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Hadlima approved as fourth adalimumab biosimilar in U.S.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
Visit the AGA GI Patient Center for information to share with your patients about biologics and biosimilars at https://www.gastro.org/practice-guidance/gi-patient-center/topic/biosimilars.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
Visit the AGA GI Patient Center for information to share with your patients about biologics and biosimilars at https://www.gastro.org/practice-guidance/gi-patient-center/topic/biosimilars.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
Visit the AGA GI Patient Center for information to share with your patients about biologics and biosimilars at https://www.gastro.org/practice-guidance/gi-patient-center/topic/biosimilars.
Probiotic protects against aspirin-related intestinal damage
Source: American Gastroenterological Association
Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).
NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.
“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.
“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”
The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.
After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.
“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”
Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.
“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.
“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.
The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.
SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.
Gastrointestinal bleeding related to nonsteroidal anti-inflammatory drug (NSAID) use is a significant cause of morbidity and mortality in patients taking these drugs. The risk of NSAID-related peptic ulcer can be reduced by proton pump inhibitor therapy, but no intervention has been proven to reduce ulceration beyond the duodenum in NSAID users. Animal models suggest the gut microbiota may be important in the development of NSAID-related small-bowel intestinal injury, but how this translates to patients is unclear.
Paul Moayyedi, MB ChB, MPH, PhD, is the Audrey Campbell Ulcerative Colitis Research Chair and assistant dean of research at McMaster University. He is also the principal investigator of the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects network. He has no conflicts of interest.
Gastrointestinal bleeding related to nonsteroidal anti-inflammatory drug (NSAID) use is a significant cause of morbidity and mortality in patients taking these drugs. The risk of NSAID-related peptic ulcer can be reduced by proton pump inhibitor therapy, but no intervention has been proven to reduce ulceration beyond the duodenum in NSAID users. Animal models suggest the gut microbiota may be important in the development of NSAID-related small-bowel intestinal injury, but how this translates to patients is unclear.
Paul Moayyedi, MB ChB, MPH, PhD, is the Audrey Campbell Ulcerative Colitis Research Chair and assistant dean of research at McMaster University. He is also the principal investigator of the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects network. He has no conflicts of interest.
Gastrointestinal bleeding related to nonsteroidal anti-inflammatory drug (NSAID) use is a significant cause of morbidity and mortality in patients taking these drugs. The risk of NSAID-related peptic ulcer can be reduced by proton pump inhibitor therapy, but no intervention has been proven to reduce ulceration beyond the duodenum in NSAID users. Animal models suggest the gut microbiota may be important in the development of NSAID-related small-bowel intestinal injury, but how this translates to patients is unclear.
Paul Moayyedi, MB ChB, MPH, PhD, is the Audrey Campbell Ulcerative Colitis Research Chair and assistant dean of research at McMaster University. He is also the principal investigator of the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects network. He has no conflicts of interest.
Source: American Gastroenterological Association
Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).
NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.
“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.
“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”
The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.
After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.
“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”
Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.
“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.
“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.
The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.
SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.
Source: American Gastroenterological Association
Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).
NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.
“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.
“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”
The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.
After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.
“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”
Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.
“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.
“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.
The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.
SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.
FROM GASTROENTEROLOGY
Beyond C. difficile: The future of fecal microbial transplantation
SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.
Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).
Obesity
Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.
The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.
Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.
There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”
In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.
These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.
This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.
Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.
IBS
Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.
“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.
“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.
“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.
Small intestine
And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.
“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.
In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”
“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”
Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.
This story was updated on July 30, 2019.
SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.
Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).
Obesity
Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.
The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.
Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.
There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”
In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.
These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.
This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.
Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.
IBS
Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.
“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.
“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.
“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.
Small intestine
And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.
“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.
In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”
“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”
Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.
This story was updated on July 30, 2019.
SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.
Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).
Obesity
Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.
The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.
Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.
There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”
In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.
These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.
This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.
Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.
IBS
Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.
“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.
“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.
“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.
Small intestine
And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.
“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.
In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”
“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”
Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.
This story was updated on July 30, 2019.
EXPERT ANALYSIS FROM DDW 2019
AGA issues guideline for watery diarrhea
A new guideline from the American Gastroenterological Association (AGA) aims to help physicians diagnose the cause of chronic watery diarrhea, particularly to exclude diagnoses other than functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS). The guideline, published in Gastroenterology, does not apply to patients with concerning presentations like weight loss/anemia, diarrhea with signs of fat malabsorption, bloody diarrhea, cases with a family history of inflammatory bowel disease (IBD), colon cancer, or celiac disease or to those who have traveled to diarrheal disease–related regions.
