From the AGA Journals

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions, and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of the gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, including AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions, and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of the gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, including AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions, and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of the gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, including AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, include AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, include AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, include AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

The proper management of subepithelial lesions (SELs) depends on the size, histopathology, malignant potential, and presence of symptoms, according to a new American Gastroenterological Association clinical practice update published in Clinical Gastroenterology and Hepatology.

“SELs are found in 1 in every 300 endoscopies, and two-thirds of these lesions are located in the stomach,” explained Kaveh Sharzehi, MD, an associate professor of medicine in the division of gastroenterology and hepatology at Oregon Health & Science University, Portland, and colleagues. “They represent a heterogeneous group of lesions including nonneoplastic lesions such as ectopic pancreatic tissue and neoplastic lesions. The neoplastic SELs can vary from lesions with no malignant potential such as lipomas to those with malignant potential such as gastrointestinal stromal tumors (GISTs). The majority of SELs are small and found incidentally.”

The authors developed 10 clinical practice advice statements on the diagnosis and management of subepithelial lesions based on a review of the published literature and expert opinion.

First, standard mucosal biopsies often don’t reach deep enough to obtain a pathologic diagnosis for SELs because the lesions have normal overlying mucosa. Forceps bite-on-bite/deep-well biopsies or tunnel biopsies may help to establish a pathologic diagnosis.

Used as an adjunct to standard endoscopy, endoscopic ultrasound (EUS) has become the primary method for determining diagnostic and prognostic characteristics of SELs – such as the layer of origin, echogenicity, and presence of blood vessels within the lesion. It can also help with tissue acquisition.

For SELs arising from the submucosa, EUS-guided fine-needle aspiration and fine-needle biopsy have evolved as widely used methods for obtaining tissue. For SELs arising from muscularis propria, fine-needle aspiration and fine-needle biopsy should be used to determine whether the lesion is a GIST or leiomyoma. Using structural assessment and staining will allow for the differentiation of mesenchymal tumors and assessment of their malignant potential.

To remove SELs, multiple endoscopic resection techniques may be appropriate, depending on the layer of origin, size, and location, with the goal of complete, en bloc resection with no disruption to the wall or capsule of the lesion. These techniques should be limited to endoscopists skilled in advanced tissue resection.

SELs without malignant potential, such as lipoma or pancreatic rest, don’t need further evaluation or surveillance.

SELs that are ulcerated, bleeding, or causing symptoms should be considered for resection.

Other lesions are managed with resection or surveillance based on pathology. For example, leiomyomas, which are benign and most often found in the esophagus, generally don’t require surveillance or resection. On the other hand, all GISTs have some malignant potential, and management varies by size, location, and presence of symptoms. GISTs larger than 2 cm, should be considered for resection. Some GISTs between 2 cm and 4 cm without high-risk features can be removed by using advanced endoscopic resection techniques.

The determination for resection in all cases should include a multidisciplinary approach, with confirmation of a low mitotic index and lack of metastatic disease on cross-sectional imaging.

“The ultimate goal of endoscopic resection is to have a complete resection,” the authors wrote. “Determining the layer of involvement by EUS is critical in planning resection techniques.”

The authors reported no grant support or funding sources for this report. One author serves as a consultant for Boston Scientific, Fujifilm, Intuitive Surgical, Medtronic, and Olympus. The remaining authors disclosed no conflicts.

The proper management of subepithelial lesions (SELs) depends on the size, histopathology, malignant potential, and presence of symptoms, according to a new American Gastroenterological Association clinical practice update published in Clinical Gastroenterology and Hepatology.

“SELs are found in 1 in every 300 endoscopies, and two-thirds of these lesions are located in the stomach,” explained Kaveh Sharzehi, MD, an associate professor of medicine in the division of gastroenterology and hepatology at Oregon Health & Science University, Portland, and colleagues. “They represent a heterogeneous group of lesions including nonneoplastic lesions such as ectopic pancreatic tissue and neoplastic lesions. The neoplastic SELs can vary from lesions with no malignant potential such as lipomas to those with malignant potential such as gastrointestinal stromal tumors (GISTs). The majority of SELs are small and found incidentally.”

The authors developed 10 clinical practice advice statements on the diagnosis and management of subepithelial lesions based on a review of the published literature and expert opinion.

First, standard mucosal biopsies often don’t reach deep enough to obtain a pathologic diagnosis for SELs because the lesions have normal overlying mucosa. Forceps bite-on-bite/deep-well biopsies or tunnel biopsies may help to establish a pathologic diagnosis.

Used as an adjunct to standard endoscopy, endoscopic ultrasound (EUS) has become the primary method for determining diagnostic and prognostic characteristics of SELs – such as the layer of origin, echogenicity, and presence of blood vessels within the lesion. It can also help with tissue acquisition.

For SELs arising from the submucosa, EUS-guided fine-needle aspiration and fine-needle biopsy have evolved as widely used methods for obtaining tissue. For SELs arising from muscularis propria, fine-needle aspiration and fine-needle biopsy should be used to determine whether the lesion is a GIST or leiomyoma. Using structural assessment and staining will allow for the differentiation of mesenchymal tumors and assessment of their malignant potential.

To remove SELs, multiple endoscopic resection techniques may be appropriate, depending on the layer of origin, size, and location, with the goal of complete, en bloc resection with no disruption to the wall or capsule of the lesion. These techniques should be limited to endoscopists skilled in advanced tissue resection.

SELs without malignant potential, such as lipoma or pancreatic rest, don’t need further evaluation or surveillance.

SELs that are ulcerated, bleeding, or causing symptoms should be considered for resection.

Other lesions are managed with resection or surveillance based on pathology. For example, leiomyomas, which are benign and most often found in the esophagus, generally don’t require surveillance or resection. On the other hand, all GISTs have some malignant potential, and management varies by size, location, and presence of symptoms. GISTs larger than 2 cm, should be considered for resection. Some GISTs between 2 cm and 4 cm without high-risk features can be removed by using advanced endoscopic resection techniques.

The determination for resection in all cases should include a multidisciplinary approach, with confirmation of a low mitotic index and lack of metastatic disease on cross-sectional imaging.

“The ultimate goal of endoscopic resection is to have a complete resection,” the authors wrote. “Determining the layer of involvement by EUS is critical in planning resection techniques.”

The authors reported no grant support or funding sources for this report. One author serves as a consultant for Boston Scientific, Fujifilm, Intuitive Surgical, Medtronic, and Olympus. The remaining authors disclosed no conflicts.

The proper management of subepithelial lesions (SELs) depends on the size, histopathology, malignant potential, and presence of symptoms, according to a new American Gastroenterological Association clinical practice update published in Clinical Gastroenterology and Hepatology.

“SELs are found in 1 in every 300 endoscopies, and two-thirds of these lesions are located in the stomach,” explained Kaveh Sharzehi, MD, an associate professor of medicine in the division of gastroenterology and hepatology at Oregon Health & Science University, Portland, and colleagues. “They represent a heterogeneous group of lesions including nonneoplastic lesions such as ectopic pancreatic tissue and neoplastic lesions. The neoplastic SELs can vary from lesions with no malignant potential such as lipomas to those with malignant potential such as gastrointestinal stromal tumors (GISTs). The majority of SELs are small and found incidentally.”

The authors developed 10 clinical practice advice statements on the diagnosis and management of subepithelial lesions based on a review of the published literature and expert opinion.

First, standard mucosal biopsies often don’t reach deep enough to obtain a pathologic diagnosis for SELs because the lesions have normal overlying mucosa. Forceps bite-on-bite/deep-well biopsies or tunnel biopsies may help to establish a pathologic diagnosis.

Used as an adjunct to standard endoscopy, endoscopic ultrasound (EUS) has become the primary method for determining diagnostic and prognostic characteristics of SELs – such as the layer of origin, echogenicity, and presence of blood vessels within the lesion. It can also help with tissue acquisition.

For SELs arising from the submucosa, EUS-guided fine-needle aspiration and fine-needle biopsy have evolved as widely used methods for obtaining tissue. For SELs arising from muscularis propria, fine-needle aspiration and fine-needle biopsy should be used to determine whether the lesion is a GIST or leiomyoma. Using structural assessment and staining will allow for the differentiation of mesenchymal tumors and assessment of their malignant potential.

To remove SELs, multiple endoscopic resection techniques may be appropriate, depending on the layer of origin, size, and location, with the goal of complete, en bloc resection with no disruption to the wall or capsule of the lesion. These techniques should be limited to endoscopists skilled in advanced tissue resection.

SELs without malignant potential, such as lipoma or pancreatic rest, don’t need further evaluation or surveillance.

SELs that are ulcerated, bleeding, or causing symptoms should be considered for resection.

Other lesions are managed with resection or surveillance based on pathology. For example, leiomyomas, which are benign and most often found in the esophagus, generally don’t require surveillance or resection. On the other hand, all GISTs have some malignant potential, and management varies by size, location, and presence of symptoms. GISTs larger than 2 cm, should be considered for resection. Some GISTs between 2 cm and 4 cm without high-risk features can be removed by using advanced endoscopic resection techniques.

The determination for resection in all cases should include a multidisciplinary approach, with confirmation of a low mitotic index and lack of metastatic disease on cross-sectional imaging.

“The ultimate goal of endoscopic resection is to have a complete resection,” the authors wrote. “Determining the layer of involvement by EUS is critical in planning resection techniques.”

The authors reported no grant support or funding sources for this report. One author serves as a consultant for Boston Scientific, Fujifilm, Intuitive Surgical, Medtronic, and Olympus. The remaining authors disclosed no conflicts.

The diagnosis and management of refractory celiac disease remains challenging, but ongoing studies can provide the proper diagnostic criteria and identify the optimal management strategies, according to a new American Gastroenterological Association expert review published in Gastroenterology.

Celiac disease is present in about 1% of the U.S. population and can cause various symptoms, wrote Peter H. R. Green, MD, director of the Celiac Disease Center at Columbia University, New York, and colleagues. Adhering to a strict gluten-free diet can improve symptoms, normalize serum antibody levels, and reverse small bowel villous atrophy. However, persistent or recurrent symptoms and elevated celiac antibodies can persist in some patients after a year of trying a gluten-free diet, a condition called nonresponsive celiac disease. In some patients, this raises concern for refractory celiac disease, or RCD.

“RCD is believed to occur in only approximately 1% of patients with celiac disease, although this may be an overestimate, as data are obtained from referral centers,” the authors wrote.

RCD can be classified into two subtypes with different diagnostic criteria, prognoses, and therapy responses. The first, called RCD1, is characterized by villous atrophy but has intraepithelial lymphocytes similar to conventional celiac disease. The other, called RCD2, is characterized by aberrant clonal T-cell expansion in the intestinal tract and other organs, has a poorer prognosis than RCD1, and has a risk of developing ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

The experts developed 10 clinical practice advice statements based on a review of the published literature and expert opinion.

