92), but not perianal CD or CD-related hospitalization.
After 5 years, half of the patients (49.7%) who underwent ileocecal resection were not receiving any treatment for CD. At the same timepoint, a slightly lower percentage of this group (46.3%) had started immunomodulator therapy, while 16.8% started anti-TNF therapy. Just 1.8% of these patients required a second intestinal resection.
“To our knowledge, these are the first real-world data in a population-based cohort with long-term follow-up of early ileocecal resection compared with anti-TNF therapy for newly diagnosed ileal and ileocecal CD,” the investigators wrote. “These data suggest that ileocecal resection may have a role as first-line therapy in Crohn’s disease management and challenge the current paradigm of reserving surgery for complicated Crohn’s disease refractory or intolerant to medications.”
Corresponding author Manasi Agrawal, MD, of Icahn School of Medicine at Mount Sinai, New York, suggested that “validation of our findings in external cohorts [is needed], and understanding of factors associated with improved outcomes following ileocecal resection.”
For clinicians and patients choosing between first-line anti-TNF therapy versus ileocecal resection using currently available evidence, Dr. Agrawal suggested that a variety of factors need to be considered, including disease location, extent of terminal ileum involved, presence of complications such as stricture, fistula, comorbid conditions, access to biologics, financial considerations, and patient preferences.
Benjamin Cohen, MD, staff physician and co-section head and clinical director for inflammatory bowel diseases in the department of gastroenterology, hepatology, and nutrition at Cleveland Clinic, called this “an important study” because it offers the first real-world evidence to support the findings from the LIR!C trial.
Dr. Cohen agreed with Dr. Agrawal that more work is needed to determine which patients benefit most from early ileocecal resection, although he suggested that known risk factors for worse outcomes — such as early age at diagnosis, penetrating features of disease, or perianal disease — may increase strength of surgical candidacy.
Still, based on the “fairly strong” body of data now available, he suggested that all patients should be educated about first-line ileocecal resection, as it is “reasonable” approach.
“It’s always important to present surgery as a treatment option,” Dr. Cohen said in an interview. “We don’t want to think of surgery as a last resort, or a failure, because that really colors it in a negative light, and then that ultimately impacts patients’ quality of life, and their perception of outcomes.”
The study was supported by the Danish National Research Foundation. The investigators disclosed no conflicts of interest. Dr. Cohen disclosed consulting and speaking honoraria from AbbVie.
FROM GASTROENTEROLOGY
NAFLD familial risk score outperforms FIB-4 index for identifying advanced fibrosis
By leveraging basic clinical factors instead of more advanced diagnostic findings, the NAFLD Familial Risk Score is more scalable than existing strategies for identifying advanced fibrosis, reported lead author Rohit Loomba, MD, of the University of California San Diego, La Jolla, and colleagues.
“[G]iven the enormous global burden of NAFLD, it is not possible to perform an imaging-based fibrosis assessment on all individuals with NAFLD,” the investigators wrote in Clinical Gastroenterology and Hepatology. “The ability to identify individuals at risk for advanced fibrosis using routine clinical history taking is a major unmet need in clinical practice.”
To this end, the investigators conducted a prospective, cross-sectional, familial study that comprised 242 consecutive probands and 396 first-degree relatives. All participants underwent liver fibrosis evaluation, most with magnetic resonance elastography.
Dr. Loomba and colleagues first developed the risk model by analyzing data from a derivation cohort of 220 individuals in San Diego, among whom 92 were first-degree relatives of probands without advanced fibrosis and 128 were first-degree relatives of probands with NAFLD and advanced fibrosis.
Their analysis identified the following four risk factors for advanced fibrosis: age of 50 years or more, presence of type 2 diabetes mellitus, obesity, and family history of NAFLD with advanced fibrosis. These variables were used to construct the NAFLD Familial Risk Score, with age and diabetes each accounting for one point, and obesity and family history contributing two points each, for a possible total of six points.
Within the derivation cohort, this scoring system demonstrated an area under the receiver operating characteristic curve (AUROC) of 0.85 (95% CI, 0.76-0.92), suggesting high accuracy for identifying advanced fibrosis.
When applied to a validation cohort of 176 individuals in Finland, the AUROC was higher still, at 0.94 (95% CI, 0.89-0.99). For comparison, in the same group, the FIB-4 index had a significantly lower AUROC of 0.70 (P = .02).
“The NAFLD Familial Risk Score potentially can be used by family members who are aware of the diagnosis of advanced fibrosis in the proband,” the investigators wrote. “Information on how to calculate and interpret the score can be conveyed to first-degree relatives by the proband, or by medical staff to first-degree relatives who accompany the proband to medical appointments. First-degree relatives with a score of four points or more (corresponding to 13% risk of NAFLD with advanced fibrosis) may consider undergoing an imaging-based fibrosis assessment.”
