IBD & Intestinal Disorders

CHICAGO – In celiac disease, one of the most promising areas of research includes the development of treatments that target HLA-DQ2 gene variants associated with the condition.

There are a number of clinical trials underway, including one for the investigational drug TPM502, which carries three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene. And, research is underway for the novel KAN-101, which aims to restore the immune tolerance of gluten by targeting receptors on the liver. It received Fast Track designation by the Food and Drug Administration in 2022.

During the annual Digestive Disease Week® (DDW), researchers shared the results from a new proof-of-concept study for DONQ52, a bispecific antibody that targets HLA-DQ2.5. DONQ52 was found to be highly effective in blocking gluten-specific T cells, said investigator Jason A. Tye-Din, PhD, a researcher with The Walter and Eliza Hall Institute of Medical Research, Melbourne, and an investigator with Chugai Pharmaceutical, which is funding the DONQ52 research which has since advanced to a phase 1 study of 56 patients.

There are no existing drug therapies for celiac disease, which leaves patients with a lifelong, and strict, gluten-free diet as treatment. This strategy, however, often fails to induce mucosal healing or symptom control, and has stimulated a search for novel therapies, said Melinda Y. Hardy, PhD, a postdoctoral researcher with the University of Melbourne, and the first author of the DONQ52 study. While targeting the gluten-specific immune response is highly attractive, it presents safety and pharmacokinetic challenges, so a better alternative would be to develop antibodies that selectively bind to HLA-DQ2.5, which is found in 80%-90% of celiac disease patients, she said. DONQ52 blocks at least 25 gluten peptides, and binds specifically to complexes of HLA-DQ2.5 and a range of immunogenic gluten peptides.

The study included 20 patients who consumed wheat bread for 3 days. Blood samples were taken 1 day before the start of the trial and 6 days after it concluded. Twenty patients were found to be wheat challenged, 10 were barley challenged, and 14 were rye challenged.

All were tested for gluten-specific T-cell responses in the presence or absence of DONQ52, which was designed to reduce the wheat-specific T-cell response because 90% of gluten intake is from wheat. “If you have celiac disease, you have a reservoir of these gluten-specific T cells. When you eat gluten, they’ll be activated and switched on and that’s what we want to block,” Dr. Tye-Din said.

The main assessment – a day 6 wheat challenge among 15 responders – revealed a more than 80% reduction in T-cell responses to a peptide cocktail. DONQ52 also reduced barley and rye T cell responses in a day 6 challenge, although to a lesser degree (40%/80%).

“DONQ52 is designed to target individual peptides that trigger the disease, and we showed that it did it very well to the wheat peptides, well over 80%. That’s a very impressive reduction in responses,” he said. A further test among 20 samples showed that DONQ52 did not activate T-cells nonspecifically. “You don’t want to trigger an unnecessary response,” Dr. Tye-Din added.

“DONQ52 effectively reduces activation of wheat gluten-specific T cells. It also has broad reactivity extending to barley and rye T-cell epitopes,” said Dr. Hardy.

The study was funded by Chugai Pharmaceutical. Dr. Hardy is a coinventor on a provisional patent describing oats peptides in celiac disease therapeutics and diagnostics. Dr. Tye-Din disclosed associations with Chugai, Genentech, Janssen, and Takeda, among others.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

CHICAGO – In celiac disease, one of the most promising areas of research includes the development of treatments that target HLA-DQ2 gene variants associated with the condition.

There are a number of clinical trials underway, including one for the investigational drug TPM502, which carries three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene. And, research is underway for the novel KAN-101, which aims to restore the immune tolerance of gluten by targeting receptors on the liver. It received Fast Track designation by the Food and Drug Administration in 2022.

During the annual Digestive Disease Week® (DDW), researchers shared the results from a new proof-of-concept study for DONQ52, a bispecific antibody that targets HLA-DQ2.5. DONQ52 was found to be highly effective in blocking gluten-specific T cells, said investigator Jason A. Tye-Din, PhD, a researcher with The Walter and Eliza Hall Institute of Medical Research, Melbourne, and an investigator with Chugai Pharmaceutical, which is funding the DONQ52 research which has since advanced to a phase 1 study of 56 patients.

There are no existing drug therapies for celiac disease, which leaves patients with a lifelong, and strict, gluten-free diet as treatment. This strategy, however, often fails to induce mucosal healing or symptom control, and has stimulated a search for novel therapies, said Melinda Y. Hardy, PhD, a postdoctoral researcher with the University of Melbourne, and the first author of the DONQ52 study. While targeting the gluten-specific immune response is highly attractive, it presents safety and pharmacokinetic challenges, so a better alternative would be to develop antibodies that selectively bind to HLA-DQ2.5, which is found in 80%-90% of celiac disease patients, she said. DONQ52 blocks at least 25 gluten peptides, and binds specifically to complexes of HLA-DQ2.5 and a range of immunogenic gluten peptides.

The study included 20 patients who consumed wheat bread for 3 days. Blood samples were taken 1 day before the start of the trial and 6 days after it concluded. Twenty patients were found to be wheat challenged, 10 were barley challenged, and 14 were rye challenged.

All were tested for gluten-specific T-cell responses in the presence or absence of DONQ52, which was designed to reduce the wheat-specific T-cell response because 90% of gluten intake is from wheat. “If you have celiac disease, you have a reservoir of these gluten-specific T cells. When you eat gluten, they’ll be activated and switched on and that’s what we want to block,” Dr. Tye-Din said.

The main assessment – a day 6 wheat challenge among 15 responders – revealed a more than 80% reduction in T-cell responses to a peptide cocktail. DONQ52 also reduced barley and rye T cell responses in a day 6 challenge, although to a lesser degree (40%/80%).

“DONQ52 is designed to target individual peptides that trigger the disease, and we showed that it did it very well to the wheat peptides, well over 80%. That’s a very impressive reduction in responses,” he said. A further test among 20 samples showed that DONQ52 did not activate T-cells nonspecifically. “You don’t want to trigger an unnecessary response,” Dr. Tye-Din added.

“DONQ52 effectively reduces activation of wheat gluten-specific T cells. It also has broad reactivity extending to barley and rye T-cell epitopes,” said Dr. Hardy.

The study was funded by Chugai Pharmaceutical. Dr. Hardy is a coinventor on a provisional patent describing oats peptides in celiac disease therapeutics and diagnostics. Dr. Tye-Din disclosed associations with Chugai, Genentech, Janssen, and Takeda, among others.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

CHICAGO – In celiac disease, one of the most promising areas of research includes the development of treatments that target HLA-DQ2 gene variants associated with the condition.

There are a number of clinical trials underway, including one for the investigational drug TPM502, which carries three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene. And, research is underway for the novel KAN-101, which aims to restore the immune tolerance of gluten by targeting receptors on the liver. It received Fast Track designation by the Food and Drug Administration in 2022.

During the annual Digestive Disease Week® (DDW), researchers shared the results from a new proof-of-concept study for DONQ52, a bispecific antibody that targets HLA-DQ2.5. DONQ52 was found to be highly effective in blocking gluten-specific T cells, said investigator Jason A. Tye-Din, PhD, a researcher with The Walter and Eliza Hall Institute of Medical Research, Melbourne, and an investigator with Chugai Pharmaceutical, which is funding the DONQ52 research which has since advanced to a phase 1 study of 56 patients.

There are no existing drug therapies for celiac disease, which leaves patients with a lifelong, and strict, gluten-free diet as treatment. This strategy, however, often fails to induce mucosal healing or symptom control, and has stimulated a search for novel therapies, said Melinda Y. Hardy, PhD, a postdoctoral researcher with the University of Melbourne, and the first author of the DONQ52 study. While targeting the gluten-specific immune response is highly attractive, it presents safety and pharmacokinetic challenges, so a better alternative would be to develop antibodies that selectively bind to HLA-DQ2.5, which is found in 80%-90% of celiac disease patients, she said. DONQ52 blocks at least 25 gluten peptides, and binds specifically to complexes of HLA-DQ2.5 and a range of immunogenic gluten peptides.

The study included 20 patients who consumed wheat bread for 3 days. Blood samples were taken 1 day before the start of the trial and 6 days after it concluded. Twenty patients were found to be wheat challenged, 10 were barley challenged, and 14 were rye challenged.

All were tested for gluten-specific T-cell responses in the presence or absence of DONQ52, which was designed to reduce the wheat-specific T-cell response because 90% of gluten intake is from wheat. “If you have celiac disease, you have a reservoir of these gluten-specific T cells. When you eat gluten, they’ll be activated and switched on and that’s what we want to block,” Dr. Tye-Din said.

The main assessment – a day 6 wheat challenge among 15 responders – revealed a more than 80% reduction in T-cell responses to a peptide cocktail. DONQ52 also reduced barley and rye T cell responses in a day 6 challenge, although to a lesser degree (40%/80%).

“DONQ52 is designed to target individual peptides that trigger the disease, and we showed that it did it very well to the wheat peptides, well over 80%. That’s a very impressive reduction in responses,” he said. A further test among 20 samples showed that DONQ52 did not activate T-cells nonspecifically. “You don’t want to trigger an unnecessary response,” Dr. Tye-Din added.

“DONQ52 effectively reduces activation of wheat gluten-specific T cells. It also has broad reactivity extending to barley and rye T-cell epitopes,” said Dr. Hardy.

The study was funded by Chugai Pharmaceutical. Dr. Hardy is a coinventor on a provisional patent describing oats peptides in celiac disease therapeutics and diagnostics. Dr. Tye-Din disclosed associations with Chugai, Genentech, Janssen, and Takeda, among others.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

CHICAGO – Irrespective of the number of infliximab switches, multiple, successive switches from infliximab originator to biosimilars are effective and safe in patients with inflammatory bowel disease (IBD), according to analysis of a real world IBD cohort presented at the annual Digestive Disease Week® (DDW).

“These findings are of major socioeconomic importance, especially in low- and middle-income countries where the access to health care may be limited,” said study author Beatriz Gros, MD, an advanced clinical fellow in gastroenterology at Western General Hospital of Edinburgh.

While switching from originator infliximab to biosimilar infliximab is known observationally to be safe and effective, data on single and double switches are scarce, and are lacking on triple switches. Infliximab, the first monoclonal antibody biologic inhibiting anti–tumor necrosis factor was approved by the Food and Drug Administration and by the European Medicines Agency in 1998 and 1999, respectively. Economic pressures led to the development of biosimilars, with the first EMA approval in 2013 and FDA approval in 2016. Uptake in Europe has been broad and expanding following evidence that early therapy is associated with better outcomes. In the United States, a recent RAND Corporation study estimated savings to be $38.4 billion or 5.9% of projected total spending on biologics from 2021 to 2025, Dr. Gros reported.

The Edinburgh IBD unit has undertaken three switch programs starting with originator to CT-P13 in 2016, CT-P13 to SB2 in 2020, and SB2 to CT-P13 in 2021. Their prospective, observational cohort study assessing safety and efficacy after switching from SB2 to CT-P13 has, as a primary endpoint, CT-P13 persistence following the switch from SB2. Stratification of persistence according to the number of switches, effectiveness, immunogenicity, and safety were secondary outcomes.

During routine virtual biologic clinic care, researchers collected clinical disease activity scores (Harvey-Bradshaw Index; partial Mayo score), laboratory parameters (including C-reactive protein [CRP], IFX trough, and antibody levels), and fecal calprotectin on 297 IBD patients (median age, 37 years; 61.6% male). Among them, 67 had three switches, 138 had two switches, and 92 had one switch. Median disease duration was longer (11.4 years) for those with three switches than for two switches (6.3 years) or one switch (2.3 years) (P < .0001)

Infliximab persistence

Out of 297 patients, 269 (90.6%) remained on infliximab at week 24. Reasons for discontinuing treatment were immunogenicity (15/297; 5.1%), secondary loss of response (7/297, 2.4%), adverse events (3/297, 1%), patient’s choice (2/297, 0.7%), and primary nonresponse (1/297, 0.3%).

