Carolyn Crist

Vedolizumab appears to be effective at reducing intestinal inflammation and inducing remission in patients who developed chronic pouchitis after undergoing ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, according to a phase 4 trial.

The incidence of modified Pouchitis Disease Activity Index (mPDAI)–defined remission after 14 weeks was 31% for vedolizumab, compared with 10% for placebo.

“Vedolizumab works in both ulcerative colitis and Crohn’s disease, so it appeared rational to test its efficacy in chronic, antibiotic-resistant pouchitis,” lead author Simon Travis, DPhil, professor of clinical gastroenterology at the University of Oxford’s Kennedy Institute of Rheumatology and Translational Gastroenterology Unit in the United Kingdom, said in an interview.

“Vedolizumab works for antibiotic-resistant pouchitis,” he said. “It is the first advanced therapy licensed for chronic pouchitis in Europe and can be a game changer for patients who develop pouchitis after experiencing ulcerative colitis severe enough to need colectomy who might have thought that surgery would be the ultimate solution.”

The study was published online in The New England Journal of Medicine.


 

Treating chronic pouchitis

About half of patients with ulcerative colitis who undergo restorative proctocolectomy with IPAA will develop pouchitis within 5 years, the authors write. Among those, about one-fifth will have chronic pouchitis, with symptoms that last longer than 4 weeks. Symptoms include increased stool frequency, abdominal pain, fecal urgency, and impaired quality of life.

Typically, antibiotics are recommended as first-line treatment for acute pouchitis, but antibiotic resistance is common. Previous studies have suggested that tumor necrosis factor antagonists and the monoclonal antibodies vedolizumab and ustekinumab may be effective in pouchitis that is refractory to antibiotics.

The U.S. Food and Drug Administration has approved vedolizumab as a treatment for moderate to severe ulcerative colitis and Crohn’s disease. In early 2022, the European Commission approved vedolizumab for adult patients with moderate to severe active chronic pouchitis who had undergone proctocolectomy with IPAA and had an inadequate response to antibiotic therapy. The approval was based on results from the EARNEST trial.

As part of the EARNEST trial, Dr. Travis and colleagues at 31 sites in North America and Europe conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab for chronic pouchitis after IPAA for ulcerative colitis.

Between October 2016 and March 2020, researchers identified 102 adult patients who met the study criteria. They were eligible if they had undergone proctocolectomy at least 1 year before screening and had active chronic pouchitis, which was defined by an mPDAI score of 5 or more and a minimum subscore of 2 on the endoscopic domain.

After a 28-day screening period, patients were randomly assigned in a 1:1 ratio to receive 300 mg of intravenous vedolizumab or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All patients also received 500 mg of oral ciprofloxacin twice daily from weeks 1 to 4. Additional courses of antibiotics were allowed, as needed, for pouchitis flares that occurred after week 14.

The primary endpoint was mPDAI-defined remission, or an mPDAI score of 4 or less and a reduction of 2 or more points on the 12-point scale at week 14.

Other endpoints included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction of 2 or more points) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of 6 or less and a reduction of 3 or more points on the 18-point scale) at weeks 14 and 34. The mPDAI is based on clinical symptoms and endoscopic findings, whereas the PDAI is based on clinical symptoms, endoscopic findings, and histologic findings.

Overall, 36 patients (71%) in the vedolizumab group and 32 patients (63%) in the placebo group completed treatment and received all infusions through week 30. Eight patients in each group discontinued vedolizumab or placebo owing to a lack of efficacy. Demographic and clinical characteristics were similar in the two groups – about 84% of the patients were White, and the majority were men.

At the 14-week mark, 16 of 51 patients (31%) in the vedolizumab group and 5 of 51 patients (10%) in the placebo group achieved mPDAI-defined remission (a 21–percentage point difference; 95% CI, 5-38; P = .01). At week 34, 35% of the vedolizumab group and 18% of the placebo group reached remission. A post hoc analysis found that a high percentage of patients in the vedolizumab group reached remission regardless of whether concomitant antibiotics were used before week 14 or 34.

“Concomitant antibiotic use after week 4 was reported in a higher percentage of patients in the vedolizumab group than in the placebo group, a finding that was unexpected,” the authors write. “However, the use of additional antibiotics was not considered to be a treatment failure because antibiotics are the current standard of care for chronic pouchitis.”
 

Additional findings

Vedolizumab showed major differences in the other endpoints as well. The percentage of patients with PDAI-defined remission was 35% in the vedolizumab group versus 10% in the placebo group at week 14, and 37% versus 18% at week 34.

The percentage of patients with mPDAI-defined response at week 14 was 63% among the vedolizumab group and 33% among the placebo group. By week 34, the between-group difference was 51% versus 29%.

Vedolizumab also showed greater changes in total PDAI scores, including endoscopic and histologic subscores, as well as remission and response defined by the Inflammatory Bowel Disease Questionnaire (IBDQ). However, there were no significant differences in changes from baseline for the IBDQ or the Cleveland Global Quality of Life (CGQL) score.

The vedolizumab group had a higher percentage of patients with sustained mPDAI-defined remission (difference, 22 percentage points; 95% CI, 6-37) and sustained PDAI-defined remission (difference, 23 percentage points; 95% CI, 8-39).

Adverse events were reported in 47 patients (92%) in the vedolizumab group and 44 patients (86%) in the placebo group. Pouchitis was reported as an adverse event in 24 patients (47%) in the vedolizumab group and 20 patients (39%) in the placebo group. More patients in the vedolizumab group also reported upper respiratory tract infections and headaches.

Serious adverse events occurred in three patients (6%) in the vedolizumab group and four patients (8%) in the placebo group. One adverse event led to discontinuation of vedolizumab, and no serious adverse events were related to vedolizumab or led to discontinuation of vedolizumab.
 

‘Landmark study’

“This is a landmark study that shows us that a biologic that we have used for Crohn’s disease and ulcerative colitis may also be used to treat chronic pouchitis. This is a large unmet need for our patients and an important advancement for the field,” Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic, told this news organization.

The Cleveland Clinic has one of the highest referral rates in the country for IPAA, noted Dr. Regueiro, who wasn’t involved with this study. Colleagues are currently conducting studies to determine who may develop pouchitis and understand why certain patients develop pouchitis after the procedure, he said.

One question the EARNEST trial leaves unanswered is whether vedolizumab will be required as a sustained medicine to control pouchitis or could be stopped at some point, he said. “My sense is that, as is the case with any IBD, chronic treatment will be required,” he added.

The higher rate of ciprofloxacin use among patients who received vedolizumab is interesting, Dr. Regueiro said.

“[The researchers] note that ciprofloxacin was used for symptoms and do not know if there was active inflammation. It’s possible that bacterial overgrowth caused symptoms and the antibiotic treated that, and in a study this small, it is difficult to say anything more,” he said.

The study was sponsored by Takeda, the manufacturer of vedolizumab. Several authors reported speaking fees and consultant roles for numerous pharmaceutical companies, including Takeda. Three of the authors are employees of Takeda. Dr. Regueiro reported no relevant disclosures.

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

Vedolizumab appears to be effective at reducing intestinal inflammation and inducing remission in patients who developed chronic pouchitis after undergoing ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, according to a phase 4 trial.

The incidence of modified Pouchitis Disease Activity Index (mPDAI)–defined remission after 14 weeks was 31% for vedolizumab, compared with 10% for placebo.

“Vedolizumab works in both ulcerative colitis and Crohn’s disease, so it appeared rational to test its efficacy in chronic, antibiotic-resistant pouchitis,” lead author Simon Travis, DPhil, professor of clinical gastroenterology at the University of Oxford’s Kennedy Institute of Rheumatology and Translational Gastroenterology Unit in the United Kingdom, said in an interview.

“Vedolizumab works for antibiotic-resistant pouchitis,” he said. “It is the first advanced therapy licensed for chronic pouchitis in Europe and can be a game changer for patients who develop pouchitis after experiencing ulcerative colitis severe enough to need colectomy who might have thought that surgery would be the ultimate solution.”

The study was published online in The New England Journal of Medicine.


 

Treating chronic pouchitis

About half of patients with ulcerative colitis who undergo restorative proctocolectomy with IPAA will develop pouchitis within 5 years, the authors write. Among those, about one-fifth will have chronic pouchitis, with symptoms that last longer than 4 weeks. Symptoms include increased stool frequency, abdominal pain, fecal urgency, and impaired quality of life.

Typically, antibiotics are recommended as first-line treatment for acute pouchitis, but antibiotic resistance is common. Previous studies have suggested that tumor necrosis factor antagonists and the monoclonal antibodies vedolizumab and ustekinumab may be effective in pouchitis that is refractory to antibiotics.

The U.S. Food and Drug Administration has approved vedolizumab as a treatment for moderate to severe ulcerative colitis and Crohn’s disease. In early 2022, the European Commission approved vedolizumab for adult patients with moderate to severe active chronic pouchitis who had undergone proctocolectomy with IPAA and had an inadequate response to antibiotic therapy. The approval was based on results from the EARNEST trial.

As part of the EARNEST trial, Dr. Travis and colleagues at 31 sites in North America and Europe conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab for chronic pouchitis after IPAA for ulcerative colitis.

Between October 2016 and March 2020, researchers identified 102 adult patients who met the study criteria. They were eligible if they had undergone proctocolectomy at least 1 year before screening and had active chronic pouchitis, which was defined by an mPDAI score of 5 or more and a minimum subscore of 2 on the endoscopic domain.

After a 28-day screening period, patients were randomly assigned in a 1:1 ratio to receive 300 mg of intravenous vedolizumab or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All patients also received 500 mg of oral ciprofloxacin twice daily from weeks 1 to 4. Additional courses of antibiotics were allowed, as needed, for pouchitis flares that occurred after week 14.

The primary endpoint was mPDAI-defined remission, or an mPDAI score of 4 or less and a reduction of 2 or more points on the 12-point scale at week 14.

Other endpoints included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction of 2 or more points) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of 6 or less and a reduction of 3 or more points on the 18-point scale) at weeks 14 and 34. The mPDAI is based on clinical symptoms and endoscopic findings, whereas the PDAI is based on clinical symptoms, endoscopic findings, and histologic findings.

Overall, 36 patients (71%) in the vedolizumab group and 32 patients (63%) in the placebo group completed treatment and received all infusions through week 30. Eight patients in each group discontinued vedolizumab or placebo owing to a lack of efficacy. Demographic and clinical characteristics were similar in the two groups – about 84% of the patients were White, and the majority were men.

At the 14-week mark, 16 of 51 patients (31%) in the vedolizumab group and 5 of 51 patients (10%) in the placebo group achieved mPDAI-defined remission (a 21–percentage point difference; 95% CI, 5-38; P = .01). At week 34, 35% of the vedolizumab group and 18% of the placebo group reached remission. A post hoc analysis found that a high percentage of patients in the vedolizumab group reached remission regardless of whether concomitant antibiotics were used before week 14 or 34.

“Concomitant antibiotic use after week 4 was reported in a higher percentage of patients in the vedolizumab group than in the placebo group, a finding that was unexpected,” the authors write. “However, the use of additional antibiotics was not considered to be a treatment failure because antibiotics are the current standard of care for chronic pouchitis.”
 

Additional findings

Vedolizumab showed major differences in the other endpoints as well. The percentage of patients with PDAI-defined remission was 35% in the vedolizumab group versus 10% in the placebo group at week 14, and 37% versus 18% at week 34.

The percentage of patients with mPDAI-defined response at week 14 was 63% among the vedolizumab group and 33% among the placebo group. By week 34, the between-group difference was 51% versus 29%.

Vedolizumab also showed greater changes in total PDAI scores, including endoscopic and histologic subscores, as well as remission and response defined by the Inflammatory Bowel Disease Questionnaire (IBDQ). However, there were no significant differences in changes from baseline for the IBDQ or the Cleveland Global Quality of Life (CGQL) score.

The vedolizumab group had a higher percentage of patients with sustained mPDAI-defined remission (difference, 22 percentage points; 95% CI, 6-37) and sustained PDAI-defined remission (difference, 23 percentage points; 95% CI, 8-39).

Adverse events were reported in 47 patients (92%) in the vedolizumab group and 44 patients (86%) in the placebo group. Pouchitis was reported as an adverse event in 24 patients (47%) in the vedolizumab group and 20 patients (39%) in the placebo group. More patients in the vedolizumab group also reported upper respiratory tract infections and headaches.

Serious adverse events occurred in three patients (6%) in the vedolizumab group and four patients (8%) in the placebo group. One adverse event led to discontinuation of vedolizumab, and no serious adverse events were related to vedolizumab or led to discontinuation of vedolizumab.
 

‘Landmark study’

“This is a landmark study that shows us that a biologic that we have used for Crohn’s disease and ulcerative colitis may also be used to treat chronic pouchitis. This is a large unmet need for our patients and an important advancement for the field,” Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic, told this news organization.

The Cleveland Clinic has one of the highest referral rates in the country for IPAA, noted Dr. Regueiro, who wasn’t involved with this study. Colleagues are currently conducting studies to determine who may develop pouchitis and understand why certain patients develop pouchitis after the procedure, he said.

One question the EARNEST trial leaves unanswered is whether vedolizumab will be required as a sustained medicine to control pouchitis or could be stopped at some point, he said. “My sense is that, as is the case with any IBD, chronic treatment will be required,” he added.

The higher rate of ciprofloxacin use among patients who received vedolizumab is interesting, Dr. Regueiro said.

“[The researchers] note that ciprofloxacin was used for symptoms and do not know if there was active inflammation. It’s possible that bacterial overgrowth caused symptoms and the antibiotic treated that, and in a study this small, it is difficult to say anything more,” he said.

The study was sponsored by Takeda, the manufacturer of vedolizumab. Several authors reported speaking fees and consultant roles for numerous pharmaceutical companies, including Takeda. Three of the authors are employees of Takeda. Dr. Regueiro reported no relevant disclosures.

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

Vedolizumab appears to be effective at reducing intestinal inflammation and inducing remission in patients who developed chronic pouchitis after undergoing ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, according to a phase 4 trial.

The incidence of modified Pouchitis Disease Activity Index (mPDAI)–defined remission after 14 weeks was 31% for vedolizumab, compared with 10% for placebo.

“Vedolizumab works in both ulcerative colitis and Crohn’s disease, so it appeared rational to test its efficacy in chronic, antibiotic-resistant pouchitis,” lead author Simon Travis, DPhil, professor of clinical gastroenterology at the University of Oxford’s Kennedy Institute of Rheumatology and Translational Gastroenterology Unit in the United Kingdom, said in an interview.

“Vedolizumab works for antibiotic-resistant pouchitis,” he said. “It is the first advanced therapy licensed for chronic pouchitis in Europe and can be a game changer for patients who develop pouchitis after experiencing ulcerative colitis severe enough to need colectomy who might have thought that surgery would be the ultimate solution.”

The study was published online in The New England Journal of Medicine.


 

Treating chronic pouchitis

About half of patients with ulcerative colitis who undergo restorative proctocolectomy with IPAA will develop pouchitis within 5 years, the authors write. Among those, about one-fifth will have chronic pouchitis, with symptoms that last longer than 4 weeks. Symptoms include increased stool frequency, abdominal pain, fecal urgency, and impaired quality of life.

Typically, antibiotics are recommended as first-line treatment for acute pouchitis, but antibiotic resistance is common. Previous studies have suggested that tumor necrosis factor antagonists and the monoclonal antibodies vedolizumab and ustekinumab may be effective in pouchitis that is refractory to antibiotics.