Dr. Loomba and colleagues highlighted the simplicity of their scoring system, which does not require a calculator or any information more complex than a basic clinical history.
“It may be a helpful alternative to FIB-4 for identifying NAFLD with advanced fibrosis among first-degree relatives in clinical practice because it does not require laboratory tests,” they wrote, noting that this, along with the other comparative advantages of the new risk score, “may have implications for surveillance in NAFLD.”
The study was supported by the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and others. The investigators disclosed relationships with Aardvark Therapeutics, Altimmune, Anylam/Regeneron, and others.
My patients with metabolic dysfunction associated steatotic liver disease (MASLD) and advanced fibrosis and cirrhosis often worry about the risk of MASLD and advanced fibrosis among their relatives, especially their children and siblings. Based on my clinical experience, I tell them that their first-degree relatives get checked for MASLD with liver enzymes and a liver ultrasound. I advise if either of these tests is abnormal, they should see a gastroenterologist for further evaluation. In this paper, Huang and colleagues developed and validated a NAFLD Familial Risk Score to identify advanced fibrosis in the first-degree relatives of patients with NAFLD and advanced fibrosis. This score consists of age greater than 50 years (one point), BMI greater than 30 kg/m2 (two points), type 2 diabetes (one point), and a first-degree relative with NAFLD and advanced fibrosis (two points). 
Naga Chalasani, MD, AGAF, is a practicing hepatologist and David W. Crabb Professor of Gastroenterology and vice president for academic affairs at Indiana University School of Medicine and Indiana University Health in Indianapolis. He declared no conflicts of interests for this commentary.
My patients with metabolic dysfunction associated steatotic liver disease (MASLD) and advanced fibrosis and cirrhosis often worry about the risk of MASLD and advanced fibrosis among their relatives, especially their children and siblings. Based on my clinical experience, I tell them that their first-degree relatives get checked for MASLD with liver enzymes and a liver ultrasound. I advise if either of these tests is abnormal, they should see a gastroenterologist for further evaluation. In this paper, Huang and colleagues developed and validated a NAFLD Familial Risk Score to identify advanced fibrosis in the first-degree relatives of patients with NAFLD and advanced fibrosis. This score consists of age greater than 50 years (one point), BMI greater than 30 kg/m2 (two points), type 2 diabetes (one point), and a first-degree relative with NAFLD and advanced fibrosis (two points).
Naga Chalasani, MD, AGAF, is a practicing hepatologist and David W. Crabb Professor of Gastroenterology and vice president for academic affairs at Indiana University School of Medicine and Indiana University Health in Indianapolis. He declared no conflicts of interests for this commentary.
My patients with metabolic dysfunction associated steatotic liver disease (MASLD) and advanced fibrosis and cirrhosis often worry about the risk of MASLD and advanced fibrosis among their relatives, especially their children and siblings. Based on my clinical experience, I tell them that their first-degree relatives get checked for MASLD with liver enzymes and a liver ultrasound. I advise if either of these tests is abnormal, they should see a gastroenterologist for further evaluation. In this paper, Huang and colleagues developed and validated a NAFLD Familial Risk Score to identify advanced fibrosis in the first-degree relatives of patients with NAFLD and advanced fibrosis. This score consists of age greater than 50 years (one point), BMI greater than 30 kg/m2 (two points), type 2 diabetes (one point), and a first-degree relative with NAFLD and advanced fibrosis (two points).
Naga Chalasani, MD, AGAF, is a practicing hepatologist and David W. Crabb Professor of Gastroenterology and vice president for academic affairs at Indiana University School of Medicine and Indiana University Health in Indianapolis. He declared no conflicts of interests for this commentary.
By leveraging basic clinical factors instead of more advanced diagnostic findings, the NAFLD Familial Risk Score is more scalable than existing strategies for identifying advanced fibrosis, reported lead author Rohit Loomba, MD, of the University of California San Diego, La Jolla, and colleagues.
“[G]iven the enormous global burden of NAFLD, it is not possible to perform an imaging-based fibrosis assessment on all individuals with NAFLD,” the investigators wrote in Clinical Gastroenterology and Hepatology. “The ability to identify individuals at risk for advanced fibrosis using routine clinical history taking is a major unmet need in clinical practice.”
To this end, the investigators conducted a prospective, cross-sectional, familial study that comprised 242 consecutive probands and 396 first-degree relatives. All participants underwent liver fibrosis evaluation, most with magnetic resonance elastography.
Dr. Loomba and colleagues first developed the risk model by analyzing data from a derivation cohort of 220 individuals in San Diego, among whom 92 were first-degree relatives of probands without advanced fibrosis and 128 were first-degree relatives of probands with NAFLD and advanced fibrosis.