While infliximab persistence was 82.6%, 92.8% and 97% in patients with one, two and three infliximab switches, respectively (P = .003), after confounder adjustment, the number of switches was not independently associated with infliximab persistence, Dr. Gros said.

What factors actually did predict infliximab persistence? Multivariable analysis identified absence of biochemical remission (CRP > 5 mg/L [hazard ratio, 3.21; 95% confidence interval, 1.43-7.24]); a diagnosis of ulcerative colitis/ inflammatory bowel disease unclassified (HR, 2.69; 95% CI, 1.19-6.06), detectable antibodies against infliximab at switch (HR, 5.81; 95% CI, 2.27-12.84) and time on infliximab (HR, 0.77; 95% CI, 0.62-0.95) as independent predictors for infliximab persistence rather than number of infliximab switches.

Clinical (P = .77), biochemical (P = .75), and fecal biomarker (P = .63) remission rates, Dr. Gros reported, were comparable at baseline, week 12 and week 24, with baseline rates for clinical, biochemical and fecal biomarker remission at 79.4%, 85.2%, and 85.3%, respectively, and at 81%, 86.5%, and 84.4% at week 24.

“Immunogenicity has been a major concern regarding multiple switches, although both our study and previous literature demonstrated that this seemed to be not happening more often to patients who had multiple switches compared to those who had fewer or none. Our study found that, of the 14 (7.1%) patients who developed de novo antibodies, none of them underwent three switches,” she said.

Dr. Gros disclosed relationships with Pfizer, AbbVie, and Jansen.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

CHICAGO – Irrespective of the number of infliximab switches, multiple, successive switches from infliximab originator to biosimilars are effective and safe in patients with inflammatory bowel disease (IBD), according to analysis of a real world IBD cohort presented at the annual Digestive Disease Week® (DDW).

“These findings are of major socioeconomic importance, especially in low- and middle-income countries where the access to health care may be limited,” said study author Beatriz Gros, MD, an advanced clinical fellow in gastroenterology at Western General Hospital of Edinburgh.

While switching from originator infliximab to biosimilar infliximab is known observationally to be safe and effective, data on single and double switches are scarce, and are lacking on triple switches. Infliximab, the first monoclonal antibody biologic inhibiting anti–tumor necrosis factor was approved by the Food and Drug Administration and by the European Medicines Agency in 1998 and 1999, respectively. Economic pressures led to the development of biosimilars, with the first EMA approval in 2013 and FDA approval in 2016. Uptake in Europe has been broad and expanding following evidence that early therapy is associated with better outcomes. In the United States, a recent RAND Corporation study estimated savings to be $38.4 billion or 5.9% of projected total spending on biologics from 2021 to 2025, Dr. Gros reported.

The Edinburgh IBD unit has undertaken three switch programs starting with originator to CT-P13 in 2016, CT-P13 to SB2 in 2020, and SB2 to CT-P13 in 2021. Their prospective, observational cohort study assessing safety and efficacy after switching from SB2 to CT-P13 has, as a primary endpoint, CT-P13 persistence following the switch from SB2. Stratification of persistence according to the number of switches, effectiveness, immunogenicity, and safety were secondary outcomes.

During routine virtual biologic clinic care, researchers collected clinical disease activity scores (Harvey-Bradshaw Index; partial Mayo score), laboratory parameters (including C-reactive protein [CRP], IFX trough, and antibody levels), and fecal calprotectin on 297 IBD patients (median age, 37 years; 61.6% male). Among them, 67 had three switches, 138 had two switches, and 92 had one switch. Median disease duration was longer (11.4 years) for those with three switches than for two switches (6.3 years) or one switch (2.3 years) (P < .0001)

Infliximab persistence

Out of 297 patients, 269 (90.6%) remained on infliximab at week 24. Reasons for discontinuing treatment were immunogenicity (15/297; 5.1%), secondary loss of response (7/297, 2.4%), adverse events (3/297, 1%), patient’s choice (2/297, 0.7%), and primary nonresponse (1/297, 0.3%).

While infliximab persistence was 82.6%, 92.8% and 97% in patients with one, two and three infliximab switches, respectively (P = .003), after confounder adjustment, the number of switches was not independently associated with infliximab persistence, Dr. Gros said.

What factors actually did predict infliximab persistence? Multivariable analysis identified absence of biochemical remission (CRP > 5 mg/L [hazard ratio, 3.21; 95% confidence interval, 1.43-7.24]); a diagnosis of ulcerative colitis/ inflammatory bowel disease unclassified (HR, 2.69; 95% CI, 1.19-6.06), detectable antibodies against infliximab at switch (HR, 5.81; 95% CI, 2.27-12.84) and time on infliximab (HR, 0.77; 95% CI, 0.62-0.95) as independent predictors for infliximab persistence rather than number of infliximab switches.

Clinical (P = .77), biochemical (P = .75), and fecal biomarker (P = .63) remission rates, Dr. Gros reported, were comparable at baseline, week 12 and week 24, with baseline rates for clinical, biochemical and fecal biomarker remission at 79.4%, 85.2%, and 85.3%, respectively, and at 81%, 86.5%, and 84.4% at week 24.

“Immunogenicity has been a major concern regarding multiple switches, although both our study and previous literature demonstrated that this seemed to be not happening more often to patients who had multiple switches compared to those who had fewer or none. Our study found that, of the 14 (7.1%) patients who developed de novo antibodies, none of them underwent three switches,” she said.

Dr. Gros disclosed relationships with Pfizer, AbbVie, and Jansen.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

CHICAGO – Irrespective of the number of infliximab switches, multiple, successive switches from infliximab originator to biosimilars are effective and safe in patients with inflammatory bowel disease (IBD), according to analysis of a real world IBD cohort presented at the annual Digestive Disease Week® (DDW).

“These findings are of major socioeconomic importance, especially in low- and middle-income countries where the access to health care may be limited,” said study author Beatriz Gros, MD, an advanced clinical fellow in gastroenterology at Western General Hospital of Edinburgh.

While switching from originator infliximab to biosimilar infliximab is known observationally to be safe and effective, data on single and double switches are scarce, and are lacking on triple switches. Infliximab, the first monoclonal antibody biologic inhibiting anti–tumor necrosis factor was approved by the Food and Drug Administration and by the European Medicines Agency in 1998 and 1999, respectively. Economic pressures led to the development of biosimilars, with the first EMA approval in 2013 and FDA approval in 2016. Uptake in Europe has been broad and expanding following evidence that early therapy is associated with better outcomes. In the United States, a recent RAND Corporation study estimated savings to be $38.4 billion or 5.9% of projected total spending on biologics from 2021 to 2025, Dr. Gros reported.

The Edinburgh IBD unit has undertaken three switch programs starting with originator to CT-P13 in 2016, CT-P13 to SB2 in 2020, and SB2 to CT-P13 in 2021. Their prospective, observational cohort study assessing safety and efficacy after switching from SB2 to CT-P13 has, as a primary endpoint, CT-P13 persistence following the switch from SB2. Stratification of persistence according to the number of switches, effectiveness, immunogenicity, and safety were secondary outcomes.

During routine virtual biologic clinic care, researchers collected clinical disease activity scores (Harvey-Bradshaw Index; partial Mayo score), laboratory parameters (including C-reactive protein [CRP], IFX trough, and antibody levels), and fecal calprotectin on 297 IBD patients (median age, 37 years; 61.6% male). Among them, 67 had three switches, 138 had two switches, and 92 had one switch. Median disease duration was longer (11.4 years) for those with three switches than for two switches (6.3 years) or one switch (2.3 years) (P < .0001)

Infliximab persistence

Out of 297 patients, 269 (90.6%) remained on infliximab at week 24. Reasons for discontinuing treatment were immunogenicity (15/297; 5.1%), secondary loss of response (7/297, 2.4%), adverse events (3/297, 1%), patient’s choice (2/297, 0.7%), and primary nonresponse (1/297, 0.3%).

While infliximab persistence was 82.6%, 92.8% and 97% in patients with one, two and three infliximab switches, respectively (P = .003), after confounder adjustment, the number of switches was not independently associated with infliximab persistence, Dr. Gros said.

What factors actually did predict infliximab persistence? Multivariable analysis identified absence of biochemical remission (CRP > 5 mg/L [hazard ratio, 3.21; 95% confidence interval, 1.43-7.24]); a diagnosis of ulcerative colitis/ inflammatory bowel disease unclassified (HR, 2.69; 95% CI, 1.19-6.06), detectable antibodies against infliximab at switch (HR, 5.81; 95% CI, 2.27-12.84) and time on infliximab (HR, 0.77; 95% CI, 0.62-0.95) as independent predictors for infliximab persistence rather than number of infliximab switches.

Clinical (P = .77), biochemical (P = .75), and fecal biomarker (P = .63) remission rates, Dr. Gros reported, were comparable at baseline, week 12 and week 24, with baseline rates for clinical, biochemical and fecal biomarker remission at 79.4%, 85.2%, and 85.3%, respectively, and at 81%, 86.5%, and 84.4% at week 24.

“Immunogenicity has been a major concern regarding multiple switches, although both our study and previous literature demonstrated that this seemed to be not happening more often to patients who had multiple switches compared to those who had fewer or none. Our study found that, of the 14 (7.1%) patients who developed de novo antibodies, none of them underwent three switches,” she said.

Dr. Gros disclosed relationships with Pfizer, AbbVie, and Jansen.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

The Food and Drug Administration has approved the oral Janus kinase (JAK) inhibitor upadacitinib for adults with moderately to severely active Crohn’s disease whose condition failed to respond adequately or who can’t tolerate one or more tumor necrosis factor (TNF) inhibitors, the company has announced.

Upadacitinib (Rinvoq, AbbVie) is the first oral small molecule approved by the FDA for Crohn’s disease, which is noteworthy, said Kristin E. Burke, MD, MPH, medical director of clinical operations for the Massachusetts General Hospital Crohn’s and Colitis Center, Boston.

Massachusetts General Hospital

“Crohn’s disease is a complex immune-mediated disease for which more effective and fast-acting treatment options are needed. The approval of upadacitinib for anti-TNF refractory Crohn’s disease represents an important milestone in the expansion of treatment options for this disease as the first oral small molecule available,” she said.

The approval for Crohn’s disease was supported by data from two induction studies (U-EXCEED and U-EXCEL) and one maintenance study (U-ENDURE).

In the two induction studies, 857 patients were randomly assigned to receive upadacitinib 45 mg or placebo once daily for 12 weeks. At week 12, a greater proportion of patients who received upadacitinib (vs. those who received placebo) achieved clinical remission, as determined on the basis of the Crohn’s Disease Activity Index (CDAI), and improvement in intestinal inflammation as assessed by colonoscopy.

In the maintenance study, 343 patients who responded to induction therapy with upadacitinib were randomly assigned to receive either a maintenance regimen of 15 or 30 mg once daily or placebo for 52 weeks.

At week 52, a greater proportion of patients who were treated with upadacitinib 15 mg or 30 mg, compared with those who received placebo, achieved clinical remission.

Data from the trials of upadacitinib in Crohn’s disease were presented at the European Crohn’s and Colitis Organisation (ECCO) 2023 Congress in March.

“Symptoms of moderately to severely active Crohn’s disease can be disruptive and uncomfortable for patients, so relief as early as possible is key. Given the progressive nature of the disease, endoscopic response is just as important,” U-EXCEL study investigator Edward V. Loftus Jr., MD, professor of medicine in the division of gastroenterology and hepatology at Mayo Clinic in Rochester, Minn., said in a news release.

“Based on the clinical trial results, treatment with Rinvoq shows both early and long-term symptom relief along with evidence of a visible reduction of damage to the intestinal lining caused by excess inflammation,” he said.

Patients should initially be given 45 mg of upadacitinib once daily for 12 weeks. After 12 weeks, the recommended maintenance dosage is 15 mg once a day. A maintenance dose of 30 mg once daily can be considered for patients with refractory, severe, or extensive Crohn’s disease, the FDA said in a statement announcing approval.

The most common side effects of upadacitinib in patients with Crohn’s disease are upper respiratory tract infection, anemia, fever, acne, herpes zoster, and headache.

Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological therapies for Crohn’s disease, or with strong immunosuppressants, such as azathioprine and cyclosporine.

Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis have occurred with JAK inhibitors such as upadacitinib.

The indication in Crohn’s disease marks the seventh in the United States for the JAK inhibitor. Other indications include rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Full prescribing information is available online.

Dr. Burke disclosed no conflicts. Dr. Loftus is a consultant and adviser for AbbVie.
 

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

The Food and Drug Administration has approved the oral Janus kinase (JAK) inhibitor upadacitinib for adults with moderately to severely active Crohn’s disease whose condition failed to respond adequately or who can’t tolerate one or more tumor necrosis factor (TNF) inhibitors, the company has announced.

Upadacitinib (Rinvoq, AbbVie) is the first oral small molecule approved by the FDA for Crohn’s disease, which is noteworthy, said Kristin E. Burke, MD, MPH, medical director of clinical operations for the Massachusetts General Hospital Crohn’s and Colitis Center, Boston.

Massachusetts General Hospital

“Crohn’s disease is a complex immune-mediated disease for which more effective and fast-acting treatment options are needed. The approval of upadacitinib for anti-TNF refractory Crohn’s disease represents an important milestone in the expansion of treatment options for this disease as the first oral small molecule available,” she said.

The approval for Crohn’s disease was supported by data from two induction studies (U-EXCEED and U-EXCEL) and one maintenance study (U-ENDURE).

In the two induction studies, 857 patients were randomly assigned to receive upadacitinib 45 mg or placebo once daily for 12 weeks. At week 12, a greater proportion of patients who received upadacitinib (vs. those who received placebo) achieved clinical remission, as determined on the basis of the Crohn’s Disease Activity Index (CDAI), and improvement in intestinal inflammation as assessed by colonoscopy.

In the maintenance study, 343 patients who responded to induction therapy with upadacitinib were randomly assigned to receive either a maintenance regimen of 15 or 30 mg once daily or placebo for 52 weeks.

At week 52, a greater proportion of patients who were treated with upadacitinib 15 mg or 30 mg, compared with those who received placebo, achieved clinical remission.

Data from the trials of upadacitinib in Crohn’s disease were presented at the European Crohn’s and Colitis Organisation (ECCO) 2023 Congress in March.

“Symptoms of moderately to severely active Crohn’s disease can be disruptive and uncomfortable for patients, so relief as early as possible is key. Given the progressive nature of the disease, endoscopic response is just as important,” U-EXCEL study investigator Edward V. Loftus Jr., MD, professor of medicine in the division of gastroenterology and hepatology at Mayo Clinic in Rochester, Minn., said in a news release.

“Based on the clinical trial results, treatment with Rinvoq shows both early and long-term symptom relief along with evidence of a visible reduction of damage to the intestinal lining caused by excess inflammation,” he said.

Patients should initially be given 45 mg of upadacitinib once daily for 12 weeks. After 12 weeks, the recommended maintenance dosage is 15 mg once a day. A maintenance dose of 30 mg once daily can be considered for patients with refractory, severe, or extensive Crohn’s disease, the FDA said in a statement announcing approval.

The most common side effects of upadacitinib in patients with Crohn’s disease are upper respiratory tract infection, anemia, fever, acne, herpes zoster, and headache.

Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological therapies for Crohn’s disease, or with strong immunosuppressants, such as azathioprine and cyclosporine.

Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis have occurred with JAK inhibitors such as upadacitinib.

The indication in Crohn’s disease marks the seventh in the United States for the JAK inhibitor. Other indications include rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Full prescribing information is available online.

Dr. Burke disclosed no conflicts. Dr. Loftus is a consultant and adviser for AbbVie.
 

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

The Food and Drug Administration has approved the oral Janus kinase (JAK) inhibitor upadacitinib for adults with moderately to severely active Crohn’s disease whose condition failed to respond adequately or who can’t tolerate one or more tumor necrosis factor (TNF) inhibitors, the company has announced.

Upadacitinib (Rinvoq, AbbVie) is the first oral small molecule approved by the FDA for Crohn’s disease, which is noteworthy, said Kristin E. Burke, MD, MPH, medical director of clinical operations for the Massachusetts General Hospital Crohn’s and Colitis Center, Boston.

Massachusetts General Hospital

“Crohn’s disease is a complex immune-mediated disease for which more effective and fast-acting treatment options are needed. The approval of upadacitinib for anti-TNF refractory Crohn’s disease represents an important milestone in the expansion of treatment options for this disease as the first oral small molecule available,” she said.

The approval for Crohn’s disease was supported by data from two induction studies (U-EXCEED and U-EXCEL) and one maintenance study (U-ENDURE).

In the two induction studies, 857 patients were randomly assigned to receive upadacitinib 45 mg or placebo once daily for 12 weeks. At week 12, a greater proportion of patients who received upadacitinib (vs. those who received placebo) achieved clinical remission, as determined on the basis of the Crohn’s Disease Activity Index (CDAI), and improvement in intestinal inflammation as assessed by colonoscopy.

In the maintenance study, 343 patients who responded to induction therapy with upadacitinib were randomly assigned to receive either a maintenance regimen of 15 or 30 mg once daily or placebo for 52 weeks.

At week 52, a greater proportion of patients who were treated with upadacitinib 15 mg or 30 mg, compared with those who received placebo, achieved clinical remission.

Data from the trials of upadacitinib in Crohn’s disease were presented at the European Crohn’s and Colitis Organisation (ECCO) 2023 Congress in March.

“Symptoms of moderately to severely active Crohn’s disease can be disruptive and uncomfortable for patients, so relief as early as possible is key. Given the progressive nature of the disease, endoscopic response is just as important,” U-EXCEL study investigator Edward V. Loftus Jr., MD, professor of medicine in the division of gastroenterology and hepatology at Mayo Clinic in Rochester, Minn., said in a news release.

“Based on the clinical trial results, treatment with Rinvoq shows both early and long-term symptom relief along with evidence of a visible reduction of damage to the intestinal lining caused by excess inflammation,” he said.

Patients should initially be given 45 mg of upadacitinib once daily for 12 weeks. After 12 weeks, the recommended maintenance dosage is 15 mg once a day. A maintenance dose of 30 mg once daily can be considered for patients with refractory, severe, or extensive Crohn’s disease, the FDA said in a statement announcing approval.

The most common side effects of upadacitinib in patients with Crohn’s disease are upper respiratory tract infection, anemia, fever, acne, herpes zoster, and headache.

Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological therapies for Crohn’s disease, or with strong immunosuppressants, such as azathioprine and cyclosporine.

Serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis have occurred with JAK inhibitors such as upadacitinib.

The indication in Crohn’s disease marks the seventh in the United States for the JAK inhibitor. Other indications include rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Full prescribing information is available online.

Dr. Burke disclosed no conflicts. Dr. Loftus is a consultant and adviser for AbbVie.
 

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

CHICAGO – New data from an ongoing study shows that regular meat consumption is associated with inflammatory bowel disease (IBD) flares, specifically for patients with ulcerative colitis.

The data, which was presented on May 7 in Chicago at the annual Digestive Disease Week® meeting, is based on an analysis of data from the PREdiCCt study (Prognostic Effect of Environmental Factors in Crohn’s and Colitis) in which diets of patients with IBD were tracked over 2-3 months with 2-year follow-ups. While the study itself includes nearly 3,000 patients from the United Kingdom who are in clinical remission, this analysis included 497 patients with Crohn’s disease and 520 with ulcerative colitis.

The highest level of patient-reported meat consumption was associated with doubled risk for hard flares – defined as an increase in symptoms plus elevation in c-reactive protein (CRP) and fecal calprotection (FCAL) plus a change in IBD therapy – in patients with ulcerative colitis, said study author Charlie W Lees, PhD, FRCP(Ed), Western General Hospital and University of Edinburgh.

Investigators also evaluated the occurrence of soft flares, which was defined as a negative response to the question, “Do you think your disease has been well controlled in the past month or since you last logged on to the portal?”

After a median follow-up of 1,481.5 days, hard flares occurred at a rate of 5.6% per year, but it did not differ by IBD subtype. However, soft flares accumulated rapidly. Hard flares with baseline FCAL levels in the 50-250 mcg/g range, as well as FCAL levels above 250 mcg, were associated with flares.

The mean baseline total protein intake was 91.9 g per day of which 35.8 g came from animal sources. The hazard ratio for the highest vs. lowest quartile of meat intake in the ulcerative colitis group was 2.08. They found no associations between hard flares with intake of total dietary fiber, N-6 polyunsaturated acids, or ultraprocessed foods, which Dr. Lees found surprising.

“Perhaps most intriguingly, when we look at ultraprocessed food intake, no difference in Crohn’s disease, and no difference in ulcerative colitis,” Dr. Lees said.

The finding is in contradiction to a study reported at the Crohn’s & Colitis Congress this year that found additives in ultraprocessed foods appear to have deleterious effects on intestinal microbiota, while others may exert their influence through mechanisms, such as endoplasmic stress.

However, the new data are consistent with a previously reported association between meat consumption and ulcerative colitis development, and suggests that reducing meat consumption could help to reduce the risk of flare in patients with ulcerative colitis.

PREdiCCt is designed to examine dietary, environmental, genetic, and microbiotic factors that are associated with disease flares in patients with Crohn’s disease and ulcerative colitis. Investigators are evaluating potential contributions to disease flares from total animal protein intake, dietary fiber, N-6 polyunsaturated fatty acids, dietary emulsifiers, and ultraprocessed foods, and total bacterial gene count in stool samples. They aim to examine data from 2,500 microbiome samples currently being sequenced at the Wellcome Sanger Institute in Hinxton, England, to determine whether the association between meat and ulcerative colitis flares could be related, as they hypothesize, to diet-induced alterations in the gut microbiome.

The research is preliminary with many unanswered questions, said Russell D. Cohen, MD, director of the inflammatory bowel disease center at the University of Chicago.

“I think he still has to evaluate a lot of the data that he has already collected because, are you talking about meat? Are you talking about poultry? Are you talking about fish? It is interesting, but it still needs to be evaluated further before we make any conclusive decisions,” he said. Dr. Cohen was not involved in the research.

He said the presumed effect of meat consumption on disease exacerbation appeared to take years, “which is a little surprising. If you really thought that IBD was due to something in diet, you would see the response right away, so it doesn’t follow timewise. Why does it takes 5 years? It should be within 5 weeks or 5 days.”

Dr. Lees disclosed relationships with Abbvie, Takeda, Pfizer, Galapagos, and BDD Pharma, among others.

DDW is sponsored by the American Gastroenterological Association, the American Association for the Study of Liver Diseases, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

CHICAGO – New data from an ongoing study shows that regular meat consumption is associated with inflammatory bowel disease (IBD) flares, specifically for patients with ulcerative colitis.

The data, which was presented on May 7 in Chicago at the annual Digestive Disease Week® meeting, is based on an analysis of data from the PREdiCCt study (Prognostic Effect of Environmental Factors in Crohn’s and Colitis) in which diets of patients with IBD were tracked over 2-3 months with 2-year follow-ups. While the study itself includes nearly 3,000 patients from the United Kingdom who are in clinical remission, this analysis included 497 patients with Crohn’s disease and 520 with ulcerative colitis.

The highest level of patient-reported meat consumption was associated with doubled risk for hard flares – defined as an increase in symptoms plus elevation in c-reactive protein (CRP) and fecal calprotection (FCAL) plus a change in IBD therapy – in patients with ulcerative colitis, said study author Charlie W Lees, PhD, FRCP(Ed), Western General Hospital and University of Edinburgh.

Investigators also evaluated the occurrence of soft flares, which was defined as a negative response to the question, “Do you think your disease has been well controlled in the past month or since you last logged on to the portal?”

After a median follow-up of 1,481.5 days, hard flares occurred at a rate of 5.6% per year, but it did not differ by IBD subtype. However, soft flares accumulated rapidly. Hard flares with baseline FCAL levels in the 50-250 mcg/g range, as well as FCAL levels above 250 mcg, were associated with flares.

