IBD & Intestinal Disorders

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

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

*This story was updated 2/1/2023.

AURORA, COLO. – The therapeutic action of 5-aminosalicylic acid (5-ASA), one of the most frequently prescribed drugs for inflammatory bowel disease (IBD), can be defeated by enzymes that reside in the very gut that the drug is designed to treat.

“What we found is two gut microbial acetyltransferase families that were previously unknown to be participating in drug metabolism that directly inactivate the drug 5-ASA. It seems that in turn, having a subset of these microbial acetyltransferases is prospectively linked with treatment failure, and could potentially explain why some of these patients of ours fail on the drug,”  Raaj S. Mehta, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

More than half of all patients with IBD treated with 5-ASA either lose their response to the drug or never respond to it at all, including some of his own patients, Dr. Mehta said.

There is an urgent need for a way to predict which patients will be likely to respond to 5-ASA and other drugs to treat IBD, he said.
 

The same old story

In the early 1990s, investigators at St. Radboud Hospital, Nijmegen, the Netherlands, studied cultured feces from patients with IBD treated with 5-ASA, and found in some patients that the drug was metabolized into N-acetyl-5-ASA. In an earlier, double-blind comparison trial in patients with idiopathic proctitis, the same investigators found N-acetyl-5-ASA to be “no better than placebo.”

“But prior to our work, we didn’t know which specific bacteria or enzymes performed this conversion ... of the drug, and we didn’t know if having these enzymes in your intestines or colon could explain why people are at risk for failing on 5-ASA,” Dr. Mehta said.
 

New evidence

Dr. Mehta and his colleagues first turned to the Human Microbiome Project 2, a cohort of 132 persons with IBD followed for 1 year each, with the goal of generating molecular profiles of host and microbial activity over time.

The patients provided stool samples about every 2 weeks, as well as blood and biopsy specimens, and reported details on their use of medications.

The investigators generated metagenomic, metatranscriptomic, genomic, and metabolomic profiles from the data, and then narrowed their focus to 45 participants who used 5-ASA and 34 who did not.

They found that “5-ASA has a major impact on the fecal metabolome,” with significant increases in fecal drug levels of both 5-ASA and the inactive metabolites, as well as more than 2,000 other metabolites.

Looking at the gemomics of gut microbiota, the investigators identified gene clusters in two superfamilies of enzymes, thiolases and acyl CoA N-acyltransferases. They identified 12 candidates.

To bolster their findings, they then expressed one gene from each superfamily in Escherichia coli and purified the protein. When they cocultured it with acetylCoA and 5-ASA, there was a greater than 25% conversion of the drug within 1 hour.

They also found that microbial thiolases appear to step outside of their normal roles to inactivate 5-ASA in a manner similar to that of an N-acetyltrasferase not found in persons with IBD.
 

Clinical relevance

To see whether their findings had clinical implications, the investigators conducted a case-cohort study nested within the Human Microbiome Project 2 cohort. They saw that, after adjusting for age, sex, IBD type, smoking, and N-acetyltransferase (NAT2) phenotype, 4 of the 12 acetyltranfserase candidates were associated with a roughly threefold increase in steroid use, suggesting that 5-ASA treatment had failed the patients.

“So then to take it one step further, we turned to the SPARC IBD cohort,” Dr. Mehta said.

SPARC IBD is an ongoing prospective cohort of patients who provide stool samples and detailed medication and symptom data.

They identified 208 cohort members who were on 5-ASA, were free of steroids at baseline, and who had fecal metabolomic data available. In this group, there were 60 cases of new corticosteroid prescriptions after about 8 months of follow-up.

The authors found that having three or four of the suspect acetyltransferases in gut microbiota was associated with a an overall odds ratio for 5-ASA treatment failure of 3.12 (95% confidence interval, 1.41-6.89).

“Taken together, I think this advances the idea of using the microbiome for personalized medicine in IBD,” Dr. Mehta said.

“Right now it’s an ideal outcome for a patient with [ulcerative colitis] to retain a robust remission on 5-ASA alone,” commented session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., who was not involved in the study.

Asked in an interview whether the findings would be likely to change clinical practice, Dr. Rosen replied that “I think it’s fairly early stage, but I think it’s wonderful that they sort of rediscovered this older data and are modernizing it to understand why [5-ASA] may not work for some patients. It certainly seems like it might be a tractable approach to use the microbiome to personalize therapy and potentially increase the effectiveness of 5-ASA.”

The study was supported by grants from Pfizer, the National Institutes of Health, American College of Gastroenterology, and the Crohn’s & Colitis Foundation. Dr. Mehta disclosed that his team has filed a provisional patent application related to the work. Dr. Rosen reported no relevant conflict of interest.

AURORA, COLO. – The therapeutic action of 5-aminosalicylic acid (5-ASA), one of the most frequently prescribed drugs for inflammatory bowel disease (IBD), can be defeated by enzymes that reside in the very gut that the drug is designed to treat.

“What we found is two gut microbial acetyltransferase families that were previously unknown to be participating in drug metabolism that directly inactivate the drug 5-ASA. It seems that in turn, having a subset of these microbial acetyltransferases is prospectively linked with treatment failure, and could potentially explain why some of these patients of ours fail on the drug,”  Raaj S. Mehta, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

More than half of all patients with IBD treated with 5-ASA either lose their response to the drug or never respond to it at all, including some of his own patients, Dr. Mehta said.

There is an urgent need for a way to predict which patients will be likely to respond to 5-ASA and other drugs to treat IBD, he said.
 

The same old story

In the early 1990s, investigators at St. Radboud Hospital, Nijmegen, the Netherlands, studied cultured feces from patients with IBD treated with 5-ASA, and found in some patients that the drug was metabolized into N-acetyl-5-ASA. In an earlier, double-blind comparison trial in patients with idiopathic proctitis, the same investigators found N-acetyl-5-ASA to be “no better than placebo.”

“But prior to our work, we didn’t know which specific bacteria or enzymes performed this conversion ... of the drug, and we didn’t know if having these enzymes in your intestines or colon could explain why people are at risk for failing on 5-ASA,” Dr. Mehta said.
 

New evidence

Dr. Mehta and his colleagues first turned to the Human Microbiome Project 2, a cohort of 132 persons with IBD followed for 1 year each, with the goal of generating molecular profiles of host and microbial activity over time.

The patients provided stool samples about every 2 weeks, as well as blood and biopsy specimens, and reported details on their use of medications.

The investigators generated metagenomic, metatranscriptomic, genomic, and metabolomic profiles from the data, and then narrowed their focus to 45 participants who used 5-ASA and 34 who did not.

They found that “5-ASA has a major impact on the fecal metabolome,” with significant increases in fecal drug levels of both 5-ASA and the inactive metabolites, as well as more than 2,000 other metabolites.

Looking at the gemomics of gut microbiota, the investigators identified gene clusters in two superfamilies of enzymes, thiolases and acyl CoA N-acyltransferases. They identified 12 candidates.

To bolster their findings, they then expressed one gene from each superfamily in Escherichia coli and purified the protein. When they cocultured it with acetylCoA and 5-ASA, there was a greater than 25% conversion of the drug within 1 hour.

They also found that microbial thiolases appear to step outside of their normal roles to inactivate 5-ASA in a manner similar to that of an N-acetyltrasferase not found in persons with IBD.
 

Clinical relevance

To see whether their findings had clinical implications, the investigators conducted a case-cohort study nested within the Human Microbiome Project 2 cohort. They saw that, after adjusting for age, sex, IBD type, smoking, and N-acetyltransferase (NAT2) phenotype, 4 of the 12 acetyltranfserase candidates were associated with a roughly threefold increase in steroid use, suggesting that 5-ASA treatment had failed the patients.

“So then to take it one step further, we turned to the SPARC IBD cohort,” Dr. Mehta said.

SPARC IBD is an ongoing prospective cohort of patients who provide stool samples and detailed medication and symptom data.

They identified 208 cohort members who were on 5-ASA, were free of steroids at baseline, and who had fecal metabolomic data available. In this group, there were 60 cases of new corticosteroid prescriptions after about 8 months of follow-up.

The authors found that having three or four of the suspect acetyltransferases in gut microbiota was associated with a an overall odds ratio for 5-ASA treatment failure of 3.12 (95% confidence interval, 1.41-6.89).

“Taken together, I think this advances the idea of using the microbiome for personalized medicine in IBD,” Dr. Mehta said.

“Right now it’s an ideal outcome for a patient with [ulcerative colitis] to retain a robust remission on 5-ASA alone,” commented session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., who was not involved in the study.

Asked in an interview whether the findings would be likely to change clinical practice, Dr. Rosen replied that “I think it’s fairly early stage, but I think it’s wonderful that they sort of rediscovered this older data and are modernizing it to understand why [5-ASA] may not work for some patients. It certainly seems like it might be a tractable approach to use the microbiome to personalize therapy and potentially increase the effectiveness of 5-ASA.”

The study was supported by grants from Pfizer, the National Institutes of Health, American College of Gastroenterology, and the Crohn’s & Colitis Foundation. Dr. Mehta disclosed that his team has filed a provisional patent application related to the work. Dr. Rosen reported no relevant conflict of interest.

AURORA, COLO. – The therapeutic action of 5-aminosalicylic acid (5-ASA), one of the most frequently prescribed drugs for inflammatory bowel disease (IBD), can be defeated by enzymes that reside in the very gut that the drug is designed to treat.

“What we found is two gut microbial acetyltransferase families that were previously unknown to be participating in drug metabolism that directly inactivate the drug 5-ASA. It seems that in turn, having a subset of these microbial acetyltransferases is prospectively linked with treatment failure, and could potentially explain why some of these patients of ours fail on the drug,”  Raaj S. Mehta, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

More than half of all patients with IBD treated with 5-ASA either lose their response to the drug or never respond to it at all, including some of his own patients, Dr. Mehta said.

There is an urgent need for a way to predict which patients will be likely to respond to 5-ASA and other drugs to treat IBD, he said.
 

The same old story

In the early 1990s, investigators at St. Radboud Hospital, Nijmegen, the Netherlands, studied cultured feces from patients with IBD treated with 5-ASA, and found in some patients that the drug was metabolized into N-acetyl-5-ASA. In an earlier, double-blind comparison trial in patients with idiopathic proctitis, the same investigators found N-acetyl-5-ASA to be “no better than placebo.”

“But prior to our work, we didn’t know which specific bacteria or enzymes performed this conversion ... of the drug, and we didn’t know if having these enzymes in your intestines or colon could explain why people are at risk for failing on 5-ASA,” Dr. Mehta said.
 

New evidence

Dr. Mehta and his colleagues first turned to the Human Microbiome Project 2, a cohort of 132 persons with IBD followed for 1 year each, with the goal of generating molecular profiles of host and microbial activity over time.

The patients provided stool samples about every 2 weeks, as well as blood and biopsy specimens, and reported details on their use of medications.

The investigators generated metagenomic, metatranscriptomic, genomic, and metabolomic profiles from the data, and then narrowed their focus to 45 participants who used 5-ASA and 34 who did not.

They found that “5-ASA has a major impact on the fecal metabolome,” with significant increases in fecal drug levels of both 5-ASA and the inactive metabolites, as well as more than 2,000 other metabolites.

Looking at the gemomics of gut microbiota, the investigators identified gene clusters in two superfamilies of enzymes, thiolases and acyl CoA N-acyltransferases. They identified 12 candidates.

To bolster their findings, they then expressed one gene from each superfamily in Escherichia coli and purified the protein. When they cocultured it with acetylCoA and 5-ASA, there was a greater than 25% conversion of the drug within 1 hour.

They also found that microbial thiolases appear to step outside of their normal roles to inactivate 5-ASA in a manner similar to that of an N-acetyltrasferase not found in persons with IBD.
 

