From the AGA Journals

Cryoballoon and cryospray ablation were equivalent for eradicating dysplastic Barrett’s esophagus, according to the findings of a single-center retrospective study of 71 ablation-naive patients.

At 18 months, rates of complete eradication of dysplasia were 95.6% in patients who received cryoballoon therapy and 96% in recipients of cryospray, reported Mohammed Alshelleh, MD, of Northwell Health System, a tertiary care system in New Hyde Park, N.Y. Rates of complete eradication of intestinal metaplasia were 84.75% and 80%, respectively. However, selection bias was likely, and a post hoc power calculation suggested that the cryospray group was underpowered by four patients. “Prospective studies are needed to confirm [these] data,” Dr. Alshelleh and associates wrote in Techniques and Innovations in Gastrointestinal Endoscopy.

Cryotherapy is common for treating dysplastic Barrett’s esophagus when patients do not achieve remission with radiofrequency ablation. For treatment-naive individuals, prospective studies suggest that cryotherapy may be less painful and as effective as radiofrequency ablation, but no studies have directly compared the two commercially available systems: a cryogenic balloon catheter (C2 Cryoballoon, Pentax Medical, Montvale, N.J.) that delivers cryogenic nitrous oxide (–85° C) into an inflated balloon in direct contact with the esophageal mucosa, and a spray cryotherapy system (truFreeze, Steris Endoscopy, Mentor, Ohio), which flash-freezes the mucosa to –196° C by delivering liquid nitrogen through a low-pressure catheter that is not directly in contact with the esophagus.

For the study, the investigators retrospectively compared rates of complete eradication of dysplasia, and complete eradication of intestinal metaplasia, among ablation-naive patients at their institution who had received one of these two cryogenic modalities between 2015 and 2019. All patients were treated at least twice, at 3-month intervals, and were followed for least 12 months, or until complete eradication of intestinal metaplasia was confirmed by at least one endoscopic biopsy. In all, 46 patients received cryoballoon therapy and 25 received cryospray. Outcomes between the two modalities showed no significant differences in subgroups stratified by baseline histology, nor were there significant differences in rates of postprocedural stricture (8.7% in the cryoballoon group vs. 12% in the cryospray group). However, the investigators acknowledged that the study was underpowered. Overall, clinicians tended to prefer cryoballoon because it uses prefilled nitrous oxide cartridges, making it unnecessary to fill up a large nitrogen tank or use a “cumbersome decompression tube,” the investigators wrote. “However, in patients with a very large hiatal hernia or if there was a need to treat in a retroflexed position, spray cryotherapy was used given its ease of use over cryoballoon in these scenarios. Finally, cryospray is more amenable to treat larger surface areas of Barrett’s versus the focal cryoballoon that treats focal areas, and thus was the cryotherapy choice for a long segment of Barrett’s.”

The investigators reported receiving no grant support. One investigator disclosed ties to Olympus America, Pentax Medical Research, and Ninepoint Medical.

SOURCE: Alshelleh M et al. Tech Innov Gastrointest Endosc. 2020 Jul 26. doi: 10.1016/j.tige.2020.07.004.

Cryoballoon and cryospray ablation were equivalent for eradicating dysplastic Barrett’s esophagus, according to the findings of a single-center retrospective study of 71 ablation-naive patients.

At 18 months, rates of complete eradication of dysplasia were 95.6% in patients who received cryoballoon therapy and 96% in recipients of cryospray, reported Mohammed Alshelleh, MD, of Northwell Health System, a tertiary care system in New Hyde Park, N.Y. Rates of complete eradication of intestinal metaplasia were 84.75% and 80%, respectively. However, selection bias was likely, and a post hoc power calculation suggested that the cryospray group was underpowered by four patients. “Prospective studies are needed to confirm [these] data,” Dr. Alshelleh and associates wrote in Techniques and Innovations in Gastrointestinal Endoscopy.

Cryotherapy is common for treating dysplastic Barrett’s esophagus when patients do not achieve remission with radiofrequency ablation. For treatment-naive individuals, prospective studies suggest that cryotherapy may be less painful and as effective as radiofrequency ablation, but no studies have directly compared the two commercially available systems: a cryogenic balloon catheter (C2 Cryoballoon, Pentax Medical, Montvale, N.J.) that delivers cryogenic nitrous oxide (–85° C) into an inflated balloon in direct contact with the esophageal mucosa, and a spray cryotherapy system (truFreeze, Steris Endoscopy, Mentor, Ohio), which flash-freezes the mucosa to –196° C by delivering liquid nitrogen through a low-pressure catheter that is not directly in contact with the esophagus.

For the study, the investigators retrospectively compared rates of complete eradication of dysplasia, and complete eradication of intestinal metaplasia, among ablation-naive patients at their institution who had received one of these two cryogenic modalities between 2015 and 2019. All patients were treated at least twice, at 3-month intervals, and were followed for least 12 months, or until complete eradication of intestinal metaplasia was confirmed by at least one endoscopic biopsy. In all, 46 patients received cryoballoon therapy and 25 received cryospray. Outcomes between the two modalities showed no significant differences in subgroups stratified by baseline histology, nor were there significant differences in rates of postprocedural stricture (8.7% in the cryoballoon group vs. 12% in the cryospray group). However, the investigators acknowledged that the study was underpowered. Overall, clinicians tended to prefer cryoballoon because it uses prefilled nitrous oxide cartridges, making it unnecessary to fill up a large nitrogen tank or use a “cumbersome decompression tube,” the investigators wrote. “However, in patients with a very large hiatal hernia or if there was a need to treat in a retroflexed position, spray cryotherapy was used given its ease of use over cryoballoon in these scenarios. Finally, cryospray is more amenable to treat larger surface areas of Barrett’s versus the focal cryoballoon that treats focal areas, and thus was the cryotherapy choice for a long segment of Barrett’s.”

The investigators reported receiving no grant support. One investigator disclosed ties to Olympus America, Pentax Medical Research, and Ninepoint Medical.

SOURCE: Alshelleh M et al. Tech Innov Gastrointest Endosc. 2020 Jul 26. doi: 10.1016/j.tige.2020.07.004.

Cryoballoon and cryospray ablation were equivalent for eradicating dysplastic Barrett’s esophagus, according to the findings of a single-center retrospective study of 71 ablation-naive patients.

At 18 months, rates of complete eradication of dysplasia were 95.6% in patients who received cryoballoon therapy and 96% in recipients of cryospray, reported Mohammed Alshelleh, MD, of Northwell Health System, a tertiary care system in New Hyde Park, N.Y. Rates of complete eradication of intestinal metaplasia were 84.75% and 80%, respectively. However, selection bias was likely, and a post hoc power calculation suggested that the cryospray group was underpowered by four patients. “Prospective studies are needed to confirm [these] data,” Dr. Alshelleh and associates wrote in Techniques and Innovations in Gastrointestinal Endoscopy.

Cryotherapy is common for treating dysplastic Barrett’s esophagus when patients do not achieve remission with radiofrequency ablation. For treatment-naive individuals, prospective studies suggest that cryotherapy may be less painful and as effective as radiofrequency ablation, but no studies have directly compared the two commercially available systems: a cryogenic balloon catheter (C2 Cryoballoon, Pentax Medical, Montvale, N.J.) that delivers cryogenic nitrous oxide (–85° C) into an inflated balloon in direct contact with the esophageal mucosa, and a spray cryotherapy system (truFreeze, Steris Endoscopy, Mentor, Ohio), which flash-freezes the mucosa to –196° C by delivering liquid nitrogen through a low-pressure catheter that is not directly in contact with the esophagus.

For the study, the investigators retrospectively compared rates of complete eradication of dysplasia, and complete eradication of intestinal metaplasia, among ablation-naive patients at their institution who had received one of these two cryogenic modalities between 2015 and 2019. All patients were treated at least twice, at 3-month intervals, and were followed for least 12 months, or until complete eradication of intestinal metaplasia was confirmed by at least one endoscopic biopsy. In all, 46 patients received cryoballoon therapy and 25 received cryospray. Outcomes between the two modalities showed no significant differences in subgroups stratified by baseline histology, nor were there significant differences in rates of postprocedural stricture (8.7% in the cryoballoon group vs. 12% in the cryospray group). However, the investigators acknowledged that the study was underpowered. Overall, clinicians tended to prefer cryoballoon because it uses prefilled nitrous oxide cartridges, making it unnecessary to fill up a large nitrogen tank or use a “cumbersome decompression tube,” the investigators wrote. “However, in patients with a very large hiatal hernia or if there was a need to treat in a retroflexed position, spray cryotherapy was used given its ease of use over cryoballoon in these scenarios. Finally, cryospray is more amenable to treat larger surface areas of Barrett’s versus the focal cryoballoon that treats focal areas, and thus was the cryotherapy choice for a long segment of Barrett’s.”

The investigators reported receiving no grant support. One investigator disclosed ties to Olympus America, Pentax Medical Research, and Ninepoint Medical.

SOURCE: Alshelleh M et al. Tech Innov Gastrointest Endosc. 2020 Jul 26. doi: 10.1016/j.tige.2020.07.004.

Together, Bifidobacterium dentium and its acetate metabolite regulate key parts of the serotonergic system and are associated with “a functional change in adult behavior,” according to a report published in Cellular and Molecular Gastroenterology and Hepatology.

Human gut microbiota had been known to regulate serotonin (5-hydroxytryptamine) production by gut cells, but underlying mechanisms had been unclear. This study showed that a common bacterial colonizer of the healthy adult gut stimulates serotonin (5-hydroxytryptamine, or 5-HT) release from enterochromaffin cells in both mice (in vivo) and humans (in vitro), wrote Melinda A. Engevik, PhD, of Baylor College of Medicine, Houston, and associates. “B. dentium modulates the serotonergic system in both the intestine and the brain [, which] likely influences behavior, and suggests that supplementation with a single, carefully selected, bacterial strain may be able to partially rescue behavioral deficits induced by shifts in the intestinal microbiota,” they added.

In a prior study, B. dentium modulated sensory neurons in rats with visceral hypersensitivity. In mammals, serotonin is primarily produced and released by enterochromaffin cells in the gut. To discover whether acetate – a short-chain fatty acid metabolite of B. dentium and some other microbiota – induces this pathway, the researchers first confirmed that B. dentium itself lacks the gene pathway for 5-HT production, and that growth media inoculated with B. dentium do not subsequently contain 5-HT. Next, they treated adult germ-free mice with either sterile media, live B. dentium, heat-killed B. dentium, or live Bacteroides ovatus (another commensal gut microbe). Gram staining and fluorescence in situ hybridization (FISH) confirmed that live B. dentium colonized mouse ileum and colon. Mass spectrometry, immunostaining, and quantitative PCR showed that mice treated with live B. dentium, but not B. ovatus, had greater intestinal concentrations of acetate, 5-HT, 5-HT receptors (2a and 4), serotonin transporter, and the gene that encodes free fatty acid receptor 2 (FFAR2), through which acetate signals. Furthermore, “[i]ncreases in 5-HT were observed in enteroendocrine cells directly above enteric neurons,” the researchers said.

They also performed RNA in situ hybridization of mouse brain tissue, which showed significantly increased expression of 5-HT-receptor 2a in the B. dentium–treated compared with germ-free controls. Mice were caged with specified numbers of marbles so the researchers could find out if these changes also modified behavior. Those with complete gut microbiota buried an average of 25% of the marbles, B. dentium­–monocolonized mice buried 15%, and germ-free mice buried fewer marbles. Hence, even short-term monocolonization by a bacterium that acts on the serotonergic system might help normalize behavior, even later in life, the researchers said. They noted that B. dentium–treated and germ-free mice performed similarly on both balance beam and footprint tests, suggesting that treatment with B. dentium does not affect motor coordination.

In humans, enterochromaffin cells released more 5-HT when exposed to B. dentium or acetate. Taken together, the findings “highlight the importance of Bifidobacterium species, and specifically B. dentium, in the adult microbiome-gut-brain axis,” the researchers wrote. Probiotic strains such as Lactobacillus and Bifidobacterium species are thought to improve health by means of signaling pathways, including the serotonergic system, they noted. “Our findings support the modulation of the serotonergic system by a model gut microbe, B. dentium, and provide a potential mechanism by which select microbes and their metabolites can promote endogenous, localized 5-HT biosynthesis. We speculate this may be an important bridging signal in the microbiome-gut-brain axis.”