The U.S. Food and Drug Administration has approved vedolizumab as a treatment for moderate to severe ulcerative colitis and Crohn’s disease. In early 2022, the European Commission approved vedolizumab for adult patients with moderate to severe active chronic pouchitis who had undergone proctocolectomy with IPAA and had an inadequate response to antibiotic therapy. The approval was based on results from the EARNEST trial.

As part of the EARNEST trial, Dr. Travis and colleagues at 31 sites in North America and Europe conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab for chronic pouchitis after IPAA for ulcerative colitis.

Between October 2016 and March 2020, researchers identified 102 adult patients who met the study criteria. They were eligible if they had undergone proctocolectomy at least 1 year before screening and had active chronic pouchitis, which was defined by an mPDAI score of 5 or more and a minimum subscore of 2 on the endoscopic domain.

After a 28-day screening period, patients were randomly assigned in a 1:1 ratio to receive 300 mg of intravenous vedolizumab or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All patients also received 500 mg of oral ciprofloxacin twice daily from weeks 1 to 4. Additional courses of antibiotics were allowed, as needed, for pouchitis flares that occurred after week 14.

The primary endpoint was mPDAI-defined remission, or an mPDAI score of 4 or less and a reduction of 2 or more points on the 12-point scale at week 14.

Other endpoints included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction of 2 or more points) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of 6 or less and a reduction of 3 or more points on the 18-point scale) at weeks 14 and 34. The mPDAI is based on clinical symptoms and endoscopic findings, whereas the PDAI is based on clinical symptoms, endoscopic findings, and histologic findings.

Overall, 36 patients (71%) in the vedolizumab group and 32 patients (63%) in the placebo group completed treatment and received all infusions through week 30. Eight patients in each group discontinued vedolizumab or placebo owing to a lack of efficacy. Demographic and clinical characteristics were similar in the two groups – about 84% of the patients were White, and the majority were men.

At the 14-week mark, 16 of 51 patients (31%) in the vedolizumab group and 5 of 51 patients (10%) in the placebo group achieved mPDAI-defined remission (a 21–percentage point difference; 95% CI, 5-38; P = .01). At week 34, 35% of the vedolizumab group and 18% of the placebo group reached remission. A post hoc analysis found that a high percentage of patients in the vedolizumab group reached remission regardless of whether concomitant antibiotics were used before week 14 or 34.

“Concomitant antibiotic use after week 4 was reported in a higher percentage of patients in the vedolizumab group than in the placebo group, a finding that was unexpected,” the authors write. “However, the use of additional antibiotics was not considered to be a treatment failure because antibiotics are the current standard of care for chronic pouchitis.”
 

Additional findings

Vedolizumab showed major differences in the other endpoints as well. The percentage of patients with PDAI-defined remission was 35% in the vedolizumab group versus 10% in the placebo group at week 14, and 37% versus 18% at week 34.

The percentage of patients with mPDAI-defined response at week 14 was 63% among the vedolizumab group and 33% among the placebo group. By week 34, the between-group difference was 51% versus 29%.

Vedolizumab also showed greater changes in total PDAI scores, including endoscopic and histologic subscores, as well as remission and response defined by the Inflammatory Bowel Disease Questionnaire (IBDQ). However, there were no significant differences in changes from baseline for the IBDQ or the Cleveland Global Quality of Life (CGQL) score.

The vedolizumab group had a higher percentage of patients with sustained mPDAI-defined remission (difference, 22 percentage points; 95% CI, 6-37) and sustained PDAI-defined remission (difference, 23 percentage points; 95% CI, 8-39).

Adverse events were reported in 47 patients (92%) in the vedolizumab group and 44 patients (86%) in the placebo group. Pouchitis was reported as an adverse event in 24 patients (47%) in the vedolizumab group and 20 patients (39%) in the placebo group. More patients in the vedolizumab group also reported upper respiratory tract infections and headaches.

Serious adverse events occurred in three patients (6%) in the vedolizumab group and four patients (8%) in the placebo group. One adverse event led to discontinuation of vedolizumab, and no serious adverse events were related to vedolizumab or led to discontinuation of vedolizumab.
 

‘Landmark study’

“This is a landmark study that shows us that a biologic that we have used for Crohn’s disease and ulcerative colitis may also be used to treat chronic pouchitis. This is a large unmet need for our patients and an important advancement for the field,” Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic, told this news organization.

The Cleveland Clinic has one of the highest referral rates in the country for IPAA, noted Dr. Regueiro, who wasn’t involved with this study. Colleagues are currently conducting studies to determine who may develop pouchitis and understand why certain patients develop pouchitis after the procedure, he said.

One question the EARNEST trial leaves unanswered is whether vedolizumab will be required as a sustained medicine to control pouchitis or could be stopped at some point, he said. “My sense is that, as is the case with any IBD, chronic treatment will be required,” he added.

The higher rate of ciprofloxacin use among patients who received vedolizumab is interesting, Dr. Regueiro said.

“[The researchers] note that ciprofloxacin was used for symptoms and do not know if there was active inflammation. It’s possible that bacterial overgrowth caused symptoms and the antibiotic treated that, and in a study this small, it is difficult to say anything more,” he said.

The study was sponsored by Takeda, the manufacturer of vedolizumab. Several authors reported speaking fees and consultant roles for numerous pharmaceutical companies, including Takeda. Three of the authors are employees of Takeda. Dr. Regueiro reported no relevant disclosures.

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

Semaglutide didn’t significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis, compared with placebo, according to a phase 2 trial.

However, the glucagonlike peptide–1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low-density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis,” lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, said in an interview.

“Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and noninvasive biomarkers of fibrosis,” he said.

The study was published online  in The Lancet Gastroenterology & Hepatology.
 

Analyzing safety and efficacy

Dr. Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) of at least 27 kg/m² were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average hemoglobin A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement, compared with seven patients (29%) in the placebo group (odds ratio, 0.28; 95% confidence interval, 0.06-1.24, P = .087).

There also wasn’t a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution, compared with 5 patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide versus placebo, although the difference wasn’t significant. In the semaglutide group, three patients (6%) achieved both, compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide versus placebo.
 

Some improvements seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as ALT, AST, and gamma-glutamyltransferase.

Body weight decreased by 8.83% in the semaglutide group, compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren’t significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event, compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial because of adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

“GLP-1 analogue exposure – among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes – for the treatment of diabetes appears to be well-tolerated and may be safe,” Dr. Loomba said. “Further studies are needed in this study population.”
 

Considering next steps

Dr. Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

“As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients,” Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, said in an interview.

Dr. Bril, who wasn’t involved with this study, wrote an accompanying editorial in The Lancet Gastroenterology & Hepatology.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

“This emphasizes that early diagnosis of patients with NASH is crucial,” he said.

“Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease.”

In further research, investigators may want to consider the lack of NASH resolution, a result that could be caused by this study being underpowered, Dr. Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

“While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes,” he said. “Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications.”

At the same time, it’s important to note that NASH can’t be oversimplified as “a matter of weight,” Dr. Bril said. Significant weight loss in the study didn’t result in histologic improvement, which means other strategies are needed to treat the disease.

“Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis,” he said. “In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH.”

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Dr. Bril had no relevant disclosures.

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

Semaglutide didn’t significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis, compared with placebo, according to a phase 2 trial.

However, the glucagonlike peptide–1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low-density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis,” lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, said in an interview.

“Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and noninvasive biomarkers of fibrosis,” he said.

The study was published online  in The Lancet Gastroenterology & Hepatology.
 

Analyzing safety and efficacy

Dr. Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) of at least 27 kg/m² were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average hemoglobin A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement, compared with seven patients (29%) in the placebo group (odds ratio, 0.28; 95% confidence interval, 0.06-1.24, P = .087).

There also wasn’t a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution, compared with 5 patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide versus placebo, although the difference wasn’t significant. In the semaglutide group, three patients (6%) achieved both, compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide versus placebo.
 

Some improvements seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as ALT, AST, and gamma-glutamyltransferase.

Body weight decreased by 8.83% in the semaglutide group, compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren’t significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event, compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial because of adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

“GLP-1 analogue exposure – among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes – for the treatment of diabetes appears to be well-tolerated and may be safe,” Dr. Loomba said. “Further studies are needed in this study population.”
 

Considering next steps

Dr. Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

“As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients,” Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, said in an interview.

Dr. Bril, who wasn’t involved with this study, wrote an accompanying editorial in The Lancet Gastroenterology & Hepatology.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

“This emphasizes that early diagnosis of patients with NASH is crucial,” he said.

“Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease.”

In further research, investigators may want to consider the lack of NASH resolution, a result that could be caused by this study being underpowered, Dr. Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

“While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes,” he said. “Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications.”

At the same time, it’s important to note that NASH can’t be oversimplified as “a matter of weight,” Dr. Bril said. Significant weight loss in the study didn’t result in histologic improvement, which means other strategies are needed to treat the disease.

“Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis,” he said. “In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH.”

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Dr. Bril had no relevant disclosures.

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

Semaglutide didn’t significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis, compared with placebo, according to a phase 2 trial.

However, the glucagonlike peptide–1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low-density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis,” lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, said in an interview.

“Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and noninvasive biomarkers of fibrosis,” he said.

The study was published online  in The Lancet Gastroenterology & Hepatology.
 

Analyzing safety and efficacy

Dr. Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) of at least 27 kg/m² were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average hemoglobin A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement, compared with seven patients (29%) in the placebo group (odds ratio, 0.28; 95% confidence interval, 0.06-1.24, P = .087).

There also wasn’t a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution, compared with 5 patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide versus placebo, although the difference wasn’t significant. In the semaglutide group, three patients (6%) achieved both, compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide versus placebo.
 

Some improvements seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as ALT, AST, and gamma-glutamyltransferase.

Body weight decreased by 8.83% in the semaglutide group, compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren’t significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event, compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial because of adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

“GLP-1 analogue exposure – among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes – for the treatment of diabetes appears to be well-tolerated and may be safe,” Dr. Loomba said. “Further studies are needed in this study population.”
 

Considering next steps

Dr. Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

“As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients,” Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, said in an interview.

Dr. Bril, who wasn’t involved with this study, wrote an accompanying editorial in The Lancet Gastroenterology & Hepatology.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

“This emphasizes that early diagnosis of patients with NASH is crucial,” he said.

“Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease.”

In further research, investigators may want to consider the lack of NASH resolution, a result that could be caused by this study being underpowered, Dr. Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

“While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes,” he said. “Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications.”

At the same time, it’s important to note that NASH can’t be oversimplified as “a matter of weight,” Dr. Bril said. Significant weight loss in the study didn’t result in histologic improvement, which means other strategies are needed to treat the disease.

“Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis,” he said. “In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH.”

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Dr. Bril had no relevant disclosures.

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

Nearly one in four children diagnosed with type 2 diabetes for 5 years or more develop diabetic retinopathy, according to a new report.

The global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes is about 7%, which appears to increase with age.

“In our clinical practice, we have seen an increase in children presenting with type 2 diabetes over the past few years. These patients present with multiple simultaneous comorbidities and complications like hypertension, fatty liver, and other conditions,” senior author M. Constantine Samaan, MD, told this news organization.

“The exact scale of diabetes-related eye disease was not clear, and we decided to quantify it,” said Dr. Samaan, associate professor of pediatrics at McMaster University and pediatric endocrinologist at McMaster Children’s Hospital in Hamilton, Ont.

“What we found was that in pediatric patients with type 2 diabetes, diabetic retinopathy is present in 1 in 14 youth. The risk of retinopathy increased significantly 5 years after diagnosis to almost one in four,” he noted.

“While we acknowledged that the number of diabetic retinopathy cases was relatively small and there was heterogeneity in studies, we were surprised that retinopathy rates rose so fast in the first few years after diabetes diagnosis,” Dr. Samaan indicated.

The findings signal that the increase in the prevalence of diabetic retinopathy is emerging decades earlier among children compared with adults with type 2 diabetes, the authors wrote in their article published online in JAMA Network Open.

“While the guidelines for eye care in children with type 2 diabetes recommend screening at diagnosis and annually afterward, these recommendations are not followed in almost half of these patients,” Dr. Samaan said. “There is a need to ensure that patients get screened to try and prevent or delay retinopathy onset and progression.”
 

Analyzing prevalence rates

Diabetic retinopathy is the leading cause of blindness in patients with type 2 diabetes. Between 21% and 39% of adults have diabetic retinopathy at diagnosis, with rates subsequently increasing, the authors wrote.

Dr. Samaan and colleagues conducted a systematic review and meta-analysis to estimate the global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes. They included studies that had a study population of at least 10 participants diagnosed at age 21 and younger, an observational study design, and prevalence data on diabetic retinopathy.

Among the 29 studies included, 6 were cross-sectional, 13 had a retrospective cohort design, and 10 had a prospective cohort design. Patients were diagnosed between age 6.5 and 21 years, and the diabetes duration ranged from 0 to 15 years after diagnosis.

The overall global prevalence of diabetic retinopathy in 5,924 pediatric patients was 7.0%. Prevalence varied by study design, ranging from 1.1% in cross-sectional studies to 6.5% in prospective cohort studies and 11.3% in retrospective cohort studies.

In the nine studies that reported diabetic retinopathy classification based on criteria, the prevalence of minimal-to-moderate nonproliferative diabetic retinopathy was 11.2%, the prevalence of severe nonproliferative diabetic retinopathy was 2.6%, the prevalence of proliferative diabetic retinopathy was 2.4%, and the prevalence of macular edema was 3.1%.

In the five studies that reported diabetic retinopathy diagnosis using fundoscopy, the prevalence was 0.5%. In the four studies that used 7-field stereoscopic fundus photography, the prevalence was 13.6%.

In the pooled analysis of 27 studies, the prevalence of diabetic retinopathy was 1.8% less than 2.5 years after diabetes diagnosis but more than doubled to 5.1% in years 2.5 to 5 and jumped to 28.8% more than 5 years after diagnosis.
 

Differences by sex, ethnicity

“We were also surprised that there was very limited evidence to understand the sex and race differences in retinopathy risk,” said Dr. Samaan. “Further research is warranted, considering that more girls develop type 2 diabetes than boys, and the risk of type 2 diabetes is higher in some racial groups.”

In addition, older age, longer diabetes duration, and higher hypertension prevalence were associated with diabetic retinopathy prevalence. There were no associations with obesity prevalence or mean age at diabetes diagnosis. However, patients who developed diabetic retinopathy had a higher mean A1c level of 1.4% compared to those without retinopathy.

Dr. Samaan and colleagues are continuing to research the comorbidities and complications that children with type 2 diabetes face as well as mechanisms that drive diabetes outcomes among children and adolescents.

For now, the findings highlight the importance of retinopathy screening and personalized diabetes treatment to protect vision, Dr. Samaan reiterated.

No funding source for the study was reported. The authors have reported no relevant financial relationships.
 

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

Nearly one in four children diagnosed with type 2 diabetes for 5 years or more develop diabetic retinopathy, according to a new report.

The global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes is about 7%, which appears to increase with age.

“In our clinical practice, we have seen an increase in children presenting with type 2 diabetes over the past few years. These patients present with multiple simultaneous comorbidities and complications like hypertension, fatty liver, and other conditions,” senior author M. Constantine Samaan, MD, told this news organization.

“The exact scale of diabetes-related eye disease was not clear, and we decided to quantify it,” said Dr. Samaan, associate professor of pediatrics at McMaster University and pediatric endocrinologist at McMaster Children’s Hospital in Hamilton, Ont.