Clinical relevance

To see whether their findings had clinical implications, the investigators conducted a case-cohort study nested within the Human Microbiome Project 2 cohort. They saw that, after adjusting for age, sex, IBD type, smoking, and N-acetyltransferase (NAT2) phenotype, 4 of the 12 acetyltranfserase candidates were associated with a roughly threefold increase in steroid use, suggesting that 5-ASA treatment had failed the patients.

“So then to take it one step further, we turned to the SPARC IBD cohort,” Dr. Mehta said.

SPARC IBD is an ongoing prospective cohort of patients who provide stool samples and detailed medication and symptom data.

They identified 208 cohort members who were on 5-ASA, were free of steroids at baseline, and who had fecal metabolomic data available. In this group, there were 60 cases of new corticosteroid prescriptions after about 8 months of follow-up.

The authors found that having three or four of the suspect acetyltransferases in gut microbiota was associated with a an overall odds ratio for 5-ASA treatment failure of 3.12 (95% confidence interval, 1.41-6.89).

“Taken together, I think this advances the idea of using the microbiome for personalized medicine in IBD,” Dr. Mehta said.

“Right now it’s an ideal outcome for a patient with [ulcerative colitis] to retain a robust remission on 5-ASA alone,” commented session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., who was not involved in the study.

Asked in an interview whether the findings would be likely to change clinical practice, Dr. Rosen replied that “I think it’s fairly early stage, but I think it’s wonderful that they sort of rediscovered this older data and are modernizing it to understand why [5-ASA] may not work for some patients. It certainly seems like it might be a tractable approach to use the microbiome to personalize therapy and potentially increase the effectiveness of 5-ASA.”

The study was supported by grants from Pfizer, the National Institutes of Health, American College of Gastroenterology, and the Crohn’s & Colitis Foundation. Dr. Mehta disclosed that his team has filed a provisional patent application related to the work. Dr. Rosen reported no relevant conflict of interest.

AURORA, COLO. – Dietary additives lurking in processed foods may contribute to the development or exacerbation of inflammatory bowel disease (IBD), a leading gastroenterologist contends.

At the annual Crohn’s & Colitis Congress^®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association, James D. Lewis, MD, MSCE, AGAF, of the University of Pennsylvania in Philadelphia, highlighted research from both animal and human studies pointing to certain widely used food additives such as carboxymethycellulose (CMC), polysorbate 80, and carrageenan as potential instigators in gastrointestinal inflammation.

“Extrapolating from mice to men, I think we can say that dietary additives may contribute to the etiology or perpetuation of IBD, but not all additives are the same,” he said.

Neil Osterweil/MDedge News

Some additives appear to have deleterious effects on intestinal microbiota, while others may exert their baleful influence through mechanisms such as endoplasmic stress.

“It looks like some people might be a little more sensitive to additives than others, and if you were going to use any of this [research] to try and give some advice, maybe we would say that patients or first-degree relatives of people with IBD may want to avoid foods that contain high levels of additives, and if for no other reason, mothers or people with a family history of IBD might be encouraged to breastfeed to avoid early exposure to additives that are in infant formulas,” he advised.
 

Processed foods defined

The typical American diet may include a large proportion of processed foods, defined as “foods that have undergone biological, chemical, or physical process to improve texture, taste, or shelf life.”

Processed foods tend to be higher in fats, added sugars, and salts, and lower in fiber and intrinsic vitamins than minimally processed foods.

There is also a category of “ultraprocessed” foods, which contain little or no whole foods but are high in energy density. Many of these super(bad) foods are staples of the American diet, such as chips, hot dogs, chicken nuggets, breakfast cereal, soda, candy, and margarine. These and similar foods contribute from 25% to 50% of daily energy intake in the United States and Canada, Dr. Lewis said.

And North America is not alone, he added, pointing to a 2015 study showing that the consumption of ultraprocessed foods in Sweden increased “dramatically” from 1960 through 2010, and that this increase mirrored an increase in obesity prevalence in that nation.
 

Emulsifiers and thickeners

Dr. Lewis focused on emulsifiers and thickeners that are commonly added to processed foods and are, according to the Food and Drug Administration, “generally recognized as safe.”

Emulsifiers are “detergent-like molecules that stabilize mixtures of immiscible [nonhomegenous] liquids.”

Thickeners are additives that increase the viscosity of liquids without otherwise substantially changing their other properties.

In addition to the aforementioned products, other common additives include xanthan gum (a polysaccharide used as an emulsifier in salad dressings, baked goods, ice cream, and gluten-free products), maltodextrin (a sugar substitute marketed as “Splenda”), and soy lecithin (a soy derivative used as an emulsifier, stabilizer, and wetting agent).
 

Evidence of harm

Dr. Lewis noted that in 2013, investigators at the University of Liverpool, England, published a hypothesis suggesting that consumption of emulsifiers in processed foods may promote Crohn’s disease by increasing bacterial translocation. Their hypothesis was based in part on evidence that “very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. “

The authors also suggested that their hypothesis could be tested in clinical trials comparing enteral feeding with and without emulsifiers.

Other suggestive if not definitive evidence of a potential link between additives and IBD are data showing that IBD is very rare in young children.

“In your early stages of your life, you’re not consuming a lot of ultraprocessed foods. Indeed, the rate of intake of at least fast foods, which you can think of almost as a surrogate for ultraprocessed foods, goes up dramatically when people get to their teens, and this is the same time as we see, really, the big uptick in the incidence of IBD,” Dr. Lewis said.

A link between ultraprocessed food consumption and later development of IBD, primarily Crohn’s disease, is also suggested by data from the Nurses Health Study I and II and Health Professionals Follow-Up study. Among 245,112 participants with about 5.5 million person-years of follow-up, the highest vs. lowest quartile of consumption of ultraprocessed foods was associated with a 70% increase in risk for developing Crohn’s (hazard ratio 1.70, P = .0008).
 

Animal studies

Evidence for a possible mechanism whereby emulsifiers and thickeners cause intestinal changes comes from a study published in Nature in 2015 showing that adding CMC and PS80 to the drinking water of mice resulted in major shifts in the gut microbiota in both wild-type and interleukin 10 knockout mice, a model for IBD.

When the additives were put into the water the mice had a thinning of the mucus layer, allowing bacteria in closer proximity to the epithelium.

“When you put these into the drinking water of IL-10 knockout mice that are already predisposed to developing colitis, they were far more likely to go on to develop colitis over the course of 3 months,” Dr. Lewis said.
 

From mouse to man

Dr. Lewis briefly summarized results of the FRESH study that he and colleagues recently published in Gastronterology. In this trial, 16 healthy adult volunteers who agreed to stay and eat all meals at the research center were randomized to receive either an emulsifier-free diet or the identical diet enriched with 15 g of CMC daily for 11 days.

“I will comment that that’s a lot of carboxymethycellulose,” Dr. Lewis said.

The volunteers fed the CMC-enriched diet had a slight increase in abdominal discomfort after eating and a reduction in species diversity in the gut microbiota. In addition, these participants had reductions in levels of short-chain fatty acids and free amino acids, both of which are signs of a health gut environment.

“Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition,” the investigators wrote.

Dr. Lewis cited a separate small study by investigators at the University of Illinois at Chicago and the University of Chicago. These investigators randomized patients with UC in remission to take supplements containing carrageenan – a seaweed-derived food additive that has been shown to cause inflammation in both in vitro and animal models – or placebo . The amount of carrageenan in the capsules was less than that found in an average daily Western diet, the authors noted.

The participants were followed with telephone calls every 2 weeks or until relapse, which was defined as an increase of 2 or more points on the Simple Clinical Colitis Activity Index (SCCAI) and intensification of treatment for UC.

Of the 12 patients who completed the study, 3 in the carrageenan group experienced relapses, compared with none of the patients in the placebo group (P = .046). The relapse occurred at 5, 32, and 42 weeks of follow-up.
 

Exceptions to the rule

“It’s not clear that all additives are harmful,” Dr. Lewis said, pointing to a placebo-controlled study suggesting a beneficial effect of soy lecithin in patients with UC. The additive is composed of at least 30% of phosphatidycholine, a component of intestinal mucus.

He also noted that there is an ongoing randomized, placebo-controlled trial comparing a low-additive diet to a habitual diet in 154 patients with mildly active, stable Crohn’s disease.

Session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., told this news organization that dietary components do appear to have an influence on the disease course in patients with IBD.

“I do think there are patients with IBD who are maybe genetically predisposed to being sensitive to certain components of diet,” he said in an interview seeking objective commentary.

“Particularly in pediatrics there are lines of evidence of diets maybe having some efficacy in treatment. It needs further study, but one commonality about those diets is that they tend to eliminate processed foods and focus on whole foods,” he said.

Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has served as a consultant to and data safety monitoring board member for several entitities. Dr. Rosen reported no conflicts of interest to disclose.

AURORA, COLO. – Dietary additives lurking in processed foods may contribute to the development or exacerbation of inflammatory bowel disease (IBD), a leading gastroenterologist contends.

At the annual Crohn’s & Colitis Congress^®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association, James D. Lewis, MD, MSCE, AGAF, of the University of Pennsylvania in Philadelphia, highlighted research from both animal and human studies pointing to certain widely used food additives such as carboxymethycellulose (CMC), polysorbate 80, and carrageenan as potential instigators in gastrointestinal inflammation.

“Extrapolating from mice to men, I think we can say that dietary additives may contribute to the etiology or perpetuation of IBD, but not all additives are the same,” he said.

Neil Osterweil/MDedge News

Some additives appear to have deleterious effects on intestinal microbiota, while others may exert their baleful influence through mechanisms such as endoplasmic stress.

“It looks like some people might be a little more sensitive to additives than others, and if you were going to use any of this [research] to try and give some advice, maybe we would say that patients or first-degree relatives of people with IBD may want to avoid foods that contain high levels of additives, and if for no other reason, mothers or people with a family history of IBD might be encouraged to breastfeed to avoid early exposure to additives that are in infant formulas,” he advised.
 

Processed foods defined

The typical American diet may include a large proportion of processed foods, defined as “foods that have undergone biological, chemical, or physical process to improve texture, taste, or shelf life.”

Processed foods tend to be higher in fats, added sugars, and salts, and lower in fiber and intrinsic vitamins than minimally processed foods.

There is also a category of “ultraprocessed” foods, which contain little or no whole foods but are high in energy density. Many of these super(bad) foods are staples of the American diet, such as chips, hot dogs, chicken nuggets, breakfast cereal, soda, candy, and margarine. These and similar foods contribute from 25% to 50% of daily energy intake in the United States and Canada, Dr. Lewis said.

And North America is not alone, he added, pointing to a 2015 study showing that the consumption of ultraprocessed foods in Sweden increased “dramatically” from 1960 through 2010, and that this increase mirrored an increase in obesity prevalence in that nation.
 

Emulsifiers and thickeners

Dr. Lewis focused on emulsifiers and thickeners that are commonly added to processed foods and are, according to the Food and Drug Administration, “generally recognized as safe.”

Emulsifiers are “detergent-like molecules that stabilize mixtures of immiscible [nonhomegenous] liquids.”

Thickeners are additives that increase the viscosity of liquids without otherwise substantially changing their other properties.

In addition to the aforementioned products, other common additives include xanthan gum (a polysaccharide used as an emulsifier in salad dressings, baked goods, ice cream, and gluten-free products), maltodextrin (a sugar substitute marketed as “Splenda”), and soy lecithin (a soy derivative used as an emulsifier, stabilizer, and wetting agent).
 

Evidence of harm

Dr. Lewis noted that in 2013, investigators at the University of Liverpool, England, published a hypothesis suggesting that consumption of emulsifiers in processed foods may promote Crohn’s disease by increasing bacterial translocation. Their hypothesis was based in part on evidence that “very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. “

The authors also suggested that their hypothesis could be tested in clinical trials comparing enteral feeding with and without emulsifiers.