First, in patients who have persistent or recurring symptoms, an initial celiac disease diagnosis should be confirmed through review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. Celiac disease can overlap with other gastrointestinal conditions, and some pathologic findings aren’t specific to celiac disease. Results of serologic testing with tissue transglutaminase immunoglobulin A, deamidated gliadin peptide IgA and IgG, and endomysial antibodies should be reviewed or obtained if not previously performed.

Next, in those with confirmed but nonresponsive celiac disease, ongoing gluten ingestion should be excluded as a cause of symptoms with serologic testing, dietitian review, and potentially detection of immunogenic peptides in stool or urine samples. The authors noted that persistent gluten ingestion, whether intentional or inadvertent, accounts for 40%-50% of patients with nonresponsive celiac disease. In these cases, esophagogastroduodenoscopy and small bowel biopsies should be performed to look for persistent villous atrophy, which can also be caused by common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. Patients with villous atrophy due to other causes won’t respond to a gluten-free diet.

After excluding gluten, clinicians should perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, lactose or fructose intolerance, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial growth. Irritable bowel syndrome, for instance, may contribute to persistent symptoms and respond to fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) restriction. RCD should be strongly considered in patients with persistent symptoms or signs of malabsorption after the exclusion of the other causes.

To distinguish between the two subtypes of RCD and exclude enteropathy-associated T-cell lymphoma, clinicians should use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies. RCD1 has a normal intraepithelial lymphocyte population, and RCD2 has an aberrant, clonal intraepithelial lymphocyte population. Consulting with a hematopathologist may be necessary to interpret these studies.

After RCD2 is diagnosed, complications such as enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis should be excluded through small bowel imaging with capsule endoscopy and either computed tomography (CT) or magnetic resonance enterography. In general, the extent and severity of villous atrophy is greater in patients with RCD2, compared with RCD1.

In patients diagnosed with RCD, clinicians should complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies. Check albumin as an independent prognostic factor. Then, try to correct deficiencies with oral supplements. Malnourished patients may need enteral support, and those with severe malnutrition due to malabsorption may need parenteral support.

So far, RCD management suggestions are based on small retrospective studies and expert opinion, with minimal prospective data and no Food and Drug Administration–approved therapies. The goals should be to improve symptoms and duodenal mucosal abnormalities, manage malnutrition, and prevent lymphoma. Glucocorticoids are considered first-line therapy, typically open-capsule budesonide given as 3 mg three times daily. Prednisone serves as an alternative with proven efficacy but a higher risk for adverse effects.

The optimal choice for second-line therapy is unknown, but the addition of an immunosuppressant agent to steroids appears to be effective in RCD1, including azathioprine, mercaptopurine, and tioguanine. The best treatment for RCD2 is unknown, though clinical response has been reported with steroids, and cladribine has been well tolerated in some patients.

Patients with RCD who don’t respond to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. Frequent medical visits are advised until the disease is well controlled, with regular follow-up after that. 

Ultimately, “patients with RCD benefit from evaluation and regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy,” the authors wrote. “Identify local experts with expertise in celiac disease to assist with management.”

The authors reported no grant support or funding sources for this study. One author has received research report from Freenome, and another is on the celiac disease advisory board for Takeda. The remaining authors disclosed no conflicts.

The diagnosis and management of refractory celiac disease remains challenging, but ongoing studies can provide the proper diagnostic criteria and identify the optimal management strategies, according to a new American Gastroenterological Association expert review published in Gastroenterology.

Celiac disease is present in about 1% of the U.S. population and can cause various symptoms, wrote Peter H. R. Green, MD, director of the Celiac Disease Center at Columbia University, New York, and colleagues. Adhering to a strict gluten-free diet can improve symptoms, normalize serum antibody levels, and reverse small bowel villous atrophy. However, persistent or recurrent symptoms and elevated celiac antibodies can persist in some patients after a year of trying a gluten-free diet, a condition called nonresponsive celiac disease. In some patients, this raises concern for refractory celiac disease, or RCD.

“RCD is believed to occur in only approximately 1% of patients with celiac disease, although this may be an overestimate, as data are obtained from referral centers,” the authors wrote.

RCD can be classified into two subtypes with different diagnostic criteria, prognoses, and therapy responses. The first, called RCD1, is characterized by villous atrophy but has intraepithelial lymphocytes similar to conventional celiac disease. The other, called RCD2, is characterized by aberrant clonal T-cell expansion in the intestinal tract and other organs, has a poorer prognosis than RCD1, and has a risk of developing ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

The experts developed 10 clinical practice advice statements based on a review of the published literature and expert opinion.

First, in patients who have persistent or recurring symptoms, an initial celiac disease diagnosis should be confirmed through review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. Celiac disease can overlap with other gastrointestinal conditions, and some pathologic findings aren’t specific to celiac disease. Results of serologic testing with tissue transglutaminase immunoglobulin A, deamidated gliadin peptide IgA and IgG, and endomysial antibodies should be reviewed or obtained if not previously performed.

Next, in those with confirmed but nonresponsive celiac disease, ongoing gluten ingestion should be excluded as a cause of symptoms with serologic testing, dietitian review, and potentially detection of immunogenic peptides in stool or urine samples. The authors noted that persistent gluten ingestion, whether intentional or inadvertent, accounts for 40%-50% of patients with nonresponsive celiac disease. In these cases, esophagogastroduodenoscopy and small bowel biopsies should be performed to look for persistent villous atrophy, which can also be caused by common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. Patients with villous atrophy due to other causes won’t respond to a gluten-free diet.

After excluding gluten, clinicians should perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, lactose or fructose intolerance, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial growth. Irritable bowel syndrome, for instance, may contribute to persistent symptoms and respond to fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) restriction. RCD should be strongly considered in patients with persistent symptoms or signs of malabsorption after the exclusion of the other causes.

To distinguish between the two subtypes of RCD and exclude enteropathy-associated T-cell lymphoma, clinicians should use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies. RCD1 has a normal intraepithelial lymphocyte population, and RCD2 has an aberrant, clonal intraepithelial lymphocyte population. Consulting with a hematopathologist may be necessary to interpret these studies.

After RCD2 is diagnosed, complications such as enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis should be excluded through small bowel imaging with capsule endoscopy and either computed tomography (CT) or magnetic resonance enterography. In general, the extent and severity of villous atrophy is greater in patients with RCD2, compared with RCD1.

In patients diagnosed with RCD, clinicians should complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies. Check albumin as an independent prognostic factor. Then, try to correct deficiencies with oral supplements. Malnourished patients may need enteral support, and those with severe malnutrition due to malabsorption may need parenteral support.

So far, RCD management suggestions are based on small retrospective studies and expert opinion, with minimal prospective data and no Food and Drug Administration–approved therapies. The goals should be to improve symptoms and duodenal mucosal abnormalities, manage malnutrition, and prevent lymphoma. Glucocorticoids are considered first-line therapy, typically open-capsule budesonide given as 3 mg three times daily. Prednisone serves as an alternative with proven efficacy but a higher risk for adverse effects.

The optimal choice for second-line therapy is unknown, but the addition of an immunosuppressant agent to steroids appears to be effective in RCD1, including azathioprine, mercaptopurine, and tioguanine. The best treatment for RCD2 is unknown, though clinical response has been reported with steroids, and cladribine has been well tolerated in some patients.

Patients with RCD who don’t respond to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. Frequent medical visits are advised until the disease is well controlled, with regular follow-up after that. 

Ultimately, “patients with RCD benefit from evaluation and regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy,” the authors wrote. “Identify local experts with expertise in celiac disease to assist with management.”

The authors reported no grant support or funding sources for this study. One author has received research report from Freenome, and another is on the celiac disease advisory board for Takeda. The remaining authors disclosed no conflicts.

The diagnosis and management of refractory celiac disease remains challenging, but ongoing studies can provide the proper diagnostic criteria and identify the optimal management strategies, according to a new American Gastroenterological Association expert review published in Gastroenterology.

Celiac disease is present in about 1% of the U.S. population and can cause various symptoms, wrote Peter H. R. Green, MD, director of the Celiac Disease Center at Columbia University, New York, and colleagues. Adhering to a strict gluten-free diet can improve symptoms, normalize serum antibody levels, and reverse small bowel villous atrophy. However, persistent or recurrent symptoms and elevated celiac antibodies can persist in some patients after a year of trying a gluten-free diet, a condition called nonresponsive celiac disease. In some patients, this raises concern for refractory celiac disease, or RCD.

“RCD is believed to occur in only approximately 1% of patients with celiac disease, although this may be an overestimate, as data are obtained from referral centers,” the authors wrote.

RCD can be classified into two subtypes with different diagnostic criteria, prognoses, and therapy responses. The first, called RCD1, is characterized by villous atrophy but has intraepithelial lymphocytes similar to conventional celiac disease. The other, called RCD2, is characterized by aberrant clonal T-cell expansion in the intestinal tract and other organs, has a poorer prognosis than RCD1, and has a risk of developing ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.

The experts developed 10 clinical practice advice statements based on a review of the published literature and expert opinion.

First, in patients who have persistent or recurring symptoms, an initial celiac disease diagnosis should be confirmed through review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. Celiac disease can overlap with other gastrointestinal conditions, and some pathologic findings aren’t specific to celiac disease. Results of serologic testing with tissue transglutaminase immunoglobulin A, deamidated gliadin peptide IgA and IgG, and endomysial antibodies should be reviewed or obtained if not previously performed.

Next, in those with confirmed but nonresponsive celiac disease, ongoing gluten ingestion should be excluded as a cause of symptoms with serologic testing, dietitian review, and potentially detection of immunogenic peptides in stool or urine samples. The authors noted that persistent gluten ingestion, whether intentional or inadvertent, accounts for 40%-50% of patients with nonresponsive celiac disease. In these cases, esophagogastroduodenoscopy and small bowel biopsies should be performed to look for persistent villous atrophy, which can also be caused by common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. Patients with villous atrophy due to other causes won’t respond to a gluten-free diet.

After excluding gluten, clinicians should perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, lactose or fructose intolerance, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial growth. Irritable bowel syndrome, for instance, may contribute to persistent symptoms and respond to fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) restriction. RCD should be strongly considered in patients with persistent symptoms or signs of malabsorption after the exclusion of the other causes.

To distinguish between the two subtypes of RCD and exclude enteropathy-associated T-cell lymphoma, clinicians should use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies. RCD1 has a normal intraepithelial lymphocyte population, and RCD2 has an aberrant, clonal intraepithelial lymphocyte population. Consulting with a hematopathologist may be necessary to interpret these studies.

