From the AGA Journals

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For adults with eosinophilic esophagitis, maintenance treatment with swallowed topical steroids was associated with significantly higher remission rates when compared with “steroid holidays” in a single-center retrospective observational study presented in the February issue of Clinical Gastroenterology and Hepatology.

At a median follow-up time of 5 years, the rate of complete (including clinical, endoscopic, and histologic) remission was 16.1% when patients were receiving swallowed topical steroids but only 1.3% when they were not on these or other maintenance therapies (that is, on “drug holidays”), reported Thomas Greuter, MD, of University Hospital Zürich and the Mayo Clinic in Rochester, Minn., and his associates. Swallowed topical steroids also were associated with significantly higher rates of each individual endpoint (P less than .001). Swallowed topical steroid therapy did not appear to cause dysplasia or mucosal atrophy, although esophageal candidiasis was confirmed in 2.7% of visits when patients were on treatment. “Given the good safety profile of low-dose swallowed topical steroid therapy, we advocate for prolonged treatment. Dose-finding trials are needed to achieve higher remission rates,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Several studies have confirmed the efficacy of short-term swallowed topical steroids for treating eosinophilic esophagitis, but only one small randomized trial has evaluated longer-term treatment, and participants were followed for only 1 year. Dr. Greuter and his associates therefore analyzed retrospective data from 229 adults in Switzerland who received swallowed topical steroids for eosinophilic esophagitis between 2000 and 2014. Induction therapy consisted of 1 mg swallowed topical steroids twice daily, allowing 2-4 weeks for a clinical response. Patients then received infinite maintenance therapy with 0.25 mg swallowed topical steroids twice daily. Patients tended to be male and diagnosed in their late 30s. Endoscopy commonly showed corrugated rings, white exudates, edema, and furrows, and 35% of patients had strictures. Peak eosinophil count typically was 25 cells per high-power frame.

Among 819 follow-up visits, 336 (41%) occurred when patients were on maintenance swallowed topical steroid therapy. The median duration of maintenance therapy prior to a follow-up visit was 347 days (interquartile range, 90-750 days) or 677 doses (IQR, 280-1413 doses). The rate of clinical remission was 31% when patients were on maintenance treatment but only 4.5% when they were not (P less than .001). Respective rates of endoscopic and histologic remission were 48.8% versus 17.8% (P less than .001) and 44.8% versus 10.1% (P less than .001). After accounting for numerous demographic and clinical variables, the only significant predictors of clinical remission were treatment with swallowed topical steroids (odds ratio, 16.98; 95% confidence interval, 6.69-43.09) and a negative family history of esophageal eosinophilia (OR, 4.02; 95% CI, 1.41-11.47).

This study excluded patients whose eosinophilic esophagitis had responded to proton pump inhibitor therapy. Also, the maintenance dose of swallowed topical steroid dose (0.25 mg twice daily) probably was too low to achieve efficacious drug levels in the esophageal mucosa, which could explain the high proportion of treatment-refractory cases, according to the researchers. Evaluating a higher maintenance dose “would be of particular interest in the future,” they added.

The Swiss National Science Foundation provided partial funding. Dr. Greuter disclosed a travel grant from Falk Pharma GmbH and Vifor and an unrestricted research grant from Novartis.

SOURCE: Greuter T et al. Clin Gastroenterol Hepatol. 2018 Jun 11.

For adults with eosinophilic esophagitis, maintenance treatment with swallowed topical steroids was associated with significantly higher remission rates when compared with “steroid holidays” in a single-center retrospective observational study presented in the February issue of Clinical Gastroenterology and Hepatology.

At a median follow-up time of 5 years, the rate of complete (including clinical, endoscopic, and histologic) remission was 16.1% when patients were receiving swallowed topical steroids but only 1.3% when they were not on these or other maintenance therapies (that is, on “drug holidays”), reported Thomas Greuter, MD, of University Hospital Zürich and the Mayo Clinic in Rochester, Minn., and his associates. Swallowed topical steroids also were associated with significantly higher rates of each individual endpoint (P less than .001). Swallowed topical steroid therapy did not appear to cause dysplasia or mucosal atrophy, although esophageal candidiasis was confirmed in 2.7% of visits when patients were on treatment. “Given the good safety profile of low-dose swallowed topical steroid therapy, we advocate for prolonged treatment. Dose-finding trials are needed to achieve higher remission rates,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Several studies have confirmed the efficacy of short-term swallowed topical steroids for treating eosinophilic esophagitis, but only one small randomized trial has evaluated longer-term treatment, and participants were followed for only 1 year. Dr. Greuter and his associates therefore analyzed retrospective data from 229 adults in Switzerland who received swallowed topical steroids for eosinophilic esophagitis between 2000 and 2014. Induction therapy consisted of 1 mg swallowed topical steroids twice daily, allowing 2-4 weeks for a clinical response. Patients then received infinite maintenance therapy with 0.25 mg swallowed topical steroids twice daily. Patients tended to be male and diagnosed in their late 30s. Endoscopy commonly showed corrugated rings, white exudates, edema, and furrows, and 35% of patients had strictures. Peak eosinophil count typically was 25 cells per high-power frame.