The mean baseline total protein intake was 91.9 g per day of which 35.8 g came from animal sources. The hazard ratio for the highest vs. lowest quartile of meat intake in the ulcerative colitis group was 2.08. They found no associations between hard flares with intake of total dietary fiber, N-6 polyunsaturated acids, or ultraprocessed foods, which Dr. Lees found surprising.

“Perhaps most intriguingly, when we look at ultraprocessed food intake, no difference in Crohn’s disease, and no difference in ulcerative colitis,” Dr. Lees said.

The finding is in contradiction to a study reported at the Crohn’s & Colitis Congress this year that found additives in ultraprocessed foods appear to have deleterious effects on intestinal microbiota, while others may exert their influence through mechanisms, such as endoplasmic stress.

However, the new data are consistent with a previously reported association between meat consumption and ulcerative colitis development, and suggests that reducing meat consumption could help to reduce the risk of flare in patients with ulcerative colitis.

PREdiCCt is designed to examine dietary, environmental, genetic, and microbiotic factors that are associated with disease flares in patients with Crohn’s disease and ulcerative colitis. Investigators are evaluating potential contributions to disease flares from total animal protein intake, dietary fiber, N-6 polyunsaturated fatty acids, dietary emulsifiers, and ultraprocessed foods, and total bacterial gene count in stool samples. They aim to examine data from 2,500 microbiome samples currently being sequenced at the Wellcome Sanger Institute in Hinxton, England, to determine whether the association between meat and ulcerative colitis flares could be related, as they hypothesize, to diet-induced alterations in the gut microbiome.

The research is preliminary with many unanswered questions, said Russell D. Cohen, MD, director of the inflammatory bowel disease center at the University of Chicago.

“I think he still has to evaluate a lot of the data that he has already collected because, are you talking about meat? Are you talking about poultry? Are you talking about fish? It is interesting, but it still needs to be evaluated further before we make any conclusive decisions,” he said. Dr. Cohen was not involved in the research.

He said the presumed effect of meat consumption on disease exacerbation appeared to take years, “which is a little surprising. If you really thought that IBD was due to something in diet, you would see the response right away, so it doesn’t follow timewise. Why does it takes 5 years? It should be within 5 weeks or 5 days.”

Dr. Lees disclosed relationships with Abbvie, Takeda, Pfizer, Galapagos, and BDD Pharma, among others.

DDW is sponsored by the American Gastroenterological Association, the American Association for the Study of Liver Diseases, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

CHICAGO – New data from an ongoing study shows that regular meat consumption is associated with inflammatory bowel disease (IBD) flares, specifically for patients with ulcerative colitis.

The data, which was presented on May 7 in Chicago at the annual Digestive Disease Week® meeting, is based on an analysis of data from the PREdiCCt study (Prognostic Effect of Environmental Factors in Crohn’s and Colitis) in which diets of patients with IBD were tracked over 2-3 months with 2-year follow-ups. While the study itself includes nearly 3,000 patients from the United Kingdom who are in clinical remission, this analysis included 497 patients with Crohn’s disease and 520 with ulcerative colitis.

The highest level of patient-reported meat consumption was associated with doubled risk for hard flares – defined as an increase in symptoms plus elevation in c-reactive protein (CRP) and fecal calprotection (FCAL) plus a change in IBD therapy – in patients with ulcerative colitis, said study author Charlie W Lees, PhD, FRCP(Ed), Western General Hospital and University of Edinburgh.

Investigators also evaluated the occurrence of soft flares, which was defined as a negative response to the question, “Do you think your disease has been well controlled in the past month or since you last logged on to the portal?”

After a median follow-up of 1,481.5 days, hard flares occurred at a rate of 5.6% per year, but it did not differ by IBD subtype. However, soft flares accumulated rapidly. Hard flares with baseline FCAL levels in the 50-250 mcg/g range, as well as FCAL levels above 250 mcg, were associated with flares.

The mean baseline total protein intake was 91.9 g per day of which 35.8 g came from animal sources. The hazard ratio for the highest vs. lowest quartile of meat intake in the ulcerative colitis group was 2.08. They found no associations between hard flares with intake of total dietary fiber, N-6 polyunsaturated acids, or ultraprocessed foods, which Dr. Lees found surprising.

“Perhaps most intriguingly, when we look at ultraprocessed food intake, no difference in Crohn’s disease, and no difference in ulcerative colitis,” Dr. Lees said.

The finding is in contradiction to a study reported at the Crohn’s & Colitis Congress this year that found additives in ultraprocessed foods appear to have deleterious effects on intestinal microbiota, while others may exert their influence through mechanisms, such as endoplasmic stress.

However, the new data are consistent with a previously reported association between meat consumption and ulcerative colitis development, and suggests that reducing meat consumption could help to reduce the risk of flare in patients with ulcerative colitis.

PREdiCCt is designed to examine dietary, environmental, genetic, and microbiotic factors that are associated with disease flares in patients with Crohn’s disease and ulcerative colitis. Investigators are evaluating potential contributions to disease flares from total animal protein intake, dietary fiber, N-6 polyunsaturated fatty acids, dietary emulsifiers, and ultraprocessed foods, and total bacterial gene count in stool samples. They aim to examine data from 2,500 microbiome samples currently being sequenced at the Wellcome Sanger Institute in Hinxton, England, to determine whether the association between meat and ulcerative colitis flares could be related, as they hypothesize, to diet-induced alterations in the gut microbiome.

The research is preliminary with many unanswered questions, said Russell D. Cohen, MD, director of the inflammatory bowel disease center at the University of Chicago.

“I think he still has to evaluate a lot of the data that he has already collected because, are you talking about meat? Are you talking about poultry? Are you talking about fish? It is interesting, but it still needs to be evaluated further before we make any conclusive decisions,” he said. Dr. Cohen was not involved in the research.

He said the presumed effect of meat consumption on disease exacerbation appeared to take years, “which is a little surprising. If you really thought that IBD was due to something in diet, you would see the response right away, so it doesn’t follow timewise. Why does it takes 5 years? It should be within 5 weeks or 5 days.”

Dr. Lees disclosed relationships with Abbvie, Takeda, Pfizer, Galapagos, and BDD Pharma, among others.

DDW is sponsored by the American Gastroenterological Association, the American Association for the Study of Liver Diseases, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

CHICAGO – The standard approaches to measuring flares in people with Crohn’s disease have some limitations, including an inability to signal a change in disease activity without laboratory testing or before symptoms arise.

A new device developed at Massachusetts Institute of Technology could change all that.

Using data collected via a passive at-home monitoring device (Emerald sensor, Emerald Innovations Inc.), researchers found that increases in breathing rate, more awakenings at night, and slower walking speed accurately predicted that a person’s Crohn’s disease activity was about to flare, according to a study presented May 7 at Digestive Disease Week^® (DDW) 2023.

In some cases, the prediction of a flare came up to 25 days sooner than via traditional measures.

“In order to provide optimal care, providers need to monitor patients closely with regard to accurate active disease.” said Joshua Korzenik, MD, a gastroenterologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School in Boston. “The problem is the clinical symptoms are not accurate.”
 

Tracking flares with technology

Traditionally, measuring flares in Crohn’s disease activity depends on imaging, colonoscopy, and/or laboratory measures of calprotectin or other biomarkers. These approaches can be costly, can involve delays, and can carry risks, Dr. Korzenik said.

“They are also a single snapshot in time,” he added.

To determine how well a noninvasive device could perform, investigators enrolled 120 people with 105 continuing in the study long enough to be evaluable; 44 people whose Crohn’s disease was in remission, 35 with active Crohn’s disease, as well as 26 healthy controls. Among those with Crohn’s disease, 83% were on biologic therapy.

The groups were matched for age and gender, with a mean age of 47 years and mean disease duration of 13 years.

People with certain medical conditions were excluded, as was anyone who owned a large dog that sometimes slept in bed with them because that might throw off the readings.

The participants put the device – which resembles a closed laptop or a large Wi-Fi router – in their homes and were monitored for a mean 306 days. Participants wore an ankle bracelet the first 2 weeks of the study so the device could learn to distinguish them from others in the home.

The device sent out radio waves with frequencies like Wi-Fi for researchers to measure the factors that may be associated with flares, such as sleep quality and cycles, breathing rate, and gait speed.

Traditional clinical measures based on blood and stool samples, along with patient-reported outcome surveys, were taken to compare with the accuracy of the device.

Data from the device were collected and transmitted securely to a cloud database without any interaction from the participant. Data included information on more than 25,000 nights of sleep, 200,000 hours of breathing signals, and 400,000 measurements of walking speed.

Sleep quality and cycles were straightforward, as was breathing rate. But gait speed was a little more complicated to measure. To illustrate, Dr. Korzenik showed the layout of an example apartment with data on how someone moved around. To distill the data, the researchers focused on one path in the home, relatively straight and not obstructed by furniture, and limited the measurements to a certain amount of time. People who spent more time at home during the COVID-19 pandemic did not skew the results, according to Dr. Korzenik, who added that it wasn’t total time walking around but a snippet in time.

A variety of sleep, breathing, and mobility metrics extracted by the device were integrated to assess disease activity. Investigators noted that during flares, sleep quality decreased, and more nocturnal awakenings occurred. They also found that gait speed slowed, and respiratory rate increased with flares.

When the investigators looked at sleep as a function of disease activity in the patient-reported surveys, they found a significant difference between people in remission and those with active disease. For example, people with active disease had a greater number of awakenings at night (P = .0016), less REM sleep at night (P = .0000), and less time in deep sleep (P = .000) compared with those in remission.

The technology “can identify flares with a predictive value that approaches fecal calprotectin,” Dr. Korzenik said.

Machine learning was used to look at severity of disease vs. fecal calprotectin values and “showed the data could be used as a marker of disease,” he added.

Use of a remote monitor, the comparison of validated vs. conventional data, and the large dataset were among the strengths of the study. The single-center design and exclusion of people with some comorbidities are potential limitations.

Further studies are warranted to confirm these findings and guide optimal care of people with Crohn’s disease, the investigators noted.
 

Earlier detection, earlier intervention

“The study is really important,” said session comoderator Raymond K. Cross Jr., MD, professor of medicine and director of the IBD program at the University of Maryland, Baltimore.

Monitoring devices like this “could be very useful,” Dr. Cross said. “It is not invasive, unless you consider a device in your house invasive. But, to me, I don’t think a box in my bedroom would be unnerving to me.”

Dr. Cross shared a couple of caveats. “The one devil in the details is always going to be cost,” he said. Also, it’s unclear who will read and interpret all the data generated by the device among “providers who are already overwhelmed with the volume of information.”

Moving forward, a device like this could offer multiple uses, Dr. Cross noted. If the device can detect relapses earlier, physicians could intervene sooner, he said. Also, the device could potentially flag people who are not taking their medications as recommended, or it could be used as a guide to optimize treatment response.

Whether data from the device could indicate when it’s appropriate to reduce the frequency or dose of medication or even when to withdraw therapy would be “really aspirational,” Dr. Cross added.

The study was funded by The Leona M. and Harry B. Helmsley Charitable Trust. Dr. Korzenik and Dr. Cross report no relevant financial relationships.
 

DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).

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

CHICAGO – The standard approaches to measuring flares in people with Crohn’s disease have some limitations, including an inability to signal a change in disease activity without laboratory testing or before symptoms arise.

A new device developed at Massachusetts Institute of Technology could change all that.

Using data collected via a passive at-home monitoring device (Emerald sensor, Emerald Innovations Inc.), researchers found that increases in breathing rate, more awakenings at night, and slower walking speed accurately predicted that a person’s Crohn’s disease activity was about to flare, according to a study presented May 7 at Digestive Disease Week^® (DDW) 2023.

In some cases, the prediction of a flare came up to 25 days sooner than via traditional measures.

“In order to provide optimal care, providers need to monitor patients closely with regard to accurate active disease.” said Joshua Korzenik, MD, a gastroenterologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School in Boston. “The problem is the clinical symptoms are not accurate.”
 

Tracking flares with technology

Traditionally, measuring flares in Crohn’s disease activity depends on imaging, colonoscopy, and/or laboratory measures of calprotectin or other biomarkers. These approaches can be costly, can involve delays, and can carry risks, Dr. Korzenik said.