“What we found was that in pediatric patients with type 2 diabetes, diabetic retinopathy is present in 1 in 14 youth. The risk of retinopathy increased significantly 5 years after diagnosis to almost one in four,” he noted.

“While we acknowledged that the number of diabetic retinopathy cases was relatively small and there was heterogeneity in studies, we were surprised that retinopathy rates rose so fast in the first few years after diabetes diagnosis,” Dr. Samaan indicated.

The findings signal that the increase in the prevalence of diabetic retinopathy is emerging decades earlier among children compared with adults with type 2 diabetes, the authors wrote in their article published online in JAMA Network Open.

“While the guidelines for eye care in children with type 2 diabetes recommend screening at diagnosis and annually afterward, these recommendations are not followed in almost half of these patients,” Dr. Samaan said. “There is a need to ensure that patients get screened to try and prevent or delay retinopathy onset and progression.”
 

Analyzing prevalence rates

Diabetic retinopathy is the leading cause of blindness in patients with type 2 diabetes. Between 21% and 39% of adults have diabetic retinopathy at diagnosis, with rates subsequently increasing, the authors wrote.

Dr. Samaan and colleagues conducted a systematic review and meta-analysis to estimate the global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes. They included studies that had a study population of at least 10 participants diagnosed at age 21 and younger, an observational study design, and prevalence data on diabetic retinopathy.

Among the 29 studies included, 6 were cross-sectional, 13 had a retrospective cohort design, and 10 had a prospective cohort design. Patients were diagnosed between age 6.5 and 21 years, and the diabetes duration ranged from 0 to 15 years after diagnosis.

The overall global prevalence of diabetic retinopathy in 5,924 pediatric patients was 7.0%. Prevalence varied by study design, ranging from 1.1% in cross-sectional studies to 6.5% in prospective cohort studies and 11.3% in retrospective cohort studies.

In the nine studies that reported diabetic retinopathy classification based on criteria, the prevalence of minimal-to-moderate nonproliferative diabetic retinopathy was 11.2%, the prevalence of severe nonproliferative diabetic retinopathy was 2.6%, the prevalence of proliferative diabetic retinopathy was 2.4%, and the prevalence of macular edema was 3.1%.

In the five studies that reported diabetic retinopathy diagnosis using fundoscopy, the prevalence was 0.5%. In the four studies that used 7-field stereoscopic fundus photography, the prevalence was 13.6%.

In the pooled analysis of 27 studies, the prevalence of diabetic retinopathy was 1.8% less than 2.5 years after diabetes diagnosis but more than doubled to 5.1% in years 2.5 to 5 and jumped to 28.8% more than 5 years after diagnosis.
 

Differences by sex, ethnicity

“We were also surprised that there was very limited evidence to understand the sex and race differences in retinopathy risk,” said Dr. Samaan. “Further research is warranted, considering that more girls develop type 2 diabetes than boys, and the risk of type 2 diabetes is higher in some racial groups.”

In addition, older age, longer diabetes duration, and higher hypertension prevalence were associated with diabetic retinopathy prevalence. There were no associations with obesity prevalence or mean age at diabetes diagnosis. However, patients who developed diabetic retinopathy had a higher mean A1c level of 1.4% compared to those without retinopathy.

Dr. Samaan and colleagues are continuing to research the comorbidities and complications that children with type 2 diabetes face as well as mechanisms that drive diabetes outcomes among children and adolescents.

For now, the findings highlight the importance of retinopathy screening and personalized diabetes treatment to protect vision, Dr. Samaan reiterated.

No funding source for the study was reported. The authors have reported no relevant financial relationships.
 

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

Nearly one in four children diagnosed with type 2 diabetes for 5 years or more develop diabetic retinopathy, according to a new report.

The global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes is about 7%, which appears to increase with age.

“In our clinical practice, we have seen an increase in children presenting with type 2 diabetes over the past few years. These patients present with multiple simultaneous comorbidities and complications like hypertension, fatty liver, and other conditions,” senior author M. Constantine Samaan, MD, told this news organization.

“The exact scale of diabetes-related eye disease was not clear, and we decided to quantify it,” said Dr. Samaan, associate professor of pediatrics at McMaster University and pediatric endocrinologist at McMaster Children’s Hospital in Hamilton, Ont.

“What we found was that in pediatric patients with type 2 diabetes, diabetic retinopathy is present in 1 in 14 youth. The risk of retinopathy increased significantly 5 years after diagnosis to almost one in four,” he noted.

“While we acknowledged that the number of diabetic retinopathy cases was relatively small and there was heterogeneity in studies, we were surprised that retinopathy rates rose so fast in the first few years after diabetes diagnosis,” Dr. Samaan indicated.

The findings signal that the increase in the prevalence of diabetic retinopathy is emerging decades earlier among children compared with adults with type 2 diabetes, the authors wrote in their article published online in JAMA Network Open.

“While the guidelines for eye care in children with type 2 diabetes recommend screening at diagnosis and annually afterward, these recommendations are not followed in almost half of these patients,” Dr. Samaan said. “There is a need to ensure that patients get screened to try and prevent or delay retinopathy onset and progression.”
 

Analyzing prevalence rates

Diabetic retinopathy is the leading cause of blindness in patients with type 2 diabetes. Between 21% and 39% of adults have diabetic retinopathy at diagnosis, with rates subsequently increasing, the authors wrote.

Dr. Samaan and colleagues conducted a systematic review and meta-analysis to estimate the global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes. They included studies that had a study population of at least 10 participants diagnosed at age 21 and younger, an observational study design, and prevalence data on diabetic retinopathy.

Among the 29 studies included, 6 were cross-sectional, 13 had a retrospective cohort design, and 10 had a prospective cohort design. Patients were diagnosed between age 6.5 and 21 years, and the diabetes duration ranged from 0 to 15 years after diagnosis.

The overall global prevalence of diabetic retinopathy in 5,924 pediatric patients was 7.0%. Prevalence varied by study design, ranging from 1.1% in cross-sectional studies to 6.5% in prospective cohort studies and 11.3% in retrospective cohort studies.

In the nine studies that reported diabetic retinopathy classification based on criteria, the prevalence of minimal-to-moderate nonproliferative diabetic retinopathy was 11.2%, the prevalence of severe nonproliferative diabetic retinopathy was 2.6%, the prevalence of proliferative diabetic retinopathy was 2.4%, and the prevalence of macular edema was 3.1%.

In the five studies that reported diabetic retinopathy diagnosis using fundoscopy, the prevalence was 0.5%. In the four studies that used 7-field stereoscopic fundus photography, the prevalence was 13.6%.

In the pooled analysis of 27 studies, the prevalence of diabetic retinopathy was 1.8% less than 2.5 years after diabetes diagnosis but more than doubled to 5.1% in years 2.5 to 5 and jumped to 28.8% more than 5 years after diagnosis.
 

Differences by sex, ethnicity

“We were also surprised that there was very limited evidence to understand the sex and race differences in retinopathy risk,” said Dr. Samaan. “Further research is warranted, considering that more girls develop type 2 diabetes than boys, and the risk of type 2 diabetes is higher in some racial groups.”

In addition, older age, longer diabetes duration, and higher hypertension prevalence were associated with diabetic retinopathy prevalence. There were no associations with obesity prevalence or mean age at diabetes diagnosis. However, patients who developed diabetic retinopathy had a higher mean A1c level of 1.4% compared to those without retinopathy.

Dr. Samaan and colleagues are continuing to research the comorbidities and complications that children with type 2 diabetes face as well as mechanisms that drive diabetes outcomes among children and adolescents.

For now, the findings highlight the importance of retinopathy screening and personalized diabetes treatment to protect vision, Dr. Samaan reiterated.

No funding source for the study was reported. The authors have reported no relevant financial relationships.
 

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

The Mediterranean diet appears to be associated with a lower incidence of cardiovascular disease (CVD) and mortality in women, new observational data suggest.

Those who had a higher adherence to a Mediterranean diet had a 24% lower risk for cardiovascular disease and 23% lower risk for death.

“A healthy diet is a huge factor in preventing heart disease. However, current guidelines on preventing heart disease lack sex-specific recommendations,” said senior author Sarah Zaman, MBBS, PhD, an associate professor of medicine and principal research fellow at the University of Sydney’s Westmead Applied Research Centre.

Mediterranean_diet_2_web.jpg

Analyzing cardiovascular outcomes

Dr. Zaman and colleagues conducted a systematic review and meta-analysis of 16 studies published between 2006 and 2021 that reported a Mediterranean diet score and included either all women or had stratified outcomes by sex. They excluded studies that referred to only certain components of the Mediterranean diet or combined it with other lifestyle-related factors.

The studies, which were mainly conducted in the United States and Europe, included 722,495 adult women without previous clinical or subclinical CVD, with a median follow-up of 12.5 years.

Higher Mediterranean diet adherence was defined as the highest category reporting the highest range of Mediterranean diet scores, and lower adherence was defined as the lowest category reporting lowest scores. Incident CVD included coronary heart disease, myocardial infarction, stroke, heart failure, cardiovascular death, major adverse cardiovascular events, major adverse cardiac cerebrovascular events, and patient-reported CVD.

Overall, higher adherence to a Mediterranean diet was associated with lower CVD incidence (hazard ratio, 0.76; 95% confidence interval, 0.72-0.81), total mortality (HR, 0.77; 95% CI, 0.74-0.80), and coronary heart disease (HR, 0.75; 95% CI, 0.65-0.87).

Stroke incidence was also lower among women who adhered to the Mediterranean diet, although it wasn’t considered statistically significant (HR, 0.87; 95% CI, 0.76-1.01).

Additional analyses found similar reductions in risk across women of different ethnicities. Higher Mediterranean diet adherence was associated with lower CVD incidence for both women of European descent (HR, 0.76; 95% CI, 0.59-0.98) and women of non-European descent – Asian, Native Hawaiian, and African American – (HR, 0.79; 95% CI, 0.72-0.87).

The results didn’t materially change in sensitivity analyses, the authors note. Excluding one study at a time, the pooled HRs for the highest versus the lowest Mediterranean diet adherence ranged from 0.76 (95% CI, 0.72-0.80) to 0.83 (95% CI, 0.70-0.98) for incident CVD and from 0.77 (95% CI, 0.75-0.80) to 0.77 (95% CI, 0.74-0.81) for total mortality among women.

At the same time, the authors pointed to several limitations, including the observational nature of all of the studies, the reliance on self-reported food frequency questionnaires, and heterogeneity in the adjustments for influential factors across the studies.
 

Additional considerations

Dr. Zaman and colleagues called for more sex-specific research in cardiology, including risk factors related to premature menopause, preeclampsia, gestational diabetes, and autoimmune diseases such as systemic lupus.

Future studies should also explore the underlying mechanisms that may explain the links between the Mediterranean diet, cardiovascular disease, and death, the authors write. For instance, the diet may reduce inflammation and cardiovascular risk factors through antioxidant and beneficial gut microbiome pathways. Other components of the diet – such as polyphenols, nitrates, omega-3 fatty acids, higher fiber intake, and reduced glycemic load – may also play a role.

“It was striking to see how strong the long-term cardioprotective properties of a Mediterranean-type dietary pattern were,” said Samia Mora, MD, MHS, a professor of medicine at Harvard Medical School and director of the Center for Lipid Metabolomics at Brigham and Women’s Hospital.

Dr. Mora, who wasn’t involved with this study, has researched potential mechanisms related to the Mediterranean diet, cardiovascular events, and diabetes in women. She and colleagues have found that women with high adherence to the diet are more likely to have lower inflammation, insulin resistance, body mass index, and blood pressure, as well as improved lipid and metabolic profiles.

“This could represent an opportunity to intervene earlier and more intensively on improving inflammation, insulin resistance, and cardiometabolic health through evidence-based dietary approaches such as the Mediterranean diet,” she said. “As health care providers, we should promote the healthy dietary attributes of the Mediterranean diet, especially as many of our patients in the U.S. are less familiar with the Mediterranean diet and how to incorporate its components into daily food intake.”

The study did not receive any funding. Dr. Zaman was supported by a Heart Foundation Future Leader Fellowship. The authors declared no conflicts of interest. Dr. Mora reported no relevant financial relationships.

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

The Mediterranean diet appears to be associated with a lower incidence of cardiovascular disease (CVD) and mortality in women, new observational data suggest.

Those who had a higher adherence to a Mediterranean diet had a 24% lower risk for cardiovascular disease and 23% lower risk for death.

“A healthy diet is a huge factor in preventing heart disease. However, current guidelines on preventing heart disease lack sex-specific recommendations,” said senior author Sarah Zaman, MBBS, PhD, an associate professor of medicine and principal research fellow at the University of Sydney’s Westmead Applied Research Centre.

Mediterranean_diet_2_web.jpg

Analyzing cardiovascular outcomes

Dr. Zaman and colleagues conducted a systematic review and meta-analysis of 16 studies published between 2006 and 2021 that reported a Mediterranean diet score and included either all women or had stratified outcomes by sex. They excluded studies that referred to only certain components of the Mediterranean diet or combined it with other lifestyle-related factors.

The studies, which were mainly conducted in the United States and Europe, included 722,495 adult women without previous clinical or subclinical CVD, with a median follow-up of 12.5 years.

Higher Mediterranean diet adherence was defined as the highest category reporting the highest range of Mediterranean diet scores, and lower adherence was defined as the lowest category reporting lowest scores. Incident CVD included coronary heart disease, myocardial infarction, stroke, heart failure, cardiovascular death, major adverse cardiovascular events, major adverse cardiac cerebrovascular events, and patient-reported CVD.

Overall, higher adherence to a Mediterranean diet was associated with lower CVD incidence (hazard ratio, 0.76; 95% confidence interval, 0.72-0.81), total mortality (HR, 0.77; 95% CI, 0.74-0.80), and coronary heart disease (HR, 0.75; 95% CI, 0.65-0.87).

Stroke incidence was also lower among women who adhered to the Mediterranean diet, although it wasn’t considered statistically significant (HR, 0.87; 95% CI, 0.76-1.01).

Additional analyses found similar reductions in risk across women of different ethnicities. Higher Mediterranean diet adherence was associated with lower CVD incidence for both women of European descent (HR, 0.76; 95% CI, 0.59-0.98) and women of non-European descent – Asian, Native Hawaiian, and African American – (HR, 0.79; 95% CI, 0.72-0.87).

The results didn’t materially change in sensitivity analyses, the authors note. Excluding one study at a time, the pooled HRs for the highest versus the lowest Mediterranean diet adherence ranged from 0.76 (95% CI, 0.72-0.80) to 0.83 (95% CI, 0.70-0.98) for incident CVD and from 0.77 (95% CI, 0.75-0.80) to 0.77 (95% CI, 0.74-0.81) for total mortality among women.

At the same time, the authors pointed to several limitations, including the observational nature of all of the studies, the reliance on self-reported food frequency questionnaires, and heterogeneity in the adjustments for influential factors across the studies.
 

Additional considerations

Dr. Zaman and colleagues called for more sex-specific research in cardiology, including risk factors related to premature menopause, preeclampsia, gestational diabetes, and autoimmune diseases such as systemic lupus.

Future studies should also explore the underlying mechanisms that may explain the links between the Mediterranean diet, cardiovascular disease, and death, the authors write. For instance, the diet may reduce inflammation and cardiovascular risk factors through antioxidant and beneficial gut microbiome pathways. Other components of the diet – such as polyphenols, nitrates, omega-3 fatty acids, higher fiber intake, and reduced glycemic load – may also play a role.