Among 819 follow-up visits, 336 (41%) occurred when patients were on maintenance swallowed topical steroid therapy. The median duration of maintenance therapy prior to a follow-up visit was 347 days (interquartile range, 90-750 days) or 677 doses (IQR, 280-1413 doses). The rate of clinical remission was 31% when patients were on maintenance treatment but only 4.5% when they were not (P less than .001). Respective rates of endoscopic and histologic remission were 48.8% versus 17.8% (P less than .001) and 44.8% versus 10.1% (P less than .001). After accounting for numerous demographic and clinical variables, the only significant predictors of clinical remission were treatment with swallowed topical steroids (odds ratio, 16.98; 95% confidence interval, 6.69-43.09) and a negative family history of esophageal eosinophilia (OR, 4.02; 95% CI, 1.41-11.47).

This study excluded patients whose eosinophilic esophagitis had responded to proton pump inhibitor therapy. Also, the maintenance dose of swallowed topical steroid dose (0.25 mg twice daily) probably was too low to achieve efficacious drug levels in the esophageal mucosa, which could explain the high proportion of treatment-refractory cases, according to the researchers. Evaluating a higher maintenance dose “would be of particular interest in the future,” they added.

The Swiss National Science Foundation provided partial funding. Dr. Greuter disclosed a travel grant from Falk Pharma GmbH and Vifor and an unrestricted research grant from Novartis.

SOURCE: Greuter T et al. Clin Gastroenterol Hepatol. 2018 Jun 11.

For adults with eosinophilic esophagitis, maintenance treatment with swallowed topical steroids was associated with significantly higher remission rates when compared with “steroid holidays” in a single-center retrospective observational study presented in the February issue of Clinical Gastroenterology and Hepatology.

At a median follow-up time of 5 years, the rate of complete (including clinical, endoscopic, and histologic) remission was 16.1% when patients were receiving swallowed topical steroids but only 1.3% when they were not on these or other maintenance therapies (that is, on “drug holidays”), reported Thomas Greuter, MD, of University Hospital Zürich and the Mayo Clinic in Rochester, Minn., and his associates. Swallowed topical steroids also were associated with significantly higher rates of each individual endpoint (P less than .001). Swallowed topical steroid therapy did not appear to cause dysplasia or mucosal atrophy, although esophageal candidiasis was confirmed in 2.7% of visits when patients were on treatment. “Given the good safety profile of low-dose swallowed topical steroid therapy, we advocate for prolonged treatment. Dose-finding trials are needed to achieve higher remission rates,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Several studies have confirmed the efficacy of short-term swallowed topical steroids for treating eosinophilic esophagitis, but only one small randomized trial has evaluated longer-term treatment, and participants were followed for only 1 year. Dr. Greuter and his associates therefore analyzed retrospective data from 229 adults in Switzerland who received swallowed topical steroids for eosinophilic esophagitis between 2000 and 2014. Induction therapy consisted of 1 mg swallowed topical steroids twice daily, allowing 2-4 weeks for a clinical response. Patients then received infinite maintenance therapy with 0.25 mg swallowed topical steroids twice daily. Patients tended to be male and diagnosed in their late 30s. Endoscopy commonly showed corrugated rings, white exudates, edema, and furrows, and 35% of patients had strictures. Peak eosinophil count typically was 25 cells per high-power frame.

Among 819 follow-up visits, 336 (41%) occurred when patients were on maintenance swallowed topical steroid therapy. The median duration of maintenance therapy prior to a follow-up visit was 347 days (interquartile range, 90-750 days) or 677 doses (IQR, 280-1413 doses). The rate of clinical remission was 31% when patients were on maintenance treatment but only 4.5% when they were not (P less than .001). Respective rates of endoscopic and histologic remission were 48.8% versus 17.8% (P less than .001) and 44.8% versus 10.1% (P less than .001). After accounting for numerous demographic and clinical variables, the only significant predictors of clinical remission were treatment with swallowed topical steroids (odds ratio, 16.98; 95% confidence interval, 6.69-43.09) and a negative family history of esophageal eosinophilia (OR, 4.02; 95% CI, 1.41-11.47).

This study excluded patients whose eosinophilic esophagitis had responded to proton pump inhibitor therapy. Also, the maintenance dose of swallowed topical steroid dose (0.25 mg twice daily) probably was too low to achieve efficacious drug levels in the esophageal mucosa, which could explain the high proportion of treatment-refractory cases, according to the researchers. Evaluating a higher maintenance dose “would be of particular interest in the future,” they added.

The Swiss National Science Foundation provided partial funding. Dr. Greuter disclosed a travel grant from Falk Pharma GmbH and Vifor and an unrestricted research grant from Novartis.

SOURCE: Greuter T et al. Clin Gastroenterol Hepatol. 2018 Jun 11.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease (IBD).

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in the January issue of Clinical Gastroenterology and Hepatology.

In UC patients who had not previously received tumor necrosis factor (TNF) antagonists, 22% of vedolizumab recipients, compared with 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported decreases in abdominal pain and loose stools at treatment week 2, compared with 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in the January issue of Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.
 

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer SB et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease (IBD).

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in the January issue of Clinical Gastroenterology and Hepatology.

In UC patients who had not previously received tumor necrosis factor (TNF) antagonists, 22% of vedolizumab recipients, compared with 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported decreases in abdominal pain and loose stools at treatment week 2, compared with 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in the January issue of Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.
 

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer SB et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease (IBD).