Their analysis identified the following four risk factors for advanced fibrosis: age of 50 years or more, presence of type 2 diabetes mellitus, obesity, and family history of NAFLD with advanced fibrosis. These variables were used to construct the NAFLD Familial Risk Score, with age and diabetes each accounting for one point, and obesity and family history contributing two points each, for a possible total of six points.
Within the derivation cohort, this scoring system demonstrated an area under the receiver operating characteristic curve (AUROC) of 0.85 (95% CI, 0.76-0.92), suggesting high accuracy for identifying advanced fibrosis.
When applied to a validation cohort of 176 individuals in Finland, the AUROC was higher still, at 0.94 (95% CI, 0.89-0.99). For comparison, in the same group, the FIB-4 index had a significantly lower AUROC of 0.70 (P = .02).
“The NAFLD Familial Risk Score potentially can be used by family members who are aware of the diagnosis of advanced fibrosis in the proband,” the investigators wrote. “Information on how to calculate and interpret the score can be conveyed to first-degree relatives by the proband, or by medical staff to first-degree relatives who accompany the proband to medical appointments. First-degree relatives with a score of four points or more (corresponding to 13% risk of NAFLD with advanced fibrosis) may consider undergoing an imaging-based fibrosis assessment.”
Dr. Loomba and colleagues highlighted the simplicity of their scoring system, which does not require a calculator or any information more complex than a basic clinical history.
“It may be a helpful alternative to FIB-4 for identifying NAFLD with advanced fibrosis among first-degree relatives in clinical practice because it does not require laboratory tests,” they wrote, noting that this, along with the other comparative advantages of the new risk score, “may have implications for surveillance in NAFLD.”
The study was supported by the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and others. The investigators disclosed relationships with Aardvark Therapeutics, Altimmune, Anylam/Regeneron, and others.
By leveraging basic clinical factors instead of more advanced diagnostic findings, the NAFLD Familial Risk Score is more scalable than existing strategies for identifying advanced fibrosis, reported lead author Rohit Loomba, MD, of the University of California San Diego, La Jolla, and colleagues.
“[G]iven the enormous global burden of NAFLD, it is not possible to perform an imaging-based fibrosis assessment on all individuals with NAFLD,” the investigators wrote in Clinical Gastroenterology and Hepatology. “The ability to identify individuals at risk for advanced fibrosis using routine clinical history taking is a major unmet need in clinical practice.”
To this end, the investigators conducted a prospective, cross-sectional, familial study that comprised 242 consecutive probands and 396 first-degree relatives. All participants underwent liver fibrosis evaluation, most with magnetic resonance elastography.
Dr. Loomba and colleagues first developed the risk model by analyzing data from a derivation cohort of 220 individuals in San Diego, among whom 92 were first-degree relatives of probands without advanced fibrosis and 128 were first-degree relatives of probands with NAFLD and advanced fibrosis.
Their analysis identified the following four risk factors for advanced fibrosis: age of 50 years or more, presence of type 2 diabetes mellitus, obesity, and family history of NAFLD with advanced fibrosis. These variables were used to construct the NAFLD Familial Risk Score, with age and diabetes each accounting for one point, and obesity and family history contributing two points each, for a possible total of six points.
Within the derivation cohort, this scoring system demonstrated an area under the receiver operating characteristic curve (AUROC) of 0.85 (95% CI, 0.76-0.92), suggesting high accuracy for identifying advanced fibrosis.
When applied to a validation cohort of 176 individuals in Finland, the AUROC was higher still, at 0.94 (95% CI, 0.89-0.99). For comparison, in the same group, the FIB-4 index had a significantly lower AUROC of 0.70 (P = .02).
“The NAFLD Familial Risk Score potentially can be used by family members who are aware of the diagnosis of advanced fibrosis in the proband,” the investigators wrote. “Information on how to calculate and interpret the score can be conveyed to first-degree relatives by the proband, or by medical staff to first-degree relatives who accompany the proband to medical appointments. First-degree relatives with a score of four points or more (corresponding to 13% risk of NAFLD with advanced fibrosis) may consider undergoing an imaging-based fibrosis assessment.”
Dr. Loomba and colleagues highlighted the simplicity of their scoring system, which does not require a calculator or any information more complex than a basic clinical history.
“It may be a helpful alternative to FIB-4 for identifying NAFLD with advanced fibrosis among first-degree relatives in clinical practice because it does not require laboratory tests,” they wrote, noting that this, along with the other comparative advantages of the new risk score, “may have implications for surveillance in NAFLD.”
The study was supported by the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and others. The investigators disclosed relationships with Aardvark Therapeutics, Altimmune, Anylam/Regeneron, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA clinical practice guideline affirms role of biomarkers in Crohn’s disease management
, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity.
Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was published online Nov. 17 in Gastroenterology.