“It was striking to see how strong the long-term cardioprotective properties of a Mediterranean-type dietary pattern were,” said Samia Mora, MD, MHS, a professor of medicine at Harvard Medical School and director of the Center for Lipid Metabolomics at Brigham and Women’s Hospital.

Dr. Mora, who wasn’t involved with this study, has researched potential mechanisms related to the Mediterranean diet, cardiovascular events, and diabetes in women. She and colleagues have found that women with high adherence to the diet are more likely to have lower inflammation, insulin resistance, body mass index, and blood pressure, as well as improved lipid and metabolic profiles.

“This could represent an opportunity to intervene earlier and more intensively on improving inflammation, insulin resistance, and cardiometabolic health through evidence-based dietary approaches such as the Mediterranean diet,” she said. “As health care providers, we should promote the healthy dietary attributes of the Mediterranean diet, especially as many of our patients in the U.S. are less familiar with the Mediterranean diet and how to incorporate its components into daily food intake.”

The study did not receive any funding. Dr. Zaman was supported by a Heart Foundation Future Leader Fellowship. The authors declared no conflicts of interest. Dr. Mora reported no relevant financial relationships.

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

The Mediterranean diet appears to be associated with a lower incidence of cardiovascular disease (CVD) and mortality in women, new observational data suggest.

Those who had a higher adherence to a Mediterranean diet had a 24% lower risk for cardiovascular disease and 23% lower risk for death.

“A healthy diet is a huge factor in preventing heart disease. However, current guidelines on preventing heart disease lack sex-specific recommendations,” said senior author Sarah Zaman, MBBS, PhD, an associate professor of medicine and principal research fellow at the University of Sydney’s Westmead Applied Research Centre.

Mediterranean_diet_2_web.jpg

Analyzing cardiovascular outcomes

Dr. Zaman and colleagues conducted a systematic review and meta-analysis of 16 studies published between 2006 and 2021 that reported a Mediterranean diet score and included either all women or had stratified outcomes by sex. They excluded studies that referred to only certain components of the Mediterranean diet or combined it with other lifestyle-related factors.

The studies, which were mainly conducted in the United States and Europe, included 722,495 adult women without previous clinical or subclinical CVD, with a median follow-up of 12.5 years.

Higher Mediterranean diet adherence was defined as the highest category reporting the highest range of Mediterranean diet scores, and lower adherence was defined as the lowest category reporting lowest scores. Incident CVD included coronary heart disease, myocardial infarction, stroke, heart failure, cardiovascular death, major adverse cardiovascular events, major adverse cardiac cerebrovascular events, and patient-reported CVD.

Overall, higher adherence to a Mediterranean diet was associated with lower CVD incidence (hazard ratio, 0.76; 95% confidence interval, 0.72-0.81), total mortality (HR, 0.77; 95% CI, 0.74-0.80), and coronary heart disease (HR, 0.75; 95% CI, 0.65-0.87).

Stroke incidence was also lower among women who adhered to the Mediterranean diet, although it wasn’t considered statistically significant (HR, 0.87; 95% CI, 0.76-1.01).

Additional analyses found similar reductions in risk across women of different ethnicities. Higher Mediterranean diet adherence was associated with lower CVD incidence for both women of European descent (HR, 0.76; 95% CI, 0.59-0.98) and women of non-European descent – Asian, Native Hawaiian, and African American – (HR, 0.79; 95% CI, 0.72-0.87).

The results didn’t materially change in sensitivity analyses, the authors note. Excluding one study at a time, the pooled HRs for the highest versus the lowest Mediterranean diet adherence ranged from 0.76 (95% CI, 0.72-0.80) to 0.83 (95% CI, 0.70-0.98) for incident CVD and from 0.77 (95% CI, 0.75-0.80) to 0.77 (95% CI, 0.74-0.81) for total mortality among women.

At the same time, the authors pointed to several limitations, including the observational nature of all of the studies, the reliance on self-reported food frequency questionnaires, and heterogeneity in the adjustments for influential factors across the studies.
 

Additional considerations

Dr. Zaman and colleagues called for more sex-specific research in cardiology, including risk factors related to premature menopause, preeclampsia, gestational diabetes, and autoimmune diseases such as systemic lupus.

Future studies should also explore the underlying mechanisms that may explain the links between the Mediterranean diet, cardiovascular disease, and death, the authors write. For instance, the diet may reduce inflammation and cardiovascular risk factors through antioxidant and beneficial gut microbiome pathways. Other components of the diet – such as polyphenols, nitrates, omega-3 fatty acids, higher fiber intake, and reduced glycemic load – may also play a role.

“It was striking to see how strong the long-term cardioprotective properties of a Mediterranean-type dietary pattern were,” said Samia Mora, MD, MHS, a professor of medicine at Harvard Medical School and director of the Center for Lipid Metabolomics at Brigham and Women’s Hospital.

Dr. Mora, who wasn’t involved with this study, has researched potential mechanisms related to the Mediterranean diet, cardiovascular events, and diabetes in women. She and colleagues have found that women with high adherence to the diet are more likely to have lower inflammation, insulin resistance, body mass index, and blood pressure, as well as improved lipid and metabolic profiles.

“This could represent an opportunity to intervene earlier and more intensively on improving inflammation, insulin resistance, and cardiometabolic health through evidence-based dietary approaches such as the Mediterranean diet,” she said. “As health care providers, we should promote the healthy dietary attributes of the Mediterranean diet, especially as many of our patients in the U.S. are less familiar with the Mediterranean diet and how to incorporate its components into daily food intake.”

The study did not receive any funding. Dr. Zaman was supported by a Heart Foundation Future Leader Fellowship. The authors declared no conflicts of interest. Dr. Mora reported no relevant financial relationships.

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

Computer-aided detection (CADe) during colonoscopy may not lead to major improvements in key measures, particularly in community-based settings, according to a new study.

In a randomized clinical trial using EndoVigilant, there wasn’t a significant difference in adenomas per colonoscopy (APC) in procedures with the CADe tool versus those without it. In addition, the adenoma detection rate (ADR) and serrated polyp detection rate were similar in the CADe and non-CADe groups.

“Although we were disappointed that AI [artificial intelligence] did not improve detection of adenomas or serrated polyps in our study, we are still optimistic that this exciting technology will eventually impact endoscopy in a very positive way,” senior author Shai Friedland, MD, a professor of medicine at Stanford (Calif.) University and gastroenterologist with the Veterans Affairs Palo Alto Health Care System, said in an interview.

“The ultimate goal should be to improve the ability of colonoscopy to prevent morbidity and mortality from colon cancer, especially for endoscopists who may not be performing as well as they could be,” he said. “AI can potentially help prevent missed lesions due to fatigue or distraction, much like a warning system that averts car accidents. It can also potentially help endoscopists recognize dangerous – but rare – subtle lesions such as small, flat, and depressed cancers.”

The study was published online in the American Journal of Gastroenterology.
 

Analyzing detection rates

Several studies have evaluated the use of different CADe devices to reduce adenoma miss rates during colonoscopy, and some have found that the technology contributed to significantly higher ADR and APC, the study authors write. However, most of these studies have been performed in academic settings.

Dr. Friedland and colleagues conducted a randomized controlled trial, called AI-SEE, to evaluate the use of CADe during colonoscopy in four community-based endoscopy centers located in California, Connecticut, Maryland, and New Jersey between September 2020 and September 2021. The trial included seven board-certified clinicians, who had ADR of 25%-37% before the study. The participants were randomly assigned to colonoscopies with or without CADe in blocks of 16 patients to ensure masking. Both groups had similar patient demographics.

The research team enrolled patients aged 45 years or older who presented for screening or low-risk surveillance colonoscopy, which was defined as a patient qualifying for a surveillance interval of 3 years or greater based on the U.S. Multi-Society Task Force 2020 Guidelines. Patients were excluded if they had a history of inflammatory bowel disease, known or suspected polyposis or hereditary colon cancer syndrome, history of colon resection, or a referral for a diagnostic colonoscopy.

Among 769 enrolled patients, 387 were randomly assigned to undergo colonoscopy with EndoVigilant, an AI-enabled CADe software for colonoscopy. It augments existing white-light colonoscopy in real time by highlighting colon polyps and displaying a graphic box around the lesion on the monitor. It can be deployed as a single- or dual-monitor device. Although the study was originally designed to use two monitors, three investigators expressed strong preference for the single-monitor mode, so the protocol allowed endoscopists to choose.

Primary outcomes included APC and adenoma per extraction (APE), which is the percentage of polyps removed that are adenomas. Secondary endpoints included procedural time, ADR, serrated polyp detection rate, serrated polyps per colonoscopy, and nonadenomatous, nonserrated polyps per colonoscopy.

Overall, the use of CADe didn’t show a significant difference in APC, at 0.73, compared with 0.67 for non-CADe.

Although the use of CADe didn’t lead to increased identification of serrated polyps per colonoscopy – both at 0.08 – CADe led to increased identification of nonadenomatous, nonserrated polyps per colonoscopy, at 0.90 versus 0.51.

There also wasn’t a significant difference in distribution regarding adenomatous polyp location, size, or morphology. However, there was a trend toward greater identification of 6-9 mm APC using CADe, at 0.13 versus 0.08.

Mean withdrawal time was longer in the CADe group, at 11.7 minutes versus 10.7 minutes. However, when no polyps were identified, the withdrawal times were similar, at 9.1 minutes versus 8.8 minutes.

In addition, there was no difference in ADR for screening colonoscopies between the non-CADe and CADe groups, at 34.6% versus 34.3%, or for surveillance procedures, at 43.9% versus 40%. CADe also didn’t improve serrated polyp detection rates for screening or surveillance.

CADe was also associated with decreased APE in all colonoscopies (44.8 vs. 56.8) as well as in screening colonoscopies (43 vs. 57.8).

A comparison of single-monitor CADe with dual-monitor CADe found no significant difference in the average number of adenomas or serrated polyps identified per colonoscopy. However, dual-monitor CADe identified significantly more non-adenomatous, nonserrated polyps per colonoscopy (1.18 vs. 0.42), more adenomas sized at least 10 mm (0.19 vs. 0.05), and more flat polyps (0.18 vs. 0).

The study was terminated early after the interim analysis point, marked by 769 valid subjects. At this point, the comparison of APC between the two groups resulted in a new sample size estimate required for final analysis of 6,557 per group. This revised large study size estimate made it impractical to continue, the study authors wrote. No adverse events were observed during the study.

“What our study shows is that current systems – and the one we used in this study performs very well when tested on a database of images or videos – don’t make a major impact on very crude outcome measures, such as the total number of adenomas detected by a group of endoscopists at typical private endoscopy centers,” Dr. Friedland said. “I’m not convinced that we have a good answer yet for where to go from here, but we need to keep working with our AI colleagues to figure out how to use this exciting technology to improve outcomes in colon cancer.”
 

Additional considerations

In a separate evaluation of EndoVigilant, the frame level sensitivity was 0.9 and the frame level specificity was 0.97. These calculations were conducted on a dataset not used in training or validation of this model, the authors noted.

In this study, it’s possible that experienced community-based endoscopists are proficient at detecting the adenomas highlighted by the CADe system, so the technology may not detect a significant number of additional adenomas, the authors wrote. It’s also possible that some endoscopists ignore lesions highlighted by CADe, including small lesions that might be difficult to identify as adenomas or are seen as clinically unimportant, which could reduce the potential benefit of CADe.

“It’s important to remember that these tools are meant to be endoscopist assistance devices, not endoscopist replacements. They provide added benefit by pointing out polyps while we do the best exam we can,” Aasma Shaukat, MD, a professor of medicine and gastroenterologist at NYU Langone Health, New York, said in an interview.

Dr. Shaukat, who wasn’t involved with this study, has researched CADe for screening and surveillance colonoscopies. She and colleagues found that CADe use improved APC without an increase in resection of nonneoplastic lesions.

“Different trials have reported different results, and at the end of the day, it’s an endoscopist assistance tool, like spellcheck in a document,” she said. “It’s nice if spellcheck points to an incorrect spelling, but you don’t have to use it. Similarly, we often don’t know in these studies what an endoscopist felt or believed about the tool when using it.”

The benefits of CADe could vary based on its software, setting, number of patients, patient characteristics, number of clinicians, provider experience and training, dual- versus single-monitor setup, and even time of day, she noted. Future studies could clarify these factors, as well as improve the technology.

“This is just the beginning of AI in this field, and while bounding boxes to indicate potential polyps is a good start, it’s not the be-all, end-all,” Dr. Shaukat said.

“We want AI software to be able to tell us more about the size of the polyp, histology, prep quality, landmarks in the colon, adequacy of resection, and more. There’s some work being geared toward developing the algorithms to do these additional aspects,” she added.

The study was sponsored by EndoVigilant. Some of the authors reported consultant roles with Neptune Medical, AgilTx, Intuitive Surgical, Capsovision, and EndoVigilant. Dr. Shaukat reported no relevant financial relationships.

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

Computer-aided detection (CADe) during colonoscopy may not lead to major improvements in key measures, particularly in community-based settings, according to a new study.

In a randomized clinical trial using EndoVigilant, there wasn’t a significant difference in adenomas per colonoscopy (APC) in procedures with the CADe tool versus those without it. In addition, the adenoma detection rate (ADR) and serrated polyp detection rate were similar in the CADe and non-CADe groups.

“Although we were disappointed that AI [artificial intelligence] did not improve detection of adenomas or serrated polyps in our study, we are still optimistic that this exciting technology will eventually impact endoscopy in a very positive way,” senior author Shai Friedland, MD, a professor of medicine at Stanford (Calif.) University and gastroenterologist with the Veterans Affairs Palo Alto Health Care System, said in an interview.

“The ultimate goal should be to improve the ability of colonoscopy to prevent morbidity and mortality from colon cancer, especially for endoscopists who may not be performing as well as they could be,” he said. “AI can potentially help prevent missed lesions due to fatigue or distraction, much like a warning system that averts car accidents. It can also potentially help endoscopists recognize dangerous – but rare – subtle lesions such as small, flat, and depressed cancers.”

The study was published online in the American Journal of Gastroenterology.
 

Analyzing detection rates

Several studies have evaluated the use of different CADe devices to reduce adenoma miss rates during colonoscopy, and some have found that the technology contributed to significantly higher ADR and APC, the study authors write. However, most of these studies have been performed in academic settings.

Dr. Friedland and colleagues conducted a randomized controlled trial, called AI-SEE, to evaluate the use of CADe during colonoscopy in four community-based endoscopy centers located in California, Connecticut, Maryland, and New Jersey between September 2020 and September 2021. The trial included seven board-certified clinicians, who had ADR of 25%-37% before the study. The participants were randomly assigned to colonoscopies with or without CADe in blocks of 16 patients to ensure masking. Both groups had similar patient demographics.

The research team enrolled patients aged 45 years or older who presented for screening or low-risk surveillance colonoscopy, which was defined as a patient qualifying for a surveillance interval of 3 years or greater based on the U.S. Multi-Society Task Force 2020 Guidelines. Patients were excluded if they had a history of inflammatory bowel disease, known or suspected polyposis or hereditary colon cancer syndrome, history of colon resection, or a referral for a diagnostic colonoscopy.

Among 769 enrolled patients, 387 were randomly assigned to undergo colonoscopy with EndoVigilant, an AI-enabled CADe software for colonoscopy. It augments existing white-light colonoscopy in real time by highlighting colon polyps and displaying a graphic box around the lesion on the monitor. It can be deployed as a single- or dual-monitor device. Although the study was originally designed to use two monitors, three investigators expressed strong preference for the single-monitor mode, so the protocol allowed endoscopists to choose.