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in the January issue of Clinical Gastroenterology and Hepatology.

In UC patients who had not previously received tumor necrosis factor (TNF) antagonists, 22% of vedolizumab recipients, compared with 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported decreases in abdominal pain and loose stools at treatment week 2, compared with 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in the January issue of Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.
 

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer SB et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

For patients with early-stage esophageal squamous cell carcinoma, minimally invasive esophageal submucosal dissection (ESD) led to significantly fewer severe adverse perioperative events than esophagectomy and was associated with similar rates of all-cause mortality and cancer recurrence or metastasis, according to the findings of a single-center retrospective cohort study.

After a median of 21 months of follow-up (range, 6-73 months), rates of all-cause mortality were 7% with ESD and 11% with esophagectomy, said Yiqun Zhang of Zhongshan Hospital, Shanghai, China, and his associates. Rates of cancer recurrence or metastasis were 9.1% and 8.9%, respectively, while disease-specific mortality was lower with ESD (3.4% vs. 7.4% with esophagectomy; P = .049). Severe nonfatal adverse perioperative events occurred in 15% of ESD cases versus 28% of esophagectomy cases (P less than .001). The findings justify more studies of ESD in carefully selected patients with early-stage (T1a-m2/m3 or T1b) esophageal squamous cell carcinoma, the researchers wrote in Clinical Gastroenterology and Hepatology.

Esophagectomy is standard for managing early-stage esophageal squamous cell carcinoma but is associated with high rates of morbidity and mortality. While ESD is minimally invasive, it is considered risky because esophageal squamous cell carcinoma so frequently metastasizes to the lymph nodes, the investigators noted. For the study, they retrospectively compared 322 ESDs and 274 esophagectomies performed during 2011-2016 in patients with T1a-m2/m3 or T1b esophageal squamous cell carcinoma. All cases were pathologically confirmed, and none were premalignant (that is, high-grade intraepithelial neoplasias).

Endoscopic submucosal dissection was associated with significantly lower rates of esophageal fistula (0.3% with ESD vs. 16% with esophagectomy; P less than .001) and pulmonary complications (0.3% vs. 3.6%, respectively; P less than .001), which explained its overall superiority in terms of severe adverse perioperative events, the researchers wrote. Perioperative deaths were rare but occurred more often with esophagectomy (four patients) than with ESD (one patient). Depth of tumor invasion was the only significant correlate of all-cause mortality (hazard ratio for T1a–m3 or deeper tumors versus T1a–m2 tumors, 3.54; 95% confidence interval, 1.08-11.62; P = .04) in a Cox regression analysis that accounted for many potential confounders, such as demographic and tumor characteristics, hypertension, chronic obstructive pulmonary disease (COPD), nodal metastasis, chemotherapy, and radiotherapy.

Perhaps esophagectomy did not improve survival in this retrospective study because follow-up time was too short, because adjuvant therapy compensated for the increased risk of tumor relapse with ESD, or because of the confounding effects of unmeasured variables, such as submucosal stages of T1b cancer, lymphovascular invasion, or tumor morphology, the researchers wrote. “Since a randomized study comparing esophagectomy and ESD alone would not be practical, a potential strategy for future research may include serial treatments – that is, ESD first, followed by esophagectomy, radiotherapy, or chemotherapy, depending on the ESD pathology findings,” they added. “A quality-of-life analysis of ESD would also be helpful because this might be one of the biggest advantages of ESD over esophagectomy and was beyond the scope of this study.”

The study was supported by the National Natural Science Foundation of China, the Shanghai Committee of Science and Technology, and Zhongshan Hospital. The investigators reported having no relevant conflicts of interest.

SOURCE: Zhang Y et al. Clin Gastroenterol Hepatol. 2018 Apr 25. doi: 10.1016/j.cgh.2018.04.038.

For patients with early-stage esophageal squamous cell carcinoma, minimally invasive esophageal submucosal dissection (ESD) led to significantly fewer severe adverse perioperative events than esophagectomy and was associated with similar rates of all-cause mortality and cancer recurrence or metastasis, according to the findings of a single-center retrospective cohort study.

After a median of 21 months of follow-up (range, 6-73 months), rates of all-cause mortality were 7% with ESD and 11% with esophagectomy, said Yiqun Zhang of Zhongshan Hospital, Shanghai, China, and his associates. Rates of cancer recurrence or metastasis were 9.1% and 8.9%, respectively, while disease-specific mortality was lower with ESD (3.4% vs. 7.4% with esophagectomy; P = .049). Severe nonfatal adverse perioperative events occurred in 15% of ESD cases versus 28% of esophagectomy cases (P less than .001). The findings justify more studies of ESD in carefully selected patients with early-stage (T1a-m2/m3 or T1b) esophageal squamous cell carcinoma, the researchers wrote in Clinical Gastroenterology and Hepatology.

Esophagectomy is standard for managing early-stage esophageal squamous cell carcinoma but is associated with high rates of morbidity and mortality. While ESD is minimally invasive, it is considered risky because esophageal squamous cell carcinoma so frequently metastasizes to the lymph nodes, the investigators noted. For the study, they retrospectively compared 322 ESDs and 274 esophagectomies performed during 2011-2016 in patients with T1a-m2/m3 or T1b esophageal squamous cell carcinoma. All cases were pathologically confirmed, and none were premalignant (that is, high-grade intraepithelial neoplasias).