The National Institutes of Health, BioGaia AB, and the RNA In Situ Hybridization Core facility supported the work. Two coinvestigators disclosed ties to BioGaia AB, Seed, Biomica, Plexus Worldwide, Tenza, Mikrovia, Probiotech, and Takeda. Dr. Engevik and the other investigators reported having no conflicts of interest.

SOURCE: Engevik MA et al. Cell Molec Gastro Hepatol. 2021;11:221-48. doi: 10.1016/j.jcmgh.2020.08.002.

Together, Bifidobacterium dentium and its acetate metabolite regulate key parts of the serotonergic system and are associated with “a functional change in adult behavior,” according to a report published in Cellular and Molecular Gastroenterology and Hepatology.

Human gut microbiota had been known to regulate serotonin (5-hydroxytryptamine) production by gut cells, but underlying mechanisms had been unclear. This study showed that a common bacterial colonizer of the healthy adult gut stimulates serotonin (5-hydroxytryptamine, or 5-HT) release from enterochromaffin cells in both mice (in vivo) and humans (in vitro), wrote Melinda A. Engevik, PhD, of Baylor College of Medicine, Houston, and associates. “B. dentium modulates the serotonergic system in both the intestine and the brain [, which] likely influences behavior, and suggests that supplementation with a single, carefully selected, bacterial strain may be able to partially rescue behavioral deficits induced by shifts in the intestinal microbiota,” they added.

In a prior study, B. dentium modulated sensory neurons in rats with visceral hypersensitivity. In mammals, serotonin is primarily produced and released by enterochromaffin cells in the gut. To discover whether acetate – a short-chain fatty acid metabolite of B. dentium and some other microbiota – induces this pathway, the researchers first confirmed that B. dentium itself lacks the gene pathway for 5-HT production, and that growth media inoculated with B. dentium do not subsequently contain 5-HT. Next, they treated adult germ-free mice with either sterile media, live B. dentium, heat-killed B. dentium, or live Bacteroides ovatus (another commensal gut microbe). Gram staining and fluorescence in situ hybridization (FISH) confirmed that live B. dentium colonized mouse ileum and colon. Mass spectrometry, immunostaining, and quantitative PCR showed that mice treated with live B. dentium, but not B. ovatus, had greater intestinal concentrations of acetate, 5-HT, 5-HT receptors (2a and 4), serotonin transporter, and the gene that encodes free fatty acid receptor 2 (FFAR2), through which acetate signals. Furthermore, “[i]ncreases in 5-HT were observed in enteroendocrine cells directly above enteric neurons,” the researchers said.

They also performed RNA in situ hybridization of mouse brain tissue, which showed significantly increased expression of 5-HT-receptor 2a in the B. dentium–treated compared with germ-free controls. Mice were caged with specified numbers of marbles so the researchers could find out if these changes also modified behavior. Those with complete gut microbiota buried an average of 25% of the marbles, B. dentium­–monocolonized mice buried 15%, and germ-free mice buried fewer marbles. Hence, even short-term monocolonization by a bacterium that acts on the serotonergic system might help normalize behavior, even later in life, the researchers said. They noted that B. dentium–treated and germ-free mice performed similarly on both balance beam and footprint tests, suggesting that treatment with B. dentium does not affect motor coordination.

In humans, enterochromaffin cells released more 5-HT when exposed to B. dentium or acetate. Taken together, the findings “highlight the importance of Bifidobacterium species, and specifically B. dentium, in the adult microbiome-gut-brain axis,” the researchers wrote. Probiotic strains such as Lactobacillus and Bifidobacterium species are thought to improve health by means of signaling pathways, including the serotonergic system, they noted. “Our findings support the modulation of the serotonergic system by a model gut microbe, B. dentium, and provide a potential mechanism by which select microbes and their metabolites can promote endogenous, localized 5-HT biosynthesis. We speculate this may be an important bridging signal in the microbiome-gut-brain axis.”

The National Institutes of Health, BioGaia AB, and the RNA In Situ Hybridization Core facility supported the work. Two coinvestigators disclosed ties to BioGaia AB, Seed, Biomica, Plexus Worldwide, Tenza, Mikrovia, Probiotech, and Takeda. Dr. Engevik and the other investigators reported having no conflicts of interest.

SOURCE: Engevik MA et al. Cell Molec Gastro Hepatol. 2021;11:221-48. doi: 10.1016/j.jcmgh.2020.08.002.

Together, Bifidobacterium dentium and its acetate metabolite regulate key parts of the serotonergic system and are associated with “a functional change in adult behavior,” according to a report published in Cellular and Molecular Gastroenterology and Hepatology.

Human gut microbiota had been known to regulate serotonin (5-hydroxytryptamine) production by gut cells, but underlying mechanisms had been unclear. This study showed that a common bacterial colonizer of the healthy adult gut stimulates serotonin (5-hydroxytryptamine, or 5-HT) release from enterochromaffin cells in both mice (in vivo) and humans (in vitro), wrote Melinda A. Engevik, PhD, of Baylor College of Medicine, Houston, and associates. “B. dentium modulates the serotonergic system in both the intestine and the brain [, which] likely influences behavior, and suggests that supplementation with a single, carefully selected, bacterial strain may be able to partially rescue behavioral deficits induced by shifts in the intestinal microbiota,” they added.

In a prior study, B. dentium modulated sensory neurons in rats with visceral hypersensitivity. In mammals, serotonin is primarily produced and released by enterochromaffin cells in the gut. To discover whether acetate – a short-chain fatty acid metabolite of B. dentium and some other microbiota – induces this pathway, the researchers first confirmed that B. dentium itself lacks the gene pathway for 5-HT production, and that growth media inoculated with B. dentium do not subsequently contain 5-HT. Next, they treated adult germ-free mice with either sterile media, live B. dentium, heat-killed B. dentium, or live Bacteroides ovatus (another commensal gut microbe). Gram staining and fluorescence in situ hybridization (FISH) confirmed that live B. dentium colonized mouse ileum and colon. Mass spectrometry, immunostaining, and quantitative PCR showed that mice treated with live B. dentium, but not B. ovatus, had greater intestinal concentrations of acetate, 5-HT, 5-HT receptors (2a and 4), serotonin transporter, and the gene that encodes free fatty acid receptor 2 (FFAR2), through which acetate signals. Furthermore, “[i]ncreases in 5-HT were observed in enteroendocrine cells directly above enteric neurons,” the researchers said.

They also performed RNA in situ hybridization of mouse brain tissue, which showed significantly increased expression of 5-HT-receptor 2a in the B. dentium–treated compared with germ-free controls. Mice were caged with specified numbers of marbles so the researchers could find out if these changes also modified behavior. Those with complete gut microbiota buried an average of 25% of the marbles, B. dentium­–monocolonized mice buried 15%, and germ-free mice buried fewer marbles. Hence, even short-term monocolonization by a bacterium that acts on the serotonergic system might help normalize behavior, even later in life, the researchers said. They noted that B. dentium–treated and germ-free mice performed similarly on both balance beam and footprint tests, suggesting that treatment with B. dentium does not affect motor coordination.

In humans, enterochromaffin cells released more 5-HT when exposed to B. dentium or acetate. Taken together, the findings “highlight the importance of Bifidobacterium species, and specifically B. dentium, in the adult microbiome-gut-brain axis,” the researchers wrote. Probiotic strains such as Lactobacillus and Bifidobacterium species are thought to improve health by means of signaling pathways, including the serotonergic system, they noted. “Our findings support the modulation of the serotonergic system by a model gut microbe, B. dentium, and provide a potential mechanism by which select microbes and their metabolites can promote endogenous, localized 5-HT biosynthesis. We speculate this may be an important bridging signal in the microbiome-gut-brain axis.”

The National Institutes of Health, BioGaia AB, and the RNA In Situ Hybridization Core facility supported the work. Two coinvestigators disclosed ties to BioGaia AB, Seed, Biomica, Plexus Worldwide, Tenza, Mikrovia, Probiotech, and Takeda. Dr. Engevik and the other investigators reported having no conflicts of interest.

SOURCE: Engevik MA et al. Cell Molec Gastro Hepatol. 2021;11:221-48. doi: 10.1016/j.jcmgh.2020.08.002.

The American Gastroenterological Association has published new guidance for the diagnosis and management of seronegative enteropathies.

Seronegative enteropathies are commonly encountered by gastroenterologists, but accurate diagnosis can be complicated by a wide array of etiologies, misinterpreted histologic findings, suboptimal serology testing, and use of immunosuppressive agents that mask serology findings, reported lead author Maureen M. Leonard, MD, of MassGeneral Hospital for Children in Boston, and colleagues.

“Previous work detailing the prevalence of seronegative celiac disease [CeD], diagnosis of seronegative villous atrophy, and management recommendations for seronegative villous atrophy are available,” the investigators wrote in Gastroenterology. “However, there is limited evidence to guide clinicians regarding the minimal serologic tests necessary, the role of the gluten-free diet in diagnosis and management, and the role of an expert pathologist in evaluating the diagnosis of seronegative enteropathy.”

Patients with seronegative enteropathy tend to a have a poorer prognosis than those with classic CeD and other causes of villous atrophy, the investigators noted, but with an accurate diagnosis, distinct therapies can be highly effective.

After a comprehensive literature review, Dr. Leonard and colleagues reached consensus on eight best practice advice statements.

First, the investigators advised clinicians to review histologic findings with an experienced pathologist specializing in gastroenterology, as an expert can ensure proper duodenal orientation, and possibly link a specific finding with an etiology, such as granulomas with Crohn’s disease, or decreased goblet cells with autoimmune enteropathy. Communications with pathologists should also incorporate medical, travel, and medication history.

“Clinicians should pay particular attention to obtaining a thorough medication history to determine whether a patient is taking an angiotensin II receptor antagonist, such as olmesartan, which has been described as causing enteropathy,” the investigators wrote. “In some cases, this has led patients to be incorrectly diagnosis with refractory CeD. Other medications, including azathioprine and mycophenolate mofetil, among others, also have been reported to cause enteropathy, which resolves with discontinuation of medication.”

According to Dr. Leonard and colleagues, histologic findings suggestive of Crohn’s disease should prompt HLA testing, which requires careful attention to detail.

“It is prudent that the gastroenterologist or CeD specialist review all alleles tested and reported (or obtain the alleles if not reported) by the laboratory because commercial and academic laboratories might not report all possible alleles associated with CeD,” they wrote.

If HLA testing is positive, then the patient should begin empiric treatment with a gluten-free diet, followed by clinical and endoscopic reassessment after 1-3 years.

If HLA testing is negative, then a battery of tests may be needed to detect alternative etiologies, such as giardiasis, small intestinal bacterial overgrowth, HIV, and others.

“In cases where an underlying cause was identified, a follow-up esophagogastroduodenoscopy with biopsy might not be indicated, according to the etiology identified, treatment, and clinical status,” the investigators wrote.

Even with a comprehensive work-up, clinicians may be unable to identify an etiology. This outcome may be relatively common, the investigators suggested, citing a study of 200 cases of seronegative villous atrophy, of which 18% had no identifiable etiology. Yet finding an etiology may ultimately be unnecessary, as 72% of idiopathic cases resolved without intervention within 9 months, suggesting transient villous atrophy.

Still, intervention is needed for clinically unstable patients with idiopathic seronegative villous atrophy. Dr. Leonard and colleagues recommended first-line treatment with budesonide, starting at 9 mg daily. Depending on clinical status and response, subsequent therapies may include azathioprine or prednisone.

The clinical practice update was commissioned and approved by the AGA. The investigators disclosed additional relationships with Takeda Pharmaceuticals, HealthMode, Anokion, and others.

SOURCE: Leonard MM et al. Gastroenterology. 2020 Sep 30. doi: 10.1053/j.gastro.2020.08.061.

The American Gastroenterological Association has published new guidance for the diagnosis and management of seronegative enteropathies.

Seronegative enteropathies are commonly encountered by gastroenterologists, but accurate diagnosis can be complicated by a wide array of etiologies, misinterpreted histologic findings, suboptimal serology testing, and use of immunosuppressive agents that mask serology findings, reported lead author Maureen M. Leonard, MD, of MassGeneral Hospital for Children in Boston, and colleagues.