Other suggestive if not definitive evidence of a potential link between additives and IBD are data showing that IBD is very rare in young children.

“In your early stages of your life, you’re not consuming a lot of ultraprocessed foods. Indeed, the rate of intake of at least fast foods, which you can think of almost as a surrogate for ultraprocessed foods, goes up dramatically when people get to their teens, and this is the same time as we see, really, the big uptick in the incidence of IBD,” Dr. Lewis said.

A link between ultraprocessed food consumption and later development of IBD, primarily Crohn’s disease, is also suggested by data from the Nurses Health Study I and II and Health Professionals Follow-Up study. Among 245,112 participants with about 5.5 million person-years of follow-up, the highest vs. lowest quartile of consumption of ultraprocessed foods was associated with a 70% increase in risk for developing Crohn’s (hazard ratio 1.70, P = .0008).
 

Animal studies

Evidence for a possible mechanism whereby emulsifiers and thickeners cause intestinal changes comes from a study published in Nature in 2015 showing that adding CMC and PS80 to the drinking water of mice resulted in major shifts in the gut microbiota in both wild-type and interleukin 10 knockout mice, a model for IBD.

When the additives were put into the water the mice had a thinning of the mucus layer, allowing bacteria in closer proximity to the epithelium.

“When you put these into the drinking water of IL-10 knockout mice that are already predisposed to developing colitis, they were far more likely to go on to develop colitis over the course of 3 months,” Dr. Lewis said.
 

From mouse to man

Dr. Lewis briefly summarized results of the FRESH study that he and colleagues recently published in Gastronterology. In this trial, 16 healthy adult volunteers who agreed to stay and eat all meals at the research center were randomized to receive either an emulsifier-free diet or the identical diet enriched with 15 g of CMC daily for 11 days.

“I will comment that that’s a lot of carboxymethycellulose,” Dr. Lewis said.

The volunteers fed the CMC-enriched diet had a slight increase in abdominal discomfort after eating and a reduction in species diversity in the gut microbiota. In addition, these participants had reductions in levels of short-chain fatty acids and free amino acids, both of which are signs of a health gut environment.

“Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition,” the investigators wrote.

Dr. Lewis cited a separate small study by investigators at the University of Illinois at Chicago and the University of Chicago. These investigators randomized patients with UC in remission to take supplements containing carrageenan – a seaweed-derived food additive that has been shown to cause inflammation in both in vitro and animal models – or placebo . The amount of carrageenan in the capsules was less than that found in an average daily Western diet, the authors noted.

The participants were followed with telephone calls every 2 weeks or until relapse, which was defined as an increase of 2 or more points on the Simple Clinical Colitis Activity Index (SCCAI) and intensification of treatment for UC.

Of the 12 patients who completed the study, 3 in the carrageenan group experienced relapses, compared with none of the patients in the placebo group (P = .046). The relapse occurred at 5, 32, and 42 weeks of follow-up.
 

Exceptions to the rule

“It’s not clear that all additives are harmful,” Dr. Lewis said, pointing to a placebo-controlled study suggesting a beneficial effect of soy lecithin in patients with UC. The additive is composed of at least 30% of phosphatidycholine, a component of intestinal mucus.

He also noted that there is an ongoing randomized, placebo-controlled trial comparing a low-additive diet to a habitual diet in 154 patients with mildly active, stable Crohn’s disease.

Session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., told this news organization that dietary components do appear to have an influence on the disease course in patients with IBD.

“I do think there are patients with IBD who are maybe genetically predisposed to being sensitive to certain components of diet,” he said in an interview seeking objective commentary.

“Particularly in pediatrics there are lines of evidence of diets maybe having some efficacy in treatment. It needs further study, but one commonality about those diets is that they tend to eliminate processed foods and focus on whole foods,” he said.

Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has served as a consultant to and data safety monitoring board member for several entitities. Dr. Rosen reported no conflicts of interest to disclose.

AURORA, COLO. – Dietary additives lurking in processed foods may contribute to the development or exacerbation of inflammatory bowel disease (IBD), a leading gastroenterologist contends.

At the annual Crohn’s & Colitis Congress^®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association, James D. Lewis, MD, MSCE, AGAF, of the University of Pennsylvania in Philadelphia, highlighted research from both animal and human studies pointing to certain widely used food additives such as carboxymethycellulose (CMC), polysorbate 80, and carrageenan as potential instigators in gastrointestinal inflammation.

“Extrapolating from mice to men, I think we can say that dietary additives may contribute to the etiology or perpetuation of IBD, but not all additives are the same,” he said.

Neil Osterweil/MDedge News

Some additives appear to have deleterious effects on intestinal microbiota, while others may exert their baleful influence through mechanisms such as endoplasmic stress.

“It looks like some people might be a little more sensitive to additives than others, and if you were going to use any of this [research] to try and give some advice, maybe we would say that patients or first-degree relatives of people with IBD may want to avoid foods that contain high levels of additives, and if for no other reason, mothers or people with a family history of IBD might be encouraged to breastfeed to avoid early exposure to additives that are in infant formulas,” he advised.
 

Processed foods defined

The typical American diet may include a large proportion of processed foods, defined as “foods that have undergone biological, chemical, or physical process to improve texture, taste, or shelf life.”

Processed foods tend to be higher in fats, added sugars, and salts, and lower in fiber and intrinsic vitamins than minimally processed foods.

There is also a category of “ultraprocessed” foods, which contain little or no whole foods but are high in energy density. Many of these super(bad) foods are staples of the American diet, such as chips, hot dogs, chicken nuggets, breakfast cereal, soda, candy, and margarine. These and similar foods contribute from 25% to 50% of daily energy intake in the United States and Canada, Dr. Lewis said.

And North America is not alone, he added, pointing to a 2015 study showing that the consumption of ultraprocessed foods in Sweden increased “dramatically” from 1960 through 2010, and that this increase mirrored an increase in obesity prevalence in that nation.
 

Emulsifiers and thickeners

Dr. Lewis focused on emulsifiers and thickeners that are commonly added to processed foods and are, according to the Food and Drug Administration, “generally recognized as safe.”

Emulsifiers are “detergent-like molecules that stabilize mixtures of immiscible [nonhomegenous] liquids.”

Thickeners are additives that increase the viscosity of liquids without otherwise substantially changing their other properties.

In addition to the aforementioned products, other common additives include xanthan gum (a polysaccharide used as an emulsifier in salad dressings, baked goods, ice cream, and gluten-free products), maltodextrin (a sugar substitute marketed as “Splenda”), and soy lecithin (a soy derivative used as an emulsifier, stabilizer, and wetting agent).
 

Evidence of harm

Dr. Lewis noted that in 2013, investigators at the University of Liverpool, England, published a hypothesis suggesting that consumption of emulsifiers in processed foods may promote Crohn’s disease by increasing bacterial translocation. Their hypothesis was based in part on evidence that “very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. “

The authors also suggested that their hypothesis could be tested in clinical trials comparing enteral feeding with and without emulsifiers.

Other suggestive if not definitive evidence of a potential link between additives and IBD are data showing that IBD is very rare in young children.

“In your early stages of your life, you’re not consuming a lot of ultraprocessed foods. Indeed, the rate of intake of at least fast foods, which you can think of almost as a surrogate for ultraprocessed foods, goes up dramatically when people get to their teens, and this is the same time as we see, really, the big uptick in the incidence of IBD,” Dr. Lewis said.

A link between ultraprocessed food consumption and later development of IBD, primarily Crohn’s disease, is also suggested by data from the Nurses Health Study I and II and Health Professionals Follow-Up study. Among 245,112 participants with about 5.5 million person-years of follow-up, the highest vs. lowest quartile of consumption of ultraprocessed foods was associated with a 70% increase in risk for developing Crohn’s (hazard ratio 1.70, P = .0008).
 

Animal studies

Evidence for a possible mechanism whereby emulsifiers and thickeners cause intestinal changes comes from a study published in Nature in 2015 showing that adding CMC and PS80 to the drinking water of mice resulted in major shifts in the gut microbiota in both wild-type and interleukin 10 knockout mice, a model for IBD.

When the additives were put into the water the mice had a thinning of the mucus layer, allowing bacteria in closer proximity to the epithelium.

“When you put these into the drinking water of IL-10 knockout mice that are already predisposed to developing colitis, they were far more likely to go on to develop colitis over the course of 3 months,” Dr. Lewis said.
 

From mouse to man

Dr. Lewis briefly summarized results of the FRESH study that he and colleagues recently published in Gastronterology. In this trial, 16 healthy adult volunteers who agreed to stay and eat all meals at the research center were randomized to receive either an emulsifier-free diet or the identical diet enriched with 15 g of CMC daily for 11 days.

“I will comment that that’s a lot of carboxymethycellulose,” Dr. Lewis said.

The volunteers fed the CMC-enriched diet had a slight increase in abdominal discomfort after eating and a reduction in species diversity in the gut microbiota. In addition, these participants had reductions in levels of short-chain fatty acids and free amino acids, both of which are signs of a health gut environment.

“Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition,” the investigators wrote.

Dr. Lewis cited a separate small study by investigators at the University of Illinois at Chicago and the University of Chicago. These investigators randomized patients with UC in remission to take supplements containing carrageenan – a seaweed-derived food additive that has been shown to cause inflammation in both in vitro and animal models – or placebo . The amount of carrageenan in the capsules was less than that found in an average daily Western diet, the authors noted.

The participants were followed with telephone calls every 2 weeks or until relapse, which was defined as an increase of 2 or more points on the Simple Clinical Colitis Activity Index (SCCAI) and intensification of treatment for UC.

Of the 12 patients who completed the study, 3 in the carrageenan group experienced relapses, compared with none of the patients in the placebo group (P = .046). The relapse occurred at 5, 32, and 42 weeks of follow-up.
 

Exceptions to the rule

“It’s not clear that all additives are harmful,” Dr. Lewis said, pointing to a placebo-controlled study suggesting a beneficial effect of soy lecithin in patients with UC. The additive is composed of at least 30% of phosphatidycholine, a component of intestinal mucus.

He also noted that there is an ongoing randomized, placebo-controlled trial comparing a low-additive diet to a habitual diet in 154 patients with mildly active, stable Crohn’s disease.

Session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., told this news organization that dietary components do appear to have an influence on the disease course in patients with IBD.

“I do think there are patients with IBD who are maybe genetically predisposed to being sensitive to certain components of diet,” he said in an interview seeking objective commentary.

“Particularly in pediatrics there are lines of evidence of diets maybe having some efficacy in treatment. It needs further study, but one commonality about those diets is that they tend to eliminate processed foods and focus on whole foods,” he said.

Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has served as a consultant to and data safety monitoring board member for several entitities. Dr. Rosen reported no conflicts of interest to disclose.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

The American College of Gastroenterology issued updated guidelines for celiac disease diagnosis, management, and screening that incorporates research conducted since the last update in 2013.

The guidelines offer evidence-based recommendations for common clinical questions on topics that include nonbiopsy diagnosis, gluten-free oats, probiotic use, and gluten-detection devices. They also point to areas for ongoing research.

“The main message of the guideline is all about quality of care,” Alberto Rubio-Tapia, MD, a gastroenterologist at the Cleveland Clinic, said in an interview.

“A precise celiac disease diagnosis is just the beginning of the role of the gastroenterologist,” he said. “But most importantly, we need to take care of our patients’ needs with good goal-directed follow-up using a multidisciplinary approach, with experienced dietitians playing an important role.”

The update was published in the American Journal of Gastroenterology.
 

Diagnosis recommendations

The ACG assembled a team of celiac disease experts and expert guideline methodologists to develop an update with high-quality evidence, Dr. Rubio-Tapia said. The authors made recommendations and suggestions for future research regarding eight questions concerning diagnosis, disease management, and screening.