Endoscopic submucosal dissection was associated with significantly lower rates of esophageal fistula (0.3% with ESD vs. 16% with esophagectomy; P less than .001) and pulmonary complications (0.3% vs. 3.6%, respectively; P less than .001), which explained its overall superiority in terms of severe adverse perioperative events, the researchers wrote. Perioperative deaths were rare but occurred more often with esophagectomy (four patients) than with ESD (one patient). Depth of tumor invasion was the only significant correlate of all-cause mortality (hazard ratio for T1a–m3 or deeper tumors versus T1a–m2 tumors, 3.54; 95% confidence interval, 1.08-11.62; P = .04) in a Cox regression analysis that accounted for many potential confounders, such as demographic and tumor characteristics, hypertension, chronic obstructive pulmonary disease (COPD), nodal metastasis, chemotherapy, and radiotherapy.

Perhaps esophagectomy did not improve survival in this retrospective study because follow-up time was too short, because adjuvant therapy compensated for the increased risk of tumor relapse with ESD, or because of the confounding effects of unmeasured variables, such as submucosal stages of T1b cancer, lymphovascular invasion, or tumor morphology, the researchers wrote. “Since a randomized study comparing esophagectomy and ESD alone would not be practical, a potential strategy for future research may include serial treatments – that is, ESD first, followed by esophagectomy, radiotherapy, or chemotherapy, depending on the ESD pathology findings,” they added. “A quality-of-life analysis of ESD would also be helpful because this might be one of the biggest advantages of ESD over esophagectomy and was beyond the scope of this study.”

The study was supported by the National Natural Science Foundation of China, the Shanghai Committee of Science and Technology, and Zhongshan Hospital. The investigators reported having no relevant conflicts of interest.

SOURCE: Zhang Y et al. Clin Gastroenterol Hepatol. 2018 Apr 25. doi: 10.1016/j.cgh.2018.04.038.

For patients with early-stage esophageal squamous cell carcinoma, minimally invasive esophageal submucosal dissection (ESD) led to significantly fewer severe adverse perioperative events than esophagectomy and was associated with similar rates of all-cause mortality and cancer recurrence or metastasis, according to the findings of a single-center retrospective cohort study.

After a median of 21 months of follow-up (range, 6-73 months), rates of all-cause mortality were 7% with ESD and 11% with esophagectomy, said Yiqun Zhang of Zhongshan Hospital, Shanghai, China, and his associates. Rates of cancer recurrence or metastasis were 9.1% and 8.9%, respectively, while disease-specific mortality was lower with ESD (3.4% vs. 7.4% with esophagectomy; P = .049). Severe nonfatal adverse perioperative events occurred in 15% of ESD cases versus 28% of esophagectomy cases (P less than .001). The findings justify more studies of ESD in carefully selected patients with early-stage (T1a-m2/m3 or T1b) esophageal squamous cell carcinoma, the researchers wrote in Clinical Gastroenterology and Hepatology.

Esophagectomy is standard for managing early-stage esophageal squamous cell carcinoma but is associated with high rates of morbidity and mortality. While ESD is minimally invasive, it is considered risky because esophageal squamous cell carcinoma so frequently metastasizes to the lymph nodes, the investigators noted. For the study, they retrospectively compared 322 ESDs and 274 esophagectomies performed during 2011-2016 in patients with T1a-m2/m3 or T1b esophageal squamous cell carcinoma. All cases were pathologically confirmed, and none were premalignant (that is, high-grade intraepithelial neoplasias).

Endoscopic submucosal dissection was associated with significantly lower rates of esophageal fistula (0.3% with ESD vs. 16% with esophagectomy; P less than .001) and pulmonary complications (0.3% vs. 3.6%, respectively; P less than .001), which explained its overall superiority in terms of severe adverse perioperative events, the researchers wrote. Perioperative deaths were rare but occurred more often with esophagectomy (four patients) than with ESD (one patient). Depth of tumor invasion was the only significant correlate of all-cause mortality (hazard ratio for T1a–m3 or deeper tumors versus T1a–m2 tumors, 3.54; 95% confidence interval, 1.08-11.62; P = .04) in a Cox regression analysis that accounted for many potential confounders, such as demographic and tumor characteristics, hypertension, chronic obstructive pulmonary disease (COPD), nodal metastasis, chemotherapy, and radiotherapy.

Perhaps esophagectomy did not improve survival in this retrospective study because follow-up time was too short, because adjuvant therapy compensated for the increased risk of tumor relapse with ESD, or because of the confounding effects of unmeasured variables, such as submucosal stages of T1b cancer, lymphovascular invasion, or tumor morphology, the researchers wrote. “Since a randomized study comparing esophagectomy and ESD alone would not be practical, a potential strategy for future research may include serial treatments – that is, ESD first, followed by esophagectomy, radiotherapy, or chemotherapy, depending on the ESD pathology findings,” they added. “A quality-of-life analysis of ESD would also be helpful because this might be one of the biggest advantages of ESD over esophagectomy and was beyond the scope of this study.”

The study was supported by the National Natural Science Foundation of China, the Shanghai Committee of Science and Technology, and Zhongshan Hospital. The investigators reported having no relevant conflicts of interest.