After RCD2 is diagnosed, complications such as enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis should be excluded through small bowel imaging with capsule endoscopy and either computed tomography (CT) or magnetic resonance enterography. In general, the extent and severity of villous atrophy is greater in patients with RCD2, compared with RCD1.

In patients diagnosed with RCD, clinicians should complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies. Check albumin as an independent prognostic factor. Then, try to correct deficiencies with oral supplements. Malnourished patients may need enteral support, and those with severe malnutrition due to malabsorption may need parenteral support.

So far, RCD management suggestions are based on small retrospective studies and expert opinion, with minimal prospective data and no Food and Drug Administration–approved therapies. The goals should be to improve symptoms and duodenal mucosal abnormalities, manage malnutrition, and prevent lymphoma. Glucocorticoids are considered first-line therapy, typically open-capsule budesonide given as 3 mg three times daily. Prednisone serves as an alternative with proven efficacy but a higher risk for adverse effects.

The optimal choice for second-line therapy is unknown, but the addition of an immunosuppressant agent to steroids appears to be effective in RCD1, including azathioprine, mercaptopurine, and tioguanine. The best treatment for RCD2 is unknown, though clinical response has been reported with steroids, and cladribine has been well tolerated in some patients.

Patients with RCD who don’t respond to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. Frequent medical visits are advised until the disease is well controlled, with regular follow-up after that. 

Ultimately, “patients with RCD benefit from evaluation and regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy,” the authors wrote. “Identify local experts with expertise in celiac disease to assist with management.”

The authors reported no grant support or funding sources for this study. One author has received research report from Freenome, and another is on the celiac disease advisory board for Takeda. The remaining authors disclosed no conflicts.

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

A version of this article first appeared on Medscape.com.

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

A version of this article first appeared on Medscape.com.

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

A version of this article first appeared on Medscape.com.

Patients with inflammatory bowel disease (IBD) taking ustekinumab (Stelara) are less likely to have infections as a side effect than those taking tofacitinib (Xeljanz) or anti–tumor necrosis factor-alpha (anti-TNF), researchers say.

Although the risk of infections is not large for any of these drugs, clinicians should nonetheless take it into account, given their similar efficacy, said Ashwin Ananthakrishnan, MD, associate professor of medicine at Massachusetts General Hospital, Boston.

“These findings may not dramatically change prescribing patterns, but in those who may be particularly vulnerable for infection, they could point toward the safer biologic being Stelara,” he told this news organization.

The study by Dr. Ananthakrishnan and his colleagues was published in Clinical Gastroenterology and Hepatology.

Biologic and small-molecule immunosuppressive therapies have emerged as effective treatments for Crohn’s disease and ulcerative colitis, the two conditions that comprise IBD.

But the recent proliferation of drugs in these classes with different mechanisms of action has made prescribing decisions complicated. And because the drugs suppress the immune system, they can make patients vulnerable to infection.

Randomized controlled trials, even those comparing the drugs head to head, have not been large enough to compare safety outcomes with statistical accuracy, Dr. Ananthakrishnan and his colleagues found.
 

Accessing a large, real-world cohort

To help fill this gap, they analyzed data on 89,972,617 people enrolled in Aetna, the nationwide U.S. health insurance plan, from 2008-2019.

They identified 19,096 patients whose IBD was treated with anti-TNF agents, 2,420 with ustekinumab, and 305 with tofacitinib. The number of patients taking tofacitinib is small because it is a newer drug, Dr. Ananthakrishnan said.

They found a higher rate of infection and rate of infection-related hospitalization for the patients taking anti-TNF agents (44% and 7%, respectively), compared with those taking ustekinumab (32% and 4%, respectively) over the course of up to a year.

The researchers adjusted for age, sex, IBD duration, prior corticosteroid use, prior immunomodulator use, prior IBD hospitalization, and comorbidities, after which they then compared the risks of infection.

They found that patients taking ustekinumab were 7% less likely to have any infection than patients taking anti-TNF agents (hazard ratio, 0.93), a statistically significant difference (95% confidence interval, 0.86-0.99; P = .041). The reduction in the risk of infection-related hospitalizations was similar but not statistically significant.

The advantage with ustekinumab over anti-TNF agents was larger for patients with comorbidities. There was a 25% reduction in the risk of infections for patients taking ustekinumab who had a Charlson comorbidity index score of at least 2 and who were younger than 65 years (HRm 0.71; 95% CI, 0.58-0.87; P < .001).

For patients taking tofacitinib, there were no significant differences in the rate of infection (HR, 0.97; 95% CI, 0.75-1.24) or infection-related hospitalizations (HR, 0.59; 95% CI, 0.27-1.05), compared with TNF-antagonists.

The respiratory system and the urinary tract were the most common sites of infections. Bacterial, viral, and fungal infections were similarly distributed in the three groups.
 

Remaining questions

Further research is needed, said Dr. Ananthakrishnan, as “to understand the comparative safety may be particularly important for vulnerable populations, like those who are older or have other underlying comorbidity, where safety is increasingly an important issue.”

The findings are similar to those of other studies comparing infections in association with ustekinumab to anti-TNF medications for related conditions, such as psoriatic arthritis and psoriasis, he said.

Clinicians have seen similar differences among the drugs in clinical practice, said Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at Cleveland Clinic, Ohio, who was not involved in the study.

“It aligns well with what we’ve thought, but it’s nice to see in a publication,” he said in an interview.

The implications of the study are limited, because it was not a prospective randomized trial and because the number of patients taking tofacitinib was so small, Dr. Regueiro added.

Another limitation is that the patients who were admitted to the hospital in this database were not necessarily admitted because of their infections, said Stephen Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who also was not involved in the study.

Dr. Hanauer told this news organization that comparisons with other agents would be helpful.

“They didn’t look at vedolizumab (Entyvio) in this database,” he said. “Entyvio is generally considered to be safer than TNF inhibitors or tofacitinib with fairly comparable safety to ustekinumab.”

Dr. Ananthakrishnan reported financial relationships with Gilead, Ikena Therapeutics, and Sun Pharma. Dr. Regueiro reported financial relationships with AbbVie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead, UCB, Miraca Labs, Amgen, Celgene, Seres, Allergan, Salix, Prometheus, Lilly, TARGET Pharma Solutions, Alfasigigma, and BMS. Dr. Hanauer reported financial relationships with Janssen Pharmaceuticals, AbbVie, Takeda Pharmaceutical, and Pfizer.

A version of this article first appeared on Medscape.com.

Patients with inflammatory bowel disease (IBD) taking ustekinumab (Stelara) are less likely to have infections as a side effect than those taking tofacitinib (Xeljanz) or anti–tumor necrosis factor-alpha (anti-TNF), researchers say.

Although the risk of infections is not large for any of these drugs, clinicians should nonetheless take it into account, given their similar efficacy, said Ashwin Ananthakrishnan, MD, associate professor of medicine at Massachusetts General Hospital, Boston.

“These findings may not dramatically change prescribing patterns, but in those who may be particularly vulnerable for infection, they could point toward the safer biologic being Stelara,” he told this news organization.

The study by Dr. Ananthakrishnan and his colleagues was published in Clinical Gastroenterology and Hepatology.

Biologic and small-molecule immunosuppressive therapies have emerged as effective treatments for Crohn’s disease and ulcerative colitis, the two conditions that comprise IBD.

But the recent proliferation of drugs in these classes with different mechanisms of action has made prescribing decisions complicated. And because the drugs suppress the immune system, they can make patients vulnerable to infection.

Randomized controlled trials, even those comparing the drugs head to head, have not been large enough to compare safety outcomes with statistical accuracy, Dr. Ananthakrishnan and his colleagues found.
 

Accessing a large, real-world cohort

To help fill this gap, they analyzed data on 89,972,617 people enrolled in Aetna, the nationwide U.S. health insurance plan, from 2008-2019.

They identified 19,096 patients whose IBD was treated with anti-TNF agents, 2,420 with ustekinumab, and 305 with tofacitinib. The number of patients taking tofacitinib is small because it is a newer drug, Dr. Ananthakrishnan said.

They found a higher rate of infection and rate of infection-related hospitalization for the patients taking anti-TNF agents (44% and 7%, respectively), compared with those taking ustekinumab (32% and 4%, respectively) over the course of up to a year.

The researchers adjusted for age, sex, IBD duration, prior corticosteroid use, prior immunomodulator use, prior IBD hospitalization, and comorbidities, after which they then compared the risks of infection.

They found that patients taking ustekinumab were 7% less likely to have any infection than patients taking anti-TNF agents (hazard ratio, 0.93), a statistically significant difference (95% confidence interval, 0.86-0.99; P = .041). The reduction in the risk of infection-related hospitalizations was similar but not statistically significant.

The advantage with ustekinumab over anti-TNF agents was larger for patients with comorbidities. There was a 25% reduction in the risk of infections for patients taking ustekinumab who had a Charlson comorbidity index score of at least 2 and who were younger than 65 years (HRm 0.71; 95% CI, 0.58-0.87; P < .001).

For patients taking tofacitinib, there were no significant differences in the rate of infection (HR, 0.97; 95% CI, 0.75-1.24) or infection-related hospitalizations (HR, 0.59; 95% CI, 0.27-1.05), compared with TNF-antagonists.

The respiratory system and the urinary tract were the most common sites of infections. Bacterial, viral, and fungal infections were similarly distributed in the three groups.
 

Remaining questions

Further research is needed, said Dr. Ananthakrishnan, as “to understand the comparative safety may be particularly important for vulnerable populations, like those who are older or have other underlying comorbidity, where safety is increasingly an important issue.”

The findings are similar to those of other studies comparing infections in association with ustekinumab to anti-TNF medications for related conditions, such as psoriatic arthritis and psoriasis, he said.

Clinicians have seen similar differences among the drugs in clinical practice, said Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at Cleveland Clinic, Ohio, who was not involved in the study.

“It aligns well with what we’ve thought, but it’s nice to see in a publication,” he said in an interview.

The implications of the study are limited, because it was not a prospective randomized trial and because the number of patients taking tofacitinib was so small, Dr. Regueiro added.

Another limitation is that the patients who were admitted to the hospital in this database were not necessarily admitted because of their infections, said Stephen Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who also was not involved in the study.

Dr. Hanauer told this news organization that comparisons with other agents would be helpful.

“They didn’t look at vedolizumab (Entyvio) in this database,” he said. “Entyvio is generally considered to be safer than TNF inhibitors or tofacitinib with fairly comparable safety to ustekinumab.”

Dr. Ananthakrishnan reported financial relationships with Gilead, Ikena Therapeutics, and Sun Pharma. Dr. Regueiro reported financial relationships with AbbVie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead, UCB, Miraca Labs, Amgen, Celgene, Seres, Allergan, Salix, Prometheus, Lilly, TARGET Pharma Solutions, Alfasigigma, and BMS. Dr. Hanauer reported financial relationships with Janssen Pharmaceuticals, AbbVie, Takeda Pharmaceutical, and Pfizer.