“Previous work detailing the prevalence of seronegative celiac disease [CeD], diagnosis of seronegative villous atrophy, and management recommendations for seronegative villous atrophy are available,” the investigators wrote in Gastroenterology. “However, there is limited evidence to guide clinicians regarding the minimal serologic tests necessary, the role of the gluten-free diet in diagnosis and management, and the role of an expert pathologist in evaluating the diagnosis of seronegative enteropathy.”

Patients with seronegative enteropathy tend to a have a poorer prognosis than those with classic CeD and other causes of villous atrophy, the investigators noted, but with an accurate diagnosis, distinct therapies can be highly effective.

After a comprehensive literature review, Dr. Leonard and colleagues reached consensus on eight best practice advice statements.

First, the investigators advised clinicians to review histologic findings with an experienced pathologist specializing in gastroenterology, as an expert can ensure proper duodenal orientation, and possibly link a specific finding with an etiology, such as granulomas with Crohn’s disease, or decreased goblet cells with autoimmune enteropathy. Communications with pathologists should also incorporate medical, travel, and medication history.

“Clinicians should pay particular attention to obtaining a thorough medication history to determine whether a patient is taking an angiotensin II receptor antagonist, such as olmesartan, which has been described as causing enteropathy,” the investigators wrote. “In some cases, this has led patients to be incorrectly diagnosis with refractory CeD. Other medications, including azathioprine and mycophenolate mofetil, among others, also have been reported to cause enteropathy, which resolves with discontinuation of medication.”

According to Dr. Leonard and colleagues, histologic findings suggestive of Crohn’s disease should prompt HLA testing, which requires careful attention to detail.

“It is prudent that the gastroenterologist or CeD specialist review all alleles tested and reported (or obtain the alleles if not reported) by the laboratory because commercial and academic laboratories might not report all possible alleles associated with CeD,” they wrote.

If HLA testing is positive, then the patient should begin empiric treatment with a gluten-free diet, followed by clinical and endoscopic reassessment after 1-3 years.

If HLA testing is negative, then a battery of tests may be needed to detect alternative etiologies, such as giardiasis, small intestinal bacterial overgrowth, HIV, and others.

“In cases where an underlying cause was identified, a follow-up esophagogastroduodenoscopy with biopsy might not be indicated, according to the etiology identified, treatment, and clinical status,” the investigators wrote.

Even with a comprehensive work-up, clinicians may be unable to identify an etiology. This outcome may be relatively common, the investigators suggested, citing a study of 200 cases of seronegative villous atrophy, of which 18% had no identifiable etiology. Yet finding an etiology may ultimately be unnecessary, as 72% of idiopathic cases resolved without intervention within 9 months, suggesting transient villous atrophy.

Still, intervention is needed for clinically unstable patients with idiopathic seronegative villous atrophy. Dr. Leonard and colleagues recommended first-line treatment with budesonide, starting at 9 mg daily. Depending on clinical status and response, subsequent therapies may include azathioprine or prednisone.

The clinical practice update was commissioned and approved by the AGA. The investigators disclosed additional relationships with Takeda Pharmaceuticals, HealthMode, Anokion, and others.

SOURCE: Leonard MM et al. Gastroenterology. 2020 Sep 30. doi: 10.1053/j.gastro.2020.08.061.

The American Gastroenterological Association has published new guidance for the diagnosis and management of seronegative enteropathies.

Seronegative enteropathies are commonly encountered by gastroenterologists, but accurate diagnosis can be complicated by a wide array of etiologies, misinterpreted histologic findings, suboptimal serology testing, and use of immunosuppressive agents that mask serology findings, reported lead author Maureen M. Leonard, MD, of MassGeneral Hospital for Children in Boston, and colleagues.

“Previous work detailing the prevalence of seronegative celiac disease [CeD], diagnosis of seronegative villous atrophy, and management recommendations for seronegative villous atrophy are available,” the investigators wrote in Gastroenterology. “However, there is limited evidence to guide clinicians regarding the minimal serologic tests necessary, the role of the gluten-free diet in diagnosis and management, and the role of an expert pathologist in evaluating the diagnosis of seronegative enteropathy.”

Patients with seronegative enteropathy tend to a have a poorer prognosis than those with classic CeD and other causes of villous atrophy, the investigators noted, but with an accurate diagnosis, distinct therapies can be highly effective.

After a comprehensive literature review, Dr. Leonard and colleagues reached consensus on eight best practice advice statements.

First, the investigators advised clinicians to review histologic findings with an experienced pathologist specializing in gastroenterology, as an expert can ensure proper duodenal orientation, and possibly link a specific finding with an etiology, such as granulomas with Crohn’s disease, or decreased goblet cells with autoimmune enteropathy. Communications with pathologists should also incorporate medical, travel, and medication history.

“Clinicians should pay particular attention to obtaining a thorough medication history to determine whether a patient is taking an angiotensin II receptor antagonist, such as olmesartan, which has been described as causing enteropathy,” the investigators wrote. “In some cases, this has led patients to be incorrectly diagnosis with refractory CeD. Other medications, including azathioprine and mycophenolate mofetil, among others, also have been reported to cause enteropathy, which resolves with discontinuation of medication.”

According to Dr. Leonard and colleagues, histologic findings suggestive of Crohn’s disease should prompt HLA testing, which requires careful attention to detail.

“It is prudent that the gastroenterologist or CeD specialist review all alleles tested and reported (or obtain the alleles if not reported) by the laboratory because commercial and academic laboratories might not report all possible alleles associated with CeD,” they wrote.

If HLA testing is positive, then the patient should begin empiric treatment with a gluten-free diet, followed by clinical and endoscopic reassessment after 1-3 years.

If HLA testing is negative, then a battery of tests may be needed to detect alternative etiologies, such as giardiasis, small intestinal bacterial overgrowth, HIV, and others.

“In cases where an underlying cause was identified, a follow-up esophagogastroduodenoscopy with biopsy might not be indicated, according to the etiology identified, treatment, and clinical status,” the investigators wrote.

Even with a comprehensive work-up, clinicians may be unable to identify an etiology. This outcome may be relatively common, the investigators suggested, citing a study of 200 cases of seronegative villous atrophy, of which 18% had no identifiable etiology. Yet finding an etiology may ultimately be unnecessary, as 72% of idiopathic cases resolved without intervention within 9 months, suggesting transient villous atrophy.

Still, intervention is needed for clinically unstable patients with idiopathic seronegative villous atrophy. Dr. Leonard and colleagues recommended first-line treatment with budesonide, starting at 9 mg daily. Depending on clinical status and response, subsequent therapies may include azathioprine or prednisone.

The clinical practice update was commissioned and approved by the AGA. The investigators disclosed additional relationships with Takeda Pharmaceuticals, HealthMode, Anokion, and others.

SOURCE: Leonard MM et al. Gastroenterology. 2020 Sep 30. doi: 10.1053/j.gastro.2020.08.061.

Despite the surgery-sparing potential demonstrated by interventional endoscopic ultrasound (I-EUS), widespread clinical adoption will require more prospective trials, formalized training programs for endoscopists, and greater support from key stakeholders, according to an AGA white paper.

The publication, which was conceived during a session at the 2019 AGA Tech Summit, addresses the current status and future directions of I-EUS, included EUS-guided access, EUS-guided tumor ablation, and endohepatology.

“We hope this white paper guides those interested in adoption of these technologies into clinical practice and serves as a foundation for future research and innovation in the field,” the investigators wrote in Clinical Gastroenterology and Hepatology.

According to senior author senior author Joo Ha Hwang, MD, PhD, of Stanford (Calif.) University, and colleagues, some of the described techniques are not new, but they have yet to be fully realized.

“Some of these techniques initially were reported more than a decade ago,” the investigators wrote, “however, with further device development and refinement in technique there is potential for expanding the application of these techniques and new technologies to a broader group of interventional gastroenterologists.”

For each I-EUS modality, Dr. Hwang and colleagues reviewed available evidence, and if group consensus was reached, offered practical recommendations.
 

EUS-guided access

“There has been exponential growth in EUS-guided biliary (including gallbladder) access and drainage procedures, as well as entero-enteric anastomotic procedures in recent years,” the investigators wrote. “This change can be attributed to the availability of lumen-apposing metal stents (LAMS).”

Previous studies have reported promising success rates with LAMS across a variety of EUS-guided procedures, including biliary drainage (equal to or greater than 85%), gallbladder drainage (90%-98%), and gastrojejunostomy (greater than 90%).

Success with other techniques, however, has been mixed.

While LAMS “have gained popularity in the management of pseudocysts and walled-off necrotic collections,” data regarding superiority over plastic stents have been conflicting, and LAMS may increase risk of bleeding in necrotic cavities, wrote Dr. Hwang and colleagues.

“Placement of coaxial plastic stents through the lumen of LAMS has been advocated to try to minimize the risk of complications related to LAMS,” they added.

According to the white paper, EUS-guided pancreatic interventions remain most challenging; both pancreaticogastrostomy and EUS-guided pancreatic rendezvous are associated with technical failure rates up to 40%, and adverse event rates may be as high as 35%.

“Unlike other EUS-guided drainage and access procedures, there has been limited improvement in technology to make EUS-guided pancreatic access easier or safer,” the investigators noted.

Dr. Hwang and colleagues concluded this discussion of LAMS by calling for randomized prospective trials. They also noted the expense of LAMS, which may cost $4,000-$6,000.
 

EUS-guided tumor ablation

“Because of the close proximity of the gastrointestinal tract to organs such as the esophagus, liver, and pancreas, EUS would appear to be an ideal tool to provide imaging and potentially ablation of benign and malignant lesions in these locations,” wrote Dr. Hwang and colleagues.

But several challenges may stand in the way, they noted, including insufficient endoscope length and working channel caliber, “the tortuosity of the gastrointestinal lumen” and its location relative to some parts of the liver and pancreas, prohibitive tumor characteristics, and cost. In addition, concerns remain for collateral damage to surrounding organs.

“Further studies evaluating the safety and treatment response to ablation of solid neoplasms is required,” the investigators wrote, noting that this may require further development of noninvasive methods to monitor treated lesions.
 

EUS-guided liver applications

According to Dr. Hwang and colleagues, a growing body of evidence supports EUS-guided liver biopsy, including a high rate of histologic diagnoses (93.9%), Doppler-based detection of blood flow within the needle track prior to needle removal, ability to perform several needle actuations through a single puncture in the liver capsule, rapid patient recovery, ability to sample both liver lobes, potential for simultaneous endoscopy, and lower overall cost (accounting for complications, recovery time, and nondiagnostic yield).

And biopsies may be the first of many EUS-guided liver procedures to come, the investigators suggested.

“[EUS-guided liver biopsy] likely will be followed by EUS-guided portal pressure gradient measurement and EUS-guided shear wave elastography,” the investigators wrote. “There now is potential for a one-stop-shop diagnosis and staging of liver disease.”

Still, work is needed to facilitate greater clinical adoption of interventional EUS.

“[W]idespread implementation of interventional EUS is likely to require support from gastrointestinal societies and buy-in from other key stakeholders including payors,” wrote Dr. Hwang and colleagues. “Continued work by the gastrointestinal societies and manufacturers in providing training programs, and creating instruments, environments, and policies that motivate endoscopists to adopt new practices, is essential for growing the field of interventional EUS.”

The white paper was resulted from a session focused on interventional EUS a the 2019 ASGA Tech Summit, organized by the AGA Center for GI Innovation and Technology. The investigators disclosed additional relationships with Boston Scientific Corporation, Vyaire Medical, Cook Medical, and others.

SOURCE: DeWitt JM et al. Clin Gastroenterol Hepatol. 2020 Sep 17. doi: 10.1016/j.cgh.2020.09.029.

This story was updated on 12/4/2020.

Despite the surgery-sparing potential demonstrated by interventional endoscopic ultrasound (I-EUS), widespread clinical adoption will require more prospective trials, formalized training programs for endoscopists, and greater support from key stakeholders, according to an AGA white paper.

The publication, which was conceived during a session at the 2019 AGA Tech Summit, addresses the current status and future directions of I-EUS, included EUS-guided access, EUS-guided tumor ablation, and endohepatology.