SOURCE: Zhang Y et al. Clin Gastroenterol Hepatol. 2018 Apr 25. doi: 10.1016/j.cgh.2018.04.038.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease.

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in Clinical Gastroenterology and Hepatology.

Among UC patients who had not previously received tumor necrosis factor (TNF) antagonist therapy, 22% of vedolizumab recipients, compared with only 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported meaningful decreases in abdominal pain and loose stools at treatment week 2, compared with only 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage; hence, the importance of evaluating the treatment effects of vedolizumab in biologic-naive patients.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer S et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease.

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in Clinical Gastroenterology and Hepatology.

Among UC patients who had not previously received tumor necrosis factor (TNF) antagonist therapy, 22% of vedolizumab recipients, compared with only 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported meaningful decreases in abdominal pain and loose stools at treatment week 2, compared with only 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage; hence, the importance of evaluating the treatment effects of vedolizumab in biologic-naive patients.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer S et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease.

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in Clinical Gastroenterology and Hepatology.

Among UC patients who had not previously received tumor necrosis factor (TNF) antagonist therapy, 22% of vedolizumab recipients, compared with only 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported meaningful decreases in abdominal pain and loose stools at treatment week 2, compared with only 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage; hence, the importance of evaluating the treatment effects of vedolizumab in biologic-naive patients.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer S et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.

In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.

A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”

NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).

In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.

The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.

Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.

The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.

SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.

Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.

In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.

A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”

NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).

In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.

The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.

Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.

The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.

SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.

Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.

In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.

A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”

NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).

In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.

The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.

Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.

The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.

SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.

Patients who died from colorectal cancer were significantly more likely than controls not to have been screened, to have missed screenings, or not to have followed up on an abnormal result, according to the results of a large retrospective case-control study.

Source: American Gastroenterological Association

The findings signify “potentially modifiable” screening failures in a population known for relatively high uptake of colorectal cancer screening, wrote Chyke A. Doubeni, MD, MPH, of the University of Pennsylvania, Philadelphia, and his associates in Gastroenterology. Strikingly, 76% of patients who died from colorectal cancer were not current on screening versus 55% of cancer-free patients, they said. Being up to date on screening decreased the odds of dying from colorectal cancer by 62% (odds ratio, 0.38; 95% confidence interval, 0.33-0.44), even after adjustment for race, ethnicity, socioeconomic status, comorbidities, and frequency of contact with primary care providers, they added.

Colonoscopy, sigmoidoscopy, and fecal testing are effective and recommended screening techniques that help prevent deaths from colorectal cancer. Therefore, most such deaths are thought to result from “breakdowns in the screening process,” the researchers wrote. However, interval cancers and missed lesions also play a role, and no prior study has examined detailed screening histories and their association with colorectal cancer mortality.

Accordingly, the researchers reviewed medical records and registry data for 1,750 enrollees in the Kaiser Permanente Northern and Southern California systems who died from colorectal cancer during 2002-2012 and were part of the health plan for at least 5 years before their cancer diagnosis. They compared these patients with 3,486 cancer-free controls matched by age, sex, study site, and numbers of years enrolled in the health plan. Patients were considered up to date on screening if they were screened at intervals recommended by the 2008 multisociety colorectal cancer screening guidelines – that is, if they had received a colonoscopy within 10 years of colorectal cancer diagnosis or sigmoidoscopy or barium enema within 5 years of it. For fecal testing, the investigators used a 2-year interval based on its efficacy in clinical trials.

Among patients who died from colorectal cancer, only 24% were up to date on screening versus 45% of cancer-free-patients, the investigators determined. Furthermore, 68% of patients who died from colorectal cancer were never screened or were not screened at appropriate intervals, compared with 53% of cancer-free patients.

Additionally, while 8% of colorectal cancer deaths occurred in patients who had not followed up on abnormal screening results, only 2% of controls who had received abnormal screening results had failed to follow up.

“In two health systems with high rates of screening, we observed that most patients dying from colorectal cancer had potentially modifiable failures of the screening process,” the researchers concluded. “This study suggests that, even in settings with high screening uptake, access to and timely uptake of screening, regular rescreening, appropriate use of testing given patient characteristics, completion of timely diagnostic testing when screening is positive, and improving the effectiveness of screening tests, particularly for right colon cancer, remain important areas of focus for further decreasing colorectal cancer deaths.”

The National Institutes of Health funded the work. The investigators reported having no conflicts of interest except that one coinvestigator is editor in chief of the journal Gastroenterology.

SOURCE: Doubeni CA et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.09.040.

Patients who died from colorectal cancer were significantly more likely than controls not to have been screened, to have missed screenings, or not to have followed up on an abnormal result, according to the results of a large retrospective case-control study.

Source: American Gastroenterological Association

The findings signify “potentially modifiable” screening failures in a population known for relatively high uptake of colorectal cancer screening, wrote Chyke A. Doubeni, MD, MPH, of the University of Pennsylvania, Philadelphia, and his associates in Gastroenterology. Strikingly, 76% of patients who died from colorectal cancer were not current on screening versus 55% of cancer-free patients, they said. Being up to date on screening decreased the odds of dying from colorectal cancer by 62% (odds ratio, 0.38; 95% confidence interval, 0.33-0.44), even after adjustment for race, ethnicity, socioeconomic status, comorbidities, and frequency of contact with primary care providers, they added.