“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”
Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed Clinical Decision Support Tool, include the following:
For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment.
For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population.
For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity.
For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment.
For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment.
All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI).
Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity.
As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.”
The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.
, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity.
Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was published online Nov. 17 in Gastroenterology.
“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”
Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed Clinical Decision Support Tool, include the following:
For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment.
For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population.
For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity.
For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment.
For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment.
All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI).
Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity.
As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.”
The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.
, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity.
Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was published online Nov. 17 in Gastroenterology.
“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”
Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed Clinical Decision Support Tool, include the following:
For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment.
For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population.
For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity.
For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment.
For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment.
All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI).
Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity.
As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.”
The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.
FROM GASTROENTEROLOGY
Acyclcarnitines could drive IBD via dysbiosis
These findings improve our understanding of IBD pathogenesis and disease course, and could prove valuable in biomarker research, reported lead author Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
In health, carnitine and acylcarnitines aid in fatty acid transport, the investigators wrote in September in Cellular and Molecular Gastroenterology and Hepatology. Acylcarnitines are also involved in metabolic signaling, and in the absence of sufficient short-chain fatty acids may serve as an alternative energy source for the intestinal epithelium.
“Recently, we and others have shown that fecal acylcarnitines are increased in patients with IBD, especially during dysbiosis,” they noted. “However, the mechanism(s) responsible for the increase of fecal acylcarnitines in IBD and their biological function have not been elucidated.”
The present study aimed to address this knowledge gap by characterizing both carnitine and acylcarnitines in pediatric IBD.
First, the investigators confirmed that both carnitine and acylcarnitines were elevated in fecal samples from pediatric patients with IBD.
Next, they analyzed fecal samples from subjects in the Food and Resulting Microbiota and Metabolome (FARMM) study, which compared microbiota recovery after gut purge and antibiotics among participants eating an omnivorous diet, a vegan diet, or an exclusive enteral nutrition (EEN) diet lacking in fiber. After the antibiotics, levels of fecal carnitine and acylcarnitines increased significantly in all groups, suggesting that microbiota were consuming these molecules.
To clarify the relationship between inflammation and levels of carnitine and acylcarnitines in the absence of microbiota, Dr. Wu and colleagues employed a germ-free mouse model with dextran sodium sulfate (DSS)–induced colitis. Levels of both molecule types were significantly increased in bile and plasma of mice with colitis versus those that were not exposed to DSS.
“Because the gut microbiota consumes both carnitine and acylcarnitines, these results are consistent with the notion that the increase of these metabolites in the feces of patients with IBD is driven by increased biliary delivery of acylcarnitines to the lumen combined with the reduced number and function of mitochondria in the colonic epithelium as previously reported,” the investigators wrote.
Further experiments with plated cultures and mice revealed that various bacterial species consumed carnitine and acylcarnitines in distinct patterns. Enterobacteriaceae demonstrated a notable proclivity for consumption in vitro and within the murine gut.
“As a high-dimensional analytic feature, the pattern of fecal acylcarnitines, perhaps together with bacterial taxonomy, may have utility as a biomarker for the presence or prognosis of IBD,” Dr. Wu and colleagues concluded. “In addition, based on currently available information about the impact of carnitine on the biology of Enterobacteriaceae, acylcarnitines also may have an important functional effect on the biology of the gut microbiota that is relevant to the pathogenesis or course of disease in patients with IBD.”
The study was supported by the Crohn’s and Colitis Foundation, the PennCHOP Microbiome Program, the Penn Center for Nutritional Science and Medicine, and others. The investigators disclosed no conflicts of interest.
The description of noninvasive biomarkers for inflammatory bowel disease (IBD) is key to better characterizing the disease pathogenesis. In this new publication, Lemons et al. describe deleterious effects of gut luminal carnitine and acylcarnitine in pediatric IBD patients, showing that these metabolites can serve as energy substrates to the microbiota, especially Enterobacteriaceae, promoting the growth of pathobionts and contributing to the persistence of dysbiosis which, in turn, may foster the course of IBD. In fact, acylcarnitine had been highlighted as a potential new target for IBD during dysbiosis by a previous multi-omics study of the gut microbiome. Moreover, Dr. Gary Wu’s team has shown that the intestinal epithelium can uptake and use acylcarnitine as an alternative source for energy production. However, epithelial mitochondrial dysfunction triggered by inflammation reduces the capacity of colonocytes to consume long-chain fatty acids, thus enhancing the fecal levels of acylcarnitine as described in IBD patients.