“They are also a single snapshot in time,” he added.

To determine how well a noninvasive device could perform, investigators enrolled 120 people with 105 continuing in the study long enough to be evaluable; 44 people whose Crohn’s disease was in remission, 35 with active Crohn’s disease, as well as 26 healthy controls. Among those with Crohn’s disease, 83% were on biologic therapy.

The groups were matched for age and gender, with a mean age of 47 years and mean disease duration of 13 years.

People with certain medical conditions were excluded, as was anyone who owned a large dog that sometimes slept in bed with them because that might throw off the readings.

The participants put the device – which resembles a closed laptop or a large Wi-Fi router – in their homes and were monitored for a mean 306 days. Participants wore an ankle bracelet the first 2 weeks of the study so the device could learn to distinguish them from others in the home.

The device sent out radio waves with frequencies like Wi-Fi for researchers to measure the factors that may be associated with flares, such as sleep quality and cycles, breathing rate, and gait speed.

Traditional clinical measures based on blood and stool samples, along with patient-reported outcome surveys, were taken to compare with the accuracy of the device.

Data from the device were collected and transmitted securely to a cloud database without any interaction from the participant. Data included information on more than 25,000 nights of sleep, 200,000 hours of breathing signals, and 400,000 measurements of walking speed.

Sleep quality and cycles were straightforward, as was breathing rate. But gait speed was a little more complicated to measure. To illustrate, Dr. Korzenik showed the layout of an example apartment with data on how someone moved around. To distill the data, the researchers focused on one path in the home, relatively straight and not obstructed by furniture, and limited the measurements to a certain amount of time. People who spent more time at home during the COVID-19 pandemic did not skew the results, according to Dr. Korzenik, who added that it wasn’t total time walking around but a snippet in time.

A variety of sleep, breathing, and mobility metrics extracted by the device were integrated to assess disease activity. Investigators noted that during flares, sleep quality decreased, and more nocturnal awakenings occurred. They also found that gait speed slowed, and respiratory rate increased with flares.

When the investigators looked at sleep as a function of disease activity in the patient-reported surveys, they found a significant difference between people in remission and those with active disease. For example, people with active disease had a greater number of awakenings at night (P = .0016), less REM sleep at night (P = .0000), and less time in deep sleep (P = .000) compared with those in remission.

The technology “can identify flares with a predictive value that approaches fecal calprotectin,” Dr. Korzenik said.

Machine learning was used to look at severity of disease vs. fecal calprotectin values and “showed the data could be used as a marker of disease,” he added.

Use of a remote monitor, the comparison of validated vs. conventional data, and the large dataset were among the strengths of the study. The single-center design and exclusion of people with some comorbidities are potential limitations.

Further studies are warranted to confirm these findings and guide optimal care of people with Crohn’s disease, the investigators noted.
 

Earlier detection, earlier intervention

“The study is really important,” said session comoderator Raymond K. Cross Jr., MD, professor of medicine and director of the IBD program at the University of Maryland, Baltimore.

Monitoring devices like this “could be very useful,” Dr. Cross said. “It is not invasive, unless you consider a device in your house invasive. But, to me, I don’t think a box in my bedroom would be unnerving to me.”

Dr. Cross shared a couple of caveats. “The one devil in the details is always going to be cost,” he said. Also, it’s unclear who will read and interpret all the data generated by the device among “providers who are already overwhelmed with the volume of information.”

Moving forward, a device like this could offer multiple uses, Dr. Cross noted. If the device can detect relapses earlier, physicians could intervene sooner, he said. Also, the device could potentially flag people who are not taking their medications as recommended, or it could be used as a guide to optimize treatment response.

Whether data from the device could indicate when it’s appropriate to reduce the frequency or dose of medication or even when to withdraw therapy would be “really aspirational,” Dr. Cross added.

The study was funded by The Leona M. and Harry B. Helmsley Charitable Trust. Dr. Korzenik and Dr. Cross report no relevant financial relationships.
 

DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).

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

CHICAGO – The standard approaches to measuring flares in people with Crohn’s disease have some limitations, including an inability to signal a change in disease activity without laboratory testing or before symptoms arise.

A new device developed at Massachusetts Institute of Technology could change all that.

Using data collected via a passive at-home monitoring device (Emerald sensor, Emerald Innovations Inc.), researchers found that increases in breathing rate, more awakenings at night, and slower walking speed accurately predicted that a person’s Crohn’s disease activity was about to flare, according to a study presented May 7 at Digestive Disease Week^® (DDW) 2023.

In some cases, the prediction of a flare came up to 25 days sooner than via traditional measures.

“In order to provide optimal care, providers need to monitor patients closely with regard to accurate active disease.” said Joshua Korzenik, MD, a gastroenterologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School in Boston. “The problem is the clinical symptoms are not accurate.”
 

Tracking flares with technology

Traditionally, measuring flares in Crohn’s disease activity depends on imaging, colonoscopy, and/or laboratory measures of calprotectin or other biomarkers. These approaches can be costly, can involve delays, and can carry risks, Dr. Korzenik said.

“They are also a single snapshot in time,” he added.

To determine how well a noninvasive device could perform, investigators enrolled 120 people with 105 continuing in the study long enough to be evaluable; 44 people whose Crohn’s disease was in remission, 35 with active Crohn’s disease, as well as 26 healthy controls. Among those with Crohn’s disease, 83% were on biologic therapy.

The groups were matched for age and gender, with a mean age of 47 years and mean disease duration of 13 years.

People with certain medical conditions were excluded, as was anyone who owned a large dog that sometimes slept in bed with them because that might throw off the readings.

The participants put the device – which resembles a closed laptop or a large Wi-Fi router – in their homes and were monitored for a mean 306 days. Participants wore an ankle bracelet the first 2 weeks of the study so the device could learn to distinguish them from others in the home.

The device sent out radio waves with frequencies like Wi-Fi for researchers to measure the factors that may be associated with flares, such as sleep quality and cycles, breathing rate, and gait speed.

Traditional clinical measures based on blood and stool samples, along with patient-reported outcome surveys, were taken to compare with the accuracy of the device.

Data from the device were collected and transmitted securely to a cloud database without any interaction from the participant. Data included information on more than 25,000 nights of sleep, 200,000 hours of breathing signals, and 400,000 measurements of walking speed.

Sleep quality and cycles were straightforward, as was breathing rate. But gait speed was a little more complicated to measure. To illustrate, Dr. Korzenik showed the layout of an example apartment with data on how someone moved around. To distill the data, the researchers focused on one path in the home, relatively straight and not obstructed by furniture, and limited the measurements to a certain amount of time. People who spent more time at home during the COVID-19 pandemic did not skew the results, according to Dr. Korzenik, who added that it wasn’t total time walking around but a snippet in time.

A variety of sleep, breathing, and mobility metrics extracted by the device were integrated to assess disease activity. Investigators noted that during flares, sleep quality decreased, and more nocturnal awakenings occurred. They also found that gait speed slowed, and respiratory rate increased with flares.

When the investigators looked at sleep as a function of disease activity in the patient-reported surveys, they found a significant difference between people in remission and those with active disease. For example, people with active disease had a greater number of awakenings at night (P = .0016), less REM sleep at night (P = .0000), and less time in deep sleep (P = .000) compared with those in remission.

The technology “can identify flares with a predictive value that approaches fecal calprotectin,” Dr. Korzenik said.

Machine learning was used to look at severity of disease vs. fecal calprotectin values and “showed the data could be used as a marker of disease,” he added.

Use of a remote monitor, the comparison of validated vs. conventional data, and the large dataset were among the strengths of the study. The single-center design and exclusion of people with some comorbidities are potential limitations.

Further studies are warranted to confirm these findings and guide optimal care of people with Crohn’s disease, the investigators noted.
 

Earlier detection, earlier intervention

“The study is really important,” said session comoderator Raymond K. Cross Jr., MD, professor of medicine and director of the IBD program at the University of Maryland, Baltimore.

Monitoring devices like this “could be very useful,” Dr. Cross said. “It is not invasive, unless you consider a device in your house invasive. But, to me, I don’t think a box in my bedroom would be unnerving to me.”

Dr. Cross shared a couple of caveats. “The one devil in the details is always going to be cost,” he said. Also, it’s unclear who will read and interpret all the data generated by the device among “providers who are already overwhelmed with the volume of information.”

Moving forward, a device like this could offer multiple uses, Dr. Cross noted. If the device can detect relapses earlier, physicians could intervene sooner, he said. Also, the device could potentially flag people who are not taking their medications as recommended, or it could be used as a guide to optimize treatment response.

Whether data from the device could indicate when it’s appropriate to reduce the frequency or dose of medication or even when to withdraw therapy would be “really aspirational,” Dr. Cross added.

The study was funded by The Leona M. and Harry B. Helmsley Charitable Trust. Dr. Korzenik and Dr. Cross report no relevant financial relationships.
 

DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).

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

CHICAGO – Infliximab was associated with fewer discontinuations for lack of efficacy than vedolizumab during the maintenance phase of ulcerative colitis treatment, an updated meta-analysis of randomized clinical trials reveals.

At 1 year, 2% of people taking the anti–tumor necrosis factor (TNF) agent infliximab discontinued for lack of efficacy, compared with 24% of patients taking vedolizumab (Entyvio), an integrin receptor antagonist.

The safety profile of each agent is also important.

“We know that vedolizumab has less safety risks than an anti-TNF agent, but we also have the gut feeling that the anti-TNF agents are more efficacious,” lead author Marc Ferrante, MD, said in an interview.

“Of course, I don’t think we can really say that vedolizumab is the safest and infliximab is not safe, but there is some difference,” added Dr. Ferrante, a professor in the department of gastroenterology and hepatology, University Hospitals Leuven (Belgium).

The study was presented as a poster at the annual Digestive Disease Week (DDW).

The researchers conducted a pooled analysis of six randomized controlled trials from the past 10 years. They analyzed the NOR-SWITCH IV Q8W, the NCT02883452 SC Q2W, and LIBERTY-UC SC Q2W studies for infliximab, and the VISIBLE 1 SC Q2W, GEMINI 1 IV Q4W, and VARSITY IV Q8W trials for vedolizumab.

Their work expands on a meta-analysis by Dr. Ferrante and colleagues presented at DDW 2022. They added the 1-year results from the phase 3 LIBERTY-UC study to increase the number of participants taking infliximab or an infliximab biosimilar.

“Luckily, the results are very similar,” Dr. Ferrante said, and noted that they support previous findings that discontinuation of infliximab was lower than that of vedolizumab.

Most of the patients in the infliximab group were taking an infliximab biosimilar, whereas the vedolizumab group received the originator. Dr. Ferrante noted that the economic considerations involved in deciding between a biosimilar and an originator were not part of the research but that “there will be a difference in costs.”
 

Same mechanism, different route

The novel finding from the study includes the subcutaneous form of infliximab, which is not yet available in the United States, noted Joshua M. Steinberg, MD, director of inflammatory bowel disease at Gastroenterology of the Rockies, Denver, when asked to comment on the study. Currently, intravenously administered infliximab and vedolizumab are available in the United States.

A better comparator in the future would be looking at subcutaneous forms of both agents, especially “with the impending launch of subcutaneous vedolizumab in the United States,” said Dr. Steinberg, who is also a clinical instructor of medicine at the University of Colorado at Denver, Aurora.

He added that it’s reassuring overall that with a newer mode of administration but same mechanism of action, it is still feasible and durable for at least 1 year.

“The general consensus is that in terms of our biologics, vedolizumab is the safest because of its targeted mechanism of action. But sometimes the ‘safest choice’ isn’t the best choice,” Dr. Steinberg said. “I think in the right patient, the most effective treatment is going to be the one that works the best, and that’s not going to be universal.”

The study was sponsored by Celltrion, which makes an infliximab biosimilar. Dr. Ferrante receives honoraria as a consultant and speaker for Celltrion. Dr. Steinberg reported no relevant financial relationships.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

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

CHICAGO – Infliximab was associated with fewer discontinuations for lack of efficacy than vedolizumab during the maintenance phase of ulcerative colitis treatment, an updated meta-analysis of randomized clinical trials reveals.