Colonoscopy, sigmoidoscopy, and fecal testing are effective and recommended screening techniques that help prevent deaths from colorectal cancer. Therefore, most such deaths are thought to result from “breakdowns in the screening process,” the researchers wrote. However, interval cancers and missed lesions also play a role, and no prior study has examined detailed screening histories and their association with colorectal cancer mortality.

Accordingly, the researchers reviewed medical records and registry data for 1,750 enrollees in the Kaiser Permanente Northern and Southern California systems who died from colorectal cancer during 2002-2012 and were part of the health plan for at least 5 years before their cancer diagnosis. They compared these patients with 3,486 cancer-free controls matched by age, sex, study site, and numbers of years enrolled in the health plan. Patients were considered up to date on screening if they were screened at intervals recommended by the 2008 multisociety colorectal cancer screening guidelines – that is, if they had received a colonoscopy within 10 years of colorectal cancer diagnosis or sigmoidoscopy or barium enema within 5 years of it. For fecal testing, the investigators used a 2-year interval based on its efficacy in clinical trials.

Among patients who died from colorectal cancer, only 24% were up to date on screening versus 45% of cancer-free-patients, the investigators determined. Furthermore, 68% of patients who died from colorectal cancer were never screened or were not screened at appropriate intervals, compared with 53% of cancer-free patients.

Additionally, while 8% of colorectal cancer deaths occurred in patients who had not followed up on abnormal screening results, only 2% of controls who had received abnormal screening results had failed to follow up.

“In two health systems with high rates of screening, we observed that most patients dying from colorectal cancer had potentially modifiable failures of the screening process,” the researchers concluded. “This study suggests that, even in settings with high screening uptake, access to and timely uptake of screening, regular rescreening, appropriate use of testing given patient characteristics, completion of timely diagnostic testing when screening is positive, and improving the effectiveness of screening tests, particularly for right colon cancer, remain important areas of focus for further decreasing colorectal cancer deaths.”

The National Institutes of Health funded the work. The investigators reported having no conflicts of interest except that one coinvestigator is editor in chief of the journal Gastroenterology.

SOURCE: Doubeni CA et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.09.040.

Patients who died from colorectal cancer were significantly more likely than controls not to have been screened, to have missed screenings, or not to have followed up on an abnormal result, according to the results of a large retrospective case-control study.

Source: American Gastroenterological Association

The findings signify “potentially modifiable” screening failures in a population known for relatively high uptake of colorectal cancer screening, wrote Chyke A. Doubeni, MD, MPH, of the University of Pennsylvania, Philadelphia, and his associates in Gastroenterology. Strikingly, 76% of patients who died from colorectal cancer were not current on screening versus 55% of cancer-free patients, they said. Being up to date on screening decreased the odds of dying from colorectal cancer by 62% (odds ratio, 0.38; 95% confidence interval, 0.33-0.44), even after adjustment for race, ethnicity, socioeconomic status, comorbidities, and frequency of contact with primary care providers, they added.

Colonoscopy, sigmoidoscopy, and fecal testing are effective and recommended screening techniques that help prevent deaths from colorectal cancer. Therefore, most such deaths are thought to result from “breakdowns in the screening process,” the researchers wrote. However, interval cancers and missed lesions also play a role, and no prior study has examined detailed screening histories and their association with colorectal cancer mortality.

Accordingly, the researchers reviewed medical records and registry data for 1,750 enrollees in the Kaiser Permanente Northern and Southern California systems who died from colorectal cancer during 2002-2012 and were part of the health plan for at least 5 years before their cancer diagnosis. They compared these patients with 3,486 cancer-free controls matched by age, sex, study site, and numbers of years enrolled in the health plan. Patients were considered up to date on screening if they were screened at intervals recommended by the 2008 multisociety colorectal cancer screening guidelines – that is, if they had received a colonoscopy within 10 years of colorectal cancer diagnosis or sigmoidoscopy or barium enema within 5 years of it. For fecal testing, the investigators used a 2-year interval based on its efficacy in clinical trials.

Among patients who died from colorectal cancer, only 24% were up to date on screening versus 45% of cancer-free-patients, the investigators determined. Furthermore, 68% of patients who died from colorectal cancer were never screened or were not screened at appropriate intervals, compared with 53% of cancer-free patients.

Additionally, while 8% of colorectal cancer deaths occurred in patients who had not followed up on abnormal screening results, only 2% of controls who had received abnormal screening results had failed to follow up.

“In two health systems with high rates of screening, we observed that most patients dying from colorectal cancer had potentially modifiable failures of the screening process,” the researchers concluded. “This study suggests that, even in settings with high screening uptake, access to and timely uptake of screening, regular rescreening, appropriate use of testing given patient characteristics, completion of timely diagnostic testing when screening is positive, and improving the effectiveness of screening tests, particularly for right colon cancer, remain important areas of focus for further decreasing colorectal cancer deaths.”

The National Institutes of Health funded the work. The investigators reported having no conflicts of interest except that one coinvestigator is editor in chief of the journal Gastroenterology.

SOURCE: Doubeni CA et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.09.040.

During a wound repair process in rats, metaplastic columnar-lined esophagus was produced and increased in length following esophagojejunostomy, which may be independent of stem cell reprogramming, according to results from an anastomosed rodent study.