The description of noninvasive biomarkers for inflammatory bowel disease (IBD) is key to better characterizing the disease pathogenesis. In this new publication, Lemons et al. describe deleterious effects of gut luminal carnitine and acylcarnitine in pediatric IBD patients, showing that these metabolites can serve as energy substrates to the microbiota, especially Enterobacteriaceae, promoting the growth of pathobionts and contributing to the persistence of dysbiosis which, in turn, may foster the course of IBD. In fact, acylcarnitine had been highlighted as a potential new target for IBD during dysbiosis by a previous multi-omics study of the gut microbiome. Moreover, Dr. Gary Wu’s team has shown that the intestinal epithelium can uptake and use acylcarnitine as an alternative source for energy production. However, epithelial mitochondrial dysfunction triggered by inflammation reduces the capacity of colonocytes to consume long-chain fatty acids, thus enhancing the fecal levels of acylcarnitine as described in IBD patients.
The description of noninvasive biomarkers for inflammatory bowel disease (IBD) is key to better characterizing the disease pathogenesis. In this new publication, Lemons et al. describe deleterious effects of gut luminal carnitine and acylcarnitine in pediatric IBD patients, showing that these metabolites can serve as energy substrates to the microbiota, especially Enterobacteriaceae, promoting the growth of pathobionts and contributing to the persistence of dysbiosis which, in turn, may foster the course of IBD. In fact, acylcarnitine had been highlighted as a potential new target for IBD during dysbiosis by a previous multi-omics study of the gut microbiome. Moreover, Dr. Gary Wu’s team has shown that the intestinal epithelium can uptake and use acylcarnitine as an alternative source for energy production. However, epithelial mitochondrial dysfunction triggered by inflammation reduces the capacity of colonocytes to consume long-chain fatty acids, thus enhancing the fecal levels of acylcarnitine as described in IBD patients.
These findings improve our understanding of IBD pathogenesis and disease course, and could prove valuable in biomarker research, reported lead author Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
In health, carnitine and acylcarnitines aid in fatty acid transport, the investigators wrote in September in Cellular and Molecular Gastroenterology and Hepatology. Acylcarnitines are also involved in metabolic signaling, and in the absence of sufficient short-chain fatty acids may serve as an alternative energy source for the intestinal epithelium.
“Recently, we and others have shown that fecal acylcarnitines are increased in patients with IBD, especially during dysbiosis,” they noted. “However, the mechanism(s) responsible for the increase of fecal acylcarnitines in IBD and their biological function have not been elucidated.”
The present study aimed to address this knowledge gap by characterizing both carnitine and acylcarnitines in pediatric IBD.
First, the investigators confirmed that both carnitine and acylcarnitines were elevated in fecal samples from pediatric patients with IBD.
Next, they analyzed fecal samples from subjects in the Food and Resulting Microbiota and Metabolome (FARMM) study, which compared microbiota recovery after gut purge and antibiotics among participants eating an omnivorous diet, a vegan diet, or an exclusive enteral nutrition (EEN) diet lacking in fiber. After the antibiotics, levels of fecal carnitine and acylcarnitines increased significantly in all groups, suggesting that microbiota were consuming these molecules.
To clarify the relationship between inflammation and levels of carnitine and acylcarnitines in the absence of microbiota, Dr. Wu and colleagues employed a germ-free mouse model with dextran sodium sulfate (DSS)–induced colitis. Levels of both molecule types were significantly increased in bile and plasma of mice with colitis versus those that were not exposed to DSS.
“Because the gut microbiota consumes both carnitine and acylcarnitines, these results are consistent with the notion that the increase of these metabolites in the feces of patients with IBD is driven by increased biliary delivery of acylcarnitines to the lumen combined with the reduced number and function of mitochondria in the colonic epithelium as previously reported,” the investigators wrote.
Further experiments with plated cultures and mice revealed that various bacterial species consumed carnitine and acylcarnitines in distinct patterns. Enterobacteriaceae demonstrated a notable proclivity for consumption in vitro and within the murine gut.
“As a high-dimensional analytic feature, the pattern of fecal acylcarnitines, perhaps together with bacterial taxonomy, may have utility as a biomarker for the presence or prognosis of IBD,” Dr. Wu and colleagues concluded. “In addition, based on currently available information about the impact of carnitine on the biology of Enterobacteriaceae, acylcarnitines also may have an important functional effect on the biology of the gut microbiota that is relevant to the pathogenesis or course of disease in patients with IBD.”
The study was supported by the Crohn’s and Colitis Foundation, the PennCHOP Microbiome Program, the Penn Center for Nutritional Science and Medicine, and others. The investigators disclosed no conflicts of interest.
These findings improve our understanding of IBD pathogenesis and disease course, and could prove valuable in biomarker research, reported lead author Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
In health, carnitine and acylcarnitines aid in fatty acid transport, the investigators wrote in September in Cellular and Molecular Gastroenterology and Hepatology. Acylcarnitines are also involved in metabolic signaling, and in the absence of sufficient short-chain fatty acids may serve as an alternative energy source for the intestinal epithelium.