Primary outcomes included APC and adenoma per extraction (APE), which is the percentage of polyps removed that are adenomas. Secondary endpoints included procedural time, ADR, serrated polyp detection rate, serrated polyps per colonoscopy, and nonadenomatous, nonserrated polyps per colonoscopy.

Overall, the use of CADe didn’t show a significant difference in APC, at 0.73, compared with 0.67 for non-CADe.

Although the use of CADe didn’t lead to increased identification of serrated polyps per colonoscopy – both at 0.08 – CADe led to increased identification of nonadenomatous, nonserrated polyps per colonoscopy, at 0.90 versus 0.51.

There also wasn’t a significant difference in distribution regarding adenomatous polyp location, size, or morphology. However, there was a trend toward greater identification of 6-9 mm APC using CADe, at 0.13 versus 0.08.

Mean withdrawal time was longer in the CADe group, at 11.7 minutes versus 10.7 minutes. However, when no polyps were identified, the withdrawal times were similar, at 9.1 minutes versus 8.8 minutes.

In addition, there was no difference in ADR for screening colonoscopies between the non-CADe and CADe groups, at 34.6% versus 34.3%, or for surveillance procedures, at 43.9% versus 40%. CADe also didn’t improve serrated polyp detection rates for screening or surveillance.

CADe was also associated with decreased APE in all colonoscopies (44.8 vs. 56.8) as well as in screening colonoscopies (43 vs. 57.8).

A comparison of single-monitor CADe with dual-monitor CADe found no significant difference in the average number of adenomas or serrated polyps identified per colonoscopy. However, dual-monitor CADe identified significantly more non-adenomatous, nonserrated polyps per colonoscopy (1.18 vs. 0.42), more adenomas sized at least 10 mm (0.19 vs. 0.05), and more flat polyps (0.18 vs. 0).

The study was terminated early after the interim analysis point, marked by 769 valid subjects. At this point, the comparison of APC between the two groups resulted in a new sample size estimate required for final analysis of 6,557 per group. This revised large study size estimate made it impractical to continue, the study authors wrote. No adverse events were observed during the study.

“What our study shows is that current systems – and the one we used in this study performs very well when tested on a database of images or videos – don’t make a major impact on very crude outcome measures, such as the total number of adenomas detected by a group of endoscopists at typical private endoscopy centers,” Dr. Friedland said. “I’m not convinced that we have a good answer yet for where to go from here, but we need to keep working with our AI colleagues to figure out how to use this exciting technology to improve outcomes in colon cancer.”
 

Additional considerations

In a separate evaluation of EndoVigilant, the frame level sensitivity was 0.9 and the frame level specificity was 0.97. These calculations were conducted on a dataset not used in training or validation of this model, the authors noted.

In this study, it’s possible that experienced community-based endoscopists are proficient at detecting the adenomas highlighted by the CADe system, so the technology may not detect a significant number of additional adenomas, the authors wrote. It’s also possible that some endoscopists ignore lesions highlighted by CADe, including small lesions that might be difficult to identify as adenomas or are seen as clinically unimportant, which could reduce the potential benefit of CADe.

“It’s important to remember that these tools are meant to be endoscopist assistance devices, not endoscopist replacements. They provide added benefit by pointing out polyps while we do the best exam we can,” Aasma Shaukat, MD, a professor of medicine and gastroenterologist at NYU Langone Health, New York, said in an interview.

Dr. Shaukat, who wasn’t involved with this study, has researched CADe for screening and surveillance colonoscopies. She and colleagues found that CADe use improved APC without an increase in resection of nonneoplastic lesions.

“Different trials have reported different results, and at the end of the day, it’s an endoscopist assistance tool, like spellcheck in a document,” she said. “It’s nice if spellcheck points to an incorrect spelling, but you don’t have to use it. Similarly, we often don’t know in these studies what an endoscopist felt or believed about the tool when using it.”

The benefits of CADe could vary based on its software, setting, number of patients, patient characteristics, number of clinicians, provider experience and training, dual- versus single-monitor setup, and even time of day, she noted. Future studies could clarify these factors, as well as improve the technology.

“This is just the beginning of AI in this field, and while bounding boxes to indicate potential polyps is a good start, it’s not the be-all, end-all,” Dr. Shaukat said.

“We want AI software to be able to tell us more about the size of the polyp, histology, prep quality, landmarks in the colon, adequacy of resection, and more. There’s some work being geared toward developing the algorithms to do these additional aspects,” she added.

The study was sponsored by EndoVigilant. Some of the authors reported consultant roles with Neptune Medical, AgilTx, Intuitive Surgical, Capsovision, and EndoVigilant. Dr. Shaukat reported no relevant financial relationships.

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

Computer-aided detection (CADe) during colonoscopy may not lead to major improvements in key measures, particularly in community-based settings, according to a new study.

In a randomized clinical trial using EndoVigilant, there wasn’t a significant difference in adenomas per colonoscopy (APC) in procedures with the CADe tool versus those without it. In addition, the adenoma detection rate (ADR) and serrated polyp detection rate were similar in the CADe and non-CADe groups.

“Although we were disappointed that AI [artificial intelligence] did not improve detection of adenomas or serrated polyps in our study, we are still optimistic that this exciting technology will eventually impact endoscopy in a very positive way,” senior author Shai Friedland, MD, a professor of medicine at Stanford (Calif.) University and gastroenterologist with the Veterans Affairs Palo Alto Health Care System, said in an interview.

“The ultimate goal should be to improve the ability of colonoscopy to prevent morbidity and mortality from colon cancer, especially for endoscopists who may not be performing as well as they could be,” he said. “AI can potentially help prevent missed lesions due to fatigue or distraction, much like a warning system that averts car accidents. It can also potentially help endoscopists recognize dangerous – but rare – subtle lesions such as small, flat, and depressed cancers.”

The study was published online in the American Journal of Gastroenterology.
 

Analyzing detection rates

Several studies have evaluated the use of different CADe devices to reduce adenoma miss rates during colonoscopy, and some have found that the technology contributed to significantly higher ADR and APC, the study authors write. However, most of these studies have been performed in academic settings.

Dr. Friedland and colleagues conducted a randomized controlled trial, called AI-SEE, to evaluate the use of CADe during colonoscopy in four community-based endoscopy centers located in California, Connecticut, Maryland, and New Jersey between September 2020 and September 2021. The trial included seven board-certified clinicians, who had ADR of 25%-37% before the study. The participants were randomly assigned to colonoscopies with or without CADe in blocks of 16 patients to ensure masking. Both groups had similar patient demographics.

The research team enrolled patients aged 45 years or older who presented for screening or low-risk surveillance colonoscopy, which was defined as a patient qualifying for a surveillance interval of 3 years or greater based on the U.S. Multi-Society Task Force 2020 Guidelines. Patients were excluded if they had a history of inflammatory bowel disease, known or suspected polyposis or hereditary colon cancer syndrome, history of colon resection, or a referral for a diagnostic colonoscopy.

Among 769 enrolled patients, 387 were randomly assigned to undergo colonoscopy with EndoVigilant, an AI-enabled CADe software for colonoscopy. It augments existing white-light colonoscopy in real time by highlighting colon polyps and displaying a graphic box around the lesion on the monitor. It can be deployed as a single- or dual-monitor device. Although the study was originally designed to use two monitors, three investigators expressed strong preference for the single-monitor mode, so the protocol allowed endoscopists to choose.

Primary outcomes included APC and adenoma per extraction (APE), which is the percentage of polyps removed that are adenomas. Secondary endpoints included procedural time, ADR, serrated polyp detection rate, serrated polyps per colonoscopy, and nonadenomatous, nonserrated polyps per colonoscopy.

Overall, the use of CADe didn’t show a significant difference in APC, at 0.73, compared with 0.67 for non-CADe.

Although the use of CADe didn’t lead to increased identification of serrated polyps per colonoscopy – both at 0.08 – CADe led to increased identification of nonadenomatous, nonserrated polyps per colonoscopy, at 0.90 versus 0.51.

There also wasn’t a significant difference in distribution regarding adenomatous polyp location, size, or morphology. However, there was a trend toward greater identification of 6-9 mm APC using CADe, at 0.13 versus 0.08.

Mean withdrawal time was longer in the CADe group, at 11.7 minutes versus 10.7 minutes. However, when no polyps were identified, the withdrawal times were similar, at 9.1 minutes versus 8.8 minutes.

In addition, there was no difference in ADR for screening colonoscopies between the non-CADe and CADe groups, at 34.6% versus 34.3%, or for surveillance procedures, at 43.9% versus 40%. CADe also didn’t improve serrated polyp detection rates for screening or surveillance.

CADe was also associated with decreased APE in all colonoscopies (44.8 vs. 56.8) as well as in screening colonoscopies (43 vs. 57.8).

A comparison of single-monitor CADe with dual-monitor CADe found no significant difference in the average number of adenomas or serrated polyps identified per colonoscopy. However, dual-monitor CADe identified significantly more non-adenomatous, nonserrated polyps per colonoscopy (1.18 vs. 0.42), more adenomas sized at least 10 mm (0.19 vs. 0.05), and more flat polyps (0.18 vs. 0).

The study was terminated early after the interim analysis point, marked by 769 valid subjects. At this point, the comparison of APC between the two groups resulted in a new sample size estimate required for final analysis of 6,557 per group. This revised large study size estimate made it impractical to continue, the study authors wrote. No adverse events were observed during the study.

“What our study shows is that current systems – and the one we used in this study performs very well when tested on a database of images or videos – don’t make a major impact on very crude outcome measures, such as the total number of adenomas detected by a group of endoscopists at typical private endoscopy centers,” Dr. Friedland said. “I’m not convinced that we have a good answer yet for where to go from here, but we need to keep working with our AI colleagues to figure out how to use this exciting technology to improve outcomes in colon cancer.”
 

Additional considerations

In a separate evaluation of EndoVigilant, the frame level sensitivity was 0.9 and the frame level specificity was 0.97. These calculations were conducted on a dataset not used in training or validation of this model, the authors noted.

In this study, it’s possible that experienced community-based endoscopists are proficient at detecting the adenomas highlighted by the CADe system, so the technology may not detect a significant number of additional adenomas, the authors wrote. It’s also possible that some endoscopists ignore lesions highlighted by CADe, including small lesions that might be difficult to identify as adenomas or are seen as clinically unimportant, which could reduce the potential benefit of CADe.

“It’s important to remember that these tools are meant to be endoscopist assistance devices, not endoscopist replacements. They provide added benefit by pointing out polyps while we do the best exam we can,” Aasma Shaukat, MD, a professor of medicine and gastroenterologist at NYU Langone Health, New York, said in an interview.

Dr. Shaukat, who wasn’t involved with this study, has researched CADe for screening and surveillance colonoscopies. She and colleagues found that CADe use improved APC without an increase in resection of nonneoplastic lesions.

“Different trials have reported different results, and at the end of the day, it’s an endoscopist assistance tool, like spellcheck in a document,” she said. “It’s nice if spellcheck points to an incorrect spelling, but you don’t have to use it. Similarly, we often don’t know in these studies what an endoscopist felt or believed about the tool when using it.”

The benefits of CADe could vary based on its software, setting, number of patients, patient characteristics, number of clinicians, provider experience and training, dual- versus single-monitor setup, and even time of day, she noted. Future studies could clarify these factors, as well as improve the technology.

“This is just the beginning of AI in this field, and while bounding boxes to indicate potential polyps is a good start, it’s not the be-all, end-all,” Dr. Shaukat said.

“We want AI software to be able to tell us more about the size of the polyp, histology, prep quality, landmarks in the colon, adequacy of resection, and more. There’s some work being geared toward developing the algorithms to do these additional aspects,” she added.

The study was sponsored by EndoVigilant. Some of the authors reported consultant roles with Neptune Medical, AgilTx, Intuitive Surgical, Capsovision, and EndoVigilant. Dr. Shaukat reported no relevant financial relationships.

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

The American College of Gastroenterology (ACG) issued a clinical guideline for the diagnosis and management of biliary strictures, or abnormal narrowing in the liver’s ductal drainage system.

The recommendations provide guidance on the care of patients with extrahepatic and perihilar strictures, with a focus on diagnosis and drainage. Although some of the principles may apply to intrahepatic strictures, the guideline doesn’t specifically address them. The new guideline is considered separate from the 2015 ACG guideline related to primary sclerosing cholangitis.

“The appropriate diagnosis and management of biliary strictures is still a big clinical challenge and has important implications in endoscopic, surgical, and oncological decision-making,” co-author Jennifer Maranki, MD, a professor of medicine and director of endoscopy at Penn State Hershey Medical Center, said in an interview.

“We wanted to provide the best possible guidance to gastroenterologists based on the available body of literature, with key shifts in diagnosis and management based on currently available modalities and tools,” she said.

The guideline was published in the March issue of the American Journal of Gastroenterology.

The recommendations were developed by a diverse group of authors from across the United States in recognition of the potential influence of commercial and intellectual conflicts of interest. The panel used a systematic process that involved structured literature searches by librarians and independent appraisal of the quality of evidence by dedicated methodologists, the authors write.

Overall, the team outlined 11 recommendations and 12 key concepts. A strong recommendation was made when the benefits of the test or intervention clearly outweighed the potential disadvantages. A conditional recommendation was made when some uncertainty remained about the balance of benefits and harms. Key concepts address important clinical questions that lack adequate evidence to inform recommendations. They are based on indirect evidence and expert opinion.

Epidemiology and diagnosis

The burden of biliary strictures is difficult to estimate, owing to the lack of a specific administrative code. The estimated cost of caring for biliary disease in the United States is about $16.9 billion annually, although this figure includes costs associated with gallbladder disease, choledocholithiasis, and other (nonobstructive) biliary disorders, the authors write.

Among the 57,000 new cases of pancreatic cancer each year, at least 60% will cause obstructive jaundice, resulting in about 34,000 annual cases of malignant extrahepatic biliary stricture, the team notes. In addition, about 3,000 cases of malignant perihilar stricture are expected in the United States each year. Patients may also seek care for benign strictures associated with chronic pancreatitis, primary sclerosing cholangitis, autoimmune disease, and post-cholecystectomy injury.

Under the first key concept, the authors note that biliary strictures in adults are more likely to be malignant than benign, except in certain well-defined scenarios. This underscores the importance of having a high index of clinical suspicion during evaluation, they add.

In general, a definitive tissue diagnosis is necessary to guide oncologic and endoscopic care for most strictures that aren’t surgically resectable at the time of presentation. For patients with extrahepatic biliary stricture due to an apparent or suspected pancreatic mass, endoscopic ultrasound (EUS) with fine-needle sampling (aspiration or biopsy) is recommended over endoscopic retrograde cholangiopancreatography (ERCP) as the preferred method of evaluation for malignancy.

For patients with suspected malignant perihilar stricture, multimodality sampling is recommended over brush cytology alone at the time of the index ERCP.

Guidance on drainage

For management, the principal objective is to restore the physiologic flow of bile into the duodenum. Although there is wide variability in the difficulty and risk of drainage, depending on location and complexity, perihilar strictures are generally more challenging and are riskier to drain than extrahepatic strictures. The goals should be to alleviate symptoms, reduce serum bilirubin to a level such that chemotherapy can be safely administered, and optimize surgical outcomes.

For benign extrahepatic biliary strictures, ERCP is the preferred modality for durable treatment. Fully covered self-expanding metallic stent (SEMS) placement is recommended over multiple plastic stents to reduce the number of procedures required for long-term treatment.