A version of this article first appeared on Medscape.com.

Patients with inflammatory bowel disease (IBD) taking ustekinumab (Stelara) are less likely to have infections as a side effect than those taking tofacitinib (Xeljanz) or anti–tumor necrosis factor-alpha (anti-TNF), researchers say.

Although the risk of infections is not large for any of these drugs, clinicians should nonetheless take it into account, given their similar efficacy, said Ashwin Ananthakrishnan, MD, associate professor of medicine at Massachusetts General Hospital, Boston.

“These findings may not dramatically change prescribing patterns, but in those who may be particularly vulnerable for infection, they could point toward the safer biologic being Stelara,” he told this news organization.

The study by Dr. Ananthakrishnan and his colleagues was published in Clinical Gastroenterology and Hepatology.

Biologic and small-molecule immunosuppressive therapies have emerged as effective treatments for Crohn’s disease and ulcerative colitis, the two conditions that comprise IBD.

But the recent proliferation of drugs in these classes with different mechanisms of action has made prescribing decisions complicated. And because the drugs suppress the immune system, they can make patients vulnerable to infection.

Randomized controlled trials, even those comparing the drugs head to head, have not been large enough to compare safety outcomes with statistical accuracy, Dr. Ananthakrishnan and his colleagues found.
 

Accessing a large, real-world cohort

To help fill this gap, they analyzed data on 89,972,617 people enrolled in Aetna, the nationwide U.S. health insurance plan, from 2008-2019.

They identified 19,096 patients whose IBD was treated with anti-TNF agents, 2,420 with ustekinumab, and 305 with tofacitinib. The number of patients taking tofacitinib is small because it is a newer drug, Dr. Ananthakrishnan said.

They found a higher rate of infection and rate of infection-related hospitalization for the patients taking anti-TNF agents (44% and 7%, respectively), compared with those taking ustekinumab (32% and 4%, respectively) over the course of up to a year.

The researchers adjusted for age, sex, IBD duration, prior corticosteroid use, prior immunomodulator use, prior IBD hospitalization, and comorbidities, after which they then compared the risks of infection.

They found that patients taking ustekinumab were 7% less likely to have any infection than patients taking anti-TNF agents (hazard ratio, 0.93), a statistically significant difference (95% confidence interval, 0.86-0.99; P = .041). The reduction in the risk of infection-related hospitalizations was similar but not statistically significant.

The advantage with ustekinumab over anti-TNF agents was larger for patients with comorbidities. There was a 25% reduction in the risk of infections for patients taking ustekinumab who had a Charlson comorbidity index score of at least 2 and who were younger than 65 years (HRm 0.71; 95% CI, 0.58-0.87; P < .001).

For patients taking tofacitinib, there were no significant differences in the rate of infection (HR, 0.97; 95% CI, 0.75-1.24) or infection-related hospitalizations (HR, 0.59; 95% CI, 0.27-1.05), compared with TNF-antagonists.

The respiratory system and the urinary tract were the most common sites of infections. Bacterial, viral, and fungal infections were similarly distributed in the three groups.
 

Remaining questions

Further research is needed, said Dr. Ananthakrishnan, as “to understand the comparative safety may be particularly important for vulnerable populations, like those who are older or have other underlying comorbidity, where safety is increasingly an important issue.”

The findings are similar to those of other studies comparing infections in association with ustekinumab to anti-TNF medications for related conditions, such as psoriatic arthritis and psoriasis, he said.

Clinicians have seen similar differences among the drugs in clinical practice, said Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at Cleveland Clinic, Ohio, who was not involved in the study.

“It aligns well with what we’ve thought, but it’s nice to see in a publication,” he said in an interview.

The implications of the study are limited, because it was not a prospective randomized trial and because the number of patients taking tofacitinib was so small, Dr. Regueiro added.

Another limitation is that the patients who were admitted to the hospital in this database were not necessarily admitted because of their infections, said Stephen Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who also was not involved in the study.

Dr. Hanauer told this news organization that comparisons with other agents would be helpful.

“They didn’t look at vedolizumab (Entyvio) in this database,” he said. “Entyvio is generally considered to be safer than TNF inhibitors or tofacitinib with fairly comparable safety to ustekinumab.”

Dr. Ananthakrishnan reported financial relationships with Gilead, Ikena Therapeutics, and Sun Pharma. Dr. Regueiro reported financial relationships with AbbVie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead, UCB, Miraca Labs, Amgen, Celgene, Seres, Allergan, Salix, Prometheus, Lilly, TARGET Pharma Solutions, Alfasigigma, and BMS. Dr. Hanauer reported financial relationships with Janssen Pharmaceuticals, AbbVie, Takeda Pharmaceutical, and Pfizer.

A version of this article first appeared on Medscape.com.

Levels of calprotectin, a biomarker used to detect intestinal inflammation, may vary in fecal samples based on an individual’s microbiome composition, according to researchers. The results, if confirmed, might help refine its use in monitoring inflammatory bowel disease (IBD).

Researchers used a new ex vivo functional assay to identify specific bacteria that degrade calprotectin and may play a role in variations found in vivo. “Microbiome-based calibration could improve sensitivity and specificity of fecal calprotectin readouts, thereby facilitating more reliable real-time monitoring and ultimately enabling more timely interventions,” the authors wrote in their research letter, which was published in Gastro Hep Advances.

The standard for diagnosing ulcerative colitis (UC) and Crohn’s disease (CD) is endoscopy and biopsy because it allows both visual and histological examination of the severity and extent of intestinal inflammation, but this cannot be used to monitor patients on an ongoing basis.

Calprotectin is a promising biomarker for intestinal inflammation, but a meta-analysis found that it has a pooled sensitivity of 85% and a pooled specificity of 75% for the diagnosis of endoscopically active inflammatory bowel disease.

The researchers investigated whether an individual’s microbiome can metabolize calprotectin, which would complicate measurement of fecal calprotectin. They recruited 22 individuals with IBD (64% female, 73% with colonic disease), who provided stool samples. They completed a symptom questionnaire in advance of a colonoscopy. Overall, 64% had endoscopically inactive disease, and 82% had clinically inactive disease.

At a cutoff of 50 mcg/g, 9 patients had normal fecal calprotectin levels, and 13 had elevated levels. Those with clinically or endoscopically active disease had higher levels of fecal calprotectin (P < .0001).

There was a significant but poor correlation between disease activity measures and fecal calprotectin levels in CD (r = 0.62; P = .008), but there was no statistically significant association for UC (r = –0.29; P = .6). Endoscopic disease activity was also significantly correlated with fecal calprotectin in CD (r = 0.83; P < .001), but not UC (r = 0.50; P = .4).

The researchers created an ex vivo functional assay to measure calprotectin metabolism by the microbiome. They anaerobically cultured fecal samples in the presence of calprotectin and measured levels of calprotectin after 24 hours. Control samples were grown without microbes, without calprotectin, or lacking both. The researchers tested samples in both standard media and in media with low levels of amino acids, reasoning that the latter condition might encourage catabolism of calprotectin. The cultures with low amino acid content had lower calprotectin levels than those with normal amino acid content (P < .0007).

The researchers found greater calprotectin degradation in the low amino acid media, and the difference was more pronounced among samples taken from individuals with UC than CD (P < .02).

They used metagenomic sequencing data from fecal samples to identify bacterial species associated with calprotectin metabolism. Similarly to previous reports, the researchers found that Firmicutes was dominant, while Subdoligranulum correlated with calprotectin degradation in low amino acid media (P = .04).

For 5 days, they cultured Subdoligranulum variabile in low amino acid media that also contained calprotectin. Calprotectin levels were lower than a control sample with cultured Akkermansia muciniphila, which was previously shown to not be associated with calprotectin degradation in low amino acid media (P = .03). Because Subdoligranulum species were not detectable in 5 of 22 fecal samples, the authors say they are unlikely to be the only species capable of metabolizing calprotectin.

Among IBD patients, only one had both endoscopically active colitis and a low fecal calprotectin level. The patient’s micobiome had Subdoligranulum present, and their fecal sample was able to metabolize calprotectin in the functional assay.

The study was limited by its small sample size, which prevented development of a calibration model for fecal calprotectin, and the researchers called for additional studies among individuals with active colitis.

Levels of calprotectin, a biomarker used to detect intestinal inflammation, may vary in fecal samples based on an individual’s microbiome composition, according to researchers. The results, if confirmed, might help refine its use in monitoring inflammatory bowel disease (IBD).

Researchers used a new ex vivo functional assay to identify specific bacteria that degrade calprotectin and may play a role in variations found in vivo. “Microbiome-based calibration could improve sensitivity and specificity of fecal calprotectin readouts, thereby facilitating more reliable real-time monitoring and ultimately enabling more timely interventions,” the authors wrote in their research letter, which was published in Gastro Hep Advances.

The standard for diagnosing ulcerative colitis (UC) and Crohn’s disease (CD) is endoscopy and biopsy because it allows both visual and histological examination of the severity and extent of intestinal inflammation, but this cannot be used to monitor patients on an ongoing basis.

Calprotectin is a promising biomarker for intestinal inflammation, but a meta-analysis found that it has a pooled sensitivity of 85% and a pooled specificity of 75% for the diagnosis of endoscopically active inflammatory bowel disease.

The researchers investigated whether an individual’s microbiome can metabolize calprotectin, which would complicate measurement of fecal calprotectin. They recruited 22 individuals with IBD (64% female, 73% with colonic disease), who provided stool samples. They completed a symptom questionnaire in advance of a colonoscopy. Overall, 64% had endoscopically inactive disease, and 82% had clinically inactive disease.

At a cutoff of 50 mcg/g, 9 patients had normal fecal calprotectin levels, and 13 had elevated levels. Those with clinically or endoscopically active disease had higher levels of fecal calprotectin (P < .0001).

There was a significant but poor correlation between disease activity measures and fecal calprotectin levels in CD (r = 0.62; P = .008), but there was no statistically significant association for UC (r = –0.29; P = .6). Endoscopic disease activity was also significantly correlated with fecal calprotectin in CD (r = 0.83; P < .001), but not UC (r = 0.50; P = .4).

The researchers created an ex vivo functional assay to measure calprotectin metabolism by the microbiome. They anaerobically cultured fecal samples in the presence of calprotectin and measured levels of calprotectin after 24 hours. Control samples were grown without microbes, without calprotectin, or lacking both. The researchers tested samples in both standard media and in media with low levels of amino acids, reasoning that the latter condition might encourage catabolism of calprotectin. The cultures with low amino acid content had lower calprotectin levels than those with normal amino acid content (P < .0007).

The researchers found greater calprotectin degradation in the low amino acid media, and the difference was more pronounced among samples taken from individuals with UC than CD (P < .02).