For diagnosis, the guidelines recommend esophagogastroduodenoscopy (EGD) with multiple duodenal biopsies – one or two from the bulb and four from the distal duodenum – for confirmation in children and adults with suspicion of celiac disease. EGD and duodenal biopsies can also be useful for the differential diagnosis of other malabsorptive disorders or enteropathies, the authors wrote.

For children, a nonbiopsy option may be considered to be reliable for diagnosis. This option includes a combination of high-level tissue transglutaminase (TTG) IgA – at greater than 10 times the upper limit of normal – and a positive endomysial antibody finding in a second blood sample. The same criteria may be considered after the fact for symptomatic adults who are unwilling or unable to undergo upper GI endoscopy.

For children younger than 2 years, the TTG-IgA is the preferred test for those who are not IgA deficient. For children with IgA deficiency, testing should be performed using IgG-based antibodies.
 

Disease management guidance

After diagnosis, intestinal healing should be the endpoint for a gluten-free diet, the guidelines recommended. Clinicians and patients should discuss individualized goals of the gluten-free diet beyond clinical and serologic remission.

The standard of care for assessing patients’ diet adherence is an interview with a dietician who has expertise in gluten-free diets, the recommendations stated. Subsequent visits should be encouraged as needed to reinforce adherence.

During disease management, upper endoscopy with intestinal biopsies can be helpful for monitoring cases in which there is a lack of clinical response or in which symptoms relapse despite a gluten-free diet, the authors noted.

In addition, after a shared decision-making conversation between the patient and provider, a follow-up biopsy could be considered for assessment of mucosal healing in adults who don’t have symptoms 2 years after starting a gluten-free diet, they wrote.

“Although most patients do well on a gluten-free diet, it’s a heavy burden of care and an important issue that impacts patients,” Joseph Murray, MD, a gastroenterologist at the Mayo Clinic in Rochester, Minn., said in an interview.

Dr. Murray, who wasn’t involved with this guideline update, contributed to the 2013 guidelines and the 2019 American Gastroenterological Association practice update on diagnosing and monitoring celiac disease. He agreed with many of the recommendations in this update.

“The goal of achieving healing is a good goal to reach. We do that routinely in my practice,” he said. “The older the patient, perhaps the more important it is to discuss, including the risk for complications. There’s a nuance involved with shared decision-making.”
 

Nutrition advice

The guidelines recommended against routine use of gluten-detection devices for food or biospecimens for patients with celiac disease. Although multiple devices have become commercially available in recent years, they are not regulated by the Food and Drug Administration and have sensitivity problems that can lead to false positive and false negative results, the authors noted. There’s also a lack of evidence that the devices enhance diet adherence or quality of life.

The evidence is insufficient to recommend for or against the use of probiotics for the treatment of celiac disease, the recommendations stated. Although dysbiosis is a feature of celiac disease, its role in disease pathogenesis and symptomatology is uncertain, the authors wrote.

Probiotics may help with functional disorders, such as irritable bowel syndrome, but because probiotics are marketed as supplements and regulations are lax, some products may contain detectable gluten despite being labeled gluten free, they added.

On the other hand, the authors recommended gluten-free oats as part of a gluten-free diet. Oat consumption appears to be safe for most patients with celiac disease, but it may be immunogenic in a subset of patients, depending on the products or quantity consumed. Given the small risk for an immune reaction to the oat protein avenin, monitoring for oat tolerance through symptoms and serology should be conducted, although the intervals for monitoring remain unknown.
 

Vaccination and screening

The guidelines also support vaccination against pneumococcal disease, since adults with celiac disease are at significantly increased risk of infection and complications. Vaccination is widely recommended for people aged 65 and older, for smokers aged 19-64, and for adults with underlying conditions that place them at higher risk, the authors noted.

Overall, the guidelines recommended case findings to increase detection of celiac disease in clinical practice but recommend against mass screening in the community. Patients with symptoms for whom there is lab evidence of malabsorption should be tested, as well as those for whom celiac disease could be a treatable cause of symptoms, the authors wrote. Those with a first-degree family member who has a confirmed diagnosis should also be tested if they have possible symptoms, and asymptomatic relatives should consider testing as well.

The updated guidelines include changes that are important for patients and patient care, and they emphasize the need for continued research on key questions, Isabel Hujoel, MD, a gastroenterologist at the University of Washington Medical Center, Seattle, told this news organization.

“In particular, the discussion on the lack of evidence behind gluten-detection devices and probiotic use in celiac disease addresses conversations that come up frequently in clinic,” said Dr. Hujoel, who wasn’t involved with the update. “The guidelines also include a new addition below each recommendation where future research questions are raised. Many of these questions address gaps in our understanding on celiac disease, such as the possibility of a nonbiopsy diagnosis in adults, which will potentially dramatically impact patient care if addressed.”

The update received no funding. The authors, Dr. Murray, and Dr. Hujoel have disclosed no relevant financial relationships.

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

The American College of Gastroenterology issued updated guidelines for celiac disease diagnosis, management, and screening that incorporates research conducted since the last update in 2013.

The guidelines offer evidence-based recommendations for common clinical questions on topics that include nonbiopsy diagnosis, gluten-free oats, probiotic use, and gluten-detection devices. They also point to areas for ongoing research.

“The main message of the guideline is all about quality of care,” Alberto Rubio-Tapia, MD, a gastroenterologist at the Cleveland Clinic, said in an interview.

“A precise celiac disease diagnosis is just the beginning of the role of the gastroenterologist,” he said. “But most importantly, we need to take care of our patients’ needs with good goal-directed follow-up using a multidisciplinary approach, with experienced dietitians playing an important role.”

The update was published in the American Journal of Gastroenterology.
 

Diagnosis recommendations

The ACG assembled a team of celiac disease experts and expert guideline methodologists to develop an update with high-quality evidence, Dr. Rubio-Tapia said. The authors made recommendations and suggestions for future research regarding eight questions concerning diagnosis, disease management, and screening.

For diagnosis, the guidelines recommend esophagogastroduodenoscopy (EGD) with multiple duodenal biopsies – one or two from the bulb and four from the distal duodenum – for confirmation in children and adults with suspicion of celiac disease. EGD and duodenal biopsies can also be useful for the differential diagnosis of other malabsorptive disorders or enteropathies, the authors wrote.

For children, a nonbiopsy option may be considered to be reliable for diagnosis. This option includes a combination of high-level tissue transglutaminase (TTG) IgA – at greater than 10 times the upper limit of normal – and a positive endomysial antibody finding in a second blood sample. The same criteria may be considered after the fact for symptomatic adults who are unwilling or unable to undergo upper GI endoscopy.

For children younger than 2 years, the TTG-IgA is the preferred test for those who are not IgA deficient. For children with IgA deficiency, testing should be performed using IgG-based antibodies.
 

Disease management guidance

After diagnosis, intestinal healing should be the endpoint for a gluten-free diet, the guidelines recommended. Clinicians and patients should discuss individualized goals of the gluten-free diet beyond clinical and serologic remission.

The standard of care for assessing patients’ diet adherence is an interview with a dietician who has expertise in gluten-free diets, the recommendations stated. Subsequent visits should be encouraged as needed to reinforce adherence.

During disease management, upper endoscopy with intestinal biopsies can be helpful for monitoring cases in which there is a lack of clinical response or in which symptoms relapse despite a gluten-free diet, the authors noted.

In addition, after a shared decision-making conversation between the patient and provider, a follow-up biopsy could be considered for assessment of mucosal healing in adults who don’t have symptoms 2 years after starting a gluten-free diet, they wrote.

“Although most patients do well on a gluten-free diet, it’s a heavy burden of care and an important issue that impacts patients,” Joseph Murray, MD, a gastroenterologist at the Mayo Clinic in Rochester, Minn., said in an interview.

Dr. Murray, who wasn’t involved with this guideline update, contributed to the 2013 guidelines and the 2019 American Gastroenterological Association practice update on diagnosing and monitoring celiac disease. He agreed with many of the recommendations in this update.

“The goal of achieving healing is a good goal to reach. We do that routinely in my practice,” he said. “The older the patient, perhaps the more important it is to discuss, including the risk for complications. There’s a nuance involved with shared decision-making.”
 

Nutrition advice

The guidelines recommended against routine use of gluten-detection devices for food or biospecimens for patients with celiac disease. Although multiple devices have become commercially available in recent years, they are not regulated by the Food and Drug Administration and have sensitivity problems that can lead to false positive and false negative results, the authors noted. There’s also a lack of evidence that the devices enhance diet adherence or quality of life.

The evidence is insufficient to recommend for or against the use of probiotics for the treatment of celiac disease, the recommendations stated. Although dysbiosis is a feature of celiac disease, its role in disease pathogenesis and symptomatology is uncertain, the authors wrote.

Probiotics may help with functional disorders, such as irritable bowel syndrome, but because probiotics are marketed as supplements and regulations are lax, some products may contain detectable gluten despite being labeled gluten free, they added.

On the other hand, the authors recommended gluten-free oats as part of a gluten-free diet. Oat consumption appears to be safe for most patients with celiac disease, but it may be immunogenic in a subset of patients, depending on the products or quantity consumed. Given the small risk for an immune reaction to the oat protein avenin, monitoring for oat tolerance through symptoms and serology should be conducted, although the intervals for monitoring remain unknown.
 

Vaccination and screening

The guidelines also support vaccination against pneumococcal disease, since adults with celiac disease are at significantly increased risk of infection and complications. Vaccination is widely recommended for people aged 65 and older, for smokers aged 19-64, and for adults with underlying conditions that place them at higher risk, the authors noted.

Overall, the guidelines recommended case findings to increase detection of celiac disease in clinical practice but recommend against mass screening in the community. Patients with symptoms for whom there is lab evidence of malabsorption should be tested, as well as those for whom celiac disease could be a treatable cause of symptoms, the authors wrote. Those with a first-degree family member who has a confirmed diagnosis should also be tested if they have possible symptoms, and asymptomatic relatives should consider testing as well.

The updated guidelines include changes that are important for patients and patient care, and they emphasize the need for continued research on key questions, Isabel Hujoel, MD, a gastroenterologist at the University of Washington Medical Center, Seattle, told this news organization.

“In particular, the discussion on the lack of evidence behind gluten-detection devices and probiotic use in celiac disease addresses conversations that come up frequently in clinic,” said Dr. Hujoel, who wasn’t involved with the update. “The guidelines also include a new addition below each recommendation where future research questions are raised. Many of these questions address gaps in our understanding on celiac disease, such as the possibility of a nonbiopsy diagnosis in adults, which will potentially dramatically impact patient care if addressed.”

The update received no funding. The authors, Dr. Murray, and Dr. Hujoel have disclosed no relevant financial relationships.

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

The American College of Gastroenterology issued updated guidelines for celiac disease diagnosis, management, and screening that incorporates research conducted since the last update in 2013.

The guidelines offer evidence-based recommendations for common clinical questions on topics that include nonbiopsy diagnosis, gluten-free oats, probiotic use, and gluten-detection devices. They also point to areas for ongoing research.

“The main message of the guideline is all about quality of care,” Alberto Rubio-Tapia, MD, a gastroenterologist at the Cleveland Clinic, said in an interview.

“A precise celiac disease diagnosis is just the beginning of the role of the gastroenterologist,” he said. “But most importantly, we need to take care of our patients’ needs with good goal-directed follow-up using a multidisciplinary approach, with experienced dietitians playing an important role.”

The update was published in the American Journal of Gastroenterology.
 

Diagnosis recommendations

The ACG assembled a team of celiac disease experts and expert guideline methodologists to develop an update with high-quality evidence, Dr. Rubio-Tapia said. The authors made recommendations and suggestions for future research regarding eight questions concerning diagnosis, disease management, and screening.