For extrahepatic strictures due to resectable pancreatic cancer or cholangiocarcinoma, the authors recommend against routine preoperative biliary drainage. However, drainage is warranted for some patients, including those with acute cholangitis, severe pruritus, very high serum bilirubin levels, those undergoing neoadjuvant therapy, and those for whom surgery is delayed.

For malignant extrahepatic strictures that are unresectable or borderline resectable, SEMS placement is recommended over plastic stents. The evidence is insufficient to recommend for or against uncovered SEMS versus fully covered SEMS.

For perihilar strictures due to suspected malignancy, the evidence is insufficient to recommend for or against ERCP versus percutaneous transhepatic biliary drainage. In addition, for malignant perihilar strictures, the evidence is insufficient to recommend for or against plastic stents versus uncovered SEMS.

For perihilar strictures due to cholangiocarcinoma in cases in which resection or transplantation is not possible, adjuvant endobiliary ablation plus plastic stent placement is recommended over plastic stent placement alone.

Overall, for patients with a biliary stricture for which ERCP is indicated but is unsuccessful or impossible, EUS-guided biliary access and drainage is recommended over PTBD, because it is associated with fewer adverse events. However, these interventional EUS procedures should be performed by an endoscopist with substantial experience.

“The workup of biliary strictures is challenging, invasive, and costly, requiring multiple diagnostic tools with highly variable yields,” co-author Victoria Gomez, MD, associate professor of medicine and director of bariatric endoscopy at Mayo Clinic, Jacksonville, Fla., said in an interview.

“Providers caring for these patients must be up to date with the most current evidence so that they can make the safest and most well-informed decisions for their patients,” she said. “These include considerations such as limiting the use of anesthesia, using tests that will result in the highest diagnostic yield, and providing effective therapies to decompress biliary obstruction.”

Future questions

Additional research is needed in several areas to strengthen recommendations and advance the field, the study authors write.

“Biliary strictures without an associated mass are a diagnostic challenge, and there are exciting opportunities to understand how new technologies, such as artificial intelligence, can be used to improve our assessment,” co-author Anna Tavakkoli, MD, assistant professor of internal medicine in digestive and liver diseases at the University of Texas Southwestern Medical Center, Dallas, said in an interview.

“Also, we highlighted several controversies in the drainage of perihilar strictures, including whether to use ERCP versus percutaneous drainage, whether metallic or plastic stents are better, and what the optimal stent placement should be,” she said. “Future multicenter studies are needed to address these key controversies.”

Although fully covered SEMS placement remains effective for benign biliary strictures, multiple plastic stents may be a better alternative in some cases. Such cases include those in which the stricture is close to the hilum, those in which the gallbladder is intact and in which crossing the cystic duct orifice cannot be avoided, those in which a fully covered SEMS has previously migrated or was not well tolerated, and those in which stricture has recurred after removal of a fully covered SEMS.

‘Comprehensive list’

“Overall, the authors have done a commendable job putting together a comprehensive list of recommendations that will invariably alter the practice of many therapeutic endoscopists for the diagnosis and management of biliary strictures,” Matthew Fasullo, DO, an advanced endoscopy and gastroenterology fellow at New York University Medical Center, told this news organization.

Dr. Fasullo, who wasn’t involved with the guideline, has published on advances in pathophysiology, diagnosis, and treatment for post-transplant biliary complications.

“The fact that ... cholangioscopy-directed biopsies after an initial negative evaluation via ERCP reveal malignancy in 54% of cases underscores the need for best practice guidelines and supports advancements in diagnostics to confidently rule in or out cancer,” he said.

“The movement toward multimodality sampling at the time of initial evaluation with a combination of brushing, fluoroscopy-directed biopsies, cholangioscopy-directed biopsies, and fluorescence in situ hybridization should become universally adopted in those with an ambiguous diagnosis,” he added. “As technology continues to improve, next-generation sequencing will prove to be an invaluable adjunct to the current pathological evaluation.”

The authors received no financial support for the guideline. One author has a consultant role for Takeda Pharmaceuticals and is an advisory board member role for Advarra. The other authors and Dr. Fasullo have disclosed no relevant financial relationships.

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

The American College of Gastroenterology (ACG) issued a clinical guideline for the diagnosis and management of biliary strictures, or abnormal narrowing in the liver’s ductal drainage system.

The recommendations provide guidance on the care of patients with extrahepatic and perihilar strictures, with a focus on diagnosis and drainage. Although some of the principles may apply to intrahepatic strictures, the guideline doesn’t specifically address them. The new guideline is considered separate from the 2015 ACG guideline related to primary sclerosing cholangitis.

“The appropriate diagnosis and management of biliary strictures is still a big clinical challenge and has important implications in endoscopic, surgical, and oncological decision-making,” co-author Jennifer Maranki, MD, a professor of medicine and director of endoscopy at Penn State Hershey Medical Center, said in an interview.

“We wanted to provide the best possible guidance to gastroenterologists based on the available body of literature, with key shifts in diagnosis and management based on currently available modalities and tools,” she said.

The guideline was published in the March issue of the American Journal of Gastroenterology.

The recommendations were developed by a diverse group of authors from across the United States in recognition of the potential influence of commercial and intellectual conflicts of interest. The panel used a systematic process that involved structured literature searches by librarians and independent appraisal of the quality of evidence by dedicated methodologists, the authors write.

Overall, the team outlined 11 recommendations and 12 key concepts. A strong recommendation was made when the benefits of the test or intervention clearly outweighed the potential disadvantages. A conditional recommendation was made when some uncertainty remained about the balance of benefits and harms. Key concepts address important clinical questions that lack adequate evidence to inform recommendations. They are based on indirect evidence and expert opinion.

Epidemiology and diagnosis

The burden of biliary strictures is difficult to estimate, owing to the lack of a specific administrative code. The estimated cost of caring for biliary disease in the United States is about $16.9 billion annually, although this figure includes costs associated with gallbladder disease, choledocholithiasis, and other (nonobstructive) biliary disorders, the authors write.

Among the 57,000 new cases of pancreatic cancer each year, at least 60% will cause obstructive jaundice, resulting in about 34,000 annual cases of malignant extrahepatic biliary stricture, the team notes. In addition, about 3,000 cases of malignant perihilar stricture are expected in the United States each year. Patients may also seek care for benign strictures associated with chronic pancreatitis, primary sclerosing cholangitis, autoimmune disease, and post-cholecystectomy injury.

Under the first key concept, the authors note that biliary strictures in adults are more likely to be malignant than benign, except in certain well-defined scenarios. This underscores the importance of having a high index of clinical suspicion during evaluation, they add.

In general, a definitive tissue diagnosis is necessary to guide oncologic and endoscopic care for most strictures that aren’t surgically resectable at the time of presentation. For patients with extrahepatic biliary stricture due to an apparent or suspected pancreatic mass, endoscopic ultrasound (EUS) with fine-needle sampling (aspiration or biopsy) is recommended over endoscopic retrograde cholangiopancreatography (ERCP) as the preferred method of evaluation for malignancy.

For patients with suspected malignant perihilar stricture, multimodality sampling is recommended over brush cytology alone at the time of the index ERCP.

Guidance on drainage

For management, the principal objective is to restore the physiologic flow of bile into the duodenum. Although there is wide variability in the difficulty and risk of drainage, depending on location and complexity, perihilar strictures are generally more challenging and are riskier to drain than extrahepatic strictures. The goals should be to alleviate symptoms, reduce serum bilirubin to a level such that chemotherapy can be safely administered, and optimize surgical outcomes.

For benign extrahepatic biliary strictures, ERCP is the preferred modality for durable treatment. Fully covered self-expanding metallic stent (SEMS) placement is recommended over multiple plastic stents to reduce the number of procedures required for long-term treatment.

For extrahepatic strictures due to resectable pancreatic cancer or cholangiocarcinoma, the authors recommend against routine preoperative biliary drainage. However, drainage is warranted for some patients, including those with acute cholangitis, severe pruritus, very high serum bilirubin levels, those undergoing neoadjuvant therapy, and those for whom surgery is delayed.

For malignant extrahepatic strictures that are unresectable or borderline resectable, SEMS placement is recommended over plastic stents. The evidence is insufficient to recommend for or against uncovered SEMS versus fully covered SEMS.

For perihilar strictures due to suspected malignancy, the evidence is insufficient to recommend for or against ERCP versus percutaneous transhepatic biliary drainage. In addition, for malignant perihilar strictures, the evidence is insufficient to recommend for or against plastic stents versus uncovered SEMS.

For perihilar strictures due to cholangiocarcinoma in cases in which resection or transplantation is not possible, adjuvant endobiliary ablation plus plastic stent placement is recommended over plastic stent placement alone.

Overall, for patients with a biliary stricture for which ERCP is indicated but is unsuccessful or impossible, EUS-guided biliary access and drainage is recommended over PTBD, because it is associated with fewer adverse events. However, these interventional EUS procedures should be performed by an endoscopist with substantial experience.

“The workup of biliary strictures is challenging, invasive, and costly, requiring multiple diagnostic tools with highly variable yields,” co-author Victoria Gomez, MD, associate professor of medicine and director of bariatric endoscopy at Mayo Clinic, Jacksonville, Fla., said in an interview.

“Providers caring for these patients must be up to date with the most current evidence so that they can make the safest and most well-informed decisions for their patients,” she said. “These include considerations such as limiting the use of anesthesia, using tests that will result in the highest diagnostic yield, and providing effective therapies to decompress biliary obstruction.”

Future questions

Additional research is needed in several areas to strengthen recommendations and advance the field, the study authors write.

“Biliary strictures without an associated mass are a diagnostic challenge, and there are exciting opportunities to understand how new technologies, such as artificial intelligence, can be used to improve our assessment,” co-author Anna Tavakkoli, MD, assistant professor of internal medicine in digestive and liver diseases at the University of Texas Southwestern Medical Center, Dallas, said in an interview.

“Also, we highlighted several controversies in the drainage of perihilar strictures, including whether to use ERCP versus percutaneous drainage, whether metallic or plastic stents are better, and what the optimal stent placement should be,” she said. “Future multicenter studies are needed to address these key controversies.”

Although fully covered SEMS placement remains effective for benign biliary strictures, multiple plastic stents may be a better alternative in some cases. Such cases include those in which the stricture is close to the hilum, those in which the gallbladder is intact and in which crossing the cystic duct orifice cannot be avoided, those in which a fully covered SEMS has previously migrated or was not well tolerated, and those in which stricture has recurred after removal of a fully covered SEMS.

‘Comprehensive list’

“Overall, the authors have done a commendable job putting together a comprehensive list of recommendations that will invariably alter the practice of many therapeutic endoscopists for the diagnosis and management of biliary strictures,” Matthew Fasullo, DO, an advanced endoscopy and gastroenterology fellow at New York University Medical Center, told this news organization.

Dr. Fasullo, who wasn’t involved with the guideline, has published on advances in pathophysiology, diagnosis, and treatment for post-transplant biliary complications.

“The fact that ... cholangioscopy-directed biopsies after an initial negative evaluation via ERCP reveal malignancy in 54% of cases underscores the need for best practice guidelines and supports advancements in diagnostics to confidently rule in or out cancer,” he said.

“The movement toward multimodality sampling at the time of initial evaluation with a combination of brushing, fluoroscopy-directed biopsies, cholangioscopy-directed biopsies, and fluorescence in situ hybridization should become universally adopted in those with an ambiguous diagnosis,” he added. “As technology continues to improve, next-generation sequencing will prove to be an invaluable adjunct to the current pathological evaluation.”

The authors received no financial support for the guideline. One author has a consultant role for Takeda Pharmaceuticals and is an advisory board member role for Advarra. The other authors and Dr. Fasullo have disclosed no relevant financial relationships.

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

The American College of Gastroenterology (ACG) issued a clinical guideline for the diagnosis and management of biliary strictures, or abnormal narrowing in the liver’s ductal drainage system.

The recommendations provide guidance on the care of patients with extrahepatic and perihilar strictures, with a focus on diagnosis and drainage. Although some of the principles may apply to intrahepatic strictures, the guideline doesn’t specifically address them. The new guideline is considered separate from the 2015 ACG guideline related to primary sclerosing cholangitis.

“The appropriate diagnosis and management of biliary strictures is still a big clinical challenge and has important implications in endoscopic, surgical, and oncological decision-making,” co-author Jennifer Maranki, MD, a professor of medicine and director of endoscopy at Penn State Hershey Medical Center, said in an interview.

“We wanted to provide the best possible guidance to gastroenterologists based on the available body of literature, with key shifts in diagnosis and management based on currently available modalities and tools,” she said.

The guideline was published in the March issue of the American Journal of Gastroenterology.

The recommendations were developed by a diverse group of authors from across the United States in recognition of the potential influence of commercial and intellectual conflicts of interest. The panel used a systematic process that involved structured literature searches by librarians and independent appraisal of the quality of evidence by dedicated methodologists, the authors write.

Overall, the team outlined 11 recommendations and 12 key concepts. A strong recommendation was made when the benefits of the test or intervention clearly outweighed the potential disadvantages. A conditional recommendation was made when some uncertainty remained about the balance of benefits and harms. Key concepts address important clinical questions that lack adequate evidence to inform recommendations. They are based on indirect evidence and expert opinion.

Epidemiology and diagnosis

The burden of biliary strictures is difficult to estimate, owing to the lack of a specific administrative code. The estimated cost of caring for biliary disease in the United States is about $16.9 billion annually, although this figure includes costs associated with gallbladder disease, choledocholithiasis, and other (nonobstructive) biliary disorders, the authors write.

Among the 57,000 new cases of pancreatic cancer each year, at least 60% will cause obstructive jaundice, resulting in about 34,000 annual cases of malignant extrahepatic biliary stricture, the team notes. In addition, about 3,000 cases of malignant perihilar stricture are expected in the United States each year. Patients may also seek care for benign strictures associated with chronic pancreatitis, primary sclerosing cholangitis, autoimmune disease, and post-cholecystectomy injury.

Under the first key concept, the authors note that biliary strictures in adults are more likely to be malignant than benign, except in certain well-defined scenarios. This underscores the importance of having a high index of clinical suspicion during evaluation, they add.

In general, a definitive tissue diagnosis is necessary to guide oncologic and endoscopic care for most strictures that aren’t surgically resectable at the time of presentation. For patients with extrahepatic biliary stricture due to an apparent or suspected pancreatic mass, endoscopic ultrasound (EUS) with fine-needle sampling (aspiration or biopsy) is recommended over endoscopic retrograde cholangiopancreatography (ERCP) as the preferred method of evaluation for malignancy.

For patients with suspected malignant perihilar stricture, multimodality sampling is recommended over brush cytology alone at the time of the index ERCP.

Guidance on drainage

For management, the principal objective is to restore the physiologic flow of bile into the duodenum. Although there is wide variability in the difficulty and risk of drainage, depending on location and complexity, perihilar strictures are generally more challenging and are riskier to drain than extrahepatic strictures. The goals should be to alleviate symptoms, reduce serum bilirubin to a level such that chemotherapy can be safely administered, and optimize surgical outcomes.

For benign extrahepatic biliary strictures, ERCP is the preferred modality for durable treatment. Fully covered self-expanding metallic stent (SEMS) placement is recommended over multiple plastic stents to reduce the number of procedures required for long-term treatment.

For extrahepatic strictures due to resectable pancreatic cancer or cholangiocarcinoma, the authors recommend against routine preoperative biliary drainage. However, drainage is warranted for some patients, including those with acute cholangitis, severe pruritus, very high serum bilirubin levels, those undergoing neoadjuvant therapy, and those for whom surgery is delayed.