“We hope this white paper guides those interested in adoption of these technologies into clinical practice and serves as a foundation for future research and innovation in the field,” the investigators wrote in Clinical Gastroenterology and Hepatology.

According to senior author senior author Joo Ha Hwang, MD, PhD, of Stanford (Calif.) University, and colleagues, some of the described techniques are not new, but they have yet to be fully realized.

“Some of these techniques initially were reported more than a decade ago,” the investigators wrote, “however, with further device development and refinement in technique there is potential for expanding the application of these techniques and new technologies to a broader group of interventional gastroenterologists.”

For each I-EUS modality, Dr. Hwang and colleagues reviewed available evidence, and if group consensus was reached, offered practical recommendations.
 

EUS-guided access

“There has been exponential growth in EUS-guided biliary (including gallbladder) access and drainage procedures, as well as entero-enteric anastomotic procedures in recent years,” the investigators wrote. “This change can be attributed to the availability of lumen-apposing metal stents (LAMS).”

Previous studies have reported promising success rates with LAMS across a variety of EUS-guided procedures, including biliary drainage (equal to or greater than 85%), gallbladder drainage (90%-98%), and gastrojejunostomy (greater than 90%).

Success with other techniques, however, has been mixed.

While LAMS “have gained popularity in the management of pseudocysts and walled-off necrotic collections,” data regarding superiority over plastic stents have been conflicting, and LAMS may increase risk of bleeding in necrotic cavities, wrote Dr. Hwang and colleagues.

“Placement of coaxial plastic stents through the lumen of LAMS has been advocated to try to minimize the risk of complications related to LAMS,” they added.

According to the white paper, EUS-guided pancreatic interventions remain most challenging; both pancreaticogastrostomy and EUS-guided pancreatic rendezvous are associated with technical failure rates up to 40%, and adverse event rates may be as high as 35%.

“Unlike other EUS-guided drainage and access procedures, there has been limited improvement in technology to make EUS-guided pancreatic access easier or safer,” the investigators noted.

Dr. Hwang and colleagues concluded this discussion of LAMS by calling for randomized prospective trials. They also noted the expense of LAMS, which may cost $4,000-$6,000.
 

EUS-guided tumor ablation

“Because of the close proximity of the gastrointestinal tract to organs such as the esophagus, liver, and pancreas, EUS would appear to be an ideal tool to provide imaging and potentially ablation of benign and malignant lesions in these locations,” wrote Dr. Hwang and colleagues.

But several challenges may stand in the way, they noted, including insufficient endoscope length and working channel caliber, “the tortuosity of the gastrointestinal lumen” and its location relative to some parts of the liver and pancreas, prohibitive tumor characteristics, and cost. In addition, concerns remain for collateral damage to surrounding organs.

“Further studies evaluating the safety and treatment response to ablation of solid neoplasms is required,” the investigators wrote, noting that this may require further development of noninvasive methods to monitor treated lesions.
 

EUS-guided liver applications

According to Dr. Hwang and colleagues, a growing body of evidence supports EUS-guided liver biopsy, including a high rate of histologic diagnoses (93.9%), Doppler-based detection of blood flow within the needle track prior to needle removal, ability to perform several needle actuations through a single puncture in the liver capsule, rapid patient recovery, ability to sample both liver lobes, potential for simultaneous endoscopy, and lower overall cost (accounting for complications, recovery time, and nondiagnostic yield).

And biopsies may be the first of many EUS-guided liver procedures to come, the investigators suggested.

“[EUS-guided liver biopsy] likely will be followed by EUS-guided portal pressure gradient measurement and EUS-guided shear wave elastography,” the investigators wrote. “There now is potential for a one-stop-shop diagnosis and staging of liver disease.”

Still, work is needed to facilitate greater clinical adoption of interventional EUS.

“[W]idespread implementation of interventional EUS is likely to require support from gastrointestinal societies and buy-in from other key stakeholders including payors,” wrote Dr. Hwang and colleagues. “Continued work by the gastrointestinal societies and manufacturers in providing training programs, and creating instruments, environments, and policies that motivate endoscopists to adopt new practices, is essential for growing the field of interventional EUS.”

The white paper was resulted from a session focused on interventional EUS a the 2019 ASGA Tech Summit, organized by the AGA Center for GI Innovation and Technology. The investigators disclosed additional relationships with Boston Scientific Corporation, Vyaire Medical, Cook Medical, and others.

SOURCE: DeWitt JM et al. Clin Gastroenterol Hepatol. 2020 Sep 17. doi: 10.1016/j.cgh.2020.09.029.

This story was updated on 12/4/2020.

Despite the surgery-sparing potential demonstrated by interventional endoscopic ultrasound (I-EUS), widespread clinical adoption will require more prospective trials, formalized training programs for endoscopists, and greater support from key stakeholders, according to an AGA white paper.

The publication, which was conceived during a session at the 2019 AGA Tech Summit, addresses the current status and future directions of I-EUS, included EUS-guided access, EUS-guided tumor ablation, and endohepatology.

“We hope this white paper guides those interested in adoption of these technologies into clinical practice and serves as a foundation for future research and innovation in the field,” the investigators wrote in Clinical Gastroenterology and Hepatology.

According to senior author senior author Joo Ha Hwang, MD, PhD, of Stanford (Calif.) University, and colleagues, some of the described techniques are not new, but they have yet to be fully realized.

“Some of these techniques initially were reported more than a decade ago,” the investigators wrote, “however, with further device development and refinement in technique there is potential for expanding the application of these techniques and new technologies to a broader group of interventional gastroenterologists.”

For each I-EUS modality, Dr. Hwang and colleagues reviewed available evidence, and if group consensus was reached, offered practical recommendations.
 

EUS-guided access

“There has been exponential growth in EUS-guided biliary (including gallbladder) access and drainage procedures, as well as entero-enteric anastomotic procedures in recent years,” the investigators wrote. “This change can be attributed to the availability of lumen-apposing metal stents (LAMS).”

Previous studies have reported promising success rates with LAMS across a variety of EUS-guided procedures, including biliary drainage (equal to or greater than 85%), gallbladder drainage (90%-98%), and gastrojejunostomy (greater than 90%).

Success with other techniques, however, has been mixed.

While LAMS “have gained popularity in the management of pseudocysts and walled-off necrotic collections,” data regarding superiority over plastic stents have been conflicting, and LAMS may increase risk of bleeding in necrotic cavities, wrote Dr. Hwang and colleagues.

“Placement of coaxial plastic stents through the lumen of LAMS has been advocated to try to minimize the risk of complications related to LAMS,” they added.

According to the white paper, EUS-guided pancreatic interventions remain most challenging; both pancreaticogastrostomy and EUS-guided pancreatic rendezvous are associated with technical failure rates up to 40%, and adverse event rates may be as high as 35%.

“Unlike other EUS-guided drainage and access procedures, there has been limited improvement in technology to make EUS-guided pancreatic access easier or safer,” the investigators noted.

Dr. Hwang and colleagues concluded this discussion of LAMS by calling for randomized prospective trials. They also noted the expense of LAMS, which may cost $4,000-$6,000.
 

EUS-guided tumor ablation

“Because of the close proximity of the gastrointestinal tract to organs such as the esophagus, liver, and pancreas, EUS would appear to be an ideal tool to provide imaging and potentially ablation of benign and malignant lesions in these locations,” wrote Dr. Hwang and colleagues.

But several challenges may stand in the way, they noted, including insufficient endoscope length and working channel caliber, “the tortuosity of the gastrointestinal lumen” and its location relative to some parts of the liver and pancreas, prohibitive tumor characteristics, and cost. In addition, concerns remain for collateral damage to surrounding organs.

“Further studies evaluating the safety and treatment response to ablation of solid neoplasms is required,” the investigators wrote, noting that this may require further development of noninvasive methods to monitor treated lesions.
 

EUS-guided liver applications

According to Dr. Hwang and colleagues, a growing body of evidence supports EUS-guided liver biopsy, including a high rate of histologic diagnoses (93.9%), Doppler-based detection of blood flow within the needle track prior to needle removal, ability to perform several needle actuations through a single puncture in the liver capsule, rapid patient recovery, ability to sample both liver lobes, potential for simultaneous endoscopy, and lower overall cost (accounting for complications, recovery time, and nondiagnostic yield).

And biopsies may be the first of many EUS-guided liver procedures to come, the investigators suggested.

“[EUS-guided liver biopsy] likely will be followed by EUS-guided portal pressure gradient measurement and EUS-guided shear wave elastography,” the investigators wrote. “There now is potential for a one-stop-shop diagnosis and staging of liver disease.”

Still, work is needed to facilitate greater clinical adoption of interventional EUS.

“[W]idespread implementation of interventional EUS is likely to require support from gastrointestinal societies and buy-in from other key stakeholders including payors,” wrote Dr. Hwang and colleagues. “Continued work by the gastrointestinal societies and manufacturers in providing training programs, and creating instruments, environments, and policies that motivate endoscopists to adopt new practices, is essential for growing the field of interventional EUS.”

The white paper was resulted from a session focused on interventional EUS a the 2019 ASGA Tech Summit, organized by the AGA Center for GI Innovation and Technology. The investigators disclosed additional relationships with Boston Scientific Corporation, Vyaire Medical, Cook Medical, and others.

SOURCE: DeWitt JM et al. Clin Gastroenterol Hepatol. 2020 Sep 17. doi: 10.1016/j.cgh.2020.09.029.

This story was updated on 12/4/2020.

Inflammatory bowel disease (IBD) is rapidly increasing among racial and ethnic minorities, which makes it important to consider for patients with compatible symptoms, experts wrote in Gastroenterology.

Crohn’s disease and ulcerative colitis are “chronic diseases with intermittent periods of flare and remission, so access to specialists, appropriate therapies, and frequent follow-up visits are vital to good outcomes,” wrote Edward L. Barnes, MD, MPH, of University of North Carolina at Chapel Hill, with his associates. However, Blacks with IBD tend to be diagnosed later than Whites, are less likely to receive recommended biologics and immunomodulators, and are more likely to receive care at an emergency department, to experience delays in colectomy, and to miss regular visits to IBD specialists because of financial and transportation barriers, they added.

These disparities are known to worsen outcomes. Compared with Whites, for example, Black patients with Crohn’s disease have higher rates of stricture and penetrating lesions and are at greater risk for postsurgical complications and death, even after potential confounders such age, sex, smoking status, time to operation, and obesity are controlled for. To help close these gaps, Dr. Barnes and his associates recommended enhanced recovery after surgery (ERAS) protocols, which “streamline [the] multidisciplinary management of patients with IBD before surgery, incorporating evidence-based practices focused on nutrition, prevention of postoperative ileus, and use of nonopioid analgesia and goal-directed fluid therapy.”

Similar approaches also might improve nonsurgical outcomes in minorities with IBD, the experts said. In the Sinai-Helmsley Alliance for Research Excellence (SHARE) study, Black patients had more complicated IBD at baseline but similar clinical outcomes and patterns of medication use as Whites when they were treated at academic IBD centers. In other studies, race and ethnicity did not affect patterns of medication use, surgery, or surgical outcomes if patients had similar access to care. Such findings “indicate that when patients of minority races and ethnicities have access to appropriate specialty care and IBD-related therapy, many previously identified disparities are resolved or reduced,” the experts said.

However, race and ethnicity do affect some aspects of IBD disease activity, genetics, and treatment safety and efficacy. Since White patients have made up the vast majority of research participants, studies of racial and ethnic minorities are needed to improve their IBD diagnosis, prevention, and treatment. Such research is particularly vital because IBD incidence is rising three times faster rates in racial and ethnic minorities than Whites, said Aline Charabaty, MD, AGAF, clinical director of the gastroenterology division at Johns Hopkins University in Baltimore, and director of the IBD Center at Sibley Memorial Hospital in Washington.

She explained that, when immigrants from countries where IBD is rare adopt the United States’ sedentary lifestyle and Western diet (low in fruits and vegetables; high in proinflammatory saturated fats, sugars, and processed foods), their gut microbiome shifts and their IBD risk increases markedly. Studies in other countries have produced similar findings, said Dr. Charabaty, who did not help author the review article.