They used metagenomic sequencing data from fecal samples to identify bacterial species associated with calprotectin metabolism. Similarly to previous reports, the researchers found that Firmicutes was dominant, while Subdoligranulum correlated with calprotectin degradation in low amino acid media (P = .04).

For 5 days, they cultured Subdoligranulum variabile in low amino acid media that also contained calprotectin. Calprotectin levels were lower than a control sample with cultured Akkermansia muciniphila, which was previously shown to not be associated with calprotectin degradation in low amino acid media (P = .03). Because Subdoligranulum species were not detectable in 5 of 22 fecal samples, the authors say they are unlikely to be the only species capable of metabolizing calprotectin.

Among IBD patients, only one had both endoscopically active colitis and a low fecal calprotectin level. The patient’s micobiome had Subdoligranulum present, and their fecal sample was able to metabolize calprotectin in the functional assay.

The study was limited by its small sample size, which prevented development of a calibration model for fecal calprotectin, and the researchers called for additional studies among individuals with active colitis.

Levels of calprotectin, a biomarker used to detect intestinal inflammation, may vary in fecal samples based on an individual’s microbiome composition, according to researchers. The results, if confirmed, might help refine its use in monitoring inflammatory bowel disease (IBD).

Researchers used a new ex vivo functional assay to identify specific bacteria that degrade calprotectin and may play a role in variations found in vivo. “Microbiome-based calibration could improve sensitivity and specificity of fecal calprotectin readouts, thereby facilitating more reliable real-time monitoring and ultimately enabling more timely interventions,” the authors wrote in their research letter, which was published in Gastro Hep Advances.

The standard for diagnosing ulcerative colitis (UC) and Crohn’s disease (CD) is endoscopy and biopsy because it allows both visual and histological examination of the severity and extent of intestinal inflammation, but this cannot be used to monitor patients on an ongoing basis.

Calprotectin is a promising biomarker for intestinal inflammation, but a meta-analysis found that it has a pooled sensitivity of 85% and a pooled specificity of 75% for the diagnosis of endoscopically active inflammatory bowel disease.

The researchers investigated whether an individual’s microbiome can metabolize calprotectin, which would complicate measurement of fecal calprotectin. They recruited 22 individuals with IBD (64% female, 73% with colonic disease), who provided stool samples. They completed a symptom questionnaire in advance of a colonoscopy. Overall, 64% had endoscopically inactive disease, and 82% had clinically inactive disease.

At a cutoff of 50 mcg/g, 9 patients had normal fecal calprotectin levels, and 13 had elevated levels. Those with clinically or endoscopically active disease had higher levels of fecal calprotectin (P < .0001).

There was a significant but poor correlation between disease activity measures and fecal calprotectin levels in CD (r = 0.62; P = .008), but there was no statistically significant association for UC (r = –0.29; P = .6). Endoscopic disease activity was also significantly correlated with fecal calprotectin in CD (r = 0.83; P < .001), but not UC (r = 0.50; P = .4).

The researchers created an ex vivo functional assay to measure calprotectin metabolism by the microbiome. They anaerobically cultured fecal samples in the presence of calprotectin and measured levels of calprotectin after 24 hours. Control samples were grown without microbes, without calprotectin, or lacking both. The researchers tested samples in both standard media and in media with low levels of amino acids, reasoning that the latter condition might encourage catabolism of calprotectin. The cultures with low amino acid content had lower calprotectin levels than those with normal amino acid content (P < .0007).

The researchers found greater calprotectin degradation in the low amino acid media, and the difference was more pronounced among samples taken from individuals with UC than CD (P < .02).

They used metagenomic sequencing data from fecal samples to identify bacterial species associated with calprotectin metabolism. Similarly to previous reports, the researchers found that Firmicutes was dominant, while Subdoligranulum correlated with calprotectin degradation in low amino acid media (P = .04).

For 5 days, they cultured Subdoligranulum variabile in low amino acid media that also contained calprotectin. Calprotectin levels were lower than a control sample with cultured Akkermansia muciniphila, which was previously shown to not be associated with calprotectin degradation in low amino acid media (P = .03). Because Subdoligranulum species were not detectable in 5 of 22 fecal samples, the authors say they are unlikely to be the only species capable of metabolizing calprotectin.

Among IBD patients, only one had both endoscopically active colitis and a low fecal calprotectin level. The patient’s micobiome had Subdoligranulum present, and their fecal sample was able to metabolize calprotectin in the functional assay.

The study was limited by its small sample size, which prevented development of a calibration model for fecal calprotectin, and the researchers called for additional studies among individuals with active colitis.

Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.
 

Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.
 

Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.
 

Caring for patients with short bowel syndrome (SBS) requires a multidisciplinary approach involving dietitians, nurses, surgeons, gastroenterologists or internists, and social workers experienced in SBS care, according to a clinical practice update expert review from the American Gastroenterological Association.

Kishore Iyer, MD, from Mount Sinai Hospital New York; John K. DiBaise, MD, from Mayo Clinic in Scottsdale, Ariz.; and Alberto Rubio-Tapia, MD, from the Cleveland Clinic, Ohio, developed 12 best practice advice statements based on available evidence. The items focus on adult patients with SBS; however, there was some overlap with the management of pediatric SBS. The review was published online in Clinical Gastroenterology and Hepatology.
 

Defining SBS

One update concerns defining SBS. The authors recommend that surgeons performing massive resections should report the residual bowel length, rather than the length of bowel resected.

“It is only the former that dictates outcome,” they wrote.

There is general agreement that a residual small intestinal length of 200 cm or less meets criteria for SBS. Measurement should be taken from “along the antimesenteric border of unstretched bowel, from the duodenojejunal flexure to the ileocecal junction, the site of any small bowel–colon anastomosis, or to the end-ostomy.”

Based on the residual bowel length, patients can be classified into three groups: end-jejunostomy, jejuno-colic, and jejuno-ileo-colic.
 

Assessing nutritional status

A dietitian experienced in SBS should perform a thorough nutritional assessment on all SBS patients. Long-term monitoring should include laboratory studies checking electrolytes and liver and kidney function, fluid balance, weight change, serum micronutrients, and bone density. Bone density should be repeated periodically, every 2-3 years.

Fluid and electrolyte problems may affect outcomes for SBS patients, particularly for those without a colon.
 

Adjusting diets

Most adult patients with SBS have significant malabsorption, so dietary intake “must be increased by at least 50% from their estimated needs,” the authors wrote. It’s best if the patient consumes the increased quantity throughout the day in 5-6 meals, they noted.

An experienced dietitian should counsel the patient based on the patient’s eating preferences. Incorporating preferences can help increase compliance with the adjustments that may become necessary based on symptoms, stool output, and weight.
 

Using pharmacologic therapy

Using antisecretory medications, including proton pump inhibitors or histamine-2 receptor antagonists, helps reduce gastric secretions, the damage of acid on the upper gut mucosa, and the function of pancreatic exocrine enzymes.

Antidiarrheals reduce intestinal motility but also cause a slight reduction in intestinal secretion. Common agents include loperamide, diphenoxylate with atropine, codeine, and tincture of opium. The review authors say loperamide should get preference over opiate drugs because it is not addictive or sedative.

Use of antidiarrheals should be guided by their effect on stool output.

“Loperamide and codeine may have a synergistic effect when used together,” the authors wrote.

Clonidine, which can be given transdermally, has also shown some benefit in treating high-output stool losses, presumably because of its effects on intestinal motility and secretion.

Weighing risks and benefits of teduglutide

The glucagonlike peptide–2 teduglutide is of particular interest for its ability to help improve intestinal absorption and hopefully wean patients off parenteral nutrition and some will achieve enteral autonomy, the authors wrote. “The very short half-life of native GLP-2 has been extended to allow daily subcutaneous injection in the recombinant molecule, teduglutide.”

However, because teduglutide is a growth factor and can boost the growth of polyps and cancer, it is contraindicated in patients with active gastrointestinal malignancies. Patients should undergo colonoscopy before treatment and periodically thereafter, the authors advised. The benefits of its use in patients with nongastrointestinal malignancy should be weighed carefully with these risks.

“The significant side effects of teduglutide and the cost mandate that teduglutide is employed only after optimizing diet and the more conventional SBS treatments described previously in carefully selected patients with [short bowel syndrome–intestinal failure],” the authors wrote.
 

Dosing drugs effectively

Medications in tablet form need to dissolve before being absorbed. Most oral medications are absorbed within the proximal jejunum, so they can be used in patients with SBS.

“However,” the authors noted, “sustained- and delayed-release medications should be avoided.”

They suggested that, when applicable, alternatives such as liquids and topical medications should be considered, as should the monitoring of medication levels in the blood.

If a patient does not respond, approaches to consider may include increasing a dose, changing dose frequency, or changing drug formulation or route of administration, such as intravenous, subcutaneous, or transdermal.
 

Including parenteral nutrition and oral rehydration

Almost all patients with SBS will need parenteral nutrition (PN) support following resection, and few will be able to stop it before discharge from the hospital.

“Although more than 50% of adults with SBS are able to be weaned completely from PN within 5 years of diagnosis, the probability of eliminating PN use is less than 6% if not successfully accomplished in the first 2 years following the individual’s last bowel resection,” the authors wrote.

For long-term PN, tunneled central venous catheters are preferred over peripherally inserted central venous catheters because of the higher risk of thrombosis and issues related to self-administration of PN with the central catheters. Also, tunneled catheters are preferred over totally implanted devices, or ports, for long-term patients because the main benefit of the port is not realized given that the device needs to be continually accessed and exchanged weekly.

“When calculating PN volume and content, changes in the patient’s weight, laboratory results, stool or ostomy output, urine output, and complaints of thirst should be monitored,” the authors noted.

The authors also discussed oral rehydration solution because patients lose more water and sodium from their stoma than they take in by mouth. Careful consideration of the glucose and sodium levels in oral fluids is important because inappropriate fluids will exacerbate fluid losses in SBS. For example, hypotonic (including water, tea, coffee, alcohol) and hypertonic (including fruit juices and sodas) solutions should be limited.

“A major misconception on the part of patients is that they should drink large quantities of water; however, this generally leads to an increase in ostomy output and creates a vicious cycle further exacerbating fluid and electrolyte disturbances,” they wrote, instead advising glucose–electrolyte rehydration solution to enhance absorption and reduce secretion.
 

Preventing complications

“A knowledge of these complications is critical for those caring for these patients to be able to not only identify and treat them when they occur but also to prevent their occurrence whenever possible,” the authors wrote. Although they considered it beyond the scope of the review to outline every complication, they indicated some complications and management strategies via an included table. These complications can include cirrhosis, osteoporosis, acute kidney disease, and central venous catheter–related infection or occlusion.