For malignant extrahepatic strictures that are unresectable or borderline resectable, SEMS placement is recommended over plastic stents. The evidence is insufficient to recommend for or against uncovered SEMS versus fully covered SEMS.

For perihilar strictures due to suspected malignancy, the evidence is insufficient to recommend for or against ERCP versus percutaneous transhepatic biliary drainage. In addition, for malignant perihilar strictures, the evidence is insufficient to recommend for or against plastic stents versus uncovered SEMS.

For perihilar strictures due to cholangiocarcinoma in cases in which resection or transplantation is not possible, adjuvant endobiliary ablation plus plastic stent placement is recommended over plastic stent placement alone.

Overall, for patients with a biliary stricture for which ERCP is indicated but is unsuccessful or impossible, EUS-guided biliary access and drainage is recommended over PTBD, because it is associated with fewer adverse events. However, these interventional EUS procedures should be performed by an endoscopist with substantial experience.

“The workup of biliary strictures is challenging, invasive, and costly, requiring multiple diagnostic tools with highly variable yields,” co-author Victoria Gomez, MD, associate professor of medicine and director of bariatric endoscopy at Mayo Clinic, Jacksonville, Fla., said in an interview.

“Providers caring for these patients must be up to date with the most current evidence so that they can make the safest and most well-informed decisions for their patients,” she said. “These include considerations such as limiting the use of anesthesia, using tests that will result in the highest diagnostic yield, and providing effective therapies to decompress biliary obstruction.”

Future questions

Additional research is needed in several areas to strengthen recommendations and advance the field, the study authors write.

“Biliary strictures without an associated mass are a diagnostic challenge, and there are exciting opportunities to understand how new technologies, such as artificial intelligence, can be used to improve our assessment,” co-author Anna Tavakkoli, MD, assistant professor of internal medicine in digestive and liver diseases at the University of Texas Southwestern Medical Center, Dallas, said in an interview.

“Also, we highlighted several controversies in the drainage of perihilar strictures, including whether to use ERCP versus percutaneous drainage, whether metallic or plastic stents are better, and what the optimal stent placement should be,” she said. “Future multicenter studies are needed to address these key controversies.”

Although fully covered SEMS placement remains effective for benign biliary strictures, multiple plastic stents may be a better alternative in some cases. Such cases include those in which the stricture is close to the hilum, those in which the gallbladder is intact and in which crossing the cystic duct orifice cannot be avoided, those in which a fully covered SEMS has previously migrated or was not well tolerated, and those in which stricture has recurred after removal of a fully covered SEMS.

‘Comprehensive list’

“Overall, the authors have done a commendable job putting together a comprehensive list of recommendations that will invariably alter the practice of many therapeutic endoscopists for the diagnosis and management of biliary strictures,” Matthew Fasullo, DO, an advanced endoscopy and gastroenterology fellow at New York University Medical Center, told this news organization.

Dr. Fasullo, who wasn’t involved with the guideline, has published on advances in pathophysiology, diagnosis, and treatment for post-transplant biliary complications.

“The fact that ... cholangioscopy-directed biopsies after an initial negative evaluation via ERCP reveal malignancy in 54% of cases underscores the need for best practice guidelines and supports advancements in diagnostics to confidently rule in or out cancer,” he said.

“The movement toward multimodality sampling at the time of initial evaluation with a combination of brushing, fluoroscopy-directed biopsies, cholangioscopy-directed biopsies, and fluorescence in situ hybridization should become universally adopted in those with an ambiguous diagnosis,” he added. “As technology continues to improve, next-generation sequencing will prove to be an invaluable adjunct to the current pathological evaluation.”

The authors received no financial support for the guideline. One author has a consultant role for Takeda Pharmaceuticals and is an advisory board member role for Advarra. The other authors and Dr. Fasullo have disclosed no relevant financial relationships.

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

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Schreiber_Rainer_GERMANY_web.jpg

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Schreiber_Rainer_GERMANY_web.jpg

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

To defend the gut from microbes and pathogens, Paneth cells rely on TMEM16A, a calcium-activated chloride channel, and TMEM16F, a phospholipid scramblase, according to a new study published in Gastro Hep Advances.

The Paneth cells in mice missing TMEM16A or TMEM16F showed defects in signaling and release of secretary factors, researchers reported.

Schreiber_Rainer_GERMANY_web.jpg

Inhibiting or activating TMEM16A and TMEM16F is likely to affect microbial content and immune functions in the small intestine, concluded Rainer Schreiber, Dr. rer. nat., of the Institute of Physiology at Universität Regensburg, Germany, and colleagues.

“Many small molecules and numerous natural or herbal compounds have been identified that either inhibit or activate TMEM16A or TMEM16F,” they wrote. “Some of these compounds may turn out to be useful therapeutics in inflammatory bowel disease, intestinal allergies, or abnormal colonization of the gut.”

Paneth cells play a central role in intestinal innate immune response, the authors wrote. Located at the base of small intestinal crypts and occasionally found in the proximal colon, these cells have defensive functions, such as protecting stem cells in response to invading microbes and eradicating ingested pathogens from intestinal crypts. Through secretion, they also regulate the composition and number of commensal intestinal bacteria. In inflammatory bowel disease, the Paneth cell zone expands due to an increase in cell size and cell number.

In previous studies, cholinergic stimulation provided enhanced protection in animals orally infected with virulent Salmonella enterica. However, the mechanisms of luminal stimulation of Paneth cell secretion in response to bacteria or lipopolysaccharide are unclear. Recent reports show that TMEM16A (also known as anoctamin 1, or ANO1) and TMEM16F (anoctamin 6, or ANO6) control intracellular calcium (Ca2+) signaling and that high local Ca2+ levels support exocytosis in intestinal cells.

The researchers analyzed the roles of the two molecules in Paneth cell secretion using mice with intestinal epithelial-specific knockout of TMEM16A or TMEM16F. They examined tissue structures and Paneth cells in the mice, as well as Paneth cell exocytosis in small intestinal organoids in vitro. They also compared Ca2+ signals between wild-type and knockout mice and analyzed bacterial colonization and intestinal apoptosis.

In wild-type mice, TMEM16A was detected at the apical pole of crypt epithelial cells, while TMEM16F was located predominantly at the basolateral side. Notably, TMEM16A was also located in intestinal smooth muscle cells.

Compared with wild-type mice, the TMEM16 knockout mice had pronounced accumulation of lysozyme in jejunal Paneth cells. This suggests a defect in Paneth cell secretion in the absence of TMEM16A and TMEM16F, the authors wrote.

Previous studies had found an accumulation of mucus in intestinal goblet cells in mice with tissue-specific knockout of TMEM16A and TMEM16F. In this study, a more detailed analysis of mucus using periodic acid-Schiff staining of duodenum, jejunum, and ileum confirmed those results and demonstrated enhanced mucus in the small intestine of knockout mice. This suggests that a lack of TMEM16A or TMEM16F causes a broad secretion defect in secretory cells, including Paneth cells, the authors wrote.

Because granules of Paneth cells contain antimicrobial peptides, cytokines, and other factors that control proliferation or epithelial cell death, the researchers analyzed the presence of Gram-positive and Gram-negative bacteria in the jejunum and ileum. Compared to wild-type mice, the number of bacteria was higher in the ileum of both TMEM16A and TMEM16F knockout mice and in the jejunum of TMEM16F knockout mice, suggesting reduced antimicrobial activity in the absence of TMEM16 proteins.

The researchers also compared regulated cell death of intestinal epithelial cells in jejuna of wild-type and knockout mice. They found largely reduced cell death in both TMEM16A and TMEM16F knockout mice.

“Intestinal inflammatory diseases such as Crohn’s disease, necrotizing enterocolitis, and intestinal microbiota dysbiosis have been related to abnormal Paneth cell physiology,” the authors wrote. “The present findings may therefore provide the basis for a novel anti-inflammatory therapy for intestinal diseases and may improve our understanding of the molecular mechanism of some of the currently available drugs.”

The study was supported by the Deutsche Forschungsgemeinschaft funding program. The authors disclosed no conflicts of interest.

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Midwives provide safe primary care for pregnant women who are at various levels of medical risk in British Columbia, Canada, new data suggest.

In most cases, for midwifery clients, birth outcomes were similar to or were better than birth outcomes of patients who had physician-led or obstetrician-led care.

In addition, midwifery clients were less likely to experience preterm births or have low-birth-weight babies and to experience cesarean deliveries or births involving instruments.

“Based on previous research, we know that midwives provide safe care for healthy childbearing people or those with no or few risk factors that might complicate the pregnancy or birth,” lead author Kathrin Stoll, PhD, a research associate in the University of British Columbia’s department of family practice, told this news organization.

“What we didn’t know until now is whether midwives provide safe care to people with moderate and high medical risks and what proportion of B.C. [British Columbia] midwifery clients are low, moderate, and high risk,” she said. “This is important to know because of the misperception that midwives only look after low-risk people. This misperception is sometimes used against midwives to justify giving them fewer resources and supports.”

The study was published  in the Canadian Medical Association Journal.
 

Increasing demand

Registered midwives have been part of the health care system in British Columbia since 1998, according to the study authors. The number of pregnant people who are attended by midwives during birth has steadily increased from 4.8% in 2004-2005 to 15.6% in 2019-2020.

The investigators analyzed 2008-2018 data from the British Columbia Perinatal Data Registry, which contains data for 99% of births, including home births. Their analysis included 425,056 births for which a family physician, an obstetrician, or a midwife was listed as the most responsible provider (MRP). The investigators assessed pregnancy risk status (low, moderate, or high), which was determined on the basis of an adapted perinatal risk scoring system used by the Alberta Perinatal Health Program. They estimated the differences in neonatal and maternal outcomes between MRP groups by calculating adjusted absolute and relative risks.

Among the 425,056 births, 63,151 (14.9%) had a midwife as the MRP, 189,679 (44.6%) had a family physician, and 172,226 (40.5%) had an obstetrician. The antenatal risk score ranged from 0 to 23 (median score, 2).

The proportion of births with midwife-led care increased from 9.2% to 19.8% from 2008-2018. In 2018, midwives were listed as the MRP for 24.3% of low-risk, 14.3% of moderate-risk, and 7.9% of high-risk births in the province. This represented an absolute increase of 9.1% for low-risk, 7.7% for moderate-risk, and 5.7% for high-risk births during the study period.

Among the 12,169 at-home births that took place during the study period, 9,776 (80.3%) were low-risk, 2,329 (19.1%) were moderate-risk, and 64 (0.5%) were high-risk births. As the risk score increased, so did the proportion of midwifery and family physician clients who were delivered by obstetricians. Across all risk strata, more family physician clients than midwifery clients underwent deliveries by obstetricians.

Overall, the risk of perinatal death for midwifery clients was similar to the risk for those under the care of family physicians across all risk levels. Low- and moderate-risk clients with midwife-led care were significantly less likely to experience a perinatal death, compared with those with obstetrician-led care, although the adjusted absolute risk differences were small. In the high-risk group, there was no significant difference in the rate of perinatal deaths between midwife-led and physician-led care.

In addition, clients with midwife-led care were significantly less likely to experience preterm birth and have a low-birth-weight baby regardless of medical risk level. The adjusted relative risk of an Apgar score of less than 7 at 5 minutes was significantly lower for midwife-led care than for physician-led care for nearly all comparisons.

The cesarean delivery rate among midwifery clients in the low-risk group was 7.2%, compared with 12.2% for family physicians and 42.3% for obstetrician clients. Cesarean delivery rates increased for midwifery clients as medical risk increased but were significantly lower than the physician rates across all medical risk levels.

Among low-risk clients, the absolute risk reduction for cesarean delivery was 34.4% with midwife-led care, compared with obstetrician-led care. The absolute risk difference increased to 55.3% for moderate-risk clients and to 42.2% for high-risk clients.
 

Labor induction varied

Although low-risk midwifery clients were significantly less likely to experience labor induction with oxytocin, high-risk midwifery clients were more than twice as likely to undergo induction with oxytocin than obstetrician clients (adjusted absolute difference, 11.3%).

For most risk levels, midwifery clients were less likely to have an assisted vaginal birth than physician clients, and they were significantly more likely to have a spontaneous vaginal birth. Low-risk clients who had a midwife as the MRP were nearly twice as likely to have a spontaneous vaginal birth than obstetricians’ clients, and moderate-risk clients were nearly four times as likely to have a spontaneous vaginal birth.

The rates of vaginal birth after cesarean delivery (VBAC) were significantly higher when a midwife was the MRP. In comparing midwifery clients with family physician clients, the relative and absolute differences were small, but they were larger when comparing midwifery clients with obstetrician clients. Among low-risk clients, the VBAC rate was 85.3% among midwifery clients, compared with 78.6% among family physician clients and 51.5% among obstetrician clients.

In general, the prevalence rates of adverse maternal outcomes (including blood transfusion, intensive care admissions, uterine rupture, and postpartum wound infection) were low for midwifery clients across all risk levels.

Breast- or chest-feeding at birth was significantly more common among midwifery clients across all risk levels as well.

Today, nearly 1 in 4 childbearing people in British Columbia receive care from a midwife at some point during pregnancy, birth, or the postpartum period, the study authors write. During the past 20 years, the profile of clients has evolved to include more moderate- and high-risk patients.

“Clients with more complex medical needs take more time and need more support,” said Dr. Stoll. “This means that midwives continue to stay on call, responding to pages and urgent medical concerns for their clients with no pay for being on call, no days off even for sick days, and unsafe working hours, often working more than 24 hours at a time. If we want to expand midwifery to communities where they are needed most, we need to provide an enabling environment.”

Additional studies are needed as to how different practice and remuneration models affect clinical outcomes, health care costs, and client and provider experiences, the study authors write. At the same time, there are several barriers to obtaining funding, conducting studies, and publishing research by and about midwives in Canada, Dr. Stoll said – barriers that she and her co-authors faced.
 

Seeking broader access

Alixandra Bacon, a registered midwife and president of the Canadian Association of Midwives, said, “These findings demonstrate that pregnant people at any level of medical risk can benefit from midwifery care. This is a testament both to the benefits of the Canadian midwifery model of care and to the seamless integration of midwifery into collaborative teams and the health system.” Ms. Bacon wasn’t involved with this study.

“If we can realize our goal of equitable access to midwifery care for all families in Canada, we can help to decrease rates of unnecessary medical intervention, preterm labor, and stillbirth,” she added.

“Midwifery is well established across most of Canada. This is yet one more piece of evidence that shows the clinical benefits of midwifery care,” Jasmin Tecson, a registered midwife and president of the Association of Ontario Midwives, said in an interview.

Ms. Tecson, who wasn’t involved with this study, noted the increasing number of clients with more complex health and social needs in Ontario. “It is time to think about how the skills and knowledge of midwives can be used with clients of different risk profiles and how the current scope of practice of midwives can be optimized and expanded,” she said. “For example, Ontario midwives are still required to prescribe medications from a limited list, despite the potential additional clinical risks and health system costs that this creates.”

The study received financial support from the University of British Columbia Stollery Fund and the University of British Columbia Work Learn Program. Dr. Stoll has an unpaid role with the Midwives Association Contract Negotiation Advisory Council. Ms. Bacon and Ms. Tecson disclosed no relevant financial relationships.

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

Midwives provide safe primary care for pregnant women who are at various levels of medical risk in British Columbia, Canada, new data suggest.

In most cases, for midwifery clients, birth outcomes were similar to or were better than birth outcomes of patients who had physician-led or obstetrician-led care.

In addition, midwifery clients were less likely to experience preterm births or have low-birth-weight babies and to experience cesarean deliveries or births involving instruments.