To rule out IBD, physicians can use either fecal calprotectin (threshold value of 50 microg/g, sensitivity, 0.81; specificity, 0.87) or fecal lactoferrin (threshold, 4.0-7.25 mcg/g; pooled sensitivity for IBD, 0.79; specificity, 0.93). Neither erythrocyte sedimentation rate (ESR) nor C-reactive protein (CRP) should be used to diagnose IBD because tests have shown low pooled sensitivity and specificity. CRP might be useful in settings in which fecal lactoferrin or calprotectin tests are not available or covered by insurance.
Patients should be tested for giardia infection, using the antigen test or PCR, because this pathogen is common in the United States and easily treated.
Patients who have not recently traveled to or from high-risk areas should not be tested for ova and parasites because this is unlikely to identify a culprit. There are other guidelines for treating patients who have traveled to high-risk countries.
Celiac disease should be tested for using immunoglobulin-A tissue transglutaminase (IgA tTG) and a second test (IgG tTG and IgG or IgA deamidated gliadin peptide, or DGP) in case the patient has IgA deficiency that could lead to a false negative on the primary test. Thresholds of 7-15 AU/mL in IgA tTG typically provide sensitivity and specificity greater than 90%. A quantitative IgA level found to be normal confirms the IgA tTG test. In abnormal findings, either IgG tTG or a test for IgG DGP can be used. If no information on IgA levels is available, IgG tTG or IgG DGP can be combined with IgA tTG. Positive celiac disease tests should be confirmed by duodenal biopsy.
Bile acid diarrhea should be tested for in the United States by measuring total bile acids in a 48-hour stool collection to document increased fecal bile acids, or serum fibroblast growth factor 19, to identify defective feedback of bile acid synthesis. The Selenium HomotauroCholic Acid Test (SeHCAT) has moderate diagnostic efficiency, but it is not available in North America. A measurement of serum levels of 7alpha-hydroxy-4-cholesten-3-one (C4), which measures bile acid synthesis, is not yet available.
No recommendation was made for using available serologic tests for the diagnosis of IBS because existing evidence suggests they lack the diagnostic accuracy needed for routine use.
The guideline development was funded by AGA and had no outside funding.
SOURCE: Smalley W et al. Gastroenterology. 2019 Jul 11. doi: 10.1053/j.gastro.2019.07.004.
A new guideline from the American Gastroenterological Association (AGA) aims to help physicians diagnose the cause of chronic watery diarrhea, particularly to exclude diagnoses other than functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS). The guideline, published in Gastroenterology, does not apply to patients with concerning presentations like weight loss/anemia, diarrhea with signs of fat malabsorption, bloody diarrhea, cases with a family history of inflammatory bowel disease (IBD), colon cancer, or celiac disease or to those who have traveled to diarrheal disease–related regions.
To rule out IBD, physicians can use either fecal calprotectin (threshold value of 50 microg/g, sensitivity, 0.81; specificity, 0.87) or fecal lactoferrin (threshold, 4.0-7.25 mcg/g; pooled sensitivity for IBD, 0.79; specificity, 0.93). Neither erythrocyte sedimentation rate (ESR) nor C-reactive protein (CRP) should be used to diagnose IBD because tests have shown low pooled sensitivity and specificity. CRP might be useful in settings in which fecal lactoferrin or calprotectin tests are not available or covered by insurance.
Patients should be tested for giardia infection, using the antigen test or PCR, because this pathogen is common in the United States and easily treated.
Patients who have not recently traveled to or from high-risk areas should not be tested for ova and parasites because this is unlikely to identify a culprit. There are other guidelines for treating patients who have traveled to high-risk countries.
Celiac disease should be tested for using immunoglobulin-A tissue transglutaminase (IgA tTG) and a second test (IgG tTG and IgG or IgA deamidated gliadin peptide, or DGP) in case the patient has IgA deficiency that could lead to a false negative on the primary test. Thresholds of 7-15 AU/mL in IgA tTG typically provide sensitivity and specificity greater than 90%. A quantitative IgA level found to be normal confirms the IgA tTG test. In abnormal findings, either IgG tTG or a test for IgG DGP can be used. If no information on IgA levels is available, IgG tTG or IgG DGP can be combined with IgA tTG. Positive celiac disease tests should be confirmed by duodenal biopsy.
Bile acid diarrhea should be tested for in the United States by measuring total bile acids in a 48-hour stool collection to document increased fecal bile acids, or serum fibroblast growth factor 19, to identify defective feedback of bile acid synthesis. The Selenium HomotauroCholic Acid Test (SeHCAT) has moderate diagnostic efficiency, but it is not available in North America. A measurement of serum levels of 7alpha-hydroxy-4-cholesten-3-one (C4), which measures bile acid synthesis, is not yet available.