She also noted that patients from communities with a historically low prevalence of IBD may not understand its chronicity or the need for long-term treatment. However, treatment adherence is a common issue for patients of all backgrounds with IBD, she said. “What is unique is barriers to continuity of care – not being able to get to the treatment center, not being able to afford treatment or take time off work if you live paycheck to paycheck, not being able to pay someone to care for your kids while you see the doctor.”

Other potential barriers to seeking IBD treatment include cultural taboos against discussing lower GI symptoms or concerns that chronic disease will harm marriage prospects, Dr. Charabaty said. Such challenges only heighten the need to ascertain IBD symptoms: “Studies show that minorities have less follow-up care and their symptoms tend to be minimized. There is a lot of unconscious bias among providers that factors into this. The barriers are multiple, and it is important to define them and find strategies to overcome them at the level of the patient, the clinician, and the health system.”

The Crohn’s and Colitis Foundation supported the work. Dr. Barnes disclosed ties to AbbVie, Gilead, Takeda, and Target Pharmasolutions. Two coauthors also disclosed relevant ties to pharmaceutical companies. Dr. Charabaty disclosed relationships with AbbVie, Takeda, Pfizer, Janssen, and UCB.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

SOURCE: Barnes EL et al. Gastroenterology. 2020 Oct 20. doi: 10.1053/j.gastro.2020.08.064.
 

Inflammatory bowel disease (IBD) is rapidly increasing among racial and ethnic minorities, which makes it important to consider for patients with compatible symptoms, experts wrote in Gastroenterology.

Crohn’s disease and ulcerative colitis are “chronic diseases with intermittent periods of flare and remission, so access to specialists, appropriate therapies, and frequent follow-up visits are vital to good outcomes,” wrote Edward L. Barnes, MD, MPH, of University of North Carolina at Chapel Hill, with his associates. However, Blacks with IBD tend to be diagnosed later than Whites, are less likely to receive recommended biologics and immunomodulators, and are more likely to receive care at an emergency department, to experience delays in colectomy, and to miss regular visits to IBD specialists because of financial and transportation barriers, they added.

These disparities are known to worsen outcomes. Compared with Whites, for example, Black patients with Crohn’s disease have higher rates of stricture and penetrating lesions and are at greater risk for postsurgical complications and death, even after potential confounders such age, sex, smoking status, time to operation, and obesity are controlled for. To help close these gaps, Dr. Barnes and his associates recommended enhanced recovery after surgery (ERAS) protocols, which “streamline [the] multidisciplinary management of patients with IBD before surgery, incorporating evidence-based practices focused on nutrition, prevention of postoperative ileus, and use of nonopioid analgesia and goal-directed fluid therapy.”

Similar approaches also might improve nonsurgical outcomes in minorities with IBD, the experts said. In the Sinai-Helmsley Alliance for Research Excellence (SHARE) study, Black patients had more complicated IBD at baseline but similar clinical outcomes and patterns of medication use as Whites when they were treated at academic IBD centers. In other studies, race and ethnicity did not affect patterns of medication use, surgery, or surgical outcomes if patients had similar access to care. Such findings “indicate that when patients of minority races and ethnicities have access to appropriate specialty care and IBD-related therapy, many previously identified disparities are resolved or reduced,” the experts said.

However, race and ethnicity do affect some aspects of IBD disease activity, genetics, and treatment safety and efficacy. Since White patients have made up the vast majority of research participants, studies of racial and ethnic minorities are needed to improve their IBD diagnosis, prevention, and treatment. Such research is particularly vital because IBD incidence is rising three times faster rates in racial and ethnic minorities than Whites, said Aline Charabaty, MD, AGAF, clinical director of the gastroenterology division at Johns Hopkins University in Baltimore, and director of the IBD Center at Sibley Memorial Hospital in Washington.

She explained that, when immigrants from countries where IBD is rare adopt the United States’ sedentary lifestyle and Western diet (low in fruits and vegetables; high in proinflammatory saturated fats, sugars, and processed foods), their gut microbiome shifts and their IBD risk increases markedly. Studies in other countries have produced similar findings, said Dr. Charabaty, who did not help author the review article.

She also noted that patients from communities with a historically low prevalence of IBD may not understand its chronicity or the need for long-term treatment. However, treatment adherence is a common issue for patients of all backgrounds with IBD, she said. “What is unique is barriers to continuity of care – not being able to get to the treatment center, not being able to afford treatment or take time off work if you live paycheck to paycheck, not being able to pay someone to care for your kids while you see the doctor.”

Other potential barriers to seeking IBD treatment include cultural taboos against discussing lower GI symptoms or concerns that chronic disease will harm marriage prospects, Dr. Charabaty said. Such challenges only heighten the need to ascertain IBD symptoms: “Studies show that minorities have less follow-up care and their symptoms tend to be minimized. There is a lot of unconscious bias among providers that factors into this. The barriers are multiple, and it is important to define them and find strategies to overcome them at the level of the patient, the clinician, and the health system.”

The Crohn’s and Colitis Foundation supported the work. Dr. Barnes disclosed ties to AbbVie, Gilead, Takeda, and Target Pharmasolutions. Two coauthors also disclosed relevant ties to pharmaceutical companies. Dr. Charabaty disclosed relationships with AbbVie, Takeda, Pfizer, Janssen, and UCB.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

SOURCE: Barnes EL et al. Gastroenterology. 2020 Oct 20. doi: 10.1053/j.gastro.2020.08.064.
 

Inflammatory bowel disease (IBD) is rapidly increasing among racial and ethnic minorities, which makes it important to consider for patients with compatible symptoms, experts wrote in Gastroenterology.

Crohn’s disease and ulcerative colitis are “chronic diseases with intermittent periods of flare and remission, so access to specialists, appropriate therapies, and frequent follow-up visits are vital to good outcomes,” wrote Edward L. Barnes, MD, MPH, of University of North Carolina at Chapel Hill, with his associates. However, Blacks with IBD tend to be diagnosed later than Whites, are less likely to receive recommended biologics and immunomodulators, and are more likely to receive care at an emergency department, to experience delays in colectomy, and to miss regular visits to IBD specialists because of financial and transportation barriers, they added.

These disparities are known to worsen outcomes. Compared with Whites, for example, Black patients with Crohn’s disease have higher rates of stricture and penetrating lesions and are at greater risk for postsurgical complications and death, even after potential confounders such age, sex, smoking status, time to operation, and obesity are controlled for. To help close these gaps, Dr. Barnes and his associates recommended enhanced recovery after surgery (ERAS) protocols, which “streamline [the] multidisciplinary management of patients with IBD before surgery, incorporating evidence-based practices focused on nutrition, prevention of postoperative ileus, and use of nonopioid analgesia and goal-directed fluid therapy.”

Similar approaches also might improve nonsurgical outcomes in minorities with IBD, the experts said. In the Sinai-Helmsley Alliance for Research Excellence (SHARE) study, Black patients had more complicated IBD at baseline but similar clinical outcomes and patterns of medication use as Whites when they were treated at academic IBD centers. In other studies, race and ethnicity did not affect patterns of medication use, surgery, or surgical outcomes if patients had similar access to care. Such findings “indicate that when patients of minority races and ethnicities have access to appropriate specialty care and IBD-related therapy, many previously identified disparities are resolved or reduced,” the experts said.

However, race and ethnicity do affect some aspects of IBD disease activity, genetics, and treatment safety and efficacy. Since White patients have made up the vast majority of research participants, studies of racial and ethnic minorities are needed to improve their IBD diagnosis, prevention, and treatment. Such research is particularly vital because IBD incidence is rising three times faster rates in racial and ethnic minorities than Whites, said Aline Charabaty, MD, AGAF, clinical director of the gastroenterology division at Johns Hopkins University in Baltimore, and director of the IBD Center at Sibley Memorial Hospital in Washington.

She explained that, when immigrants from countries where IBD is rare adopt the United States’ sedentary lifestyle and Western diet (low in fruits and vegetables; high in proinflammatory saturated fats, sugars, and processed foods), their gut microbiome shifts and their IBD risk increases markedly. Studies in other countries have produced similar findings, said Dr. Charabaty, who did not help author the review article.

She also noted that patients from communities with a historically low prevalence of IBD may not understand its chronicity or the need for long-term treatment. However, treatment adherence is a common issue for patients of all backgrounds with IBD, she said. “What is unique is barriers to continuity of care – not being able to get to the treatment center, not being able to afford treatment or take time off work if you live paycheck to paycheck, not being able to pay someone to care for your kids while you see the doctor.”

Other potential barriers to seeking IBD treatment include cultural taboos against discussing lower GI symptoms or concerns that chronic disease will harm marriage prospects, Dr. Charabaty said. Such challenges only heighten the need to ascertain IBD symptoms: “Studies show that minorities have less follow-up care and their symptoms tend to be minimized. There is a lot of unconscious bias among providers that factors into this. The barriers are multiple, and it is important to define them and find strategies to overcome them at the level of the patient, the clinician, and the health system.”

The Crohn’s and Colitis Foundation supported the work. Dr. Barnes disclosed ties to AbbVie, Gilead, Takeda, and Target Pharmasolutions. Two coauthors also disclosed relevant ties to pharmaceutical companies. Dr. Charabaty disclosed relationships with AbbVie, Takeda, Pfizer, Janssen, and UCB.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

SOURCE: Barnes EL et al. Gastroenterology. 2020 Oct 20. doi: 10.1053/j.gastro.2020.08.064.
 

For patients with malignant colorectal polyps, endoscopists should look for features of deep submucosal invasion and should retrieve, handle, and submit specimens in ways that support thorough and accurate pathologic assessment, according to new recommendations from the US Multi-Society Task Force on Colorectal Cancer.

“In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy is followed by surgical resection. In cases without features of deep submucosal invasion, en bloc resection and proper specimen handling should be considered (if feasible) for lesions with a high risk of superficial submucosal invasion,” wrote Aasma Shaukat, MD, MPH, of the Minneapolis Veterans Affairs Health Care System and her fellow experts. The recommendations were published in Gastroenterology.

Malignant colorectal polyps invade the submucosa but do not extend into the muscularis propria. Pedunculated and nonpedunculated polyps should be considered to invade the deep submucosa if they are classified as NICE (NBI International Colorectal Endoscopic) type 3, Kudo type VN (neoplastic and invasive, with an irregular arrangement), or Kudo type VI (an amorphous structure, with a loss of or decrease in pits). “Nonpedunculated lesions with these features should be biopsied (in the area of surface feature disruption), tattooed (unless in or near the cecum), and referred to surgery. Pedunculated polyps with features of deep submucosal invasion should undergo endoscopic polypectomy,” according to the MSTFCC recommendations.

Moderate-quality evidence links submucosal invasion with two types of polyp morphology: LST-NG (laterally spreading tumor, nongranular type) showing a depression or sessile shape and LST-G (laterally spreading tumor, granular type) that includes a dominant nodule. According to low-quality evidence, these lesions should be managed with en bloc rather than piecemeal resection. En bloc resection is important for all pedunculated polyps (even if large) and should be considered for LST-G lesions with a dominant nodule. Resected pedunculated polyps should be retrieved through the suction channel – if doing so does not require them to be cut – or with a net or snare during scope withdrawal. Nonpedunculated lesions with suspected submucosal invasion that are removed en bloc should be pinned peripherally around the entire circumference to a hard surface and fixed in 10% formalin. This practice helps pathologists orient specimens to correctly assess depth of invasion and margin involvement.

For both pedunculated and nonpedunculated polyps, features denoting a high risk for residual or recurrent malignancy are poor tumor differentiation, lymphovascular invasion, or more than 1 mm of submucosal invasion. For nonpedunculated polyps, additional high-risk features include tumor budding and tumor involvement of the cautery margin. The MSTFCC recommends that, when reporting on a malignant colorectal polyp, pathologists follow the structured template of the College of American Pathologists and note the lesion’s histologic type, grade of differentiation, extent of tumor extension or invasion, stalk and mucosal margin, and presence or absence of lymphovascular invasion. Specimen integrity, polyp size and morphology, and tumor budding are also useful. To reduce miscommunication and facilitate appropriate management, pathologists should avoid using the terms carcinoma and cancer when describing malignant colorectal polyps, according to the MSTFCC.