For diagnosis, the guidelines recommend esophagogastroduodenoscopy (EGD) with multiple duodenal biopsies – one or two from the bulb and four from the distal duodenum – for confirmation in children and adults with suspicion of celiac disease. EGD and duodenal biopsies can also be useful for the differential diagnosis of other malabsorptive disorders or enteropathies, the authors wrote.

For children, a nonbiopsy option may be considered to be reliable for diagnosis. This option includes a combination of high-level tissue transglutaminase (TTG) IgA – at greater than 10 times the upper limit of normal – and a positive endomysial antibody finding in a second blood sample. The same criteria may be considered after the fact for symptomatic adults who are unwilling or unable to undergo upper GI endoscopy.

For children younger than 2 years, the TTG-IgA is the preferred test for those who are not IgA deficient. For children with IgA deficiency, testing should be performed using IgG-based antibodies.
 

Disease management guidance

After diagnosis, intestinal healing should be the endpoint for a gluten-free diet, the guidelines recommended. Clinicians and patients should discuss individualized goals of the gluten-free diet beyond clinical and serologic remission.

The standard of care for assessing patients’ diet adherence is an interview with a dietician who has expertise in gluten-free diets, the recommendations stated. Subsequent visits should be encouraged as needed to reinforce adherence.

During disease management, upper endoscopy with intestinal biopsies can be helpful for monitoring cases in which there is a lack of clinical response or in which symptoms relapse despite a gluten-free diet, the authors noted.

In addition, after a shared decision-making conversation between the patient and provider, a follow-up biopsy could be considered for assessment of mucosal healing in adults who don’t have symptoms 2 years after starting a gluten-free diet, they wrote.

“Although most patients do well on a gluten-free diet, it’s a heavy burden of care and an important issue that impacts patients,” Joseph Murray, MD, a gastroenterologist at the Mayo Clinic in Rochester, Minn., said in an interview.

Dr. Murray, who wasn’t involved with this guideline update, contributed to the 2013 guidelines and the 2019 American Gastroenterological Association practice update on diagnosing and monitoring celiac disease. He agreed with many of the recommendations in this update.

“The goal of achieving healing is a good goal to reach. We do that routinely in my practice,” he said. “The older the patient, perhaps the more important it is to discuss, including the risk for complications. There’s a nuance involved with shared decision-making.”
 

Nutrition advice

The guidelines recommended against routine use of gluten-detection devices for food or biospecimens for patients with celiac disease. Although multiple devices have become commercially available in recent years, they are not regulated by the Food and Drug Administration and have sensitivity problems that can lead to false positive and false negative results, the authors noted. There’s also a lack of evidence that the devices enhance diet adherence or quality of life.

The evidence is insufficient to recommend for or against the use of probiotics for the treatment of celiac disease, the recommendations stated. Although dysbiosis is a feature of celiac disease, its role in disease pathogenesis and symptomatology is uncertain, the authors wrote.

Probiotics may help with functional disorders, such as irritable bowel syndrome, but because probiotics are marketed as supplements and regulations are lax, some products may contain detectable gluten despite being labeled gluten free, they added.

On the other hand, the authors recommended gluten-free oats as part of a gluten-free diet. Oat consumption appears to be safe for most patients with celiac disease, but it may be immunogenic in a subset of patients, depending on the products or quantity consumed. Given the small risk for an immune reaction to the oat protein avenin, monitoring for oat tolerance through symptoms and serology should be conducted, although the intervals for monitoring remain unknown.
 

Vaccination and screening

The guidelines also support vaccination against pneumococcal disease, since adults with celiac disease are at significantly increased risk of infection and complications. Vaccination is widely recommended for people aged 65 and older, for smokers aged 19-64, and for adults with underlying conditions that place them at higher risk, the authors noted.

Overall, the guidelines recommended case findings to increase detection of celiac disease in clinical practice but recommend against mass screening in the community. Patients with symptoms for whom there is lab evidence of malabsorption should be tested, as well as those for whom celiac disease could be a treatable cause of symptoms, the authors wrote. Those with a first-degree family member who has a confirmed diagnosis should also be tested if they have possible symptoms, and asymptomatic relatives should consider testing as well.

The updated guidelines include changes that are important for patients and patient care, and they emphasize the need for continued research on key questions, Isabel Hujoel, MD, a gastroenterologist at the University of Washington Medical Center, Seattle, told this news organization.

“In particular, the discussion on the lack of evidence behind gluten-detection devices and probiotic use in celiac disease addresses conversations that come up frequently in clinic,” said Dr. Hujoel, who wasn’t involved with the update. “The guidelines also include a new addition below each recommendation where future research questions are raised. Many of these questions address gaps in our understanding on celiac disease, such as the possibility of a nonbiopsy diagnosis in adults, which will potentially dramatically impact patient care if addressed.”

The update received no funding. The authors, Dr. Murray, and Dr. Hujoel have disclosed no relevant financial relationships.

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

Patients with moderate to severe active ulcerative colitis (UC) who received induction therapy with either ritlecitinib or brepocitinib showed significant improvement across multiple outcome metrics in a phase 2b “umbrella” study of the two investigational agents.

The study by William J. Sandborn, MD, division of gastroenterology, University of California, San Diego, and colleagues was published online in Clinical Gastroenterology and Hepatology.

Ritlecitinib is a dual inhibitor that selectively inhibits Janus kinase 3 (JAK3) and the TEC family of tyrosine kinases, while brepocitinib is a dual tyrosine kinase 2 (TYK2) and JAK1 inhibitor.

Both agents have demonstrated efficacy and acceptable safety in the treatment of alopecia areata and rheumatoid arthritis and are being evaluated for treating vitiligo, Crohn’s disease, and UC.

The different JAK selectivity profiles of ritlecitinib (JAK3/TEC) and brepocitinib (TYK2/JAK1), compared with other JAK inhibitors, could further the understanding of the role these pathways play in UC, the investigators note.
 

The VIBRATO study

As part of the phase 2b VIBRATO study, 317 patients with moderate to severe active UC (total Mayo Score ≥ 6) were randomly assigned to an 8-week induction course of once-daily oral ritlecitinib (20, 70, or 200 mg), brepocitinib (10, 30, or 60 mg), or matching placebo.

At week 8, compared with placebo, treatment with ritlecitinib or brepocitinib was associated with significantly lower mean total Mayo Scores (the primary endpoint) and higher rates of clinical remission, endoscopic and histologic improvement, and mucosal healing.

For both drugs, improvement on most metrics was dose dependent, with greater benefit at the highest dose.

For example, the placebo-adjusted mean total Mayo Score at week 8 was −4.6 for ritlecitinib 200 mg (P < .001) and −3.2 for brepocitinib 60 mg (P < .001). Both agents showed a “rapid” onset of action, with significant effects on the partial Mayo Score seen after just 2 weeks of treatment, the authors report.

Modified clinical remission at week 8 (a key secondary endpoint) was achieved in 36% of patients taking ritlecitinib 200 mg and 25.5% of those taking brepocitinib 60 mg (vs. 0% for patients taking placebo).

Endoscopic and histologic improvement, clinical response, mucosal healing, and the patient-reported outcome on the Inflammatory Bowel Disease Questionnaire followed a similar pattern, with a dose-dependent increase in treatment effect observed in most parameters at week 8, compared with placebo.
 

Longer-term data needed

Both agents were well tolerated with “acceptable short-term safety profiles,” the authors say.

There were no clinically significant findings for any laboratory parameters evaluated. Adverse events were mostly mild.

Infections were observed in 8.7% of patients taking ritlecitinib and 16.9% of those taking brepocitinib, compared with 4% of patients taking placebo. No serious cases of herpes zoster occurred.

One patient taking ritlecitinib suffered myocardial infarction and died, and one patient taking brepocitinib had peripheral artery thrombosis (left tibial artery). Both cases were considered unrelated to the study drug.

“As JAK inhibitors are associated with increased risk of major cardiovascular events and venous thromboembolisms, larger studies are needed for ritlecitinib and brepocitinib to fully understand their safety profiles,” the investigators say.

Limitations of the study include the small sample size and short 8-week treatment period. Longer-term safety and efficacy of both agents are being investigated.

The study was sponsored by Pfizer, which is developing both drugs. Dr. Sandborn and several coauthors have disclosed financial relationships with the company.

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

Patients with moderate to severe active ulcerative colitis (UC) who received induction therapy with either ritlecitinib or brepocitinib showed significant improvement across multiple outcome metrics in a phase 2b “umbrella” study of the two investigational agents.

The study by William J. Sandborn, MD, division of gastroenterology, University of California, San Diego, and colleagues was published online in Clinical Gastroenterology and Hepatology.

Ritlecitinib is a dual inhibitor that selectively inhibits Janus kinase 3 (JAK3) and the TEC family of tyrosine kinases, while brepocitinib is a dual tyrosine kinase 2 (TYK2) and JAK1 inhibitor.

Both agents have demonstrated efficacy and acceptable safety in the treatment of alopecia areata and rheumatoid arthritis and are being evaluated for treating vitiligo, Crohn’s disease, and UC.

The different JAK selectivity profiles of ritlecitinib (JAK3/TEC) and brepocitinib (TYK2/JAK1), compared with other JAK inhibitors, could further the understanding of the role these pathways play in UC, the investigators note.
 

The VIBRATO study

As part of the phase 2b VIBRATO study, 317 patients with moderate to severe active UC (total Mayo Score ≥ 6) were randomly assigned to an 8-week induction course of once-daily oral ritlecitinib (20, 70, or 200 mg), brepocitinib (10, 30, or 60 mg), or matching placebo.

At week 8, compared with placebo, treatment with ritlecitinib or brepocitinib was associated with significantly lower mean total Mayo Scores (the primary endpoint) and higher rates of clinical remission, endoscopic and histologic improvement, and mucosal healing.

For both drugs, improvement on most metrics was dose dependent, with greater benefit at the highest dose.

For example, the placebo-adjusted mean total Mayo Score at week 8 was −4.6 for ritlecitinib 200 mg (P < .001) and −3.2 for brepocitinib 60 mg (P < .001). Both agents showed a “rapid” onset of action, with significant effects on the partial Mayo Score seen after just 2 weeks of treatment, the authors report.

Modified clinical remission at week 8 (a key secondary endpoint) was achieved in 36% of patients taking ritlecitinib 200 mg and 25.5% of those taking brepocitinib 60 mg (vs. 0% for patients taking placebo).

Endoscopic and histologic improvement, clinical response, mucosal healing, and the patient-reported outcome on the Inflammatory Bowel Disease Questionnaire followed a similar pattern, with a dose-dependent increase in treatment effect observed in most parameters at week 8, compared with placebo.
 

Longer-term data needed

Both agents were well tolerated with “acceptable short-term safety profiles,” the authors say.

There were no clinically significant findings for any laboratory parameters evaluated. Adverse events were mostly mild.

Infections were observed in 8.7% of patients taking ritlecitinib and 16.9% of those taking brepocitinib, compared with 4% of patients taking placebo. No serious cases of herpes zoster occurred.

One patient taking ritlecitinib suffered myocardial infarction and died, and one patient taking brepocitinib had peripheral artery thrombosis (left tibial artery). Both cases were considered unrelated to the study drug.

“As JAK inhibitors are associated with increased risk of major cardiovascular events and venous thromboembolisms, larger studies are needed for ritlecitinib and brepocitinib to fully understand their safety profiles,” the investigators say.

Limitations of the study include the small sample size and short 8-week treatment period. Longer-term safety and efficacy of both agents are being investigated.

The study was sponsored by Pfizer, which is developing both drugs. Dr. Sandborn and several coauthors have disclosed financial relationships with the company.

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

Patients with moderate to severe active ulcerative colitis (UC) who received induction therapy with either ritlecitinib or brepocitinib showed significant improvement across multiple outcome metrics in a phase 2b “umbrella” study of the two investigational agents.