No recommendation was made for using available serologic tests for the diagnosis of IBS because existing evidence suggests they lack the diagnostic accuracy needed for routine use.
The guideline development was funded by AGA and had no outside funding.
SOURCE: Smalley W et al. Gastroenterology. 2019 Jul 11. doi: 10.1053/j.gastro.2019.07.004.
A new guideline from the American Gastroenterological Association (AGA) aims to help physicians diagnose the cause of chronic watery diarrhea, particularly to exclude diagnoses other than functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS). The guideline, published in Gastroenterology, does not apply to patients with concerning presentations like weight loss/anemia, diarrhea with signs of fat malabsorption, bloody diarrhea, cases with a family history of inflammatory bowel disease (IBD), colon cancer, or celiac disease or to those who have traveled to diarrheal disease–related regions.
To rule out IBD, physicians can use either fecal calprotectin (threshold value of 50 microg/g, sensitivity, 0.81; specificity, 0.87) or fecal lactoferrin (threshold, 4.0-7.25 mcg/g; pooled sensitivity for IBD, 0.79; specificity, 0.93). Neither erythrocyte sedimentation rate (ESR) nor C-reactive protein (CRP) should be used to diagnose IBD because tests have shown low pooled sensitivity and specificity. CRP might be useful in settings in which fecal lactoferrin or calprotectin tests are not available or covered by insurance.
Patients should be tested for giardia infection, using the antigen test or PCR, because this pathogen is common in the United States and easily treated.
Patients who have not recently traveled to or from high-risk areas should not be tested for ova and parasites because this is unlikely to identify a culprit. There are other guidelines for treating patients who have traveled to high-risk countries.
Celiac disease should be tested for using immunoglobulin-A tissue transglutaminase (IgA tTG) and a second test (IgG tTG and IgG or IgA deamidated gliadin peptide, or DGP) in case the patient has IgA deficiency that could lead to a false negative on the primary test. Thresholds of 7-15 AU/mL in IgA tTG typically provide sensitivity and specificity greater than 90%. A quantitative IgA level found to be normal confirms the IgA tTG test. In abnormal findings, either IgG tTG or a test for IgG DGP can be used. If no information on IgA levels is available, IgG tTG or IgG DGP can be combined with IgA tTG. Positive celiac disease tests should be confirmed by duodenal biopsy.
Bile acid diarrhea should be tested for in the United States by measuring total bile acids in a 48-hour stool collection to document increased fecal bile acids, or serum fibroblast growth factor 19, to identify defective feedback of bile acid synthesis. The Selenium HomotauroCholic Acid Test (SeHCAT) has moderate diagnostic efficiency, but it is not available in North America. A measurement of serum levels of 7alpha-hydroxy-4-cholesten-3-one (C4), which measures bile acid synthesis, is not yet available.
No recommendation was made for using available serologic tests for the diagnosis of IBS because existing evidence suggests they lack the diagnostic accuracy needed for routine use.
The guideline development was funded by AGA and had no outside funding.
SOURCE: Smalley W et al. Gastroenterology. 2019 Jul 11. doi: 10.1053/j.gastro.2019.07.004.
FROM GASTROENTEROLOGY
FDA finds increased blood clot, death risk associated with Xeljanz
The Food and Drug Administration has issued a safety alert approving new boxed warnings about increased blood clot and mortality risk associated with the 10-mg, twice-daily dose of tofacitinib (Xeljanz), as well as a new limitation for patients with ulcerative colitis receiving the medication.
Tofacitinib, a Janus kinase inhibitor, was first approved by the FDA in 2012 for the treatment of rheumatoid arthritis (RA). An indication for psoriatic arthritis was added in 2017, and one for ulcerative colitis was added in 2018.
After the 2012 approval, the FDA commissioned a postmarketing trial in patients with RA on background methotrexate to evaluate safety and the risk of cancer, heart-related events, and infection. The 5- and 10-mg tofacitinib twice daily doses are being analyzed in an ongoing study in comparison with a tumor necrosis factor (TNF) inhibitor.
An interim analysis of the trial’s data, as of January 2019, found an increased risk of blood clots and death in patients receiving 10-mg tofacitinib twice daily, compared with the TNF inhibitor and the twice-daily, 5-mg dose. Overall, there were 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared with 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. There were also 45 cases of death from all causes during follow-up for tofacitinib 10 mg twice daily, compared with 25 cases in patients who received TNF inhibitors.