“Recently, we and others have shown that fecal acylcarnitines are increased in patients with IBD, especially during dysbiosis,” they noted. “However, the mechanism(s) responsible for the increase of fecal acylcarnitines in IBD and their biological function have not been elucidated.”
The present study aimed to address this knowledge gap by characterizing both carnitine and acylcarnitines in pediatric IBD.
First, the investigators confirmed that both carnitine and acylcarnitines were elevated in fecal samples from pediatric patients with IBD.
Next, they analyzed fecal samples from subjects in the Food and Resulting Microbiota and Metabolome (FARMM) study, which compared microbiota recovery after gut purge and antibiotics among participants eating an omnivorous diet, a vegan diet, or an exclusive enteral nutrition (EEN) diet lacking in fiber. After the antibiotics, levels of fecal carnitine and acylcarnitines increased significantly in all groups, suggesting that microbiota were consuming these molecules.
To clarify the relationship between inflammation and levels of carnitine and acylcarnitines in the absence of microbiota, Dr. Wu and colleagues employed a germ-free mouse model with dextran sodium sulfate (DSS)–induced colitis. Levels of both molecule types were significantly increased in bile and plasma of mice with colitis versus those that were not exposed to DSS.
“Because the gut microbiota consumes both carnitine and acylcarnitines, these results are consistent with the notion that the increase of these metabolites in the feces of patients with IBD is driven by increased biliary delivery of acylcarnitines to the lumen combined with the reduced number and function of mitochondria in the colonic epithelium as previously reported,” the investigators wrote.
Further experiments with plated cultures and mice revealed that various bacterial species consumed carnitine and acylcarnitines in distinct patterns. Enterobacteriaceae demonstrated a notable proclivity for consumption in vitro and within the murine gut.
“As a high-dimensional analytic feature, the pattern of fecal acylcarnitines, perhaps together with bacterial taxonomy, may have utility as a biomarker for the presence or prognosis of IBD,” Dr. Wu and colleagues concluded. “In addition, based on currently available information about the impact of carnitine on the biology of Enterobacteriaceae, acylcarnitines also may have an important functional effect on the biology of the gut microbiota that is relevant to the pathogenesis or course of disease in patients with IBD.”
The study was supported by the Crohn’s and Colitis Foundation, the PennCHOP Microbiome Program, the Penn Center for Nutritional Science and Medicine, and others. The investigators disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
AGA CPU updates usage of vasoactive drugs, IV albumin, for cirrhosis
The publication, authored by Vincent Wai-Sun Wong, MBChB, MD, and colleagues, includes 12 best-practice-advice statements concerning 3 common clinical scenarios: variceal hemorrhage, ascites and spontaneous bacterial peritonitis, and acute kidney injury and hepatorenal syndrome.
These complications of liver decompensation “are manifestations of portal hypertension with a [consequent] vasodilatory–hyperdynamic circulatory state, resulting in progressive decreases in effective arterial blood volume and renal perfusion,” the update authors wrote in November in Gastroenterology. “Because a potent vasoconstrictor, terlipressin, was recently approved by the United States Food and Drug Administration and because recent trials have explored use of intravenous albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and intravenous albumin in these 3 specific scenarios.”
Variceal Hemorrhage
Comprising 70% of all upper GI hemorrhage in patients with cirrhosis, and carrying a 6-week mortality rate as high as 43%, Dr. Wong and colleagues advise immediate initiation of vasoactive drugs upon suspision of variceal hemorrhage, ideally before therapeutic and/or diagnostic endoscopy.
“The goals of management of acute variceal hemorrhage include initial hemostasis, preventing early rebleeding, and reducing in-hospital and 6-week mortality,” they wrote, noting that vasoactive drugs are effective at stopping bleeding in up to 8 out of 10 cases.
In patients with acute variceal hemorrhage undergoing endoscopic hemostasis, vasoactive agents should be continued for 2-5 days to prevent early rebleeding, according to the second best-practice-advice statement.
The third statement suggests octreotide as the drug of choice for variceal hemorrhage due to its favorable safety profile.
“Nowadays, vasopressin is no longer advised in patients with acute variceal hemorrhage because of a high risk of cardiovascular adverse events,” the update authors noted.
Ascites and Spontaneous Bacterial Peritonitis
In cases requiring large-volume (greater than 5 L) paracentesis, intravenous albumin should be administered at time of fluid removal, according to the update. In these patients, albumin reduces the risk of post-paracentesis circulatory dysfunction (defined as an increase in plasma renin activity), thereby reducing the risk of acute kidney injury.
Intravenous albumin should also be considered in patients with spontaneous bacterial peritonitis as this can overcome associated vasodilatation and decreased effective arterial blood volume, which may lead to acute kidney injury if untreated. In contrast, because of a demonstrated lack of efficacy, albumin is not advised in infections other than spontaneous bacterial peritonitis, unless associated with acute kidney injury.