The study by William J. Sandborn, MD, division of gastroenterology, University of California, San Diego, and colleagues was published online in Clinical Gastroenterology and Hepatology.

Ritlecitinib is a dual inhibitor that selectively inhibits Janus kinase 3 (JAK3) and the TEC family of tyrosine kinases, while brepocitinib is a dual tyrosine kinase 2 (TYK2) and JAK1 inhibitor.

Both agents have demonstrated efficacy and acceptable safety in the treatment of alopecia areata and rheumatoid arthritis and are being evaluated for treating vitiligo, Crohn’s disease, and UC.

The different JAK selectivity profiles of ritlecitinib (JAK3/TEC) and brepocitinib (TYK2/JAK1), compared with other JAK inhibitors, could further the understanding of the role these pathways play in UC, the investigators note.
 

The VIBRATO study

As part of the phase 2b VIBRATO study, 317 patients with moderate to severe active UC (total Mayo Score ≥ 6) were randomly assigned to an 8-week induction course of once-daily oral ritlecitinib (20, 70, or 200 mg), brepocitinib (10, 30, or 60 mg), or matching placebo.

At week 8, compared with placebo, treatment with ritlecitinib or brepocitinib was associated with significantly lower mean total Mayo Scores (the primary endpoint) and higher rates of clinical remission, endoscopic and histologic improvement, and mucosal healing.

For both drugs, improvement on most metrics was dose dependent, with greater benefit at the highest dose.

For example, the placebo-adjusted mean total Mayo Score at week 8 was −4.6 for ritlecitinib 200 mg (P < .001) and −3.2 for brepocitinib 60 mg (P < .001). Both agents showed a “rapid” onset of action, with significant effects on the partial Mayo Score seen after just 2 weeks of treatment, the authors report.

Modified clinical remission at week 8 (a key secondary endpoint) was achieved in 36% of patients taking ritlecitinib 200 mg and 25.5% of those taking brepocitinib 60 mg (vs. 0% for patients taking placebo).

Endoscopic and histologic improvement, clinical response, mucosal healing, and the patient-reported outcome on the Inflammatory Bowel Disease Questionnaire followed a similar pattern, with a dose-dependent increase in treatment effect observed in most parameters at week 8, compared with placebo.
 

Longer-term data needed

Both agents were well tolerated with “acceptable short-term safety profiles,” the authors say.

There were no clinically significant findings for any laboratory parameters evaluated. Adverse events were mostly mild.

Infections were observed in 8.7% of patients taking ritlecitinib and 16.9% of those taking brepocitinib, compared with 4% of patients taking placebo. No serious cases of herpes zoster occurred.

One patient taking ritlecitinib suffered myocardial infarction and died, and one patient taking brepocitinib had peripheral artery thrombosis (left tibial artery). Both cases were considered unrelated to the study drug.

“As JAK inhibitors are associated with increased risk of major cardiovascular events and venous thromboembolisms, larger studies are needed for ritlecitinib and brepocitinib to fully understand their safety profiles,” the investigators say.

Limitations of the study include the small sample size and short 8-week treatment period. Longer-term safety and efficacy of both agents are being investigated.

The study was sponsored by Pfizer, which is developing both drugs. Dr. Sandborn and several coauthors have disclosed financial relationships with the company.

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

Two classes of drugs may be more effective than others for the treatment of gastroparesis, though the overall quality of evidence remains low to moderate and additional data are needed, according to a new report.

Oral dopamine antagonists and tachykinin-1 antagonists appear superior to placebo, finds the study. In addition, some drugs rank higher for addressing individual symptoms.

“Gastroparesis has a substantial impact on quality of life and societal functioning for patients, and the costs to the health service are high,” Alexander Ford, MBChB, MD, a professor of gastroenterology and honorary consultant gastroenterologist at the Leeds (England) Institute of Medical Research at St. James’s, University of Leeds, said in an interview.

“There are very few licensed therapies, but some novel drugs are in the pipeline, some existing drugs that are licensed for other conditions could be repurposed if efficacious, and some older drugs that have safety concerns may be beneficial,” he said. “Given the impact on patients and their symptoms, they may be willing to accept these safety risks in return for symptom improvement.”

Only one drug, the dopamine antagonist metoclopramide, has Food and Drug Administration approval for the treatment of gastroparesis, noted Dr. Ford and colleagues. The lack of other recommended drugs or new medications has resulted in off-label use of drugs in other classes.

The study was published online in Gastroenterology.
 

Investigating treatments

To address the lack of evidence supporting the efficacy and safety of licensed and unlicensed drugs for the condition, the researchers conducted a systematic review and network meta-analysis of randomized controlled trials of drugs for gastroparesis dating from 1947 to September 2022. The trials involved more than dozen drugs in several classes.

They determined drug efficacy on the basis of global symptoms of gastroparesis and individual symptoms such as nausea, vomiting, abdominal pain, bloating, or fullness. They judged safety on the basis of total adverse events and adverse events leading to withdrawal.

The research team extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures. They reported efficacy as a pooled relative risk of symptoms not improving and ranked the drugs according to P-score.

The analysis included 29 randomized controlled trials with 3,772 patients. Only four trials were at low risk of bias.

Overall, only two drug classes were considered efficacious: oral dopamine antagonists (RR, 0.58; P-score, 0.96) and tachykinin-1 antagonists (RR, 0.69; P-score, 0.83).

On the basis of 25 trials that reported on global symptoms, clebopride ranked first for efficacy (RR, 0.30; P-score, 0.99), followed by domperidone (RR, 0.69; P-score, 0.76). None of the other drugs were superior to the placebo. After direct and indirect comparisons, clebopride was superior to all other drugs except aprepitant.

After excluding three trials with a placebo run-in and a trial where only responders to single-blind domperidone were randomized, the researchers analyzed 21 trials with 2,233 patients. In this analysis, domperidone ranked first (RR, 0.48; P-score, 0.93), followed by oral metoclopramide (RR, 0.54; P-score, 0.87). None of the other drugs were superior to placebo.

Among 16 trials, including 1,381 patients, that confirmed delayed gastric emptying among all participants, only clebopride and metoclopramide were more efficacious than placebo. Clebopride ranked first (RR, 0.30; P-score, 0.95) and metoclopramide ranked third (RR, 0.48).

Among 13 trials with 785 patients with diabetic gastroparesis, none of the active drugs were superior to placebo. Among 12 trials recruiting patients with idiopathic or mixed etiology gastroparesis, clebopride ranked first (RR, 0.30; P-score, 0.93).

On the basis of trials that assessed individual symptoms, oral metoclopramide ranked first for nausea (RR, 0.46; P-score, 0.95), fullness (RR, 0.67; P-score, 0.86), and bloating (RR, 0.53; P-score, 0.97). However, the data came from one small trial. Tradipitant and TZP-102, a ghrelin agonist, were efficacious for nausea, and TZP-102 ranked second for fullness. No drugs were more efficacious than the placebo for abdominal pain or vomiting.

Among 20 trials that reported on the total number of adverse events, camicinal was the least likely to be associated with adverse events (RR, 0.77; P-score, 0.93) and prucalopride was the most likely to be associated with adverse events (RR, 2.96; P-score, 0.10). Prucalopride, oral metoclopramide, and aprepitant also were more likely than placebo to be associated with adverse events.

In 23 trials that reported on withdrawals caused by adverse events, camicinal was the least likely to be associated with withdrawals (RR, 0.20; P-score, 0.87). Nortriptyline was the most likely to be associated with withdrawals (RR, 3.33; P-score, 0.16). However, there were no significant differences between any individual drug and placebo.
 

Urgent need remains

More trials of drugs to treat gastroparesis are needed, Ford said.

“We need to consider the reintroduction of dopamine antagonists, if patients are willing to accept the safety concerns,” he added. “The other important point is most drugs were not of benefit. There is an urgent need to find efficacious therapies, and these should be fast-tracked for licensing approval if efficacy is proven.”

The study is “helpful for practicing clinicians since it provides a comprehensive review of clinical trials in gastroparesis,” Anthony Lembo, MD, a gastroenterologist at the Cleveland Clinic, said in an interview.

Dr. Lembo, who wasn’t involved with this study, has researched several drugs for gastroparesis, including relamorelin and TZP-102. He agreed that additional research is needed.

“There is a paucity of novel treatments currently in development,” he said. “However, there is interest in developing a product similar to domperidone without cardiac side effects, as well as performing larger studies with botulinum toxin injection.”

The authors did not disclose a funding source for the study. One author disclosed research funding from the National Institutes of Health and consulting roles with various pharmaceutical companies. Ford and the other authors reported no disclosures. Dr. Lembo reported no relevant disclosures.

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

Two classes of drugs may be more effective than others for the treatment of gastroparesis, though the overall quality of evidence remains low to moderate and additional data are needed, according to a new report.

Oral dopamine antagonists and tachykinin-1 antagonists appear superior to placebo, finds the study. In addition, some drugs rank higher for addressing individual symptoms.

“Gastroparesis has a substantial impact on quality of life and societal functioning for patients, and the costs to the health service are high,” Alexander Ford, MBChB, MD, a professor of gastroenterology and honorary consultant gastroenterologist at the Leeds (England) Institute of Medical Research at St. James’s, University of Leeds, said in an interview.

“There are very few licensed therapies, but some novel drugs are in the pipeline, some existing drugs that are licensed for other conditions could be repurposed if efficacious, and some older drugs that have safety concerns may be beneficial,” he said. “Given the impact on patients and their symptoms, they may be willing to accept these safety risks in return for symptom improvement.”

Only one drug, the dopamine antagonist metoclopramide, has Food and Drug Administration approval for the treatment of gastroparesis, noted Dr. Ford and colleagues. The lack of other recommended drugs or new medications has resulted in off-label use of drugs in other classes.

The study was published online in Gastroenterology.
 

Investigating treatments

To address the lack of evidence supporting the efficacy and safety of licensed and unlicensed drugs for the condition, the researchers conducted a systematic review and network meta-analysis of randomized controlled trials of drugs for gastroparesis dating from 1947 to September 2022. The trials involved more than dozen drugs in several classes.

They determined drug efficacy on the basis of global symptoms of gastroparesis and individual symptoms such as nausea, vomiting, abdominal pain, bloating, or fullness. They judged safety on the basis of total adverse events and adverse events leading to withdrawal.

The research team extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures. They reported efficacy as a pooled relative risk of symptoms not improving and ranked the drugs according to P-score.

The analysis included 29 randomized controlled trials with 3,772 patients. Only four trials were at low risk of bias.

Overall, only two drug classes were considered efficacious: oral dopamine antagonists (RR, 0.58; P-score, 0.96) and tachykinin-1 antagonists (RR, 0.69; P-score, 0.83).

On the basis of 25 trials that reported on global symptoms, clebopride ranked first for efficacy (RR, 0.30; P-score, 0.99), followed by domperidone (RR, 0.69; P-score, 0.76). None of the other drugs were superior to the placebo. After direct and indirect comparisons, clebopride was superior to all other drugs except aprepitant.

After excluding three trials with a placebo run-in and a trial where only responders to single-blind domperidone were randomized, the researchers analyzed 21 trials with 2,233 patients. In this analysis, domperidone ranked first (RR, 0.48; P-score, 0.93), followed by oral metoclopramide (RR, 0.54; P-score, 0.87). None of the other drugs were superior to placebo.

Among 16 trials, including 1,381 patients, that confirmed delayed gastric emptying among all participants, only clebopride and metoclopramide were more efficacious than placebo. Clebopride ranked first (RR, 0.30; P-score, 0.95) and metoclopramide ranked third (RR, 0.48).

Among 13 trials with 785 patients with diabetic gastroparesis, none of the active drugs were superior to placebo. Among 12 trials recruiting patients with idiopathic or mixed etiology gastroparesis, clebopride ranked first (RR, 0.30; P-score, 0.93).