Patients with symptoms of thrombosis also receiving tofacitinib should immediately discontinue the medication. Tofacitinib should not be given to patients with ulcerative colitis unless they are not treated effectively with a TNF inhibitor or do not tolerate TNF inhibitors; ulcerative colitis patients should receive the lowest effective dosage, and if the higher dosage is necessary, it should be limited to the shortest amount of time possible, the FDA noted.
The Food and Drug Administration has issued a safety alert approving new boxed warnings about increased blood clot and mortality risk associated with the 10-mg, twice-daily dose of tofacitinib (Xeljanz), as well as a new limitation for patients with ulcerative colitis receiving the medication.
Tofacitinib, a Janus kinase inhibitor, was first approved by the FDA in 2012 for the treatment of rheumatoid arthritis (RA). An indication for psoriatic arthritis was added in 2017, and one for ulcerative colitis was added in 2018.
After the 2012 approval, the FDA commissioned a postmarketing trial in patients with RA on background methotrexate to evaluate safety and the risk of cancer, heart-related events, and infection. The 5- and 10-mg tofacitinib twice daily doses are being analyzed in an ongoing study in comparison with a tumor necrosis factor (TNF) inhibitor.
An interim analysis of the trial’s data, as of January 2019, found an increased risk of blood clots and death in patients receiving 10-mg tofacitinib twice daily, compared with the TNF inhibitor and the twice-daily, 5-mg dose. Overall, there were 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared with 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. There were also 45 cases of death from all causes during follow-up for tofacitinib 10 mg twice daily, compared with 25 cases in patients who received TNF inhibitors.
Patients with symptoms of thrombosis also receiving tofacitinib should immediately discontinue the medication. Tofacitinib should not be given to patients with ulcerative colitis unless they are not treated effectively with a TNF inhibitor or do not tolerate TNF inhibitors; ulcerative colitis patients should receive the lowest effective dosage, and if the higher dosage is necessary, it should be limited to the shortest amount of time possible, the FDA noted.
The Food and Drug Administration has issued a safety alert approving new boxed warnings about increased blood clot and mortality risk associated with the 10-mg, twice-daily dose of tofacitinib (Xeljanz), as well as a new limitation for patients with ulcerative colitis receiving the medication.
Tofacitinib, a Janus kinase inhibitor, was first approved by the FDA in 2012 for the treatment of rheumatoid arthritis (RA). An indication for psoriatic arthritis was added in 2017, and one for ulcerative colitis was added in 2018.
After the 2012 approval, the FDA commissioned a postmarketing trial in patients with RA on background methotrexate to evaluate safety and the risk of cancer, heart-related events, and infection. The 5- and 10-mg tofacitinib twice daily doses are being analyzed in an ongoing study in comparison with a tumor necrosis factor (TNF) inhibitor.
An interim analysis of the trial’s data, as of January 2019, found an increased risk of blood clots and death in patients receiving 10-mg tofacitinib twice daily, compared with the TNF inhibitor and the twice-daily, 5-mg dose. Overall, there were 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared with 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. There were also 45 cases of death from all causes during follow-up for tofacitinib 10 mg twice daily, compared with 25 cases in patients who received TNF inhibitors.
Patients with symptoms of thrombosis also receiving tofacitinib should immediately discontinue the medication. Tofacitinib should not be given to patients with ulcerative colitis unless they are not treated effectively with a TNF inhibitor or do not tolerate TNF inhibitors; ulcerative colitis patients should receive the lowest effective dosage, and if the higher dosage is necessary, it should be limited to the shortest amount of time possible, the FDA noted.
Hadlima approved as fourth adalimumab biosimilar in U.S.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
*This article was updated on July 24, 2019.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
*This article was updated on July 24, 2019.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
*This article was updated on July 24, 2019.
Are next-generation therapies for IBD ready? Are we making a difference?
A description of ulcerative colitis (UC) was first published by Wilkes in 1875. Infliximab was approved by the Food and Drug Administration for Crohn’s disease (CD) in 1998, 123 years later. However, in the following 20 years, there were eight new biologic or small-molecule agents approved for inflammatory bowel disease (IBD), with dozens more in the pipeline. These new mechanisms of action include janus kinase (JAK) inhibition, sphingosine 1 phosphate receptor 1 modulation, anti-integrins, and inhibition of the p19 subunit of interleukin-23.