The decision to recommend adjuvant surgery “is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient’s risk for surgical mortality and morbidity, and patient preferences,” the recommendations state. Because multidisciplinary management can optimize clinical outcomes for patients with malignant polyps, gastroenterologists, pathologists, oncologists, and surgeons should identify best ways to communicate with each other and share decision-making conjointly and with patients. “Patient values are important in cases where the risk of residual cancer and the risk of surgical mortality are similar,” the MSTFCC notes. “In these latter cases, shared decision-making is emphasized.”

The authors of the task force recommendations reported having no relevant conflicts of interest since 2016.

SOURCE: Shaukat A et al. Gastroenterology. 2020 Nov 4. doi: 10.1053/j.gastro.2020.08.050
 

For patients with malignant colorectal polyps, endoscopists should look for features of deep submucosal invasion and should retrieve, handle, and submit specimens in ways that support thorough and accurate pathologic assessment, according to new recommendations from the US Multi-Society Task Force on Colorectal Cancer.

“In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy is followed by surgical resection. In cases without features of deep submucosal invasion, en bloc resection and proper specimen handling should be considered (if feasible) for lesions with a high risk of superficial submucosal invasion,” wrote Aasma Shaukat, MD, MPH, of the Minneapolis Veterans Affairs Health Care System and her fellow experts. The recommendations were published in Gastroenterology.

Malignant colorectal polyps invade the submucosa but do not extend into the muscularis propria. Pedunculated and nonpedunculated polyps should be considered to invade the deep submucosa if they are classified as NICE (NBI International Colorectal Endoscopic) type 3, Kudo type VN (neoplastic and invasive, with an irregular arrangement), or Kudo type VI (an amorphous structure, with a loss of or decrease in pits). “Nonpedunculated lesions with these features should be biopsied (in the area of surface feature disruption), tattooed (unless in or near the cecum), and referred to surgery. Pedunculated polyps with features of deep submucosal invasion should undergo endoscopic polypectomy,” according to the MSTFCC recommendations.

Moderate-quality evidence links submucosal invasion with two types of polyp morphology: LST-NG (laterally spreading tumor, nongranular type) showing a depression or sessile shape and LST-G (laterally spreading tumor, granular type) that includes a dominant nodule. According to low-quality evidence, these lesions should be managed with en bloc rather than piecemeal resection. En bloc resection is important for all pedunculated polyps (even if large) and should be considered for LST-G lesions with a dominant nodule. Resected pedunculated polyps should be retrieved through the suction channel – if doing so does not require them to be cut – or with a net or snare during scope withdrawal. Nonpedunculated lesions with suspected submucosal invasion that are removed en bloc should be pinned peripherally around the entire circumference to a hard surface and fixed in 10% formalin. This practice helps pathologists orient specimens to correctly assess depth of invasion and margin involvement.

For both pedunculated and nonpedunculated polyps, features denoting a high risk for residual or recurrent malignancy are poor tumor differentiation, lymphovascular invasion, or more than 1 mm of submucosal invasion. For nonpedunculated polyps, additional high-risk features include tumor budding and tumor involvement of the cautery margin. The MSTFCC recommends that, when reporting on a malignant colorectal polyp, pathologists follow the structured template of the College of American Pathologists and note the lesion’s histologic type, grade of differentiation, extent of tumor extension or invasion, stalk and mucosal margin, and presence or absence of lymphovascular invasion. Specimen integrity, polyp size and morphology, and tumor budding are also useful. To reduce miscommunication and facilitate appropriate management, pathologists should avoid using the terms carcinoma and cancer when describing malignant colorectal polyps, according to the MSTFCC.

The decision to recommend adjuvant surgery “is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient’s risk for surgical mortality and morbidity, and patient preferences,” the recommendations state. Because multidisciplinary management can optimize clinical outcomes for patients with malignant polyps, gastroenterologists, pathologists, oncologists, and surgeons should identify best ways to communicate with each other and share decision-making conjointly and with patients. “Patient values are important in cases where the risk of residual cancer and the risk of surgical mortality are similar,” the MSTFCC notes. “In these latter cases, shared decision-making is emphasized.”

The authors of the task force recommendations reported having no relevant conflicts of interest since 2016.

SOURCE: Shaukat A et al. Gastroenterology. 2020 Nov 4. doi: 10.1053/j.gastro.2020.08.050
 

For patients with malignant colorectal polyps, endoscopists should look for features of deep submucosal invasion and should retrieve, handle, and submit specimens in ways that support thorough and accurate pathologic assessment, according to new recommendations from the US Multi-Society Task Force on Colorectal Cancer.

“In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy is followed by surgical resection. In cases without features of deep submucosal invasion, en bloc resection and proper specimen handling should be considered (if feasible) for lesions with a high risk of superficial submucosal invasion,” wrote Aasma Shaukat, MD, MPH, of the Minneapolis Veterans Affairs Health Care System and her fellow experts. The recommendations were published in Gastroenterology.

Malignant colorectal polyps invade the submucosa but do not extend into the muscularis propria. Pedunculated and nonpedunculated polyps should be considered to invade the deep submucosa if they are classified as NICE (NBI International Colorectal Endoscopic) type 3, Kudo type VN (neoplastic and invasive, with an irregular arrangement), or Kudo type VI (an amorphous structure, with a loss of or decrease in pits). “Nonpedunculated lesions with these features should be biopsied (in the area of surface feature disruption), tattooed (unless in or near the cecum), and referred to surgery. Pedunculated polyps with features of deep submucosal invasion should undergo endoscopic polypectomy,” according to the MSTFCC recommendations.

Moderate-quality evidence links submucosal invasion with two types of polyp morphology: LST-NG (laterally spreading tumor, nongranular type) showing a depression or sessile shape and LST-G (laterally spreading tumor, granular type) that includes a dominant nodule. According to low-quality evidence, these lesions should be managed with en bloc rather than piecemeal resection. En bloc resection is important for all pedunculated polyps (even if large) and should be considered for LST-G lesions with a dominant nodule. Resected pedunculated polyps should be retrieved through the suction channel – if doing so does not require them to be cut – or with a net or snare during scope withdrawal. Nonpedunculated lesions with suspected submucosal invasion that are removed en bloc should be pinned peripherally around the entire circumference to a hard surface and fixed in 10% formalin. This practice helps pathologists orient specimens to correctly assess depth of invasion and margin involvement.

For both pedunculated and nonpedunculated polyps, features denoting a high risk for residual or recurrent malignancy are poor tumor differentiation, lymphovascular invasion, or more than 1 mm of submucosal invasion. For nonpedunculated polyps, additional high-risk features include tumor budding and tumor involvement of the cautery margin. The MSTFCC recommends that, when reporting on a malignant colorectal polyp, pathologists follow the structured template of the College of American Pathologists and note the lesion’s histologic type, grade of differentiation, extent of tumor extension or invasion, stalk and mucosal margin, and presence or absence of lymphovascular invasion. Specimen integrity, polyp size and morphology, and tumor budding are also useful. To reduce miscommunication and facilitate appropriate management, pathologists should avoid using the terms carcinoma and cancer when describing malignant colorectal polyps, according to the MSTFCC.

The decision to recommend adjuvant surgery “is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient’s risk for surgical mortality and morbidity, and patient preferences,” the recommendations state. Because multidisciplinary management can optimize clinical outcomes for patients with malignant polyps, gastroenterologists, pathologists, oncologists, and surgeons should identify best ways to communicate with each other and share decision-making conjointly and with patients. “Patient values are important in cases where the risk of residual cancer and the risk of surgical mortality are similar,” the MSTFCC notes. “In these latter cases, shared decision-making is emphasized.”

The authors of the task force recommendations reported having no relevant conflicts of interest since 2016.

SOURCE: Shaukat A et al. Gastroenterology. 2020 Nov 4. doi: 10.1053/j.gastro.2020.08.050
 

Among patients with ulcerative colitis who were treated in routine practice, a point-based clinical scoring tool predicted nonresponse to vedolizumab therapy, according to study findings published online in Clinical Gastroenterology and Hepatology.

A cutoff of 26 points or less was 93% sensitive (95% confidence interval, 79%-98%) for identifying patients who did not reach corticosteroid-free remission during 26 weeks of treatment and was 88% sensitive (95% CI, 83%-92%) for identifying patients who required colectomy, reported Parambir S. Dulai, MBBS, of the University of California, San Diego, and his associates. The tool was less reliable for predicting response to tumor necrosis factor (TNF) antagonists, indicating that it is treatment specific, they noted.

Vedolizumab, an alpha-4-beta-7 anti-integrin that restricts the migration of proinflammatory lymphocytes to the gut, can induce corticosteroid-free remissions and mucosal healing in patients with ulcerative colitis. In clinical practice, 22-week rates of clinical response and remission were approximately 51% and 30%, respectively, in a recent study. Noting the lack of real-world data on predictors of response, the researchers modeled data from 620 patients who received induction and maintenance vedolizumab during the blinded phase 3 GEMINI 1 trial. They used this model to create the clinical scoring tool, which they validated in a cohort of 322 patients with ulcerative colitis who had received vedolizumab (199 patients) or TNF antagonists (123 patients) in routine practice during the Vedolizumab for Health Outcomes in Inflammatory Bowel Diseases (VICTORY) study.

In the final multivariable model, predictors of steroid-free remission were TNF antagonist naivety, at least a 2-year history of ulcerative colitis, moderate rather than severe endoscopy activity, and baseline albumin concentration. The resulting clinical scoring tool included these four variables and multiplied them by factors ranging from 0.0647 (for baseline albumin concentration) to 0.2820 (for no prior TNF antagonist exposure). In the validation cohort, patients were categorized as “high probability” (of response) if they scored 33 points or more on the tool and “low probability” if they scored 26 points or fewer. Rates of corticosteroid-free remissions were substantially different at 32% and 12%, respectively. The tool also predicted responses to vedolizumab more accurately than it did predicted responses to TNF antagonists, indicating that it was drug specific.

In the validation cohort, 46% (10 of 22) of low- or intermediate-probability patients showed least a 50% decrease in symptom activity after their vedolizumab infusion interval was shortened to address an insufficient initial response. “However, none of the high-probability patients showed a clinical response to interval shortening,” probably because they had higher vedolizumab trough concentrations to begin with, the researchers said. They called for prospective validation of this finding, “ideally in a randomized, controlled trial setting.”

The derivation and validation cohorts differed in several important ways. The validation cohort included significantly more females, smokers, patients with moderate endoscopic disease, and patients who had failed prior TNF antagonist therapy. These patients also had a significantly higher median albumin level and a longer history of disease. “The lower bound of the confidence interval for the [model’s] performance reached 0.5, suggesting that model discrimination may not be ideal,” the researchers said. “Further validation will therefore be needed to understand external validity on additional cohorts.”

An American Gastroenterological Association Research Scholar Award supported the work. Dr. Dulai reported holding a provisional patent for the prediction model and consulting relationships and other ties to Takeda, Janssen, Pfizer, and AbbVie. His coinvestigators reported ties to numerous pharmaceutical companies.

SOURCE: Dulai PS et al. Clin Gastroenterol Hepatol. 2020 Feb 13. doi: 10.1016/j.cgh.2020.02.010.

Among patients with ulcerative colitis who were treated in routine practice, a point-based clinical scoring tool predicted nonresponse to vedolizumab therapy, according to study findings published online in Clinical Gastroenterology and Hepatology.

A cutoff of 26 points or less was 93% sensitive (95% confidence interval, 79%-98%) for identifying patients who did not reach corticosteroid-free remission during 26 weeks of treatment and was 88% sensitive (95% CI, 83%-92%) for identifying patients who required colectomy, reported Parambir S. Dulai, MBBS, of the University of California, San Diego, and his associates. The tool was less reliable for predicting response to tumor necrosis factor (TNF) antagonists, indicating that it is treatment specific, they noted.

Vedolizumab, an alpha-4-beta-7 anti-integrin that restricts the migration of proinflammatory lymphocytes to the gut, can induce corticosteroid-free remissions and mucosal healing in patients with ulcerative colitis. In clinical practice, 22-week rates of clinical response and remission were approximately 51% and 30%, respectively, in a recent study. Noting the lack of real-world data on predictors of response, the researchers modeled data from 620 patients who received induction and maintenance vedolizumab during the blinded phase 3 GEMINI 1 trial. They used this model to create the clinical scoring tool, which they validated in a cohort of 322 patients with ulcerative colitis who had received vedolizumab (199 patients) or TNF antagonists (123 patients) in routine practice during the Vedolizumab for Health Outcomes in Inflammatory Bowel Diseases (VICTORY) study.