Long-term albumin administration should be avoided in patients with cirrhosis and uncomplicated ascites, whether they are hospitalized or not, as evidence is lacking to support a consistent beneficial effect.
The update also advises against vasoconstrictors in patients with uncomplicated ascites, bacterial peritonitis, and after large-volume paracentesis, again due to a lack of supporting evidence.
Acute Kidney Injury and Hepatorenal Syndrome
In hospitalized patients with cirrhosis and ascites presenting with acute kidney injury, Dr. Wong and colleagues called albumin “the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with acute kidney injury,” however, the authors caution the dose of albumin “should be tailored to the volume status of the patient.”
The update authors suggested that terlipressin and norepinephrine are suitable options for patients with cirrhosis and the hepatorenal syndrome; however, they suggest terlipressin above the others based on available evidence and suggested concomitant albumin administration as it may further improve renal blood flow by filling the central circulation.
Terlipressin also has the advantage (over norepinephrine) of being administrable via a peripheral line without the need for intensive care unit monitoring, the update authors wrote. The agent is contraindicated in patients with hypoxia or with coronary, peripheral, or mesenteric ischemia, and it should be used with caution in patients with ACLF grade 3, according to the publication. Risks of terlipressin may also outweigh benefits in patients with a serum creatine greater than 5 mg/dL and those listed for transplant with a MELD score of 35 or higher.
The Clinical Practice Update was commissioned and supported by AGA. The authors disclosed relationships with Advanz, Boehringer Ingelheim, 89bio, and others.
The publication, authored by Vincent Wai-Sun Wong, MBChB, MD, and colleagues, includes 12 best-practice-advice statements concerning 3 common clinical scenarios: variceal hemorrhage, ascites and spontaneous bacterial peritonitis, and acute kidney injury and hepatorenal syndrome.
These complications of liver decompensation “are manifestations of portal hypertension with a [consequent] vasodilatory–hyperdynamic circulatory state, resulting in progressive decreases in effective arterial blood volume and renal perfusion,” the update authors wrote in November in Gastroenterology. “Because a potent vasoconstrictor, terlipressin, was recently approved by the United States Food and Drug Administration and because recent trials have explored use of intravenous albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and intravenous albumin in these 3 specific scenarios.”
Variceal Hemorrhage
Comprising 70% of all upper GI hemorrhage in patients with cirrhosis, and carrying a 6-week mortality rate as high as 43%, Dr. Wong and colleagues advise immediate initiation of vasoactive drugs upon suspision of variceal hemorrhage, ideally before therapeutic and/or diagnostic endoscopy.
“The goals of management of acute variceal hemorrhage include initial hemostasis, preventing early rebleeding, and reducing in-hospital and 6-week mortality,” they wrote, noting that vasoactive drugs are effective at stopping bleeding in up to 8 out of 10 cases.
In patients with acute variceal hemorrhage undergoing endoscopic hemostasis, vasoactive agents should be continued for 2-5 days to prevent early rebleeding, according to the second best-practice-advice statement.
The third statement suggests octreotide as the drug of choice for variceal hemorrhage due to its favorable safety profile.
“Nowadays, vasopressin is no longer advised in patients with acute variceal hemorrhage because of a high risk of cardiovascular adverse events,” the update authors noted.
Ascites and Spontaneous Bacterial Peritonitis
In cases requiring large-volume (greater than 5 L) paracentesis, intravenous albumin should be administered at time of fluid removal, according to the update. In these patients, albumin reduces the risk of post-paracentesis circulatory dysfunction (defined as an increase in plasma renin activity), thereby reducing the risk of acute kidney injury.
Intravenous albumin should also be considered in patients with spontaneous bacterial peritonitis as this can overcome associated vasodilatation and decreased effective arterial blood volume, which may lead to acute kidney injury if untreated. In contrast, because of a demonstrated lack of efficacy, albumin is not advised in infections other than spontaneous bacterial peritonitis, unless associated with acute kidney injury.
Long-term albumin administration should be avoided in patients with cirrhosis and uncomplicated ascites, whether they are hospitalized or not, as evidence is lacking to support a consistent beneficial effect.
The update also advises against vasoconstrictors in patients with uncomplicated ascites, bacterial peritonitis, and after large-volume paracentesis, again due to a lack of supporting evidence.
Acute Kidney Injury and Hepatorenal Syndrome
In hospitalized patients with cirrhosis and ascites presenting with acute kidney injury, Dr. Wong and colleagues called albumin “the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with acute kidney injury,” however, the authors caution the dose of albumin “should be tailored to the volume status of the patient.”