Unfortunately, the rapid increase in drugs and mechanisms of action have not come with a strong understanding of which agent is most appropriate for which patient. Recent studies have tried to address parts of this question. First, we must define what the endpoints of therapy are – endoscopy, histology, or patient-reported outcomes? Then we need to understand how to achieve these endpoints. Combined immunosuppression with infliximab and azathioprine was superior to each alone in the SONIC trial (N Engl J Med. 2010;362:1383-95). The CALM study (Lancet. 2018;390:2779-89) looked at clinical management (escalation in therapy for moderate to severe CD by Crohn’s Disease Activity Index [CDAI]) and prednisone use versus a treat-to-target (T2T) approach which responded to C-reactive protein and fecal calprotectin. The T2T approach was statistically more likely to achieve endoscopic response at week 48 (45.9% vs. 30.3%). Early immunosuppression is also more likely to reduce hospitalization and surgery rates as shown in the REACT Trial (Lancet 2015;386:1825-34). This year at Digestive Disease Week, we can also add the VARSITY trial (Abstract 416A) which was a head-to-head comparison of vedolizumab to adalimumab for UC. After induction and maintenance therapy, vedolizumab was statistically more likely to induce clinical remission at week 52 than adalimumab, suggesting vedolizumab should be preferred as the first-line biologic in moderate to severe outpatient UC, particularly given its excellent safety profile.
Ustekinumab is Food and Drug Administration approved for CD. At this year’s DDW we saw that it is effective for induction and maintenance of remission in UC (Abstract 833) as well, and also has an excellent safety profile. JAK inhibitors have shown significant efficacy for UC, and more selective agents with primarily JAK1 inhibition are in studies for CD and UC. Adverse events of interest have included herpes zoster and thromboembolic events. Research has also been focusing on out-of-the-box therapies including fecal microbiota transplant for UC, dietary interventions for induction and maintenance of remission in IBD, and allogenic mesenchymal stem cells for perianal fistulizing CD.
With all of this new therapy, are we actually modifying disease history and avoiding surgery? The answer to that seems to be “yes.” Edward L. Barnes, MD, and colleagues (Abstract 708) used an insurance dataset to show that the rate of colectomy for UC has been reduced significantly between 2007 and 2016. While this may be, in part, attributable to biologic therapy, certainly change in practice guidelines, awareness of complications such as C. difficile, and enhanced disease monitoring have also played a role. Surgery itself should not be viewed as a failure. A limited ileocecal resection is more cost effective with equal or better quality of life at 1 year, compared with infliximab therapy, per the randomized LiRIC trial (Lancet Gastroenterol Hepatol 2017;2:785-92).
Therapy is evolving at a rapid pace, while the disease itself is increasing in incidence and prevalence around the world. To truly manage this patient population, we need to have a population-based intervention (diet, predictive biomarkers, etc.) to help reduce the number of people developing IBD, and a better understanding of when and how to use the mechanisms of action we already have to achieve and maintain remission in patients with IBD.
Dr. Mahadevan is professor of medicine, University of California at San Francisco Center for Colitis and Crohn’s Disease. She has disclosed receiving grant or research support from Tigenix, Pfizer, Genentech, and Celgene and being a consultant for Gilead, AbbVie, Bristol-Myers Squibb, Janssen, Takeda, and Lilly. Dr. Mahadevan made these comments during the AGA Institute Presidential Plenary at the annual Digestive Disease Week®.
A description of ulcerative colitis (UC) was first published by Wilkes in 1875. Infliximab was approved by the Food and Drug Administration for Crohn’s disease (CD) in 1998, 123 years later. However, in the following 20 years, there were eight new biologic or small-molecule agents approved for inflammatory bowel disease (IBD), with dozens more in the pipeline. These new mechanisms of action include janus kinase (JAK) inhibition, sphingosine 1 phosphate receptor 1 modulation, anti-integrins, and inhibition of the p19 subunit of interleukin-23.
Unfortunately, the rapid increase in drugs and mechanisms of action have not come with a strong understanding of which agent is most appropriate for which patient. Recent studies have tried to address parts of this question. First, we must define what the endpoints of therapy are – endoscopy, histology, or patient-reported outcomes? Then we need to understand how to achieve these endpoints. Combined immunosuppression with infliximab and azathioprine was superior to each alone in the SONIC trial (N Engl J Med. 2010;362:1383-95). The CALM study (Lancet. 2018;390:2779-89) looked at clinical management (escalation in therapy for moderate to severe CD by Crohn’s Disease Activity Index [CDAI]) and prednisone use versus a treat-to-target (T2T) approach which responded to C-reactive protein and fecal calprotectin. The T2T approach was statistically more likely to achieve endoscopic response at week 48 (45.9% vs. 30.3%). Early immunosuppression is also more likely to reduce hospitalization and surgery rates as shown in the REACT Trial (Lancet 2015;386:1825-34). This year at Digestive Disease Week, we can also add the VARSITY trial (Abstract 416A) which was a head-to-head comparison of vedolizumab to adalimumab for UC. After induction and maintenance therapy, vedolizumab was statistically more likely to induce clinical remission at week 52 than adalimumab, suggesting vedolizumab should be preferred as the first-line biologic in moderate to severe outpatient UC, particularly given its excellent safety profile.