On the basis of trials that assessed individual symptoms, oral metoclopramide ranked first for nausea (RR, 0.46; P-score, 0.95), fullness (RR, 0.67; P-score, 0.86), and bloating (RR, 0.53; P-score, 0.97). However, the data came from one small trial. Tradipitant and TZP-102, a ghrelin agonist, were efficacious for nausea, and TZP-102 ranked second for fullness. No drugs were more efficacious than the placebo for abdominal pain or vomiting.

Among 20 trials that reported on the total number of adverse events, camicinal was the least likely to be associated with adverse events (RR, 0.77; P-score, 0.93) and prucalopride was the most likely to be associated with adverse events (RR, 2.96; P-score, 0.10). Prucalopride, oral metoclopramide, and aprepitant also were more likely than placebo to be associated with adverse events.

In 23 trials that reported on withdrawals caused by adverse events, camicinal was the least likely to be associated with withdrawals (RR, 0.20; P-score, 0.87). Nortriptyline was the most likely to be associated with withdrawals (RR, 3.33; P-score, 0.16). However, there were no significant differences between any individual drug and placebo.
 

Urgent need remains

More trials of drugs to treat gastroparesis are needed, Ford said.

“We need to consider the reintroduction of dopamine antagonists, if patients are willing to accept the safety concerns,” he added. “The other important point is most drugs were not of benefit. There is an urgent need to find efficacious therapies, and these should be fast-tracked for licensing approval if efficacy is proven.”

The study is “helpful for practicing clinicians since it provides a comprehensive review of clinical trials in gastroparesis,” Anthony Lembo, MD, a gastroenterologist at the Cleveland Clinic, said in an interview.

Dr. Lembo, who wasn’t involved with this study, has researched several drugs for gastroparesis, including relamorelin and TZP-102. He agreed that additional research is needed.

“There is a paucity of novel treatments currently in development,” he said. “However, there is interest in developing a product similar to domperidone without cardiac side effects, as well as performing larger studies with botulinum toxin injection.”

The authors did not disclose a funding source for the study. One author disclosed research funding from the National Institutes of Health and consulting roles with various pharmaceutical companies. Ford and the other authors reported no disclosures. Dr. Lembo reported no relevant disclosures.

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

Two classes of drugs may be more effective than others for the treatment of gastroparesis, though the overall quality of evidence remains low to moderate and additional data are needed, according to a new report.

Oral dopamine antagonists and tachykinin-1 antagonists appear superior to placebo, finds the study. In addition, some drugs rank higher for addressing individual symptoms.

“Gastroparesis has a substantial impact on quality of life and societal functioning for patients, and the costs to the health service are high,” Alexander Ford, MBChB, MD, a professor of gastroenterology and honorary consultant gastroenterologist at the Leeds (England) Institute of Medical Research at St. James’s, University of Leeds, said in an interview.

“There are very few licensed therapies, but some novel drugs are in the pipeline, some existing drugs that are licensed for other conditions could be repurposed if efficacious, and some older drugs that have safety concerns may be beneficial,” he said. “Given the impact on patients and their symptoms, they may be willing to accept these safety risks in return for symptom improvement.”

Only one drug, the dopamine antagonist metoclopramide, has Food and Drug Administration approval for the treatment of gastroparesis, noted Dr. Ford and colleagues. The lack of other recommended drugs or new medications has resulted in off-label use of drugs in other classes.

The study was published online in Gastroenterology.
 

Investigating treatments

To address the lack of evidence supporting the efficacy and safety of licensed and unlicensed drugs for the condition, the researchers conducted a systematic review and network meta-analysis of randomized controlled trials of drugs for gastroparesis dating from 1947 to September 2022. The trials involved more than dozen drugs in several classes.

They determined drug efficacy on the basis of global symptoms of gastroparesis and individual symptoms such as nausea, vomiting, abdominal pain, bloating, or fullness. They judged safety on the basis of total adverse events and adverse events leading to withdrawal.

The research team extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures. They reported efficacy as a pooled relative risk of symptoms not improving and ranked the drugs according to P-score.

The analysis included 29 randomized controlled trials with 3,772 patients. Only four trials were at low risk of bias.

Overall, only two drug classes were considered efficacious: oral dopamine antagonists (RR, 0.58; P-score, 0.96) and tachykinin-1 antagonists (RR, 0.69; P-score, 0.83).

On the basis of 25 trials that reported on global symptoms, clebopride ranked first for efficacy (RR, 0.30; P-score, 0.99), followed by domperidone (RR, 0.69; P-score, 0.76). None of the other drugs were superior to the placebo. After direct and indirect comparisons, clebopride was superior to all other drugs except aprepitant.

After excluding three trials with a placebo run-in and a trial where only responders to single-blind domperidone were randomized, the researchers analyzed 21 trials with 2,233 patients. In this analysis, domperidone ranked first (RR, 0.48; P-score, 0.93), followed by oral metoclopramide (RR, 0.54; P-score, 0.87). None of the other drugs were superior to placebo.

Among 16 trials, including 1,381 patients, that confirmed delayed gastric emptying among all participants, only clebopride and metoclopramide were more efficacious than placebo. Clebopride ranked first (RR, 0.30; P-score, 0.95) and metoclopramide ranked third (RR, 0.48).

Among 13 trials with 785 patients with diabetic gastroparesis, none of the active drugs were superior to placebo. Among 12 trials recruiting patients with idiopathic or mixed etiology gastroparesis, clebopride ranked first (RR, 0.30; P-score, 0.93).

On the basis of trials that assessed individual symptoms, oral metoclopramide ranked first for nausea (RR, 0.46; P-score, 0.95), fullness (RR, 0.67; P-score, 0.86), and bloating (RR, 0.53; P-score, 0.97). However, the data came from one small trial. Tradipitant and TZP-102, a ghrelin agonist, were efficacious for nausea, and TZP-102 ranked second for fullness. No drugs were more efficacious than the placebo for abdominal pain or vomiting.

Among 20 trials that reported on the total number of adverse events, camicinal was the least likely to be associated with adverse events (RR, 0.77; P-score, 0.93) and prucalopride was the most likely to be associated with adverse events (RR, 2.96; P-score, 0.10). Prucalopride, oral metoclopramide, and aprepitant also were more likely than placebo to be associated with adverse events.

In 23 trials that reported on withdrawals caused by adverse events, camicinal was the least likely to be associated with withdrawals (RR, 0.20; P-score, 0.87). Nortriptyline was the most likely to be associated with withdrawals (RR, 3.33; P-score, 0.16). However, there were no significant differences between any individual drug and placebo.
 

Urgent need remains

More trials of drugs to treat gastroparesis are needed, Ford said.

“We need to consider the reintroduction of dopamine antagonists, if patients are willing to accept the safety concerns,” he added. “The other important point is most drugs were not of benefit. There is an urgent need to find efficacious therapies, and these should be fast-tracked for licensing approval if efficacy is proven.”

The study is “helpful for practicing clinicians since it provides a comprehensive review of clinical trials in gastroparesis,” Anthony Lembo, MD, a gastroenterologist at the Cleveland Clinic, said in an interview.

Dr. Lembo, who wasn’t involved with this study, has researched several drugs for gastroparesis, including relamorelin and TZP-102. He agreed that additional research is needed.

“There is a paucity of novel treatments currently in development,” he said. “However, there is interest in developing a product similar to domperidone without cardiac side effects, as well as performing larger studies with botulinum toxin injection.”

The authors did not disclose a funding source for the study. One author disclosed research funding from the National Institutes of Health and consulting roles with various pharmaceutical companies. Ford and the other authors reported no disclosures. Dr. Lembo reported no relevant disclosures.

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

For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

A new analysis finds that vonoprazan triple therapy (Voquezna) is the most cost-effective first-line regimen to eradicate Helicobacter pylori infection in the United States.

Rifabutin triple therapy (Talicia) is the second most cost-effective strategy for H. pylori eradication, followed in order of decreasing cost-effectiveness by vonoprazan dual therapy, bismuth quadruple therapy, and clarithromycin triple therapy.

The analysis is believed to be the first to report on the cost-effectiveness of vonoprazan- and rifabutin-based regimens as first-line treatments for H. pylori infection from the perspective of U.S. health care payers.

The findings “strongly” suggest that vonoprazan triple therapy would provide the greatest net health benefit and monetary benefit for U.S. payers, reported Ismaeel Yunusa, PharmD, PhD, of the University of South Carolina College of Pharmacy in Columbia, and colleagues.

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

It’s estimated that more than 114 million people in the United States have H. pylori infection. Clinical practice guidelines recommend H. pylori eradication in all patients with a positive test of active infection.

Using a Markov model, Dr. Yunusa and colleagues estimated the cost-effectiveness of five prepackaged or co-formulated H. pylori eradication regimens: clarithromycin triple therapy, bismuth quadruple therapy, vonoprazan dual therapy, vonoprazan triple therapy, and rifabutin triple therapy.

The model estimated the expected costs in 2022 U.S. dollars, expected quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICERs), and expected net monetary benefit over 20 years.

Among their key findings and conclusions:

• Bismuth quadruple therapy had the highest expected cost ($1,439) and rifabutin triple regimen had the lowest expected cost ($1,048).
• Because rifabutin triple therapy was predicted to cost less and was more effective than clarithromycin triple therapy, bismuth quadruple therapy, and vonoprazan dual therapy, it dominated all treatment strategies – except for vonoprazan triple therapy.
• Compared with rifabutin triple therapy, vonoprazan triple therapy had a higher expected cost ($1,172 vs. $1,048) and expected QALY (14.262 vs. 14.256), yielding an ICER of $22,573 per QALY. 
• Vonoprazan triple therapy had the highest expected net monetary benefit and was the most cost-effective at willingness to pay thresholds between $50,000 and $150,000 per QALY, followed by rifabutin triple therapy.
• Vonoprazan triple therapy would result on average in an incremental net benefit of $1,655 per patient than clarithromycin triple therapy.
• Because the rifabutin-based regimen was more cost-effective than all but vonoprazan triple therapy, it has a potential role as an alternative first-line treatment.
• Rifabutin triple therapy and vonoprazan dual therapy would need to be considerably discounted (by 15%-43% and by 44%-85%, respectively), to be cost-effective at commonly used cost-effectiveness thresholds.
• Vonoprazan dual therapy demonstrated limited value relative to other available options; thus, its widespread adoption as a first-line strategy seems unlikely.
• Based on the results, it would be hard to justify the use of bismuth quadruple therapy or clarithromycin triple therapy since they provide the lowest net monetary benefit and have lower eradication rates.

The investigators noted that their analysis considered only direct costs of therapy, not other costs such as appointments, travel, and time away from work.

They also assumed medical costs, including endoscopy and H. pylori testing, would not change regardless of treatment regimen. Therefore, total health care costs may be underestimated.

The study did not receive any funding. The authors have declared no relevant financial relationships.

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

A new analysis finds that vonoprazan triple therapy (Voquezna) is the most cost-effective first-line regimen to eradicate Helicobacter pylori infection in the United States.

Rifabutin triple therapy (Talicia) is the second most cost-effective strategy for H. pylori eradication, followed in order of decreasing cost-effectiveness by vonoprazan dual therapy, bismuth quadruple therapy, and clarithromycin triple therapy.

The analysis is believed to be the first to report on the cost-effectiveness of vonoprazan- and rifabutin-based regimens as first-line treatments for H. pylori infection from the perspective of U.S. health care payers.

The findings “strongly” suggest that vonoprazan triple therapy would provide the greatest net health benefit and monetary benefit for U.S. payers, reported Ismaeel Yunusa, PharmD, PhD, of the University of South Carolina College of Pharmacy in Columbia, and colleagues.

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

It’s estimated that more than 114 million people in the United States have H. pylori infection. Clinical practice guidelines recommend H. pylori eradication in all patients with a positive test of active infection.