At 1 year, 2% of people taking the anti–tumor necrosis factor (TNF) agent infliximab discontinued for lack of efficacy, compared with 24% of patients taking vedolizumab (Entyvio), an integrin receptor antagonist.

The safety profile of each agent is also important.

“We know that vedolizumab has less safety risks than an anti-TNF agent, but we also have the gut feeling that the anti-TNF agents are more efficacious,” lead author Marc Ferrante, MD, said in an interview.

“Of course, I don’t think we can really say that vedolizumab is the safest and infliximab is not safe, but there is some difference,” added Dr. Ferrante, a professor in the department of gastroenterology and hepatology, University Hospitals Leuven (Belgium).

The study was presented as a poster at the annual Digestive Disease Week (DDW).

The researchers conducted a pooled analysis of six randomized controlled trials from the past 10 years. They analyzed the NOR-SWITCH IV Q8W, the NCT02883452 SC Q2W, and LIBERTY-UC SC Q2W studies for infliximab, and the VISIBLE 1 SC Q2W, GEMINI 1 IV Q4W, and VARSITY IV Q8W trials for vedolizumab.

Their work expands on a meta-analysis by Dr. Ferrante and colleagues presented at DDW 2022. They added the 1-year results from the phase 3 LIBERTY-UC study to increase the number of participants taking infliximab or an infliximab biosimilar.

“Luckily, the results are very similar,” Dr. Ferrante said, and noted that they support previous findings that discontinuation of infliximab was lower than that of vedolizumab.

Most of the patients in the infliximab group were taking an infliximab biosimilar, whereas the vedolizumab group received the originator. Dr. Ferrante noted that the economic considerations involved in deciding between a biosimilar and an originator were not part of the research but that “there will be a difference in costs.”
 

Same mechanism, different route

The novel finding from the study includes the subcutaneous form of infliximab, which is not yet available in the United States, noted Joshua M. Steinberg, MD, director of inflammatory bowel disease at Gastroenterology of the Rockies, Denver, when asked to comment on the study. Currently, intravenously administered infliximab and vedolizumab are available in the United States.

A better comparator in the future would be looking at subcutaneous forms of both agents, especially “with the impending launch of subcutaneous vedolizumab in the United States,” said Dr. Steinberg, who is also a clinical instructor of medicine at the University of Colorado at Denver, Aurora.

He added that it’s reassuring overall that with a newer mode of administration but same mechanism of action, it is still feasible and durable for at least 1 year.

“The general consensus is that in terms of our biologics, vedolizumab is the safest because of its targeted mechanism of action. But sometimes the ‘safest choice’ isn’t the best choice,” Dr. Steinberg said. “I think in the right patient, the most effective treatment is going to be the one that works the best, and that’s not going to be universal.”

The study was sponsored by Celltrion, which makes an infliximab biosimilar. Dr. Ferrante receives honoraria as a consultant and speaker for Celltrion. Dr. Steinberg reported no relevant financial relationships.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

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

CHICAGO – Infliximab was associated with fewer discontinuations for lack of efficacy than vedolizumab during the maintenance phase of ulcerative colitis treatment, an updated meta-analysis of randomized clinical trials reveals.

At 1 year, 2% of people taking the anti–tumor necrosis factor (TNF) agent infliximab discontinued for lack of efficacy, compared with 24% of patients taking vedolizumab (Entyvio), an integrin receptor antagonist.

The safety profile of each agent is also important.

“We know that vedolizumab has less safety risks than an anti-TNF agent, but we also have the gut feeling that the anti-TNF agents are more efficacious,” lead author Marc Ferrante, MD, said in an interview.

“Of course, I don’t think we can really say that vedolizumab is the safest and infliximab is not safe, but there is some difference,” added Dr. Ferrante, a professor in the department of gastroenterology and hepatology, University Hospitals Leuven (Belgium).

The study was presented as a poster at the annual Digestive Disease Week (DDW).

The researchers conducted a pooled analysis of six randomized controlled trials from the past 10 years. They analyzed the NOR-SWITCH IV Q8W, the NCT02883452 SC Q2W, and LIBERTY-UC SC Q2W studies for infliximab, and the VISIBLE 1 SC Q2W, GEMINI 1 IV Q4W, and VARSITY IV Q8W trials for vedolizumab.

Their work expands on a meta-analysis by Dr. Ferrante and colleagues presented at DDW 2022. They added the 1-year results from the phase 3 LIBERTY-UC study to increase the number of participants taking infliximab or an infliximab biosimilar.

“Luckily, the results are very similar,” Dr. Ferrante said, and noted that they support previous findings that discontinuation of infliximab was lower than that of vedolizumab.

Most of the patients in the infliximab group were taking an infliximab biosimilar, whereas the vedolizumab group received the originator. Dr. Ferrante noted that the economic considerations involved in deciding between a biosimilar and an originator were not part of the research but that “there will be a difference in costs.”
 

Same mechanism, different route

The novel finding from the study includes the subcutaneous form of infliximab, which is not yet available in the United States, noted Joshua M. Steinberg, MD, director of inflammatory bowel disease at Gastroenterology of the Rockies, Denver, when asked to comment on the study. Currently, intravenously administered infliximab and vedolizumab are available in the United States.

A better comparator in the future would be looking at subcutaneous forms of both agents, especially “with the impending launch of subcutaneous vedolizumab in the United States,” said Dr. Steinberg, who is also a clinical instructor of medicine at the University of Colorado at Denver, Aurora.

He added that it’s reassuring overall that with a newer mode of administration but same mechanism of action, it is still feasible and durable for at least 1 year.

“The general consensus is that in terms of our biologics, vedolizumab is the safest because of its targeted mechanism of action. But sometimes the ‘safest choice’ isn’t the best choice,” Dr. Steinberg said. “I think in the right patient, the most effective treatment is going to be the one that works the best, and that’s not going to be universal.”

The study was sponsored by Celltrion, which makes an infliximab biosimilar. Dr. Ferrante receives honoraria as a consultant and speaker for Celltrion. Dr. Steinberg reported no relevant financial relationships.

DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.

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

Psyllium fiber offered protection against colitis in mice models through its effect on bile acid metabolism, which in turn reduces proinflammatory signaling through activation of the farnesoid X receptor (FXR), shows a study recently published in Cellular and Molecular Gastroenterology and Hepatology

“Our results support the notion that pharmacologic FXR activation might be useful in managing IBD [inflammatory bowel disease], and thus, further investigation of its mechanisms of action are warranted,” wrote the authors, led by Andrew Gewirtz, of the Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta.

Dr. Andrew Gewirtz

Dietary fiber has long been understood to be a key component to a healthy diet by promoting intestinal and metabolic health, but it is unclear whether dietary fiber benefits IBD, specifically Crohn’s disease and ulcerative colitis, and if so, what fiber types are best for these conditions. Some studies have suggested an association between fiber-rich diets and reduced incidence of IBD, but some IBD patients experience intolerance to fiber-rich foods and associated fiber-rich foods with disease flares. In mouse models with colitis, semi-purified fibers have been associated with both the easing and exacerbation of IBD symptoms, with soluble/fermentable fibers like inulin and pectin generally worsening colitis.

The study had two goals: Identify specific fibers that might ameliorate two models of experimental colitis in mice models and to better understand the mechanism by which fiber(s) might suppress inflammation.

Mice were fed high-fiber grain-based chow or diets enriched with semi-purified fibers that included inulin, cellulose, pectin, glucomannan, and psyllium, but only psyllium, a semi-soluble derived from Plantago seeds, improved colitis, and metabolic syndrome. The other fibers often protected against obesity but worsened colitis.

Consuming diets enriched with psyllium were found to “markedly” protected against both dextran sulfate sodium– and T-cell transfer–induced colitis. The protection was independent of fermentation and occurred in animals with minimal microbiota. The animals had increased expression of genes that influence bile acid secretion, and the researchers noted increased levels of both fecal and serum BA.

The increased serum levels prompted the researchers to investigate psyllium’s role in signaling activation through BA receptors, especially FXR. An FXR agonist also reduced colitis severity, while an FXR antagonist worsened it. FXR-deficient mice gained little benefit from psyllium supplementation, further suggesting that FXR mediates psyllium’s effect.

All soluble fibers impacted gut microbiota composition, but none more than psyllium which protected mice from developing dextran sulfate sodium colitis. While other soluble fibers increased in the abundance of bacteria (that is, fecal/luminal bacterial density), psyllium decreased in this area, which may explain why some fermentable fibers, including inulin, exacerbate colitis.

“These results indicate that psyllium’s protection against colitis involves its ability to increase circulating bile acid levels, thus activating FXR signaling,” the authors wrote.

Researchers found some evidence that prolonged psyllium supplementation could lead to mild elevations in AST and ALT, suggesting that the ability of psyllium to chelate BA could lead to lipid deficiency, especially in the presence of a low-fat diet.

“We suggest that future studies of psyllium in humans measure serum BA and consider roles for FXR activation in mediating impacts of this fiber,” the authors wrote.

The study was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. The authors disclosed no conflicts.

Psyllium fiber offered protection against colitis in mice models through its effect on bile acid metabolism, which in turn reduces proinflammatory signaling through activation of the farnesoid X receptor (FXR), shows a study recently published in Cellular and Molecular Gastroenterology and Hepatology

“Our results support the notion that pharmacologic FXR activation might be useful in managing IBD [inflammatory bowel disease], and thus, further investigation of its mechanisms of action are warranted,” wrote the authors, led by Andrew Gewirtz, of the Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta.

Dr. Andrew Gewirtz

Dietary fiber has long been understood to be a key component to a healthy diet by promoting intestinal and metabolic health, but it is unclear whether dietary fiber benefits IBD, specifically Crohn’s disease and ulcerative colitis, and if so, what fiber types are best for these conditions. Some studies have suggested an association between fiber-rich diets and reduced incidence of IBD, but some IBD patients experience intolerance to fiber-rich foods and associated fiber-rich foods with disease flares. In mouse models with colitis, semi-purified fibers have been associated with both the easing and exacerbation of IBD symptoms, with soluble/fermentable fibers like inulin and pectin generally worsening colitis.

The study had two goals: Identify specific fibers that might ameliorate two models of experimental colitis in mice models and to better understand the mechanism by which fiber(s) might suppress inflammation.

Mice were fed high-fiber grain-based chow or diets enriched with semi-purified fibers that included inulin, cellulose, pectin, glucomannan, and psyllium, but only psyllium, a semi-soluble derived from Plantago seeds, improved colitis, and metabolic syndrome. The other fibers often protected against obesity but worsened colitis.

Consuming diets enriched with psyllium were found to “markedly” protected against both dextran sulfate sodium– and T-cell transfer–induced colitis. The protection was independent of fermentation and occurred in animals with minimal microbiota. The animals had increased expression of genes that influence bile acid secretion, and the researchers noted increased levels of both fecal and serum BA.

The increased serum levels prompted the researchers to investigate psyllium’s role in signaling activation through BA receptors, especially FXR. An FXR agonist also reduced colitis severity, while an FXR antagonist worsened it. FXR-deficient mice gained little benefit from psyllium supplementation, further suggesting that FXR mediates psyllium’s effect.

All soluble fibers impacted gut microbiota composition, but none more than psyllium which protected mice from developing dextran sulfate sodium colitis. While other soluble fibers increased in the abundance of bacteria (that is, fecal/luminal bacterial density), psyllium decreased in this area, which may explain why some fermentable fibers, including inulin, exacerbate colitis.

“These results indicate that psyllium’s protection against colitis involves its ability to increase circulating bile acid levels, thus activating FXR signaling,” the authors wrote.

Researchers found some evidence that prolonged psyllium supplementation could lead to mild elevations in AST and ALT, suggesting that the ability of psyllium to chelate BA could lead to lipid deficiency, especially in the presence of a low-fat diet.

“We suggest that future studies of psyllium in humans measure serum BA and consider roles for FXR activation in mediating impacts of this fiber,” the authors wrote.