Considering further surgery or intestinal transplantation

The authors noted that any further surgery should be carefully considered, with the following three contexts having possible value: “(1) to recruit unused distal bowel, (2) to augment the function of residual bowel through specific lengthening and tapering operations, or (3) to slow intestinal transit.”

Surgeons involved in managing SBS may need to confront complex intra-abdominal problems such as massive desmoid tumors, mesenteric ischemia, or complex enterocutaneous fistulae; a multidisciplinary intestinal rehabilitation team may be better able to help these patients. The authors noted that care for patients starts even before the first operation, by taking every measure to avoid massive bowel resection and the resulting SBS.

The authors noted the importance of early referral for intestinal transplantation consideration for patients with refractory dependency on parenteral nutrition or even onset of parenteral nutrition failure, which refers to complications such as intestinal failure–associated liver disease.

“At present, nearly 50% of patients being considered for ITX are also requiring simultaneous liver replacement, indicating late referral for ITX,” they wrote, citing a data from a report by the Centers for Medicare and Medicaid.

They also noted that data have shown short- and medium-term outcomes are steadily improving; however, long-term outcomes have been challenged by opportunistic infections, long-term graft attrition, and other impediments that may be preventing early referral for intestinal transplantation.
 

Educating patients, caregivers

Long-term PN may restrict activity for patients, but patients and caregivers should know about some modifications.

One is to cycle the PN over 10-14 hours overnight to allow freedom from the infusion pump during the day. Infusion pumps can be programmable, and some can be carried in a backpack for infusing during the day.

Authors recommend patient support groups, such as the Oley Foundation, which can help with issues surrounding body image and travel.

Because of the relative rarity of SBS, nonspecialist physicians may care for patients without a dedicated multidisciplinary team and may need education support in managing patients with complex care needs. One source the authors recommend is the Learn Intestinal Failure Tele-ECHO (Expanding Community Healthcare Outcomes) (LIFT-ECHO) project. The LIFT-ECHO project has become an online educational community with case-based learning in SBS, intestinal failure, and PN.

The authors disclose relationships with Takeda, Zealand, VectivBio, Napo, and Hanmi.

Caring for patients with short bowel syndrome (SBS) requires a multidisciplinary approach involving dietitians, nurses, surgeons, gastroenterologists or internists, and social workers experienced in SBS care, according to a clinical practice update expert review from the American Gastroenterological Association.

Kishore Iyer, MD, from Mount Sinai Hospital New York; John K. DiBaise, MD, from Mayo Clinic in Scottsdale, Ariz.; and Alberto Rubio-Tapia, MD, from the Cleveland Clinic, Ohio, developed 12 best practice advice statements based on available evidence. The items focus on adult patients with SBS; however, there was some overlap with the management of pediatric SBS. The review was published online in Clinical Gastroenterology and Hepatology.
 

Defining SBS

One update concerns defining SBS. The authors recommend that surgeons performing massive resections should report the residual bowel length, rather than the length of bowel resected.

“It is only the former that dictates outcome,” they wrote.

There is general agreement that a residual small intestinal length of 200 cm or less meets criteria for SBS. Measurement should be taken from “along the antimesenteric border of unstretched bowel, from the duodenojejunal flexure to the ileocecal junction, the site of any small bowel–colon anastomosis, or to the end-ostomy.”

Based on the residual bowel length, patients can be classified into three groups: end-jejunostomy, jejuno-colic, and jejuno-ileo-colic.
 

Assessing nutritional status

A dietitian experienced in SBS should perform a thorough nutritional assessment on all SBS patients. Long-term monitoring should include laboratory studies checking electrolytes and liver and kidney function, fluid balance, weight change, serum micronutrients, and bone density. Bone density should be repeated periodically, every 2-3 years.

Fluid and electrolyte problems may affect outcomes for SBS patients, particularly for those without a colon.
 

Adjusting diets

Most adult patients with SBS have significant malabsorption, so dietary intake “must be increased by at least 50% from their estimated needs,” the authors wrote. It’s best if the patient consumes the increased quantity throughout the day in 5-6 meals, they noted.

An experienced dietitian should counsel the patient based on the patient’s eating preferences. Incorporating preferences can help increase compliance with the adjustments that may become necessary based on symptoms, stool output, and weight.
 

Using pharmacologic therapy

Using antisecretory medications, including proton pump inhibitors or histamine-2 receptor antagonists, helps reduce gastric secretions, the damage of acid on the upper gut mucosa, and the function of pancreatic exocrine enzymes.

Antidiarrheals reduce intestinal motility but also cause a slight reduction in intestinal secretion. Common agents include loperamide, diphenoxylate with atropine, codeine, and tincture of opium. The review authors say loperamide should get preference over opiate drugs because it is not addictive or sedative.

Use of antidiarrheals should be guided by their effect on stool output.

“Loperamide and codeine may have a synergistic effect when used together,” the authors wrote.

Clonidine, which can be given transdermally, has also shown some benefit in treating high-output stool losses, presumably because of its effects on intestinal motility and secretion.

Weighing risks and benefits of teduglutide

The glucagonlike peptide–2 teduglutide is of particular interest for its ability to help improve intestinal absorption and hopefully wean patients off parenteral nutrition and some will achieve enteral autonomy, the authors wrote. “The very short half-life of native GLP-2 has been extended to allow daily subcutaneous injection in the recombinant molecule, teduglutide.”

However, because teduglutide is a growth factor and can boost the growth of polyps and cancer, it is contraindicated in patients with active gastrointestinal malignancies. Patients should undergo colonoscopy before treatment and periodically thereafter, the authors advised. The benefits of its use in patients with nongastrointestinal malignancy should be weighed carefully with these risks.

“The significant side effects of teduglutide and the cost mandate that teduglutide is employed only after optimizing diet and the more conventional SBS treatments described previously in carefully selected patients with [short bowel syndrome–intestinal failure],” the authors wrote.
 

Dosing drugs effectively

Medications in tablet form need to dissolve before being absorbed. Most oral medications are absorbed within the proximal jejunum, so they can be used in patients with SBS.

“However,” the authors noted, “sustained- and delayed-release medications should be avoided.”

They suggested that, when applicable, alternatives such as liquids and topical medications should be considered, as should the monitoring of medication levels in the blood.

If a patient does not respond, approaches to consider may include increasing a dose, changing dose frequency, or changing drug formulation or route of administration, such as intravenous, subcutaneous, or transdermal.
 

Including parenteral nutrition and oral rehydration

Almost all patients with SBS will need parenteral nutrition (PN) support following resection, and few will be able to stop it before discharge from the hospital.

“Although more than 50% of adults with SBS are able to be weaned completely from PN within 5 years of diagnosis, the probability of eliminating PN use is less than 6% if not successfully accomplished in the first 2 years following the individual’s last bowel resection,” the authors wrote.

For long-term PN, tunneled central venous catheters are preferred over peripherally inserted central venous catheters because of the higher risk of thrombosis and issues related to self-administration of PN with the central catheters. Also, tunneled catheters are preferred over totally implanted devices, or ports, for long-term patients because the main benefit of the port is not realized given that the device needs to be continually accessed and exchanged weekly.

“When calculating PN volume and content, changes in the patient’s weight, laboratory results, stool or ostomy output, urine output, and complaints of thirst should be monitored,” the authors noted.

The authors also discussed oral rehydration solution because patients lose more water and sodium from their stoma than they take in by mouth. Careful consideration of the glucose and sodium levels in oral fluids is important because inappropriate fluids will exacerbate fluid losses in SBS. For example, hypotonic (including water, tea, coffee, alcohol) and hypertonic (including fruit juices and sodas) solutions should be limited.

“A major misconception on the part of patients is that they should drink large quantities of water; however, this generally leads to an increase in ostomy output and creates a vicious cycle further exacerbating fluid and electrolyte disturbances,” they wrote, instead advising glucose–electrolyte rehydration solution to enhance absorption and reduce secretion.
 

Preventing complications

“A knowledge of these complications is critical for those caring for these patients to be able to not only identify and treat them when they occur but also to prevent their occurrence whenever possible,” the authors wrote. Although they considered it beyond the scope of the review to outline every complication, they indicated some complications and management strategies via an included table. These complications can include cirrhosis, osteoporosis, acute kidney disease, and central venous catheter–related infection or occlusion.

Considering further surgery or intestinal transplantation

The authors noted that any further surgery should be carefully considered, with the following three contexts having possible value: “(1) to recruit unused distal bowel, (2) to augment the function of residual bowel through specific lengthening and tapering operations, or (3) to slow intestinal transit.”

Surgeons involved in managing SBS may need to confront complex intra-abdominal problems such as massive desmoid tumors, mesenteric ischemia, or complex enterocutaneous fistulae; a multidisciplinary intestinal rehabilitation team may be better able to help these patients. The authors noted that care for patients starts even before the first operation, by taking every measure to avoid massive bowel resection and the resulting SBS.

The authors noted the importance of early referral for intestinal transplantation consideration for patients with refractory dependency on parenteral nutrition or even onset of parenteral nutrition failure, which refers to complications such as intestinal failure–associated liver disease.

“At present, nearly 50% of patients being considered for ITX are also requiring simultaneous liver replacement, indicating late referral for ITX,” they wrote, citing a data from a report by the Centers for Medicare and Medicaid.

They also noted that data have shown short- and medium-term outcomes are steadily improving; however, long-term outcomes have been challenged by opportunistic infections, long-term graft attrition, and other impediments that may be preventing early referral for intestinal transplantation.
 

Educating patients, caregivers

Long-term PN may restrict activity for patients, but patients and caregivers should know about some modifications.

One is to cycle the PN over 10-14 hours overnight to allow freedom from the infusion pump during the day. Infusion pumps can be programmable, and some can be carried in a backpack for infusing during the day.

Authors recommend patient support groups, such as the Oley Foundation, which can help with issues surrounding body image and travel.

Because of the relative rarity of SBS, nonspecialist physicians may care for patients without a dedicated multidisciplinary team and may need education support in managing patients with complex care needs. One source the authors recommend is the Learn Intestinal Failure Tele-ECHO (Expanding Community Healthcare Outcomes) (LIFT-ECHO) project. The LIFT-ECHO project has become an online educational community with case-based learning in SBS, intestinal failure, and PN.

The authors disclose relationships with Takeda, Zealand, VectivBio, Napo, and Hanmi.

Caring for patients with short bowel syndrome (SBS) requires a multidisciplinary approach involving dietitians, nurses, surgeons, gastroenterologists or internists, and social workers experienced in SBS care, according to a clinical practice update expert review from the American Gastroenterological Association.

Kishore Iyer, MD, from Mount Sinai Hospital New York; John K. DiBaise, MD, from Mayo Clinic in Scottsdale, Ariz.; and Alberto Rubio-Tapia, MD, from the Cleveland Clinic, Ohio, developed 12 best practice advice statements based on available evidence. The items focus on adult patients with SBS; however, there was some overlap with the management of pediatric SBS. The review was published online in Clinical Gastroenterology and Hepatology.
 