Using a Markov model, Dr. Yunusa and colleagues estimated the cost-effectiveness of five prepackaged or co-formulated H. pylori eradication regimens: clarithromycin triple therapy, bismuth quadruple therapy, vonoprazan dual therapy, vonoprazan triple therapy, and rifabutin triple therapy.

The model estimated the expected costs in 2022 U.S. dollars, expected quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICERs), and expected net monetary benefit over 20 years.

Among their key findings and conclusions:

• Bismuth quadruple therapy had the highest expected cost ($1,439) and rifabutin triple regimen had the lowest expected cost ($1,048).
• Because rifabutin triple therapy was predicted to cost less and was more effective than clarithromycin triple therapy, bismuth quadruple therapy, and vonoprazan dual therapy, it dominated all treatment strategies – except for vonoprazan triple therapy.
• Compared with rifabutin triple therapy, vonoprazan triple therapy had a higher expected cost ($1,172 vs. $1,048) and expected QALY (14.262 vs. 14.256), yielding an ICER of $22,573 per QALY. 
• Vonoprazan triple therapy had the highest expected net monetary benefit and was the most cost-effective at willingness to pay thresholds between $50,000 and $150,000 per QALY, followed by rifabutin triple therapy.
• Vonoprazan triple therapy would result on average in an incremental net benefit of $1,655 per patient than clarithromycin triple therapy.
• Because the rifabutin-based regimen was more cost-effective than all but vonoprazan triple therapy, it has a potential role as an alternative first-line treatment.
• Rifabutin triple therapy and vonoprazan dual therapy would need to be considerably discounted (by 15%-43% and by 44%-85%, respectively), to be cost-effective at commonly used cost-effectiveness thresholds.
• Vonoprazan dual therapy demonstrated limited value relative to other available options; thus, its widespread adoption as a first-line strategy seems unlikely.
• Based on the results, it would be hard to justify the use of bismuth quadruple therapy or clarithromycin triple therapy since they provide the lowest net monetary benefit and have lower eradication rates.

The investigators noted that their analysis considered only direct costs of therapy, not other costs such as appointments, travel, and time away from work.

They also assumed medical costs, including endoscopy and H. pylori testing, would not change regardless of treatment regimen. Therefore, total health care costs may be underestimated.

The study did not receive any funding. The authors have declared no relevant financial relationships.

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

A new analysis finds that vonoprazan triple therapy (Voquezna) is the most cost-effective first-line regimen to eradicate Helicobacter pylori infection in the United States.

Rifabutin triple therapy (Talicia) is the second most cost-effective strategy for H. pylori eradication, followed in order of decreasing cost-effectiveness by vonoprazan dual therapy, bismuth quadruple therapy, and clarithromycin triple therapy.

The analysis is believed to be the first to report on the cost-effectiveness of vonoprazan- and rifabutin-based regimens as first-line treatments for H. pylori infection from the perspective of U.S. health care payers.

The findings “strongly” suggest that vonoprazan triple therapy would provide the greatest net health benefit and monetary benefit for U.S. payers, reported Ismaeel Yunusa, PharmD, PhD, of the University of South Carolina College of Pharmacy in Columbia, and colleagues.

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

It’s estimated that more than 114 million people in the United States have H. pylori infection. Clinical practice guidelines recommend H. pylori eradication in all patients with a positive test of active infection.

Using a Markov model, Dr. Yunusa and colleagues estimated the cost-effectiveness of five prepackaged or co-formulated H. pylori eradication regimens: clarithromycin triple therapy, bismuth quadruple therapy, vonoprazan dual therapy, vonoprazan triple therapy, and rifabutin triple therapy.

The model estimated the expected costs in 2022 U.S. dollars, expected quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICERs), and expected net monetary benefit over 20 years.

Among their key findings and conclusions:

• Bismuth quadruple therapy had the highest expected cost ($1,439) and rifabutin triple regimen had the lowest expected cost ($1,048).
• Because rifabutin triple therapy was predicted to cost less and was more effective than clarithromycin triple therapy, bismuth quadruple therapy, and vonoprazan dual therapy, it dominated all treatment strategies – except for vonoprazan triple therapy.
• Compared with rifabutin triple therapy, vonoprazan triple therapy had a higher expected cost ($1,172 vs. $1,048) and expected QALY (14.262 vs. 14.256), yielding an ICER of $22,573 per QALY. 
• Vonoprazan triple therapy had the highest expected net monetary benefit and was the most cost-effective at willingness to pay thresholds between $50,000 and $150,000 per QALY, followed by rifabutin triple therapy.
• Vonoprazan triple therapy would result on average in an incremental net benefit of $1,655 per patient than clarithromycin triple therapy.
• Because the rifabutin-based regimen was more cost-effective than all but vonoprazan triple therapy, it has a potential role as an alternative first-line treatment.
• Rifabutin triple therapy and vonoprazan dual therapy would need to be considerably discounted (by 15%-43% and by 44%-85%, respectively), to be cost-effective at commonly used cost-effectiveness thresholds.
• Vonoprazan dual therapy demonstrated limited value relative to other available options; thus, its widespread adoption as a first-line strategy seems unlikely.
• Based on the results, it would be hard to justify the use of bismuth quadruple therapy or clarithromycin triple therapy since they provide the lowest net monetary benefit and have lower eradication rates.

The investigators noted that their analysis considered only direct costs of therapy, not other costs such as appointments, travel, and time away from work.

They also assumed medical costs, including endoscopy and H. pylori testing, would not change regardless of treatment regimen. Therefore, total health care costs may be underestimated.

The study did not receive any funding. The authors have declared no relevant financial relationships.

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

Some solid food diets may aid in the treatment of inflammatory bowel disease (IBD), though the overall quality of evidence remains low and additional data are needed, according to a new report.

For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.

“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.

“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing diets

Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.

In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.

For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.

Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.

Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.

When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.

For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.

“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”

For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.

For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
 

Helping patients

Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.

“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.

Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.

Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.

“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”

As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.

“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”

The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.

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

Some solid food diets may aid in the treatment of inflammatory bowel disease (IBD), though the overall quality of evidence remains low and additional data are needed, according to a new report.

For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.

“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.

“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing diets

Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.

In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.

For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.

Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.

Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.

When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.

For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.

“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”

For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.

For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
 

Helping patients

Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.

“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.

Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.

Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.

“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”

As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.

“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”

The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.

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

Some solid food diets may aid in the treatment of inflammatory bowel disease (IBD), though the overall quality of evidence remains low and additional data are needed, according to a new report.

For Crohn’s disease, a diet low in refined carbohydrates and a symptoms-guided diet appeared to help with remission, yet reduction of refined carbohydrates or red meat didn’t reduce the risk of relapse. For ulcerative colitis, solid food diets were similar to control measures.

“The Internet has a dizzying array of diet variants touted to benefit inflammation and IBD, which has led to much confusion among patients, and even clinicians, over what is truly effective or not,” Berkeley Limketkai, MD, PhD, director of clinical research at the Center for Inflammatory Bowel Disease at the University of California, Los Angeles, said in an interview.

“Even experiences shared by well-meaning individuals might not be generalizable to others,” he said. “The lack of clarity on what is or is not effective motivated us to perform this systematic review and meta-analysis.”

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing diets

Some nutritional therapies, such as exclusive enteral nutrition, have good evidence to support their use in the treatment of IBD, Dr. Limketkai said. However, patients often find maintaining a liquid diet difficult, particularly over a long period of time, so clinicians and patients have been interested in solid food diets as a treatment for IBD.

In 2019, Dr. Limketkai and colleagues conducted a systematic review and meta-analysis of randomized controlled trials focused on solid food diets for IBD that was published with the Cochrane Collaboration. At that time, the data were considered sparse, and the certainty of evidence was very low or low. Since then, several high-quality trials have been published.

For this study, Dr. Limketkai and colleagues conducted an updated review of 36 studies and a meta-analysis of 27 studies that compared a solid food diet with a control diet in patients with Crohn’s disease or ulcerative colitis. The intervention arm had to involve a well-defined diet, not merely a “usual” diet.

Among the studies, 12 evaluated dietary interventions for inducing clinical remission in patients with active Crohn’s disease, and 639 patients were involved. Overall, a low–refined carbohydrate diet was superior to a high-carbohydrate diet or a low-fiber diet. In addition, a symptoms-guided diet, which sequentially eliminated foods that aggravated a patient’s symptoms, was superior to conventional nutrition advice. However, the studies had serious imprecisions and very low certainty of evidence.

Compared with respective controls, a highly restrictive organic diet, a low-microparticle diet, and a low-calcium diet were ineffective at inducing remission of Crohn’s disease. Studies focused on immunoglobulin G-based measures were also inconsistent.

When comparing diets touted to benefit patients with Crohn’s disease, the Specific Carbohydrate Diet was similar to the Mediterranean diet and the whole-food diet, though the certainty of evidence was low. Partial enteral nutrition was similar to exclusive enteral nutrition, though there was substantial statistical heterogeneity between studies and very low certainty of evidence.

For maintenance of Crohn’s disease remission, researchers evaluated 14 studies that included 1,211 patients with inactive disease. Partial enteral nutrition appeared to reduce the risk of relapse, although evidence certainty was very low. In contrast, reducing red meat or refined carbohydrates did not lower the risk of relapse.

“These findings seemingly contradict our belief that red meat and refined carbohydrates have proinflammatory effects, although there are other studies that appear to show inconsistent, weak, or no association between consumption of unprocessed red meat and disease,” Dr. Limketkai said. “The caveat is that our findings are based on weak evidence, which may change as more studies are performed over time.”

For induction of remission in ulcerative colitis, researchers evaluated three studies that included 124 participants with active disease. When compared with participants’ usual diet, there was no benefit from a diet that excluded symptom-provoking foods, fried foods, refined carbohydrates, additives, preservatives, most condiments, spices, and beverages other than boiled water. Other studies found no benefit from eliminating cow milk protein or gluten.

For maintenance of ulcerative colitis remission, they looked at four studies that included 101 patients with inactive disease. Overall, there was no benefit from a carrageenan-free diet, anti-inflammatory diet, or cow milk protein elimination diet.
 

Helping patients

Although the certainty of evidence remains very low or low for most dietary trials in IBD, the emerging data suggest that nutrition plays an important role in IBD management and should be considered in the overall treatment plan for patients, the study authors wrote.

“Patients continue to look for ways to control their IBD, particularly with diet. Providers continue to struggle with making evidence-based recommendations about dietary interventions for IBD. This systematic review is a useful tool for providers to advise their patients,” James D. Lewis, MD, associate director of the inflammatory bowel diseases program at the University of Pennsylvania, Philadelphia, said in an interview.

Dr. Lewis, who wasn’t involved with this study, has researched dietary interventions for IBD. He and his colleagues have found that reducing red meat does not lower the rate of Crohn’s disease flares and that the Mediterranean diet and Specific Carbohydrate Diet appear to be similar for inducing clinical remission.

Based on this review, partial enteral nutrition could be an option for patients with Crohn’s disease, Dr. Lewis said.

“Partial enteral nutrition is much easier than exclusive enteral nutrition for patients,” he said. “However, there remains uncertainty as to whether the solid food component of a partial enteral nutrition approach impacts outcomes.”

As more dietary studies become available, the certainty of evidence could improve and lead to better recommendations for patients, Dr. Limketkai and colleagues wrote. They are conducting several studies focused on the concept of precision nutrition.

“While certain diets may be helpful and effective for IBD, different diets work differently in different people. This concept is no different than the fact that different IBD medications work differently in different individuals,” Dr. Limketkai said. “However, given the current state of evidence for dietary interventions in IBD, we still have a long path of research ahead of us.”

The study received no funding. The study authors reported no conflicts of interest. Dr. Lewis reported no relevant disclosures.

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