Ustekinumab is Food and Drug Administration approved for CD. At this year’s DDW we saw that it is effective for induction and maintenance of remission in UC (Abstract 833) as well, and also has an excellent safety profile. JAK inhibitors have shown significant efficacy for UC, and more selective agents with primarily JAK1 inhibition are in studies for CD and UC. Adverse events of interest have included herpes zoster and thromboembolic events. Research has also been focusing on out-of-the-box therapies including fecal microbiota transplant for UC, dietary interventions for induction and maintenance of remission in IBD, and allogenic mesenchymal stem cells for perianal fistulizing CD.
With all of this new therapy, are we actually modifying disease history and avoiding surgery? The answer to that seems to be “yes.” Edward L. Barnes, MD, and colleagues (Abstract 708) used an insurance dataset to show that the rate of colectomy for UC has been reduced significantly between 2007 and 2016. While this may be, in part, attributable to biologic therapy, certainly change in practice guidelines, awareness of complications such as C. difficile, and enhanced disease monitoring have also played a role. Surgery itself should not be viewed as a failure. A limited ileocecal resection is more cost effective with equal or better quality of life at 1 year, compared with infliximab therapy, per the randomized LiRIC trial (Lancet Gastroenterol Hepatol 2017;2:785-92).
Therapy is evolving at a rapid pace, while the disease itself is increasing in incidence and prevalence around the world. To truly manage this patient population, we need to have a population-based intervention (diet, predictive biomarkers, etc.) to help reduce the number of people developing IBD, and a better understanding of when and how to use the mechanisms of action we already have to achieve and maintain remission in patients with IBD.
Dr. Mahadevan is professor of medicine, University of California at San Francisco Center for Colitis and Crohn’s Disease. She has disclosed receiving grant or research support from Tigenix, Pfizer, Genentech, and Celgene and being a consultant for Gilead, AbbVie, Bristol-Myers Squibb, Janssen, Takeda, and Lilly. Dr. Mahadevan made these comments during the AGA Institute Presidential Plenary at the annual Digestive Disease Week®.
A description of ulcerative colitis (UC) was first published by Wilkes in 1875. Infliximab was approved by the Food and Drug Administration for Crohn’s disease (CD) in 1998, 123 years later. However, in the following 20 years, there were eight new biologic or small-molecule agents approved for inflammatory bowel disease (IBD), with dozens more in the pipeline. These new mechanisms of action include janus kinase (JAK) inhibition, sphingosine 1 phosphate receptor 1 modulation, anti-integrins, and inhibition of the p19 subunit of interleukin-23.
Unfortunately, the rapid increase in drugs and mechanisms of action have not come with a strong understanding of which agent is most appropriate for which patient. Recent studies have tried to address parts of this question. First, we must define what the endpoints of therapy are – endoscopy, histology, or patient-reported outcomes? Then we need to understand how to achieve these endpoints. Combined immunosuppression with infliximab and azathioprine was superior to each alone in the SONIC trial (N Engl J Med. 2010;362:1383-95). The CALM study (Lancet. 2018;390:2779-89) looked at clinical management (escalation in therapy for moderate to severe CD by Crohn’s Disease Activity Index [CDAI]) and prednisone use versus a treat-to-target (T2T) approach which responded to C-reactive protein and fecal calprotectin. The T2T approach was statistically more likely to achieve endoscopic response at week 48 (45.9% vs. 30.3%). Early immunosuppression is also more likely to reduce hospitalization and surgery rates as shown in the REACT Trial (Lancet 2015;386:1825-34). This year at Digestive Disease Week, we can also add the VARSITY trial (Abstract 416A) which was a head-to-head comparison of vedolizumab to adalimumab for UC. After induction and maintenance therapy, vedolizumab was statistically more likely to induce clinical remission at week 52 than adalimumab, suggesting vedolizumab should be preferred as the first-line biologic in moderate to severe outpatient UC, particularly given its excellent safety profile.
Ustekinumab is Food and Drug Administration approved for CD. At this year’s DDW we saw that it is effective for induction and maintenance of remission in UC (Abstract 833) as well, and also has an excellent safety profile. JAK inhibitors have shown significant efficacy for UC, and more selective agents with primarily JAK1 inhibition are in studies for CD and UC. Adverse events of interest have included herpes zoster and thromboembolic events. Research has also been focusing on out-of-the-box therapies including fecal microbiota transplant for UC, dietary interventions for induction and maintenance of remission in IBD, and allogenic mesenchymal stem cells for perianal fistulizing CD.