Defining SBS

One update concerns defining SBS. The authors recommend that surgeons performing massive resections should report the residual bowel length, rather than the length of bowel resected.

“It is only the former that dictates outcome,” they wrote.

There is general agreement that a residual small intestinal length of 200 cm or less meets criteria for SBS. Measurement should be taken from “along the antimesenteric border of unstretched bowel, from the duodenojejunal flexure to the ileocecal junction, the site of any small bowel–colon anastomosis, or to the end-ostomy.”

Based on the residual bowel length, patients can be classified into three groups: end-jejunostomy, jejuno-colic, and jejuno-ileo-colic.
 

Assessing nutritional status

A dietitian experienced in SBS should perform a thorough nutritional assessment on all SBS patients. Long-term monitoring should include laboratory studies checking electrolytes and liver and kidney function, fluid balance, weight change, serum micronutrients, and bone density. Bone density should be repeated periodically, every 2-3 years.

Fluid and electrolyte problems may affect outcomes for SBS patients, particularly for those without a colon.
 

Adjusting diets

Most adult patients with SBS have significant malabsorption, so dietary intake “must be increased by at least 50% from their estimated needs,” the authors wrote. It’s best if the patient consumes the increased quantity throughout the day in 5-6 meals, they noted.

An experienced dietitian should counsel the patient based on the patient’s eating preferences. Incorporating preferences can help increase compliance with the adjustments that may become necessary based on symptoms, stool output, and weight.
 

Using pharmacologic therapy

Using antisecretory medications, including proton pump inhibitors or histamine-2 receptor antagonists, helps reduce gastric secretions, the damage of acid on the upper gut mucosa, and the function of pancreatic exocrine enzymes.

Antidiarrheals reduce intestinal motility but also cause a slight reduction in intestinal secretion. Common agents include loperamide, diphenoxylate with atropine, codeine, and tincture of opium. The review authors say loperamide should get preference over opiate drugs because it is not addictive or sedative.

Use of antidiarrheals should be guided by their effect on stool output.

“Loperamide and codeine may have a synergistic effect when used together,” the authors wrote.

Clonidine, which can be given transdermally, has also shown some benefit in treating high-output stool losses, presumably because of its effects on intestinal motility and secretion.

Weighing risks and benefits of teduglutide

The glucagonlike peptide–2 teduglutide is of particular interest for its ability to help improve intestinal absorption and hopefully wean patients off parenteral nutrition and some will achieve enteral autonomy, the authors wrote. “The very short half-life of native GLP-2 has been extended to allow daily subcutaneous injection in the recombinant molecule, teduglutide.”

However, because teduglutide is a growth factor and can boost the growth of polyps and cancer, it is contraindicated in patients with active gastrointestinal malignancies. Patients should undergo colonoscopy before treatment and periodically thereafter, the authors advised. The benefits of its use in patients with nongastrointestinal malignancy should be weighed carefully with these risks.

“The significant side effects of teduglutide and the cost mandate that teduglutide is employed only after optimizing diet and the more conventional SBS treatments described previously in carefully selected patients with [short bowel syndrome–intestinal failure],” the authors wrote.
 

Dosing drugs effectively

Medications in tablet form need to dissolve before being absorbed. Most oral medications are absorbed within the proximal jejunum, so they can be used in patients with SBS.

“However,” the authors noted, “sustained- and delayed-release medications should be avoided.”

They suggested that, when applicable, alternatives such as liquids and topical medications should be considered, as should the monitoring of medication levels in the blood.

If a patient does not respond, approaches to consider may include increasing a dose, changing dose frequency, or changing drug formulation or route of administration, such as intravenous, subcutaneous, or transdermal.
 

Including parenteral nutrition and oral rehydration

Almost all patients with SBS will need parenteral nutrition (PN) support following resection, and few will be able to stop it before discharge from the hospital.

“Although more than 50% of adults with SBS are able to be weaned completely from PN within 5 years of diagnosis, the probability of eliminating PN use is less than 6% if not successfully accomplished in the first 2 years following the individual’s last bowel resection,” the authors wrote.

For long-term PN, tunneled central venous catheters are preferred over peripherally inserted central venous catheters because of the higher risk of thrombosis and issues related to self-administration of PN with the central catheters. Also, tunneled catheters are preferred over totally implanted devices, or ports, for long-term patients because the main benefit of the port is not realized given that the device needs to be continually accessed and exchanged weekly.

“When calculating PN volume and content, changes in the patient’s weight, laboratory results, stool or ostomy output, urine output, and complaints of thirst should be monitored,” the authors noted.

The authors also discussed oral rehydration solution because patients lose more water and sodium from their stoma than they take in by mouth. Careful consideration of the glucose and sodium levels in oral fluids is important because inappropriate fluids will exacerbate fluid losses in SBS. For example, hypotonic (including water, tea, coffee, alcohol) and hypertonic (including fruit juices and sodas) solutions should be limited.

“A major misconception on the part of patients is that they should drink large quantities of water; however, this generally leads to an increase in ostomy output and creates a vicious cycle further exacerbating fluid and electrolyte disturbances,” they wrote, instead advising glucose–electrolyte rehydration solution to enhance absorption and reduce secretion.
 

Preventing complications

“A knowledge of these complications is critical for those caring for these patients to be able to not only identify and treat them when they occur but also to prevent their occurrence whenever possible,” the authors wrote. Although they considered it beyond the scope of the review to outline every complication, they indicated some complications and management strategies via an included table. These complications can include cirrhosis, osteoporosis, acute kidney disease, and central venous catheter–related infection or occlusion.

Considering further surgery or intestinal transplantation

The authors noted that any further surgery should be carefully considered, with the following three contexts having possible value: “(1) to recruit unused distal bowel, (2) to augment the function of residual bowel through specific lengthening and tapering operations, or (3) to slow intestinal transit.”

Surgeons involved in managing SBS may need to confront complex intra-abdominal problems such as massive desmoid tumors, mesenteric ischemia, or complex enterocutaneous fistulae; a multidisciplinary intestinal rehabilitation team may be better able to help these patients. The authors noted that care for patients starts even before the first operation, by taking every measure to avoid massive bowel resection and the resulting SBS.

The authors noted the importance of early referral for intestinal transplantation consideration for patients with refractory dependency on parenteral nutrition or even onset of parenteral nutrition failure, which refers to complications such as intestinal failure–associated liver disease.

“At present, nearly 50% of patients being considered for ITX are also requiring simultaneous liver replacement, indicating late referral for ITX,” they wrote, citing a data from a report by the Centers for Medicare and Medicaid.

They also noted that data have shown short- and medium-term outcomes are steadily improving; however, long-term outcomes have been challenged by opportunistic infections, long-term graft attrition, and other impediments that may be preventing early referral for intestinal transplantation.
 

Educating patients, caregivers

Long-term PN may restrict activity for patients, but patients and caregivers should know about some modifications.

One is to cycle the PN over 10-14 hours overnight to allow freedom from the infusion pump during the day. Infusion pumps can be programmable, and some can be carried in a backpack for infusing during the day.

Authors recommend patient support groups, such as the Oley Foundation, which can help with issues surrounding body image and travel.

Because of the relative rarity of SBS, nonspecialist physicians may care for patients without a dedicated multidisciplinary team and may need education support in managing patients with complex care needs. One source the authors recommend is the Learn Intestinal Failure Tele-ECHO (Expanding Community Healthcare Outcomes) (LIFT-ECHO) project. The LIFT-ECHO project has become an online educational community with case-based learning in SBS, intestinal failure, and PN.

The authors disclose relationships with Takeda, Zealand, VectivBio, Napo, and Hanmi.

Endoscopic training is increasingly complex as benchmarks for quality evolve and tools and procedures advance with innovation.

A team of experts, led by Matthew J. Whitson, MD, with Hofstra University/Northwell Health in Hempstead, N.Y., aimed to simplify challenges for educators and clinical endoscopists with a review of tools and techniques for education, as well as assessment methods.

Their review was published in the Techniques and Innovations in Gastrointestinal Endoscopy.
 

Giving feedback

Key steps to effective feedback include first talking about the goals for the endoscopy session, then careful observation, but minimal feedback during the endoscopy. Most of the feedback should come after the endoscopy, the authors wrote.

A paper by Walsh et al. demonstrated that with beginning endoscopists, giving feedback afterward led to long-term skill development as compared with short-term benefits of frequent feedback in the middle of procedures.

Feedback should be constructive and specific with emphasis on goals for the next procedure. It should be delivered in a respectful, nonthreatening way for greatest effectiveness.
 

Mastery learning

In this model, each trainee must achieve competence in specific skills to progress to the next level.

“For example, the trainee must master retroflexion in the stomach prior to attempting clip hemostasis in the stomach,” the authors wrote.

Repetitively practicing the skill is coupled with direct feedback.

Mastery learning is often paired with simulation so trainees can practice in a safe space before working with patients.
 

Cognitive load theory

Knowing the challenges of learners can help educators with instruction techniques. An important concept is cognitive load theory (CLT). CLT is focused on the working memory of a learner and the harm that an overload of information can have on learning. A learner’s working memory can process only a few pieces of information at any given time, the theory states.

One mitigation strategy by educators may be to assign a trainee a smaller piece of a specific task appropriate to the trainee’s skill level.

“For example, an early trainee endoscopist may be able to inject epinephrine for a bleeding vessel, but not be ready to perform effective BiCap cautery,” the authors suggested.
 

Different learning styles

Learning styles include visual, aural, reading/writing, and kinesthetic styles (when learners need to touch or manipulate to learn a skill).

“A study of surgical trainees demonstrated that kinesthetic learning was the most preferred unimodal learning style of those entering the field,” the authors wrote.

Dr. Whitson and coauthors gave examples of working with trainees with different learning styles.

A trainee who learns visually, they say, might need to learn about “loop reduction” by looking at images of alpha or beta loops or using ScopeGuide during endoscopy. A kinesthetic learner may need to feel a successful loop reduction with hands on the endoscope during simulation to understand the skill better.

“There is some suggestion that the millennial generation – the demographic of the current gastroenterology fellows – may have higher preferences for kinesthetic learning,” the authors wrote.
 

Role of simulation

The Accreditation Council for Graduate Medical Education, which oversees Gastroenterology Fellowship training, mandates simulation in gastroenterology education but does not specify endoscopic simulation. The American Board of Surgeons, however, does require their trainees to complete the flexible endoscopic curriculum, which is simulation-based.

Simulator use appears particularly helpful early in training. One study demonstrated that colonoscopy simulation has benefit in the first 30 colonoscopies in depth of insertion, independent completion, and ability to identify landmarks.