The update authors suggested that terlipressin and norepinephrine are suitable options for patients with cirrhosis and the hepatorenal syndrome; however, they suggest terlipressin above the others based on available evidence and suggested concomitant albumin administration as it may further improve renal blood flow by filling the central circulation.
Terlipressin also has the advantage (over norepinephrine) of being administrable via a peripheral line without the need for intensive care unit monitoring, the update authors wrote. The agent is contraindicated in patients with hypoxia or with coronary, peripheral, or mesenteric ischemia, and it should be used with caution in patients with ACLF grade 3, according to the publication. Risks of terlipressin may also outweigh benefits in patients with a serum creatine greater than 5 mg/dL and those listed for transplant with a MELD score of 35 or higher.
The Clinical Practice Update was commissioned and supported by AGA. The authors disclosed relationships with Advanz, Boehringer Ingelheim, 89bio, and others.
The publication, authored by Vincent Wai-Sun Wong, MBChB, MD, and colleagues, includes 12 best-practice-advice statements concerning 3 common clinical scenarios: variceal hemorrhage, ascites and spontaneous bacterial peritonitis, and acute kidney injury and hepatorenal syndrome.
These complications of liver decompensation “are manifestations of portal hypertension with a [consequent] vasodilatory–hyperdynamic circulatory state, resulting in progressive decreases in effective arterial blood volume and renal perfusion,” the update authors wrote in November in Gastroenterology. “Because a potent vasoconstrictor, terlipressin, was recently approved by the United States Food and Drug Administration and because recent trials have explored use of intravenous albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and intravenous albumin in these 3 specific scenarios.”
Variceal Hemorrhage
Comprising 70% of all upper GI hemorrhage in patients with cirrhosis, and carrying a 6-week mortality rate as high as 43%, Dr. Wong and colleagues advise immediate initiation of vasoactive drugs upon suspision of variceal hemorrhage, ideally before therapeutic and/or diagnostic endoscopy.
“The goals of management of acute variceal hemorrhage include initial hemostasis, preventing early rebleeding, and reducing in-hospital and 6-week mortality,” they wrote, noting that vasoactive drugs are effective at stopping bleeding in up to 8 out of 10 cases.
In patients with acute variceal hemorrhage undergoing endoscopic hemostasis, vasoactive agents should be continued for 2-5 days to prevent early rebleeding, according to the second best-practice-advice statement.
The third statement suggests octreotide as the drug of choice for variceal hemorrhage due to its favorable safety profile.
“Nowadays, vasopressin is no longer advised in patients with acute variceal hemorrhage because of a high risk of cardiovascular adverse events,” the update authors noted.
Ascites and Spontaneous Bacterial Peritonitis
In cases requiring large-volume (greater than 5 L) paracentesis, intravenous albumin should be administered at time of fluid removal, according to the update. In these patients, albumin reduces the risk of post-paracentesis circulatory dysfunction (defined as an increase in plasma renin activity), thereby reducing the risk of acute kidney injury.
Intravenous albumin should also be considered in patients with spontaneous bacterial peritonitis as this can overcome associated vasodilatation and decreased effective arterial blood volume, which may lead to acute kidney injury if untreated. In contrast, because of a demonstrated lack of efficacy, albumin is not advised in infections other than spontaneous bacterial peritonitis, unless associated with acute kidney injury.
Long-term albumin administration should be avoided in patients with cirrhosis and uncomplicated ascites, whether they are hospitalized or not, as evidence is lacking to support a consistent beneficial effect.
The update also advises against vasoconstrictors in patients with uncomplicated ascites, bacterial peritonitis, and after large-volume paracentesis, again due to a lack of supporting evidence.
Acute Kidney Injury and Hepatorenal Syndrome
In hospitalized patients with cirrhosis and ascites presenting with acute kidney injury, Dr. Wong and colleagues called albumin “the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with acute kidney injury,” however, the authors caution the dose of albumin “should be tailored to the volume status of the patient.”
The update authors suggested that terlipressin and norepinephrine are suitable options for patients with cirrhosis and the hepatorenal syndrome; however, they suggest terlipressin above the others based on available evidence and suggested concomitant albumin administration as it may further improve renal blood flow by filling the central circulation.
Terlipressin also has the advantage (over norepinephrine) of being administrable via a peripheral line without the need for intensive care unit monitoring, the update authors wrote. The agent is contraindicated in patients with hypoxia or with coronary, peripheral, or mesenteric ischemia, and it should be used with caution in patients with ACLF grade 3, according to the publication. Risks of terlipressin may also outweigh benefits in patients with a serum creatine greater than 5 mg/dL and those listed for transplant with a MELD score of 35 or higher.
The Clinical Practice Update was commissioned and supported by AGA. The authors disclosed relationships with Advanz, Boehringer Ingelheim, 89bio, and others.
FROM GASTROENTEROLOGY