The study was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. The authors disclosed no conflicts.

Psyllium fiber offered protection against colitis in mice models through its effect on bile acid metabolism, which in turn reduces proinflammatory signaling through activation of the farnesoid X receptor (FXR), shows a study recently published in Cellular and Molecular Gastroenterology and Hepatology

“Our results support the notion that pharmacologic FXR activation might be useful in managing IBD [inflammatory bowel disease], and thus, further investigation of its mechanisms of action are warranted,” wrote the authors, led by Andrew Gewirtz, of the Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta.

Dr. Andrew Gewirtz

Dietary fiber has long been understood to be a key component to a healthy diet by promoting intestinal and metabolic health, but it is unclear whether dietary fiber benefits IBD, specifically Crohn’s disease and ulcerative colitis, and if so, what fiber types are best for these conditions. Some studies have suggested an association between fiber-rich diets and reduced incidence of IBD, but some IBD patients experience intolerance to fiber-rich foods and associated fiber-rich foods with disease flares. In mouse models with colitis, semi-purified fibers have been associated with both the easing and exacerbation of IBD symptoms, with soluble/fermentable fibers like inulin and pectin generally worsening colitis.

The study had two goals: Identify specific fibers that might ameliorate two models of experimental colitis in mice models and to better understand the mechanism by which fiber(s) might suppress inflammation.

Mice were fed high-fiber grain-based chow or diets enriched with semi-purified fibers that included inulin, cellulose, pectin, glucomannan, and psyllium, but only psyllium, a semi-soluble derived from Plantago seeds, improved colitis, and metabolic syndrome. The other fibers often protected against obesity but worsened colitis.

Consuming diets enriched with psyllium were found to “markedly” protected against both dextran sulfate sodium– and T-cell transfer–induced colitis. The protection was independent of fermentation and occurred in animals with minimal microbiota. The animals had increased expression of genes that influence bile acid secretion, and the researchers noted increased levels of both fecal and serum BA.

The increased serum levels prompted the researchers to investigate psyllium’s role in signaling activation through BA receptors, especially FXR. An FXR agonist also reduced colitis severity, while an FXR antagonist worsened it. FXR-deficient mice gained little benefit from psyllium supplementation, further suggesting that FXR mediates psyllium’s effect.

All soluble fibers impacted gut microbiota composition, but none more than psyllium which protected mice from developing dextran sulfate sodium colitis. While other soluble fibers increased in the abundance of bacteria (that is, fecal/luminal bacterial density), psyllium decreased in this area, which may explain why some fermentable fibers, including inulin, exacerbate colitis.

“These results indicate that psyllium’s protection against colitis involves its ability to increase circulating bile acid levels, thus activating FXR signaling,” the authors wrote.

Researchers found some evidence that prolonged psyllium supplementation could lead to mild elevations in AST and ALT, suggesting that the ability of psyllium to chelate BA could lead to lipid deficiency, especially in the presence of a low-fat diet.

“We suggest that future studies of psyllium in humans measure serum BA and consider roles for FXR activation in mediating impacts of this fiber,” the authors wrote.

The study was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. The authors disclosed no conflicts.

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

ChrisChrisW/Getty Images

“The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker,” the authors note. “Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure,” they add.

The review was published online in the Journal of the American College of Cardiology.

“Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure,” lead author Petra Mamic, MD, Stanford (Calif.) University, told this news organization.

“We’ve also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk,” she said.

“Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap,” she added.

Dr. Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated, compared with the microbiome in healthy individuals.

“The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure,” she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Dr. Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.
 

High-fiber diet may be beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

“These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted,” Dr. Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Dr. Mamic points out that a high-fiber diet is thought to be beneficial.

“Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure,” she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, and nuts, and less intake of processed food and red meat. “In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients,” Dr. Mamic said.
 

Large variation in microbiome composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual’s gut microbiome composition.

Dr. Mamic explains: “When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment – people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences.”

It is thought that these differences may affect the response to a specific diet or medication. Dr. Mamic gives the example of fiber. “Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That’s probably because of differences in their microbiome.”

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Dr. Mamic says.
 

Manipulating the microbiome as a therapeutic strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function, compared with standard care.

Commenting on this, Dr. Mamic suggested that a more specific approach may be needed.

“Some of our preliminary data have shown people who have heart failure have severely depleted Bifidobacteria,” Dr. Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. “We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach.”

Dr. Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. “Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed.”
 

Include microbiome data in biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

“At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome,” Dr. Mamic suggests.

“If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years’ time.”

“We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug.”

Dr. Mamic believes that in the future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

“It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn’t miss the opportunity to do this,” she concluded.

Dr. Mamic reported no disclosures.

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

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

ChrisChrisW/Getty Images

“The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker,” the authors note. “Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure,” they add.

The review was published online in the Journal of the American College of Cardiology.

“Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure,” lead author Petra Mamic, MD, Stanford (Calif.) University, told this news organization.

“We’ve also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk,” she said.

“Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap,” she added.

Dr. Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated, compared with the microbiome in healthy individuals.

“The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure,” she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Dr. Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.
 

High-fiber diet may be beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

“These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted,” Dr. Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Dr. Mamic points out that a high-fiber diet is thought to be beneficial.

“Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure,” she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, and nuts, and less intake of processed food and red meat. “In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients,” Dr. Mamic said.
 

Large variation in microbiome composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual’s gut microbiome composition.

Dr. Mamic explains: “When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment – people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences.”

It is thought that these differences may affect the response to a specific diet or medication. Dr. Mamic gives the example of fiber. “Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That’s probably because of differences in their microbiome.”

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Dr. Mamic says.
 

Manipulating the microbiome as a therapeutic strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function, compared with standard care.

Commenting on this, Dr. Mamic suggested that a more specific approach may be needed.

“Some of our preliminary data have shown people who have heart failure have severely depleted Bifidobacteria,” Dr. Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. “We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach.”

Dr. Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. “Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed.”
 

Include microbiome data in biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

“At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome,” Dr. Mamic suggests.

“If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years’ time.”

“We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug.”

Dr. Mamic believes that in the future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

“It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn’t miss the opportunity to do this,” she concluded.

Dr. Mamic reported no disclosures.

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

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

ChrisChrisW/Getty Images

“The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker,” the authors note. “Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure,” they add.

The review was published online in the Journal of the American College of Cardiology.

“Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure,” lead author Petra Mamic, MD, Stanford (Calif.) University, told this news organization.

“We’ve also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk,” she said.

“Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap,” she added.

Dr. Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated, compared with the microbiome in healthy individuals.

“The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure,” she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Dr. Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.
 

High-fiber diet may be beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

“These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted,” Dr. Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Dr. Mamic points out that a high-fiber diet is thought to be beneficial.

“Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure,” she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, and nuts, and less intake of processed food and red meat. “In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients,” Dr. Mamic said.
 

Large variation in microbiome composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual’s gut microbiome composition.

Dr. Mamic explains: “When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment – people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences.”

It is thought that these differences may affect the response to a specific diet or medication. Dr. Mamic gives the example of fiber. “Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That’s probably because of differences in their microbiome.”

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Dr. Mamic says.
 

Manipulating the microbiome as a therapeutic strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function, compared with standard care.

Commenting on this, Dr. Mamic suggested that a more specific approach may be needed.

“Some of our preliminary data have shown people who have heart failure have severely depleted Bifidobacteria,” Dr. Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. “We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach.”

Dr. Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. “Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed.”
 

Include microbiome data in biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

“At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome,” Dr. Mamic suggests.

“If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years’ time.”

“We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug.”

Dr. Mamic believes that in the future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

“It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn’t miss the opportunity to do this,” she concluded.

Dr. Mamic reported no disclosures.

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

The recent approval of the first oral fecal-derived microbiota therapy to prevent the recurrence of Clostridioides difficile (C. diff) infection in patients was welcome news for physicians who’ve struggled under the weight of having too few treatment options for the prevention of C. diff recurrence.

The product, developed by Massachusetts-based Seres Therepeutics and marketed as Vowst, was approved by the U.S. Food and Drug Administration on April 26. It is approved for use in adults who have already been treated with antibiotics for a recurrent infection with C. diff bacteria.

This is the first oral treatment for the prevention of C. diff recurrence and is designed to be delivered in four capsules taken daily for 3 days.

Gastroenterologist Phillip I. Tarr, MD, division chief of gastroenterology at Washington University, St. Louis, and chair of the American Gastroenterological Association Center for Gut Microbiome Research and Education, said that prevention of recurrent C. diff infection “remains challenging,” and that Vowst “provides the first FDA-approved, orally administered microbiome therapeutic with which to achieve this goal. This advance also makes us optimistic we might soon be able to prevent other disorders by managing gut microbial communities.”

Vowst is the second therapy derived from human stool to be approved for the indication in less than 6 months. In December, the FDA approved Rebyota (Ferring), a rectally delivered treatment that also uses microbes from donor feces. Both products were given priority review, orphan drug, and breakthrough therapy designations by the agency.

C. diff infection can be aggravated by an alteration of normal gut flora associated with antibiotics treatment, leading to cycles of repeated infections. Infection can produce diarrhea, abdominal pain, fever, and severe morbidity. In the United States, an estimated 15,000 to 30,000 deaths per year are linked to C. diff. Risk factors for recurrent infection include being 65 or older, hospitalization, being in a nursing home, a weakened immune system, and previous infection with C. diff.

Therapies transplanting fecal microbiota from donors have been used since the 1950s as treatments for recurrent C. diff infection, and in the past decade, as stool banks recruiting screened donors have made fecal microbiota transplants, or FMT, standard of care. However, only in recent years have fecal-derived therapies become subject to standardized safety and efficacy testing.

Both the current FDA-approved products, Rebyota and Vowst, were shown in randomized controlled trials to reduce recurrence of C. diff infection, compared with placebo. In a phase 3 clinical trial of Rebyota (n = 262) in antibiotic-treated patients, one rectally administered dose reduced recurrence of C. diff infection by 70.6% at 8 weeks, compared with 57.5% for placebo. A phase 3 study of Vowst (n = 281) showed recurrence in treated subjects to be 12.4% at 8 weeks, compared with nearly 40% of those receiving placebo (relative risk, 0.32; 95% confidence interval, 0.18-0.58; P less than .001).

Despite screening protocols that have become increasingly homogenized and rigorous, FMT is associated with the risk of introducing pathogens. Vowst is manufactured with purified bacterial spores derived from donor feces, not whole stool. Nonetheless, FDA noted in its statement that Vowst could still potentially introduce infectious agents or allergens.
 

Antibiotics are still first-line treatment

In an interview, Jessica Allegretti, MD, MPH, AGAF, medical director of the Crohn’s and Colitis Center at Brigham & Women’s Hospital, Boston, said that having two FDA-approved therapies with different means of administration “is great for the field and great for patients. These are both meant to be used after a course of antibiotics, so antibiotics are still the mainstay of treatment for C. diff and recurrent C. diff, but we now have more options to prevent recurrence.”

The convenience of an oral therapy that can be taken at home is “very attractive,” Dr. Allegretti added, noting that there will also be patients “who either don’t want to or can’t take capsules, for whom a rectal administration [in a health care setting] may be preferred.”

Dr. Allegretti, who has used FMT to treat recurrent C. difficile for more than a decade, said that she expected traditional FMT using screened donor stool to remain available even as the new products are adopted by clinicians. FMT centers like OpenBiome “will continue to provide access for patients who either don’t have the ability to get the FDA-approved products because of insurance coverage, or for financial reasons, or maybe neither of the new products is appropriate for them,” she said. “I do think there will always be a need for the traditional option. The more options that we have available the better.”

TD Cowen analyst Joseph Thome told Reuters that the drug could be priced close to $20,000 per course, expecting peak sales of $750 million in the U.S. in 2033.

Dr. Allegretti disclosed consulting work for Seres Therapeutics, Ferring, and other manufacturers. She is a member of OpenBiome’s clinical advisory board.