In the final multivariable model, predictors of steroid-free remission were TNF antagonist naivety, at least a 2-year history of ulcerative colitis, moderate rather than severe endoscopy activity, and baseline albumin concentration. The resulting clinical scoring tool included these four variables and multiplied them by factors ranging from 0.0647 (for baseline albumin concentration) to 0.2820 (for no prior TNF antagonist exposure). In the validation cohort, patients were categorized as “high probability” (of response) if they scored 33 points or more on the tool and “low probability” if they scored 26 points or fewer. Rates of corticosteroid-free remissions were substantially different at 32% and 12%, respectively. The tool also predicted responses to vedolizumab more accurately than it did predicted responses to TNF antagonists, indicating that it was drug specific.

In the validation cohort, 46% (10 of 22) of low- or intermediate-probability patients showed least a 50% decrease in symptom activity after their vedolizumab infusion interval was shortened to address an insufficient initial response. “However, none of the high-probability patients showed a clinical response to interval shortening,” probably because they had higher vedolizumab trough concentrations to begin with, the researchers said. They called for prospective validation of this finding, “ideally in a randomized, controlled trial setting.”

The derivation and validation cohorts differed in several important ways. The validation cohort included significantly more females, smokers, patients with moderate endoscopic disease, and patients who had failed prior TNF antagonist therapy. These patients also had a significantly higher median albumin level and a longer history of disease. “The lower bound of the confidence interval for the [model’s] performance reached 0.5, suggesting that model discrimination may not be ideal,” the researchers said. “Further validation will therefore be needed to understand external validity on additional cohorts.”

An American Gastroenterological Association Research Scholar Award supported the work. Dr. Dulai reported holding a provisional patent for the prediction model and consulting relationships and other ties to Takeda, Janssen, Pfizer, and AbbVie. His coinvestigators reported ties to numerous pharmaceutical companies.

SOURCE: Dulai PS et al. Clin Gastroenterol Hepatol. 2020 Feb 13. doi: 10.1016/j.cgh.2020.02.010.

Among patients with ulcerative colitis who were treated in routine practice, a point-based clinical scoring tool predicted nonresponse to vedolizumab therapy, according to study findings published online in Clinical Gastroenterology and Hepatology.

A cutoff of 26 points or less was 93% sensitive (95% confidence interval, 79%-98%) for identifying patients who did not reach corticosteroid-free remission during 26 weeks of treatment and was 88% sensitive (95% CI, 83%-92%) for identifying patients who required colectomy, reported Parambir S. Dulai, MBBS, of the University of California, San Diego, and his associates. The tool was less reliable for predicting response to tumor necrosis factor (TNF) antagonists, indicating that it is treatment specific, they noted.

Vedolizumab, an alpha-4-beta-7 anti-integrin that restricts the migration of proinflammatory lymphocytes to the gut, can induce corticosteroid-free remissions and mucosal healing in patients with ulcerative colitis. In clinical practice, 22-week rates of clinical response and remission were approximately 51% and 30%, respectively, in a recent study. Noting the lack of real-world data on predictors of response, the researchers modeled data from 620 patients who received induction and maintenance vedolizumab during the blinded phase 3 GEMINI 1 trial. They used this model to create the clinical scoring tool, which they validated in a cohort of 322 patients with ulcerative colitis who had received vedolizumab (199 patients) or TNF antagonists (123 patients) in routine practice during the Vedolizumab for Health Outcomes in Inflammatory Bowel Diseases (VICTORY) study.

In the final multivariable model, predictors of steroid-free remission were TNF antagonist naivety, at least a 2-year history of ulcerative colitis, moderate rather than severe endoscopy activity, and baseline albumin concentration. The resulting clinical scoring tool included these four variables and multiplied them by factors ranging from 0.0647 (for baseline albumin concentration) to 0.2820 (for no prior TNF antagonist exposure). In the validation cohort, patients were categorized as “high probability” (of response) if they scored 33 points or more on the tool and “low probability” if they scored 26 points or fewer. Rates of corticosteroid-free remissions were substantially different at 32% and 12%, respectively. The tool also predicted responses to vedolizumab more accurately than it did predicted responses to TNF antagonists, indicating that it was drug specific.

In the validation cohort, 46% (10 of 22) of low- or intermediate-probability patients showed least a 50% decrease in symptom activity after their vedolizumab infusion interval was shortened to address an insufficient initial response. “However, none of the high-probability patients showed a clinical response to interval shortening,” probably because they had higher vedolizumab trough concentrations to begin with, the researchers said. They called for prospective validation of this finding, “ideally in a randomized, controlled trial setting.”

The derivation and validation cohorts differed in several important ways. The validation cohort included significantly more females, smokers, patients with moderate endoscopic disease, and patients who had failed prior TNF antagonist therapy. These patients also had a significantly higher median albumin level and a longer history of disease. “The lower bound of the confidence interval for the [model’s] performance reached 0.5, suggesting that model discrimination may not be ideal,” the researchers said. “Further validation will therefore be needed to understand external validity on additional cohorts.”

An American Gastroenterological Association Research Scholar Award supported the work. Dr. Dulai reported holding a provisional patent for the prediction model and consulting relationships and other ties to Takeda, Janssen, Pfizer, and AbbVie. His coinvestigators reported ties to numerous pharmaceutical companies.

SOURCE: Dulai PS et al. Clin Gastroenterol Hepatol. 2020 Feb 13. doi: 10.1016/j.cgh.2020.02.010.

Severe constipation affected 34% of adults with gastroparesis symptoms and showed a significant positive correlation with symptom severity in a multicenter prospective study.

Henry P. Parkman, MD, of Temple University in Philadelphia and his associates used a modified GI symptoms questionnaire, gastric-emptying scintigraphy, and wireless motility capsule studies of 338 participants in the National Institutes of Health Gastroparesis Registry, which enrolls individuals with gastroparesis symptoms (whether or not they have delayed gastric emptying). In the multivariable analysis, severe constipation (a score of 4 or 5 on a 5-point scale) correlated significantly with a higher score on the Gastroparesis Cardinal Symptoms Index (GCSI), with an odds ratio of 1.85 (95% confidence interval, 1.30-2.67). In addition, patients with gastroparesis symptoms were significantly more likely to report pain in the lower abdomen (OR, 1.34; 95% CI, 1.06-1.69) and to use medications to manage constipation (OR, 5.09; 95% CI, 2.75-9.41). The findings were published online in Clinical Gastroenterology and Hepatology.

Constipation was not significantly linked with the use of individual drug classes, including opiates, tricyclic antidepressants, 5HT3 receptor antagonists, or cannabinoids. However, many patients were taking combinations of medications, and it is unclear if these induced constipation or if patients had primary disorders, such as abnormal colonic motility or anorectal dysfunction, said Adil E. Bharucha, MBBS, MD, a professor of medicine in the gastroenterology and hepatology division and a medical director in the office of clinical trials at Mayo Clinic, Rochester, Minn., who was not involved in the study. For patients with gastroparesis and constipation, clinicians should consider withdrawing constipating medications, performing anorectal testing, and referring patients for pelvic floor biofeedback therapy if anorectal tests are positive, he said while acknowledging the need for more data on these approaches. For patients without evidence of anorectal disorders, he recommended “simple laxatives or, if necessary, prescription medications, some of which may also benefit upper gastrointestinal symptoms.”

In this study, constipation also did not correlate with gastric emptying, which suggests that “motility disturbances in the foregut are separable from those in the hindgut,” said David Levinthal, MD, PhD, director of the neurogastroenterology and motility center at the University of Pittsburgh Medical Center, who also was not involved in the work. Constipation was only marginally linked with colonic transit time (OR, 1.04; 95% CI, 1.00-1.07), and delayed gastric emptying did not predict the severity of dyspepsia, he noted. “These observations highlight that sensory mechanisms are very important factors that are not interrogated by physiological motility tests, but that nonetheless may have an outsized impact on how patients feel.”

Despite “fairly good phenotyping of patients [based on] physiological measures, medication use, and detailed symptom questionnaires,” the study’s method of grouping patients based on continuous variables could mask relevant clinical nuances, Dr. Levinthal said. He emphasized that individual physiological tests do not reliably predict the presence or severity of GI symptoms: “What would you make of a 50-hour colonic transit time [CTT]? Or a 60-hour CTT? One could have either no constipation or severe constipation with those values. In clinical practice, it is less certain how useful it is to know a specific CTT result [when] formulating a treatment plan.”

Therefore, future studies of patients with gastroparesis and constipation should forgo grouping patients based on GI motor patterns and instead validate patient-reported symptom measures by using novel sensory tests with stimuli such as eating, drinking, and balloon distension, Dr. Levinthal said. He also recommended studying cognitive and emotional functioning in this patients, given that conditions such as depression and anxiety are known to affect GI sensation.

The National Institute of Diabetes and Digestive and Kidney Diseases provided funding. The investigators reported having no conflicts of interest. Dr. Bharucha reported having filed patents for anorectal devices jointly with Minnesota Medical Technologies, Medspira, and Medtronic and receiving royalties from Medspira. Dr. Levinthal reported having served on advisory boards for Takeda Pharmaceuticals and Alexza Pharmaceuticals.

SOURCE: Parkman HP et al. Clin Gastroenterol Hepatol. 2020 Oct 28. doi: 10.1016/j.cgh.2020.10.045.
 

Severe constipation affected 34% of adults with gastroparesis symptoms and showed a significant positive correlation with symptom severity in a multicenter prospective study.

Henry P. Parkman, MD, of Temple University in Philadelphia and his associates used a modified GI symptoms questionnaire, gastric-emptying scintigraphy, and wireless motility capsule studies of 338 participants in the National Institutes of Health Gastroparesis Registry, which enrolls individuals with gastroparesis symptoms (whether or not they have delayed gastric emptying). In the multivariable analysis, severe constipation (a score of 4 or 5 on a 5-point scale) correlated significantly with a higher score on the Gastroparesis Cardinal Symptoms Index (GCSI), with an odds ratio of 1.85 (95% confidence interval, 1.30-2.67). In addition, patients with gastroparesis symptoms were significantly more likely to report pain in the lower abdomen (OR, 1.34; 95% CI, 1.06-1.69) and to use medications to manage constipation (OR, 5.09; 95% CI, 2.75-9.41). The findings were published online in Clinical Gastroenterology and Hepatology.

Constipation was not significantly linked with the use of individual drug classes, including opiates, tricyclic antidepressants, 5HT3 receptor antagonists, or cannabinoids. However, many patients were taking combinations of medications, and it is unclear if these induced constipation or if patients had primary disorders, such as abnormal colonic motility or anorectal dysfunction, said Adil E. Bharucha, MBBS, MD, a professor of medicine in the gastroenterology and hepatology division and a medical director in the office of clinical trials at Mayo Clinic, Rochester, Minn., who was not involved in the study. For patients with gastroparesis and constipation, clinicians should consider withdrawing constipating medications, performing anorectal testing, and referring patients for pelvic floor biofeedback therapy if anorectal tests are positive, he said while acknowledging the need for more data on these approaches. For patients without evidence of anorectal disorders, he recommended “simple laxatives or, if necessary, prescription medications, some of which may also benefit upper gastrointestinal symptoms.”

In this study, constipation also did not correlate with gastric emptying, which suggests that “motility disturbances in the foregut are separable from those in the hindgut,” said David Levinthal, MD, PhD, director of the neurogastroenterology and motility center at the University of Pittsburgh Medical Center, who also was not involved in the work. Constipation was only marginally linked with colonic transit time (OR, 1.04; 95% CI, 1.00-1.07), and delayed gastric emptying did not predict the severity of dyspepsia, he noted. “These observations highlight that sensory mechanisms are very important factors that are not interrogated by physiological motility tests, but that nonetheless may have an outsized impact on how patients feel.”

Despite “fairly good phenotyping of patients [based on] physiological measures, medication use, and detailed symptom questionnaires,” the study’s method of grouping patients based on continuous variables could mask relevant clinical nuances, Dr. Levinthal said. He emphasized that individual physiological tests do not reliably predict the presence or severity of GI symptoms: “What would you make of a 50-hour colonic transit time [CTT]? Or a 60-hour CTT? One could have either no constipation or severe constipation with those values. In clinical practice, it is less certain how useful it is to know a specific CTT result [when] formulating a treatment plan.”