However, another study showed simulation after 50 colonoscopies has shown no benefit, the authors wrote. Finding uses for simulators beyond diagnostics will be important for justifying buying more of them for medical centers given the high cost.
 

Procedural volume

Dr. Whitson and colleagues wrote that using sheer volume of procedures as a measure of competency is falling out of favor and there is recognition in the field that competency will come at different times and at different volumes for individual trainees.

A study assessing competency in esophagogastroduodenoscopy (EGD), for example, demonstrated that, while most trainees will achieve independent intubation rates of the second part of the duodenum by 150 procedures, it will take between 200 and 250 for the average fellow to reach competency of all motor skills for a standard EGD, and 300 to become efficient (Gastrointest Endosc. 2019;90(4):613-20).

Assessment of skills has evolved from numbers of procedures to competency-based assessments to the development of direct observation tools.
 

Coaching for the practicing endoscopist

Most studies on coaching have focused on trainees, but coaching can be used with experienced endoscopists as well.

One study investigated use of direct verbal coaching to train experienced practitioners in water immersion colonoscopy “which resulted in shorter cecal intubation times, improved [adenoma detection rate], and less use of sedation during procedures,” the authors noted. Another study currently underway in the United Kingdom uses electronic feedback coupled with education and training to change behaviors to improve polyp detection performance in colonoscopy.

The authors noted that using one of these tools or strategies does not preclude using another.

“[I]n fact educators likely will recognize the utility of incorporating multiple of these techniques in the same endoscopy session with a trainee,” the authors wrote.

One author holds stock in Boston Scientific. The remaining authors disclose no conflicts.

Endoscopic training is increasingly complex as benchmarks for quality evolve and tools and procedures advance with innovation.

A team of experts, led by Matthew J. Whitson, MD, with Hofstra University/Northwell Health in Hempstead, N.Y., aimed to simplify challenges for educators and clinical endoscopists with a review of tools and techniques for education, as well as assessment methods.

Their review was published in the Techniques and Innovations in Gastrointestinal Endoscopy.
 

Giving feedback

Key steps to effective feedback include first talking about the goals for the endoscopy session, then careful observation, but minimal feedback during the endoscopy. Most of the feedback should come after the endoscopy, the authors wrote.

A paper by Walsh et al. demonstrated that with beginning endoscopists, giving feedback afterward led to long-term skill development as compared with short-term benefits of frequent feedback in the middle of procedures.

Feedback should be constructive and specific with emphasis on goals for the next procedure. It should be delivered in a respectful, nonthreatening way for greatest effectiveness.
 

Mastery learning

In this model, each trainee must achieve competence in specific skills to progress to the next level.

“For example, the trainee must master retroflexion in the stomach prior to attempting clip hemostasis in the stomach,” the authors wrote.

Repetitively practicing the skill is coupled with direct feedback.

Mastery learning is often paired with simulation so trainees can practice in a safe space before working with patients.
 

Cognitive load theory

Knowing the challenges of learners can help educators with instruction techniques. An important concept is cognitive load theory (CLT). CLT is focused on the working memory of a learner and the harm that an overload of information can have on learning. A learner’s working memory can process only a few pieces of information at any given time, the theory states.

One mitigation strategy by educators may be to assign a trainee a smaller piece of a specific task appropriate to the trainee’s skill level.

“For example, an early trainee endoscopist may be able to inject epinephrine for a bleeding vessel, but not be ready to perform effective BiCap cautery,” the authors suggested.
 

Different learning styles

Learning styles include visual, aural, reading/writing, and kinesthetic styles (when learners need to touch or manipulate to learn a skill).

“A study of surgical trainees demonstrated that kinesthetic learning was the most preferred unimodal learning style of those entering the field,” the authors wrote.

Dr. Whitson and coauthors gave examples of working with trainees with different learning styles.

A trainee who learns visually, they say, might need to learn about “loop reduction” by looking at images of alpha or beta loops or using ScopeGuide during endoscopy. A kinesthetic learner may need to feel a successful loop reduction with hands on the endoscope during simulation to understand the skill better.

“There is some suggestion that the millennial generation – the demographic of the current gastroenterology fellows – may have higher preferences for kinesthetic learning,” the authors wrote.
 

Role of simulation

The Accreditation Council for Graduate Medical Education, which oversees Gastroenterology Fellowship training, mandates simulation in gastroenterology education but does not specify endoscopic simulation. The American Board of Surgeons, however, does require their trainees to complete the flexible endoscopic curriculum, which is simulation-based.

Simulator use appears particularly helpful early in training. One study demonstrated that colonoscopy simulation has benefit in the first 30 colonoscopies in depth of insertion, independent completion, and ability to identify landmarks.

However, another study showed simulation after 50 colonoscopies has shown no benefit, the authors wrote. Finding uses for simulators beyond diagnostics will be important for justifying buying more of them for medical centers given the high cost.
 

Procedural volume

Dr. Whitson and colleagues wrote that using sheer volume of procedures as a measure of competency is falling out of favor and there is recognition in the field that competency will come at different times and at different volumes for individual trainees.

A study assessing competency in esophagogastroduodenoscopy (EGD), for example, demonstrated that, while most trainees will achieve independent intubation rates of the second part of the duodenum by 150 procedures, it will take between 200 and 250 for the average fellow to reach competency of all motor skills for a standard EGD, and 300 to become efficient (Gastrointest Endosc. 2019;90(4):613-20).

Assessment of skills has evolved from numbers of procedures to competency-based assessments to the development of direct observation tools.
 

Coaching for the practicing endoscopist

Most studies on coaching have focused on trainees, but coaching can be used with experienced endoscopists as well.

One study investigated use of direct verbal coaching to train experienced practitioners in water immersion colonoscopy “which resulted in shorter cecal intubation times, improved [adenoma detection rate], and less use of sedation during procedures,” the authors noted. Another study currently underway in the United Kingdom uses electronic feedback coupled with education and training to change behaviors to improve polyp detection performance in colonoscopy.

The authors noted that using one of these tools or strategies does not preclude using another.

“[I]n fact educators likely will recognize the utility of incorporating multiple of these techniques in the same endoscopy session with a trainee,” the authors wrote.

One author holds stock in Boston Scientific. The remaining authors disclose no conflicts.

Endoscopic training is increasingly complex as benchmarks for quality evolve and tools and procedures advance with innovation.

A team of experts, led by Matthew J. Whitson, MD, with Hofstra University/Northwell Health in Hempstead, N.Y., aimed to simplify challenges for educators and clinical endoscopists with a review of tools and techniques for education, as well as assessment methods.

Their review was published in the Techniques and Innovations in Gastrointestinal Endoscopy.
 

Giving feedback

Key steps to effective feedback include first talking about the goals for the endoscopy session, then careful observation, but minimal feedback during the endoscopy. Most of the feedback should come after the endoscopy, the authors wrote.

A paper by Walsh et al. demonstrated that with beginning endoscopists, giving feedback afterward led to long-term skill development as compared with short-term benefits of frequent feedback in the middle of procedures.

Feedback should be constructive and specific with emphasis on goals for the next procedure. It should be delivered in a respectful, nonthreatening way for greatest effectiveness.
 

Mastery learning

In this model, each trainee must achieve competence in specific skills to progress to the next level.

“For example, the trainee must master retroflexion in the stomach prior to attempting clip hemostasis in the stomach,” the authors wrote.

Repetitively practicing the skill is coupled with direct feedback.

Mastery learning is often paired with simulation so trainees can practice in a safe space before working with patients.
 

Cognitive load theory

Knowing the challenges of learners can help educators with instruction techniques. An important concept is cognitive load theory (CLT). CLT is focused on the working memory of a learner and the harm that an overload of information can have on learning. A learner’s working memory can process only a few pieces of information at any given time, the theory states.

One mitigation strategy by educators may be to assign a trainee a smaller piece of a specific task appropriate to the trainee’s skill level.

“For example, an early trainee endoscopist may be able to inject epinephrine for a bleeding vessel, but not be ready to perform effective BiCap cautery,” the authors suggested.
 

Different learning styles

Learning styles include visual, aural, reading/writing, and kinesthetic styles (when learners need to touch or manipulate to learn a skill).

“A study of surgical trainees demonstrated that kinesthetic learning was the most preferred unimodal learning style of those entering the field,” the authors wrote.

Dr. Whitson and coauthors gave examples of working with trainees with different learning styles.

A trainee who learns visually, they say, might need to learn about “loop reduction” by looking at images of alpha or beta loops or using ScopeGuide during endoscopy. A kinesthetic learner may need to feel a successful loop reduction with hands on the endoscope during simulation to understand the skill better.

“There is some suggestion that the millennial generation – the demographic of the current gastroenterology fellows – may have higher preferences for kinesthetic learning,” the authors wrote.
 

Role of simulation

The Accreditation Council for Graduate Medical Education, which oversees Gastroenterology Fellowship training, mandates simulation in gastroenterology education but does not specify endoscopic simulation. The American Board of Surgeons, however, does require their trainees to complete the flexible endoscopic curriculum, which is simulation-based.

Simulator use appears particularly helpful early in training. One study demonstrated that colonoscopy simulation has benefit in the first 30 colonoscopies in depth of insertion, independent completion, and ability to identify landmarks.

However, another study showed simulation after 50 colonoscopies has shown no benefit, the authors wrote. Finding uses for simulators beyond diagnostics will be important for justifying buying more of them for medical centers given the high cost.
 

Procedural volume

Dr. Whitson and colleagues wrote that using sheer volume of procedures as a measure of competency is falling out of favor and there is recognition in the field that competency will come at different times and at different volumes for individual trainees.

A study assessing competency in esophagogastroduodenoscopy (EGD), for example, demonstrated that, while most trainees will achieve independent intubation rates of the second part of the duodenum by 150 procedures, it will take between 200 and 250 for the average fellow to reach competency of all motor skills for a standard EGD, and 300 to become efficient (Gastrointest Endosc. 2019;90(4):613-20).

Assessment of skills has evolved from numbers of procedures to competency-based assessments to the development of direct observation tools.
 

Coaching for the practicing endoscopist

Most studies on coaching have focused on trainees, but coaching can be used with experienced endoscopists as well.

One study investigated use of direct verbal coaching to train experienced practitioners in water immersion colonoscopy “which resulted in shorter cecal intubation times, improved [adenoma detection rate], and less use of sedation during procedures,” the authors noted. Another study currently underway in the United Kingdom uses electronic feedback coupled with education and training to change behaviors to improve polyp detection performance in colonoscopy.

The authors noted that using one of these tools or strategies does not preclude using another.

“[I]n fact educators likely will recognize the utility of incorporating multiple of these techniques in the same endoscopy session with a trainee,” the authors wrote.

One author holds stock in Boston Scientific. The remaining authors disclose no conflicts.