The recent approval of the first oral fecal-derived microbiota therapy to prevent the recurrence of Clostridioides difficile (C. diff) infection in patients was welcome news for physicians who’ve struggled under the weight of having too few treatment options for the prevention of C. diff recurrence.

The product, developed by Massachusetts-based Seres Therepeutics and marketed as Vowst, was approved by the U.S. Food and Drug Administration on April 26. It is approved for use in adults who have already been treated with antibiotics for a recurrent infection with C. diff bacteria.

This is the first oral treatment for the prevention of C. diff recurrence and is designed to be delivered in four capsules taken daily for 3 days.

Gastroenterologist Phillip I. Tarr, MD, division chief of gastroenterology at Washington University, St. Louis, and chair of the American Gastroenterological Association Center for Gut Microbiome Research and Education, said that prevention of recurrent C. diff infection “remains challenging,” and that Vowst “provides the first FDA-approved, orally administered microbiome therapeutic with which to achieve this goal. This advance also makes us optimistic we might soon be able to prevent other disorders by managing gut microbial communities.”

Vowst is the second therapy derived from human stool to be approved for the indication in less than 6 months. In December, the FDA approved Rebyota (Ferring), a rectally delivered treatment that also uses microbes from donor feces. Both products were given priority review, orphan drug, and breakthrough therapy designations by the agency.

C. diff infection can be aggravated by an alteration of normal gut flora associated with antibiotics treatment, leading to cycles of repeated infections. Infection can produce diarrhea, abdominal pain, fever, and severe morbidity. In the United States, an estimated 15,000 to 30,000 deaths per year are linked to C. diff. Risk factors for recurrent infection include being 65 or older, hospitalization, being in a nursing home, a weakened immune system, and previous infection with C. diff.

Therapies transplanting fecal microbiota from donors have been used since the 1950s as treatments for recurrent C. diff infection, and in the past decade, as stool banks recruiting screened donors have made fecal microbiota transplants, or FMT, standard of care. However, only in recent years have fecal-derived therapies become subject to standardized safety and efficacy testing.

Both the current FDA-approved products, Rebyota and Vowst, were shown in randomized controlled trials to reduce recurrence of C. diff infection, compared with placebo. In a phase 3 clinical trial of Rebyota (n = 262) in antibiotic-treated patients, one rectally administered dose reduced recurrence of C. diff infection by 70.6% at 8 weeks, compared with 57.5% for placebo. A phase 3 study of Vowst (n = 281) showed recurrence in treated subjects to be 12.4% at 8 weeks, compared with nearly 40% of those receiving placebo (relative risk, 0.32; 95% confidence interval, 0.18-0.58; P less than .001).

Despite screening protocols that have become increasingly homogenized and rigorous, FMT is associated with the risk of introducing pathogens. Vowst is manufactured with purified bacterial spores derived from donor feces, not whole stool. Nonetheless, FDA noted in its statement that Vowst could still potentially introduce infectious agents or allergens.
 

Antibiotics are still first-line treatment

In an interview, Jessica Allegretti, MD, MPH, AGAF, medical director of the Crohn’s and Colitis Center at Brigham & Women’s Hospital, Boston, said that having two FDA-approved therapies with different means of administration “is great for the field and great for patients. These are both meant to be used after a course of antibiotics, so antibiotics are still the mainstay of treatment for C. diff and recurrent C. diff, but we now have more options to prevent recurrence.”

The convenience of an oral therapy that can be taken at home is “very attractive,” Dr. Allegretti added, noting that there will also be patients “who either don’t want to or can’t take capsules, for whom a rectal administration [in a health care setting] may be preferred.”

Dr. Allegretti, who has used FMT to treat recurrent C. difficile for more than a decade, said that she expected traditional FMT using screened donor stool to remain available even as the new products are adopted by clinicians. FMT centers like OpenBiome “will continue to provide access for patients who either don’t have the ability to get the FDA-approved products because of insurance coverage, or for financial reasons, or maybe neither of the new products is appropriate for them,” she said. “I do think there will always be a need for the traditional option. The more options that we have available the better.”

TD Cowen analyst Joseph Thome told Reuters that the drug could be priced close to $20,000 per course, expecting peak sales of $750 million in the U.S. in 2033.

Dr. Allegretti disclosed consulting work for Seres Therapeutics, Ferring, and other manufacturers. She is a member of OpenBiome’s clinical advisory board.

The recent approval of the first oral fecal-derived microbiota therapy to prevent the recurrence of Clostridioides difficile (C. diff) infection in patients was welcome news for physicians who’ve struggled under the weight of having too few treatment options for the prevention of C. diff recurrence.

The product, developed by Massachusetts-based Seres Therepeutics and marketed as Vowst, was approved by the U.S. Food and Drug Administration on April 26. It is approved for use in adults who have already been treated with antibiotics for a recurrent infection with C. diff bacteria.

This is the first oral treatment for the prevention of C. diff recurrence and is designed to be delivered in four capsules taken daily for 3 days.

Gastroenterologist Phillip I. Tarr, MD, division chief of gastroenterology at Washington University, St. Louis, and chair of the American Gastroenterological Association Center for Gut Microbiome Research and Education, said that prevention of recurrent C. diff infection “remains challenging,” and that Vowst “provides the first FDA-approved, orally administered microbiome therapeutic with which to achieve this goal. This advance also makes us optimistic we might soon be able to prevent other disorders by managing gut microbial communities.”

Vowst is the second therapy derived from human stool to be approved for the indication in less than 6 months. In December, the FDA approved Rebyota (Ferring), a rectally delivered treatment that also uses microbes from donor feces. Both products were given priority review, orphan drug, and breakthrough therapy designations by the agency.

C. diff infection can be aggravated by an alteration of normal gut flora associated with antibiotics treatment, leading to cycles of repeated infections. Infection can produce diarrhea, abdominal pain, fever, and severe morbidity. In the United States, an estimated 15,000 to 30,000 deaths per year are linked to C. diff. Risk factors for recurrent infection include being 65 or older, hospitalization, being in a nursing home, a weakened immune system, and previous infection with C. diff.

Therapies transplanting fecal microbiota from donors have been used since the 1950s as treatments for recurrent C. diff infection, and in the past decade, as stool banks recruiting screened donors have made fecal microbiota transplants, or FMT, standard of care. However, only in recent years have fecal-derived therapies become subject to standardized safety and efficacy testing.

Both the current FDA-approved products, Rebyota and Vowst, were shown in randomized controlled trials to reduce recurrence of C. diff infection, compared with placebo. In a phase 3 clinical trial of Rebyota (n = 262) in antibiotic-treated patients, one rectally administered dose reduced recurrence of C. diff infection by 70.6% at 8 weeks, compared with 57.5% for placebo. A phase 3 study of Vowst (n = 281) showed recurrence in treated subjects to be 12.4% at 8 weeks, compared with nearly 40% of those receiving placebo (relative risk, 0.32; 95% confidence interval, 0.18-0.58; P less than .001).

Despite screening protocols that have become increasingly homogenized and rigorous, FMT is associated with the risk of introducing pathogens. Vowst is manufactured with purified bacterial spores derived from donor feces, not whole stool. Nonetheless, FDA noted in its statement that Vowst could still potentially introduce infectious agents or allergens.
 

Antibiotics are still first-line treatment

In an interview, Jessica Allegretti, MD, MPH, AGAF, medical director of the Crohn’s and Colitis Center at Brigham & Women’s Hospital, Boston, said that having two FDA-approved therapies with different means of administration “is great for the field and great for patients. These are both meant to be used after a course of antibiotics, so antibiotics are still the mainstay of treatment for C. diff and recurrent C. diff, but we now have more options to prevent recurrence.”

The convenience of an oral therapy that can be taken at home is “very attractive,” Dr. Allegretti added, noting that there will also be patients “who either don’t want to or can’t take capsules, for whom a rectal administration [in a health care setting] may be preferred.”

Dr. Allegretti, who has used FMT to treat recurrent C. difficile for more than a decade, said that she expected traditional FMT using screened donor stool to remain available even as the new products are adopted by clinicians. FMT centers like OpenBiome “will continue to provide access for patients who either don’t have the ability to get the FDA-approved products because of insurance coverage, or for financial reasons, or maybe neither of the new products is appropriate for them,” she said. “I do think there will always be a need for the traditional option. The more options that we have available the better.”

TD Cowen analyst Joseph Thome told Reuters that the drug could be priced close to $20,000 per course, expecting peak sales of $750 million in the U.S. in 2033.

Dr. Allegretti disclosed consulting work for Seres Therapeutics, Ferring, and other manufacturers. She is a member of OpenBiome’s clinical advisory board.

Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira) but not to infliximab therapy.

Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.

“We believe these results are practice-changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina, Chapel Hill.

All patients with pediatric Crohn’s disease starting on adalimumab and their parents should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.

“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.

The study was published online  in Gastroenterology and will be presented in early May at Digestive Disease Week® 2023.

Impactful study

“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” said Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology, and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study.

Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.

The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab versus TNFi therapy alone in 297 children with Crohn’s disease.

The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.

Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 to less than 40 kg, and 10 mg for children 20 to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.

The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following.

• Short Pediatric Crohn’s Disease Activity Index score of less than 15 by week 26
• Failure to complete a steroid taper by week 16
• SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26
• Hospitalization or surgery for Crohn’s disease beyond week 26
• Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16
• Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity

Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.

Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).

After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI, 0.19-0.81; P = .01).

There was a nonsignificant trend toward lower development of anti-drug antibodies with combination therapy (risk ratio, 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers noted.

No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
 

Shared decision-making

Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone. “This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.

Nor was the trial designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.

The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab but not infliximab,” Dr. Kappelman and colleagues said.

“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of de-implementation of combination therapy in infliximab treated patients,” they added.

The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.

“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization. The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”

The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.

The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.

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

Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira) but not to infliximab therapy.

Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.

“We believe these results are practice-changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina, Chapel Hill.

All patients with pediatric Crohn’s disease starting on adalimumab and their parents should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.

“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.

The study was published online  in Gastroenterology and will be presented in early May at Digestive Disease Week® 2023.

Impactful study

“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” said Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology, and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study.

Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.

The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab versus TNFi therapy alone in 297 children with Crohn’s disease.

The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.

Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 to less than 40 kg, and 10 mg for children 20 to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.

The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following.

• Short Pediatric Crohn’s Disease Activity Index score of less than 15 by week 26
• Failure to complete a steroid taper by week 16
• SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26
• Hospitalization or surgery for Crohn’s disease beyond week 26
• Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16
• Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity

Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.

Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).

After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI, 0.19-0.81; P = .01).

There was a nonsignificant trend toward lower development of anti-drug antibodies with combination therapy (risk ratio, 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers noted.

No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
 

Shared decision-making

Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone. “This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.

Nor was the trial designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.

The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab but not infliximab,” Dr. Kappelman and colleagues said.

“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of de-implementation of combination therapy in infliximab treated patients,” they added.

The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.

“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization. The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”

The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.

The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.

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

Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira) but not to infliximab therapy.

Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.

“We believe these results are practice-changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina, Chapel Hill.

All patients with pediatric Crohn’s disease starting on adalimumab and their parents should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.

“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.

The study was published online  in Gastroenterology and will be presented in early May at Digestive Disease Week® 2023.

Impactful study

“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” said Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology, and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study.

Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.

The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab versus TNFi therapy alone in 297 children with Crohn’s disease.

The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.

Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 to less than 40 kg, and 10 mg for children 20 to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.

The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following.

• Short Pediatric Crohn’s Disease Activity Index score of less than 15 by week 26
• Failure to complete a steroid taper by week 16
• SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26
• Hospitalization or surgery for Crohn’s disease beyond week 26
• Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16
• Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity

Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.

Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).

After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI, 0.19-0.81; P = .01).

There was a nonsignificant trend toward lower development of anti-drug antibodies with combination therapy (risk ratio, 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers noted.

No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
 

Shared decision-making

Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone. “This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.

Nor was the trial designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.

The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab but not infliximab,” Dr. Kappelman and colleagues said.

“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of de-implementation of combination therapy in infliximab treated patients,” they added.

The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.

“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization. The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”

The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.

The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.

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