The investigators studied esophageal and tissue sections of 52 rats at different time points after esophagojejunostomy and samples were analyzed for length, type, and location of columnar lining. In addition, the sections were examined immunophenotypically to elucidate the molecular changes that occur during ulceration. Agoston T. Agoston, MD, PhD, of Brigham and Women’s Hospital and the department of pathology at Harvard Medical School, Boston, and colleagues reported the findings in Cellular and Molecular Gastroenterology and Hepatology.

“This rodent columnar-lined esophagus has been proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking,” the researchers wrote.

In the model, ulceration was seen 2 weeks after surgery, which began distally at the esophagojejunal anastomosis. Representative of wound healing, reepithelialization of the ulcer region took place through formation of immature glands, which were found to bud directly from jejunal crypts.

After immunophenotypic analysis, the researchers reported that “immunohistochemical characterization of neoglandular epithelium located immediately proximal to the anastomosis showed features similar to those of the native nonproliferating jejunal epithelium located immediately distal to the anastomosis.” They further reported that “the columnar-lined esophagus’s immunoprofile was similar to jejunal crypt epithelium.”

Upon further examination of the ulcer segment, Dr. Agoston and colleagues found that columnar-lined esophagus elongated from 0.15 mm (standard error of the mean, ± 0.1) to 5.22 mm (SEM, ± 0.37) at 2 and 32 weeks post esophagojejunostomy, respectively.

“There was a highly significant linear relationship between the length of the neoglandular epithelium in the distal esophagus and the number of weeks after surgery (correlation coefficient, 0.94; P less than .0001),” the investigators stated.

Locational analysis revealed epithelial-mesenchymal transition markers being expressed by spindle-shaped cells at the leading edge of the columnar-lined esophagus. In addition, neoglands were identified within esophageal ulcer beds and actively dividing squamous epithelium was seen exclusively at the proximal ulcer border.

Following the systematic analysis, the authors noted that the columnar-lined esophagus was most likely the result of jejunal cell migration into the esophagus. They suggested that if compared, jejunal cells may competitively dominate squamous cells in the context of chronic gastroesophageal reflux disease. Furthermore, they observed that the region of ulceration following esophagojejunostomy in their model was more expansive than that reported in other comparable rodent models of reflux esophagitis.

“The reason for this difference is not clear, but we speculate that it is the result of technical aspects of our reflux-inducing surgery,” the researchers wrote. They further explained that “we intentionally fashioned a large anastomotic orifice between the esophagus and jejunum, perhaps larger than that fashioned by other investigators.” And they concluded, “we suspect that this larger orifice resulted in esophageal exposure to larger volumes of refluxate and, consequently, larger areas of ulceration.”

The authors acknowledged their results may not be fully applicable in the context of human Barrett’s esophagus, given the rodent model. However, they do believe the findings may provide a basis to help understand the wound repair process, particularly the distal edge of ulcers that border the columnar epithelium.

“Using a rat model of reflux esophagitis via surgical esophagojejunostomy, we have shown that a metaplastic, columnar-lined esophagus develops via a wound healing process, and not via genetic reprogramming of progenitor cells,” the researchers concluded.

The study was supported by grant funding from the National Institutes of Health and the Baylor Scott and White Research Institute. The authors reported no conflicts of interest.

SOURCE: Agoston AT et al. Cell Mol Gastroenterol Hepatol. 2018 Jun 26. doi: 10.1016/j.jcmgh.2018.06.007.

During a wound repair process in rats, metaplastic columnar-lined esophagus was produced and increased in length following esophagojejunostomy, which may be independent of stem cell reprogramming, according to results from an anastomosed rodent study.

The investigators studied esophageal and tissue sections of 52 rats at different time points after esophagojejunostomy and samples were analyzed for length, type, and location of columnar lining. In addition, the sections were examined immunophenotypically to elucidate the molecular changes that occur during ulceration. Agoston T. Agoston, MD, PhD, of Brigham and Women’s Hospital and the department of pathology at Harvard Medical School, Boston, and colleagues reported the findings in Cellular and Molecular Gastroenterology and Hepatology.

“This rodent columnar-lined esophagus has been proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking,” the researchers wrote.

In the model, ulceration was seen 2 weeks after surgery, which began distally at the esophagojejunal anastomosis. Representative of wound healing, reepithelialization of the ulcer region took place through formation of immature glands, which were found to bud directly from jejunal crypts.

After immunophenotypic analysis, the researchers reported that “immunohistochemical characterization of neoglandular epithelium located immediately proximal to the anastomosis showed features similar to those of the native nonproliferating jejunal epithelium located immediately distal to the anastomosis.” They further reported that “the columnar-lined esophagus’s immunoprofile was similar to jejunal crypt epithelium.”

Upon further examination of the ulcer segment, Dr. Agoston and colleagues found that columnar-lined esophagus elongated from 0.15 mm (standard error of the mean, ± 0.1) to 5.22 mm (SEM, ± 0.37) at 2 and 32 weeks post esophagojejunostomy, respectively.

“There was a highly significant linear relationship between the length of the neoglandular epithelium in the distal esophagus and the number of weeks after surgery (correlation coefficient, 0.94; P less than .0001),” the investigators stated.

Locational analysis revealed epithelial-mesenchymal transition markers being expressed by spindle-shaped cells at the leading edge of the columnar-lined esophagus. In addition, neoglands were identified within esophageal ulcer beds and actively dividing squamous epithelium was seen exclusively at the proximal ulcer border.