With all of this new therapy, are we actually modifying disease history and avoiding surgery? The answer to that seems to be “yes.” Edward L. Barnes, MD, and colleagues (Abstract 708) used an insurance dataset to show that the rate of colectomy for UC has been reduced significantly between 2007 and 2016. While this may be, in part, attributable to biologic therapy, certainly change in practice guidelines, awareness of complications such as C. difficile, and enhanced disease monitoring have also played a role. Surgery itself should not be viewed as a failure. A limited ileocecal resection is more cost effective with equal or better quality of life at 1 year, compared with infliximab therapy, per the randomized LiRIC trial (Lancet Gastroenterol Hepatol 2017;2:785-92).
Therapy is evolving at a rapid pace, while the disease itself is increasing in incidence and prevalence around the world. To truly manage this patient population, we need to have a population-based intervention (diet, predictive biomarkers, etc.) to help reduce the number of people developing IBD, and a better understanding of when and how to use the mechanisms of action we already have to achieve and maintain remission in patients with IBD.
Dr. Mahadevan is professor of medicine, University of California at San Francisco Center for Colitis and Crohn’s Disease. She has disclosed receiving grant or research support from Tigenix, Pfizer, Genentech, and Celgene and being a consultant for Gilead, AbbVie, Bristol-Myers Squibb, Janssen, Takeda, and Lilly. Dr. Mahadevan made these comments during the AGA Institute Presidential Plenary at the annual Digestive Disease Week®.
Atypical food allergies common in IBS
, with accompanying changes in epithelial tight junction proteins and eosinophils.
Among 108 patients who completed the study, 61% showed this atypical allergic response to wheat, wrote Annette Fritscher-Ravens, MD, PhD, of University Hospital Schleswig-Holstein in Kiel, Germany, and her associates. Strikingly, almost 70% of patients with atypical food allergies to wheat, yeast, milk, soy, or egg white who eliminated these foods from their diets showed at least an 80% improvement in IBS symptoms after 3 months. These findings were published in Gastroenterology.
Confocal laser endomicroscopy (CLE) “permits real-time detection and quantification of changes in intestinal tissues and cells, including increases in intraepithelial lymphocytes and fluid extravasation through epithelial leaks,” the investigators wrote. This approach helps clinicians objectively detect and measure gastrointestinal pathology in response to specific foods, potentially freeing IBS patients from highly restrictive diets that ease symptoms but are hard to follow, and are not meant for long-term use.
For the study, the researchers enrolled patients meeting Rome III IBS criteria who tested negative for common food antigens on immunoglobulin E serology and skin tests. During endoscopy, each patient underwent sequential duodenal challenges with 20-mL suspensions of wheat, yeast, milk, soy, and egg white, followed by CLE with biopsy.
Among 108 patients who finished the study, 76 (70%) were CLE positive. They and their first-degree relatives were significantly more likely to have atopic disorders than were CLE-negative patients (P = .001). The most common allergen was wheat (61% of patients), followed by yeast (20%), milk (9%), soy (7%), and egg white (4%). Also, nine patients reacted to two of the tested food antigens.
Compared with CLE-negative patients or controls, CLE-positive patients also had significantly more intraepithelial lymphocytes (P = .001) and postchallenge expression of claudin-2 (P = .023), which contributes to tight junction permeability and is known to be upregulated in intestinal barrier dysfunction, IBS, and inflammatory bowel disease. Conversely, levels of the tight junction protein occludin were significantly lower in duodenal biopsies from CLE-positive patients versus controls (P = .022). “Levels of mRNAs encoding inflammatory cytokines were unchanged in duodenal tissues after CLE challenge, but eosinophil degranulation increased,” the researchers wrote.
In a double-blind, randomized, crossover study, patients then excluded from their diet the antigen to which they had tested positive or consumed a sham (placebo) diet that excluded only some foods containing the antigen, with a 2-week washout period in between. The CLE-positive patients showed a 70% average improvement in Francis IBS severity score after 3 months of the intervention diet and a 76% improvement at 6 months. Strikingly, 68% of CLE-positive patients showed at least an 80% improvement in symptoms, while only 4% did not respond at all.
“Since we do not observe a histological mast cell/basophil increase or activation, and [we] do not find increased mast cell mediators (tryptase) in the duodenal fluid after positive challenge, we assume a nonclassical or atypical food allergy as cause of the mucosal reaction observed by CLE,” the researchers wrote. Other immune cell parameters remained unchanged, but additional studies are needed to see if these changes are truly absent or occur later after challenge. The researchers are conducting murine studies of eosinophilic food allergy to shed more light on these nonclassical food allergies.