“Based on previous research, we know that midwives provide safe care for healthy childbearing people or those with no or few risk factors that might complicate the pregnancy or birth,” lead author Kathrin Stoll, PhD, a research associate in the University of British Columbia’s department of family practice, told this news organization.

“What we didn’t know until now is whether midwives provide safe care to people with moderate and high medical risks and what proportion of B.C. [British Columbia] midwifery clients are low, moderate, and high risk,” she said. “This is important to know because of the misperception that midwives only look after low-risk people. This misperception is sometimes used against midwives to justify giving them fewer resources and supports.”

The study was published  in the Canadian Medical Association Journal.
 

Increasing demand

Registered midwives have been part of the health care system in British Columbia since 1998, according to the study authors. The number of pregnant people who are attended by midwives during birth has steadily increased from 4.8% in 2004-2005 to 15.6% in 2019-2020.

The investigators analyzed 2008-2018 data from the British Columbia Perinatal Data Registry, which contains data for 99% of births, including home births. Their analysis included 425,056 births for which a family physician, an obstetrician, or a midwife was listed as the most responsible provider (MRP). The investigators assessed pregnancy risk status (low, moderate, or high), which was determined on the basis of an adapted perinatal risk scoring system used by the Alberta Perinatal Health Program. They estimated the differences in neonatal and maternal outcomes between MRP groups by calculating adjusted absolute and relative risks.

Among the 425,056 births, 63,151 (14.9%) had a midwife as the MRP, 189,679 (44.6%) had a family physician, and 172,226 (40.5%) had an obstetrician. The antenatal risk score ranged from 0 to 23 (median score, 2).

The proportion of births with midwife-led care increased from 9.2% to 19.8% from 2008-2018. In 2018, midwives were listed as the MRP for 24.3% of low-risk, 14.3% of moderate-risk, and 7.9% of high-risk births in the province. This represented an absolute increase of 9.1% for low-risk, 7.7% for moderate-risk, and 5.7% for high-risk births during the study period.

Among the 12,169 at-home births that took place during the study period, 9,776 (80.3%) were low-risk, 2,329 (19.1%) were moderate-risk, and 64 (0.5%) were high-risk births. As the risk score increased, so did the proportion of midwifery and family physician clients who were delivered by obstetricians. Across all risk strata, more family physician clients than midwifery clients underwent deliveries by obstetricians.

Overall, the risk of perinatal death for midwifery clients was similar to the risk for those under the care of family physicians across all risk levels. Low- and moderate-risk clients with midwife-led care were significantly less likely to experience a perinatal death, compared with those with obstetrician-led care, although the adjusted absolute risk differences were small. In the high-risk group, there was no significant difference in the rate of perinatal deaths between midwife-led and physician-led care.

In addition, clients with midwife-led care were significantly less likely to experience preterm birth and have a low-birth-weight baby regardless of medical risk level. The adjusted relative risk of an Apgar score of less than 7 at 5 minutes was significantly lower for midwife-led care than for physician-led care for nearly all comparisons.

The cesarean delivery rate among midwifery clients in the low-risk group was 7.2%, compared with 12.2% for family physicians and 42.3% for obstetrician clients. Cesarean delivery rates increased for midwifery clients as medical risk increased but were significantly lower than the physician rates across all medical risk levels.

Among low-risk clients, the absolute risk reduction for cesarean delivery was 34.4% with midwife-led care, compared with obstetrician-led care. The absolute risk difference increased to 55.3% for moderate-risk clients and to 42.2% for high-risk clients.
 

Labor induction varied

Although low-risk midwifery clients were significantly less likely to experience labor induction with oxytocin, high-risk midwifery clients were more than twice as likely to undergo induction with oxytocin than obstetrician clients (adjusted absolute difference, 11.3%).

For most risk levels, midwifery clients were less likely to have an assisted vaginal birth than physician clients, and they were significantly more likely to have a spontaneous vaginal birth. Low-risk clients who had a midwife as the MRP were nearly twice as likely to have a spontaneous vaginal birth than obstetricians’ clients, and moderate-risk clients were nearly four times as likely to have a spontaneous vaginal birth.

The rates of vaginal birth after cesarean delivery (VBAC) were significantly higher when a midwife was the MRP. In comparing midwifery clients with family physician clients, the relative and absolute differences were small, but they were larger when comparing midwifery clients with obstetrician clients. Among low-risk clients, the VBAC rate was 85.3% among midwifery clients, compared with 78.6% among family physician clients and 51.5% among obstetrician clients.

In general, the prevalence rates of adverse maternal outcomes (including blood transfusion, intensive care admissions, uterine rupture, and postpartum wound infection) were low for midwifery clients across all risk levels.

Breast- or chest-feeding at birth was significantly more common among midwifery clients across all risk levels as well.

Today, nearly 1 in 4 childbearing people in British Columbia receive care from a midwife at some point during pregnancy, birth, or the postpartum period, the study authors write. During the past 20 years, the profile of clients has evolved to include more moderate- and high-risk patients.

“Clients with more complex medical needs take more time and need more support,” said Dr. Stoll. “This means that midwives continue to stay on call, responding to pages and urgent medical concerns for their clients with no pay for being on call, no days off even for sick days, and unsafe working hours, often working more than 24 hours at a time. If we want to expand midwifery to communities where they are needed most, we need to provide an enabling environment.”

Additional studies are needed as to how different practice and remuneration models affect clinical outcomes, health care costs, and client and provider experiences, the study authors write. At the same time, there are several barriers to obtaining funding, conducting studies, and publishing research by and about midwives in Canada, Dr. Stoll said – barriers that she and her co-authors faced.
 

Seeking broader access

Alixandra Bacon, a registered midwife and president of the Canadian Association of Midwives, said, “These findings demonstrate that pregnant people at any level of medical risk can benefit from midwifery care. This is a testament both to the benefits of the Canadian midwifery model of care and to the seamless integration of midwifery into collaborative teams and the health system.” Ms. Bacon wasn’t involved with this study.

“If we can realize our goal of equitable access to midwifery care for all families in Canada, we can help to decrease rates of unnecessary medical intervention, preterm labor, and stillbirth,” she added.

“Midwifery is well established across most of Canada. This is yet one more piece of evidence that shows the clinical benefits of midwifery care,” Jasmin Tecson, a registered midwife and president of the Association of Ontario Midwives, said in an interview.

Ms. Tecson, who wasn’t involved with this study, noted the increasing number of clients with more complex health and social needs in Ontario. “It is time to think about how the skills and knowledge of midwives can be used with clients of different risk profiles and how the current scope of practice of midwives can be optimized and expanded,” she said. “For example, Ontario midwives are still required to prescribe medications from a limited list, despite the potential additional clinical risks and health system costs that this creates.”

The study received financial support from the University of British Columbia Stollery Fund and the University of British Columbia Work Learn Program. Dr. Stoll has an unpaid role with the Midwives Association Contract Negotiation Advisory Council. Ms. Bacon and Ms. Tecson disclosed no relevant financial relationships.

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

Midwives provide safe primary care for pregnant women who are at various levels of medical risk in British Columbia, Canada, new data suggest.

In most cases, for midwifery clients, birth outcomes were similar to or were better than birth outcomes of patients who had physician-led or obstetrician-led care.

In addition, midwifery clients were less likely to experience preterm births or have low-birth-weight babies and to experience cesarean deliveries or births involving instruments.

“Based on previous research, we know that midwives provide safe care for healthy childbearing people or those with no or few risk factors that might complicate the pregnancy or birth,” lead author Kathrin Stoll, PhD, a research associate in the University of British Columbia’s department of family practice, told this news organization.

“What we didn’t know until now is whether midwives provide safe care to people with moderate and high medical risks and what proportion of B.C. [British Columbia] midwifery clients are low, moderate, and high risk,” she said. “This is important to know because of the misperception that midwives only look after low-risk people. This misperception is sometimes used against midwives to justify giving them fewer resources and supports.”

The study was published  in the Canadian Medical Association Journal.
 

Increasing demand

Registered midwives have been part of the health care system in British Columbia since 1998, according to the study authors. The number of pregnant people who are attended by midwives during birth has steadily increased from 4.8% in 2004-2005 to 15.6% in 2019-2020.

The investigators analyzed 2008-2018 data from the British Columbia Perinatal Data Registry, which contains data for 99% of births, including home births. Their analysis included 425,056 births for which a family physician, an obstetrician, or a midwife was listed as the most responsible provider (MRP). The investigators assessed pregnancy risk status (low, moderate, or high), which was determined on the basis of an adapted perinatal risk scoring system used by the Alberta Perinatal Health Program. They estimated the differences in neonatal and maternal outcomes between MRP groups by calculating adjusted absolute and relative risks.

Among the 425,056 births, 63,151 (14.9%) had a midwife as the MRP, 189,679 (44.6%) had a family physician, and 172,226 (40.5%) had an obstetrician. The antenatal risk score ranged from 0 to 23 (median score, 2).

The proportion of births with midwife-led care increased from 9.2% to 19.8% from 2008-2018. In 2018, midwives were listed as the MRP for 24.3% of low-risk, 14.3% of moderate-risk, and 7.9% of high-risk births in the province. This represented an absolute increase of 9.1% for low-risk, 7.7% for moderate-risk, and 5.7% for high-risk births during the study period.

Among the 12,169 at-home births that took place during the study period, 9,776 (80.3%) were low-risk, 2,329 (19.1%) were moderate-risk, and 64 (0.5%) were high-risk births. As the risk score increased, so did the proportion of midwifery and family physician clients who were delivered by obstetricians. Across all risk strata, more family physician clients than midwifery clients underwent deliveries by obstetricians.

Overall, the risk of perinatal death for midwifery clients was similar to the risk for those under the care of family physicians across all risk levels. Low- and moderate-risk clients with midwife-led care were significantly less likely to experience a perinatal death, compared with those with obstetrician-led care, although the adjusted absolute risk differences were small. In the high-risk group, there was no significant difference in the rate of perinatal deaths between midwife-led and physician-led care.

In addition, clients with midwife-led care were significantly less likely to experience preterm birth and have a low-birth-weight baby regardless of medical risk level. The adjusted relative risk of an Apgar score of less than 7 at 5 minutes was significantly lower for midwife-led care than for physician-led care for nearly all comparisons.

The cesarean delivery rate among midwifery clients in the low-risk group was 7.2%, compared with 12.2% for family physicians and 42.3% for obstetrician clients. Cesarean delivery rates increased for midwifery clients as medical risk increased but were significantly lower than the physician rates across all medical risk levels.

Among low-risk clients, the absolute risk reduction for cesarean delivery was 34.4% with midwife-led care, compared with obstetrician-led care. The absolute risk difference increased to 55.3% for moderate-risk clients and to 42.2% for high-risk clients.
 

Labor induction varied

Although low-risk midwifery clients were significantly less likely to experience labor induction with oxytocin, high-risk midwifery clients were more than twice as likely to undergo induction with oxytocin than obstetrician clients (adjusted absolute difference, 11.3%).

For most risk levels, midwifery clients were less likely to have an assisted vaginal birth than physician clients, and they were significantly more likely to have a spontaneous vaginal birth. Low-risk clients who had a midwife as the MRP were nearly twice as likely to have a spontaneous vaginal birth than obstetricians’ clients, and moderate-risk clients were nearly four times as likely to have a spontaneous vaginal birth.

The rates of vaginal birth after cesarean delivery (VBAC) were significantly higher when a midwife was the MRP. In comparing midwifery clients with family physician clients, the relative and absolute differences were small, but they were larger when comparing midwifery clients with obstetrician clients. Among low-risk clients, the VBAC rate was 85.3% among midwifery clients, compared with 78.6% among family physician clients and 51.5% among obstetrician clients.

In general, the prevalence rates of adverse maternal outcomes (including blood transfusion, intensive care admissions, uterine rupture, and postpartum wound infection) were low for midwifery clients across all risk levels.

Breast- or chest-feeding at birth was significantly more common among midwifery clients across all risk levels as well.

Today, nearly 1 in 4 childbearing people in British Columbia receive care from a midwife at some point during pregnancy, birth, or the postpartum period, the study authors write. During the past 20 years, the profile of clients has evolved to include more moderate- and high-risk patients.

“Clients with more complex medical needs take more time and need more support,” said Dr. Stoll. “This means that midwives continue to stay on call, responding to pages and urgent medical concerns for their clients with no pay for being on call, no days off even for sick days, and unsafe working hours, often working more than 24 hours at a time. If we want to expand midwifery to communities where they are needed most, we need to provide an enabling environment.”

Additional studies are needed as to how different practice and remuneration models affect clinical outcomes, health care costs, and client and provider experiences, the study authors write. At the same time, there are several barriers to obtaining funding, conducting studies, and publishing research by and about midwives in Canada, Dr. Stoll said – barriers that she and her co-authors faced.
 

Seeking broader access

Alixandra Bacon, a registered midwife and president of the Canadian Association of Midwives, said, “These findings demonstrate that pregnant people at any level of medical risk can benefit from midwifery care. This is a testament both to the benefits of the Canadian midwifery model of care and to the seamless integration of midwifery into collaborative teams and the health system.” Ms. Bacon wasn’t involved with this study.

“If we can realize our goal of equitable access to midwifery care for all families in Canada, we can help to decrease rates of unnecessary medical intervention, preterm labor, and stillbirth,” she added.

“Midwifery is well established across most of Canada. This is yet one more piece of evidence that shows the clinical benefits of midwifery care,” Jasmin Tecson, a registered midwife and president of the Association of Ontario Midwives, said in an interview.

Ms. Tecson, who wasn’t involved with this study, noted the increasing number of clients with more complex health and social needs in Ontario. “It is time to think about how the skills and knowledge of midwives can be used with clients of different risk profiles and how the current scope of practice of midwives can be optimized and expanded,” she said. “For example, Ontario midwives are still required to prescribe medications from a limited list, despite the potential additional clinical risks and health system costs that this creates.”

The study received financial support from the University of British Columbia Stollery Fund and the University of British Columbia Work Learn Program. Dr. Stoll has an unpaid role with the Midwives Association Contract Negotiation Advisory Council. Ms. Bacon and Ms. Tecson disclosed no relevant financial relationships.

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

For adults with eosinophilic esophagitis (EoE), eliminating animal milk alone appears to be as effective for treating the disease as forgoing milk and five other foods, according to a new report.

A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.

“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.

“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”

The study was published in The Lancet Gastroenterology and Hepatology.
 

Studying EOE and food elimination

Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.

In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.

In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.

Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).

If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.

At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.

There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.

The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.

Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.

“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
 

Incorporating food elimination therapy

Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.

Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.

In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.

“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”

Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.

“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.

The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
 

For adults with eosinophilic esophagitis (EoE), eliminating animal milk alone appears to be as effective for treating the disease as forgoing milk and five other foods, according to a new report.

A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.

“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.

“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”

The study was published in The Lancet Gastroenterology and Hepatology.
 

Studying EOE and food elimination

Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.

In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.

In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.

Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).

If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.

At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.

There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.

The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.

Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.

“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
 

Incorporating food elimination therapy

Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.

Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.

In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.

“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”

Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.

“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.

The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
 

For adults with eosinophilic esophagitis (EoE), eliminating animal milk alone appears to be as effective for treating the disease as forgoing milk and five other foods, according to a new report.

A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.

“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.

“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”

The study was published in The Lancet Gastroenterology and Hepatology.
 

Studying EOE and food elimination

Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.

In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.

In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.

Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).

If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.

At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.

There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.

The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.

Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.

“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
 

Incorporating food elimination therapy

Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.

Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.

In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.

“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”

Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.

“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.

The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.