Following the systematic analysis, the authors noted that the columnar-lined esophagus was most likely the result of jejunal cell migration into the esophagus. They suggested that if compared, jejunal cells may competitively dominate squamous cells in the context of chronic gastroesophageal reflux disease. Furthermore, they observed that the region of ulceration following esophagojejunostomy in their model was more expansive than that reported in other comparable rodent models of reflux esophagitis.

“The reason for this difference is not clear, but we speculate that it is the result of technical aspects of our reflux-inducing surgery,” the researchers wrote. They further explained that “we intentionally fashioned a large anastomotic orifice between the esophagus and jejunum, perhaps larger than that fashioned by other investigators.” And they concluded, “we suspect that this larger orifice resulted in esophageal exposure to larger volumes of refluxate and, consequently, larger areas of ulceration.”

The authors acknowledged their results may not be fully applicable in the context of human Barrett’s esophagus, given the rodent model. However, they do believe the findings may provide a basis to help understand the wound repair process, particularly the distal edge of ulcers that border the columnar epithelium.

“Using a rat model of reflux esophagitis via surgical esophagojejunostomy, we have shown that a metaplastic, columnar-lined esophagus develops via a wound healing process, and not via genetic reprogramming of progenitor cells,” the researchers concluded.

The study was supported by grant funding from the National Institutes of Health and the Baylor Scott and White Research Institute. The authors reported no conflicts of interest.

SOURCE: Agoston AT et al. Cell Mol Gastroenterol Hepatol. 2018 Jun 26. doi: 10.1016/j.jcmgh.2018.06.007.

During a wound repair process in rats, metaplastic columnar-lined esophagus was produced and increased in length following esophagojejunostomy, which may be independent of stem cell reprogramming, according to results from an anastomosed rodent study.

The investigators studied esophageal and tissue sections of 52 rats at different time points after esophagojejunostomy and samples were analyzed for length, type, and location of columnar lining. In addition, the sections were examined immunophenotypically to elucidate the molecular changes that occur during ulceration. Agoston T. Agoston, MD, PhD, of Brigham and Women’s Hospital and the department of pathology at Harvard Medical School, Boston, and colleagues reported the findings in Cellular and Molecular Gastroenterology and Hepatology.

“This rodent columnar-lined esophagus has been proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking,” the researchers wrote.

In the model, ulceration was seen 2 weeks after surgery, which began distally at the esophagojejunal anastomosis. Representative of wound healing, reepithelialization of the ulcer region took place through formation of immature glands, which were found to bud directly from jejunal crypts.

After immunophenotypic analysis, the researchers reported that “immunohistochemical characterization of neoglandular epithelium located immediately proximal to the anastomosis showed features similar to those of the native nonproliferating jejunal epithelium located immediately distal to the anastomosis.” They further reported that “the columnar-lined esophagus’s immunoprofile was similar to jejunal crypt epithelium.”

Upon further examination of the ulcer segment, Dr. Agoston and colleagues found that columnar-lined esophagus elongated from 0.15 mm (standard error of the mean, ± 0.1) to 5.22 mm (SEM, ± 0.37) at 2 and 32 weeks post esophagojejunostomy, respectively.

“There was a highly significant linear relationship between the length of the neoglandular epithelium in the distal esophagus and the number of weeks after surgery (correlation coefficient, 0.94; P less than .0001),” the investigators stated.

Locational analysis revealed epithelial-mesenchymal transition markers being expressed by spindle-shaped cells at the leading edge of the columnar-lined esophagus. In addition, neoglands were identified within esophageal ulcer beds and actively dividing squamous epithelium was seen exclusively at the proximal ulcer border.

Following the systematic analysis, the authors noted that the columnar-lined esophagus was most likely the result of jejunal cell migration into the esophagus. They suggested that if compared, jejunal cells may competitively dominate squamous cells in the context of chronic gastroesophageal reflux disease. Furthermore, they observed that the region of ulceration following esophagojejunostomy in their model was more expansive than that reported in other comparable rodent models of reflux esophagitis.

“The reason for this difference is not clear, but we speculate that it is the result of technical aspects of our reflux-inducing surgery,” the researchers wrote. They further explained that “we intentionally fashioned a large anastomotic orifice between the esophagus and jejunum, perhaps larger than that fashioned by other investigators.” And they concluded, “we suspect that this larger orifice resulted in esophageal exposure to larger volumes of refluxate and, consequently, larger areas of ulceration.”

The authors acknowledged their results may not be fully applicable in the context of human Barrett’s esophagus, given the rodent model. However, they do believe the findings may provide a basis to help understand the wound repair process, particularly the distal edge of ulcers that border the columnar epithelium.

“Using a rat model of reflux esophagitis via surgical esophagojejunostomy, we have shown that a metaplastic, columnar-lined esophagus develops via a wound healing process, and not via genetic reprogramming of progenitor cells,” the researchers concluded.

The study was supported by grant funding from the National Institutes of Health and the Baylor Scott and White Research Institute. The authors reported no conflicts of interest.

SOURCE: Agoston AT et al. Cell Mol Gastroenterol Hepatol. 2018 Jun 26. doi: 10.1016/j.jcmgh.2018.06.007.