Therefore, future studies of patients with gastroparesis and constipation should forgo grouping patients based on GI motor patterns and instead validate patient-reported symptom measures by using novel sensory tests with stimuli such as eating, drinking, and balloon distension, Dr. Levinthal said. He also recommended studying cognitive and emotional functioning in this patients, given that conditions such as depression and anxiety are known to affect GI sensation.

The National Institute of Diabetes and Digestive and Kidney Diseases provided funding. The investigators reported having no conflicts of interest. Dr. Bharucha reported having filed patents for anorectal devices jointly with Minnesota Medical Technologies, Medspira, and Medtronic and receiving royalties from Medspira. Dr. Levinthal reported having served on advisory boards for Takeda Pharmaceuticals and Alexza Pharmaceuticals.

SOURCE: Parkman HP et al. Clin Gastroenterol Hepatol. 2020 Oct 28. doi: 10.1016/j.cgh.2020.10.045.
 

Severe constipation affected 34% of adults with gastroparesis symptoms and showed a significant positive correlation with symptom severity in a multicenter prospective study.

Henry P. Parkman, MD, of Temple University in Philadelphia and his associates used a modified GI symptoms questionnaire, gastric-emptying scintigraphy, and wireless motility capsule studies of 338 participants in the National Institutes of Health Gastroparesis Registry, which enrolls individuals with gastroparesis symptoms (whether or not they have delayed gastric emptying). In the multivariable analysis, severe constipation (a score of 4 or 5 on a 5-point scale) correlated significantly with a higher score on the Gastroparesis Cardinal Symptoms Index (GCSI), with an odds ratio of 1.85 (95% confidence interval, 1.30-2.67). In addition, patients with gastroparesis symptoms were significantly more likely to report pain in the lower abdomen (OR, 1.34; 95% CI, 1.06-1.69) and to use medications to manage constipation (OR, 5.09; 95% CI, 2.75-9.41). The findings were published online in Clinical Gastroenterology and Hepatology.

Constipation was not significantly linked with the use of individual drug classes, including opiates, tricyclic antidepressants, 5HT3 receptor antagonists, or cannabinoids. However, many patients were taking combinations of medications, and it is unclear if these induced constipation or if patients had primary disorders, such as abnormal colonic motility or anorectal dysfunction, said Adil E. Bharucha, MBBS, MD, a professor of medicine in the gastroenterology and hepatology division and a medical director in the office of clinical trials at Mayo Clinic, Rochester, Minn., who was not involved in the study. For patients with gastroparesis and constipation, clinicians should consider withdrawing constipating medications, performing anorectal testing, and referring patients for pelvic floor biofeedback therapy if anorectal tests are positive, he said while acknowledging the need for more data on these approaches. For patients without evidence of anorectal disorders, he recommended “simple laxatives or, if necessary, prescription medications, some of which may also benefit upper gastrointestinal symptoms.”

In this study, constipation also did not correlate with gastric emptying, which suggests that “motility disturbances in the foregut are separable from those in the hindgut,” said David Levinthal, MD, PhD, director of the neurogastroenterology and motility center at the University of Pittsburgh Medical Center, who also was not involved in the work. Constipation was only marginally linked with colonic transit time (OR, 1.04; 95% CI, 1.00-1.07), and delayed gastric emptying did not predict the severity of dyspepsia, he noted. “These observations highlight that sensory mechanisms are very important factors that are not interrogated by physiological motility tests, but that nonetheless may have an outsized impact on how patients feel.”

Despite “fairly good phenotyping of patients [based on] physiological measures, medication use, and detailed symptom questionnaires,” the study’s method of grouping patients based on continuous variables could mask relevant clinical nuances, Dr. Levinthal said. He emphasized that individual physiological tests do not reliably predict the presence or severity of GI symptoms: “What would you make of a 50-hour colonic transit time [CTT]? Or a 60-hour CTT? One could have either no constipation or severe constipation with those values. In clinical practice, it is less certain how useful it is to know a specific CTT result [when] formulating a treatment plan.”

Therefore, future studies of patients with gastroparesis and constipation should forgo grouping patients based on GI motor patterns and instead validate patient-reported symptom measures by using novel sensory tests with stimuli such as eating, drinking, and balloon distension, Dr. Levinthal said. He also recommended studying cognitive and emotional functioning in this patients, given that conditions such as depression and anxiety are known to affect GI sensation.

The National Institute of Diabetes and Digestive and Kidney Diseases provided funding. The investigators reported having no conflicts of interest. Dr. Bharucha reported having filed patents for anorectal devices jointly with Minnesota Medical Technologies, Medspira, and Medtronic and receiving royalties from Medspira. Dr. Levinthal reported having served on advisory boards for Takeda Pharmaceuticals and Alexza Pharmaceuticals.

SOURCE: Parkman HP et al. Clin Gastroenterol Hepatol. 2020 Oct 28. doi: 10.1016/j.cgh.2020.10.045.
 

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

chameleonseye/Thinkstock

This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Eleven operational taxonomic units (OTUs) of fecal bacteria were less abundant in children with celiac disease than in healthy children, according to the findings of a study published in Gastroenterology.

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This microbial signature correctly identified approximately four out of five cases of celiac disease, regardless of whether children were newly diagnosed or had already modified their diet, reported Konstantina Zafeiropoulou and Ben Nichols, PhD, of the Glasgow Royal Infirmary. “It is not clear whether the microbes identified [in this study] contribute to the pathogenesis of celiac disease or are the result of it. Future research should explore the role of the disease-specific species identified here,” the researchers wrote in Gastroenterology.

Celiac disease is multifactorial. While up to 40% of people are genetically predisposed, only a small proportion develop it, suggesting that environmental factors are key to pathogenesis. Recent studies have linked celiac disease with alterations in the gut microbiome, but it is unclear whether dysbiosis is pathogenic or a secondary effect of disease processes such as nutrient malabsorption, or whether dysbiosis is present at disease onset or results from a gluten-free diet.

For the study, the researchers performed gas chromatography and 16S ribosomal RNA sequencing of fecal samples from 141 children, including 20 with newly biopsy-confirmed, previously untreated celiac disease, 45 who were previously diagnosed and on a gluten-free diet, 19 unaffected siblings, and 57 healthy children who were not on regular medications and had no history of chronic gastrointestinal symptoms. A single fecal sample was tested for all but the previously untreated children, who were tested at baseline and then after 6 and 12 months on a gluten-free diet.

Children with new-onset celiac disease showed no evidence of dysbiosis, while a gluten-free diet explained up to 2.8% of variation in microbiota between patients and controls. Microbial alpha diversity, a measure of species-level diversity, was generally similar among groups, but between 3% and 5% of all taxa differed. Irrespective of treatment, the decreased abundance of the 11 OTUs was diagnostic for celiac disease with an error rate of 21.5% (P < .001 vs. random classification). Notably, most of these 11 discrepant OTUs were associated with nutrient or food group intake and with biomarkers of gluten ingestion, the researchers said. Gas chromatography showed that, after patients started a gluten-free diet, fecal levels of butyrate and ammonia decreased.

“Even though we identified differences in the abundance of a few species between patients with untreated celiac disease and healthy controls, the profound microbial dysbiosis noted in Crohn’s disease was not observed, at least using crude diversity indices,” the investigators commented. “Although several alterations in the intestinal microbiota of children with established celiac disease appear to be effects of a gluten-free diet, there are specific bacteria that are distinct biomarkers of celiac disease.”

Future research might involve performing in vitro tests of “candidate” bacteria, coculturing these bacteria with human immune cells, and studying whether dietary interventions alter the relative abundance of these bacteria in the gut microbiome, the researchers said.

Nutricia Research Foundation, the Biotechnology and Biological Sciences Research Council, and The Catherine McEwan Foundation provided funding. Three coinvestigators disclosed ties to Nutricia, 4D Pharma, AbbVie, Celltrion, Janssen, Takeda, and several other pharmaceutical companies. One coinvestigator reported chairing the working group for ISLI Europe. The remaining investigators reported having no conflicts of interest.

SOURCE: Zafeiropoulou K et al. Gastroenterology. 2020 Aug 10;S0016-5085(20)35023-X. doi: 10.1053/j.gastro.2020.08.007.

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.

Interleukin-23 optimizes antimicrobial macrophage activity, which is reduced among persons harboring an IL-23 receptor variant that helps protect against inflammatory bowel disease (IBD), recent research has found.

“These [findings] highlight that the susceptibility to infections with therapeutic blockade of the IL-23/IL-12 pathways may be owing in part to the essential role for IL-23 in mediating antimicrobial functions in macrophages. They further highlight that carriers of the IL-23R–Q381 variant, who are relatively protected from IBD and other immune-mediated diseases, may be at increased risk for bacterial infection,” Rui Sun and Clara Abraham, MD, of Yale University, New Haven, Conn., wrote in Cellular and Molecular Gastroenterology and Hepatology.

IL-23 is key to the pathogenesis of IBD and is being studied as a therapeutic target, both alone and in combination with IL-12 blocking. Although human macrophages express low levels of IL-23 receptor, recent research reveals that IL-23R is up-regulated “within minutes of exposure to IL-23,” which promotes signaling and cytokine secretion, the investigators wrote. However, the extent to which IL-23 supports macrophage antimicrobial activity was unknown. To characterize protein expression, signaling, and bacterial uptake and clearance of bacteria by human macrophages derived from monocytes, the investigators tested these cells with Western blot, flow cytometry, and gentamicin protection, which involved coculturing human macrophages with bacteria, adding gentamicin solution, and then lysing and plating the cells onto agar to assess the extent to which the macrophages had taken up the bacteria.

After 48 hours of exposure to IL-23 or IL-12, macrophages increased their intracellular clearance of clinically relevant bacteria, including Enterococcus faecalis, adherent invasive Escherichia coli, and Salmonella typhimurium. Notably, this did not occur when the investigators reduced (“knocked down”) macrophage expression of either IL-23R or IL-12 receptor alpha 2. Additional investigations showed that in macrophages, IL-23 promotes bacterial uptake, clearance, and autophagy by inducing a pyruvate dehydrogenase kinase 1 (PDK1)–dependent pathway mediated by Janus kinase 2/tyrosine kinase 2 and by inducing reactive oxygen species (ROS) and reactive nitrogen species (RNS) pathways. IL-23 also activates two key proteins involved in autophagy (ATG5 and ATG16L1), the researchers reported. “ROS, RNS, and autophagy cooperate to mediate IL-23-induced bacterial clearance. Reduction of each ROS, RNS, and autophagy pathway partially reversed the enhanced bacterial clearance observed with chronic IL-23 treatment.”

Further tests found that IL-23 mediates antimicrobial pathways through the Janus kinase 2, tyrosine kinase 2, and STAT3 pathways, which “cooperate to mediate optimal IL-23-induced intracellular bacterial clearance in human macrophages.” Importantly, human macrophages showed less antimicrobial activity when transfected with the IL-23R–Q381 variant than with IL-23R–R381. The IL-23R-Q381 variant, which reduces susceptibility to IBD, “decreased IL-23-induced and NOD2-induced antimicrobial pathways and intracellular bacterial clearance in monocyte-derived macrophages,” the researchers explained. Evaluating actual carriers of these variants showed the same results – macrophages harboring IBD-protective IL-23R–R381/Q381 exhibited lower antimicrobial activity and less intracellular bacterial clearance compared with macrophages from carriers of IL-23R–R381/R381.

“Taken together, IL-23 promotes increased bacterial uptake and then induces a more rapid and effective clearance of these intracellular bacteria in human monocyte-derived macrophages,” the researchers wrote. “The reduced inflammatory responses observed in IL-23R Q381 carriers are associated with protection from multiple immune-mediated diseases. This would imply that loss-of-function observed with the common IL-23R–R381Q variant may lead to a disadvantage in select infectious diseases, including through [this variant’s] now identified role in promoting antimicrobial pathways in macrophages.”

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.

SOURCE: Sun R, Abraham C. Cell Molec Gastro Hepatol. 2020 May 28. doi.: 10.1016/j.jcmgh.2020.05.007.