Funders included the Rashid Hussein Charity Trust, the German Research Foundation, and the Leibniz Foundation. The researchers reported having no conflicts of interest.
SOURCE: Fritscher-Ravens A et al. Gastroenterology. 2019 May 14. doi: 10.1053/j.gastro.2019.03.046.
, with accompanying changes in epithelial tight junction proteins and eosinophils.
Among 108 patients who completed the study, 61% showed this atypical allergic response to wheat, wrote Annette Fritscher-Ravens, MD, PhD, of University Hospital Schleswig-Holstein in Kiel, Germany, and her associates. Strikingly, almost 70% of patients with atypical food allergies to wheat, yeast, milk, soy, or egg white who eliminated these foods from their diets showed at least an 80% improvement in IBS symptoms after 3 months. These findings were published in Gastroenterology.
Confocal laser endomicroscopy (CLE) “permits real-time detection and quantification of changes in intestinal tissues and cells, including increases in intraepithelial lymphocytes and fluid extravasation through epithelial leaks,” the investigators wrote. This approach helps clinicians objectively detect and measure gastrointestinal pathology in response to specific foods, potentially freeing IBS patients from highly restrictive diets that ease symptoms but are hard to follow, and are not meant for long-term use.
For the study, the researchers enrolled patients meeting Rome III IBS criteria who tested negative for common food antigens on immunoglobulin E serology and skin tests. During endoscopy, each patient underwent sequential duodenal challenges with 20-mL suspensions of wheat, yeast, milk, soy, and egg white, followed by CLE with biopsy.
Among 108 patients who finished the study, 76 (70%) were CLE positive. They and their first-degree relatives were significantly more likely to have atopic disorders than were CLE-negative patients (P = .001). The most common allergen was wheat (61% of patients), followed by yeast (20%), milk (9%), soy (7%), and egg white (4%). Also, nine patients reacted to two of the tested food antigens.
Compared with CLE-negative patients or controls, CLE-positive patients also had significantly more intraepithelial lymphocytes (P = .001) and postchallenge expression of claudin-2 (P = .023), which contributes to tight junction permeability and is known to be upregulated in intestinal barrier dysfunction, IBS, and inflammatory bowel disease. Conversely, levels of the tight junction protein occludin were significantly lower in duodenal biopsies from CLE-positive patients versus controls (P = .022). “Levels of mRNAs encoding inflammatory cytokines were unchanged in duodenal tissues after CLE challenge, but eosinophil degranulation increased,” the researchers wrote.
In a double-blind, randomized, crossover study, patients then excluded from their diet the antigen to which they had tested positive or consumed a sham (placebo) diet that excluded only some foods containing the antigen, with a 2-week washout period in between. The CLE-positive patients showed a 70% average improvement in Francis IBS severity score after 3 months of the intervention diet and a 76% improvement at 6 months. Strikingly, 68% of CLE-positive patients showed at least an 80% improvement in symptoms, while only 4% did not respond at all.
“Since we do not observe a histological mast cell/basophil increase or activation, and [we] do not find increased mast cell mediators (tryptase) in the duodenal fluid after positive challenge, we assume a nonclassical or atypical food allergy as cause of the mucosal reaction observed by CLE,” the researchers wrote. Other immune cell parameters remained unchanged, but additional studies are needed to see if these changes are truly absent or occur later after challenge. The researchers are conducting murine studies of eosinophilic food allergy to shed more light on these nonclassical food allergies.
Funders included the Rashid Hussein Charity Trust, the German Research Foundation, and the Leibniz Foundation. The researchers reported having no conflicts of interest.
SOURCE: Fritscher-Ravens A et al. Gastroenterology. 2019 May 14. doi: 10.1053/j.gastro.2019.03.046.
, with accompanying changes in epithelial tight junction proteins and eosinophils.
Among 108 patients who completed the study, 61% showed this atypical allergic response to wheat, wrote Annette Fritscher-Ravens, MD, PhD, of University Hospital Schleswig-Holstein in Kiel, Germany, and her associates. Strikingly, almost 70% of patients with atypical food allergies to wheat, yeast, milk, soy, or egg white who eliminated these foods from their diets showed at least an 80% improvement in IBS symptoms after 3 months. These findings were published in Gastroenterology.
Confocal laser endomicroscopy (CLE) “permits real-time detection and quantification of changes in intestinal tissues and cells, including increases in intraepithelial lymphocytes and fluid extravasation through epithelial leaks,” the investigators wrote. This approach helps clinicians objectively detect and measure gastrointestinal pathology in response to specific foods, potentially freeing IBS patients from highly restrictive diets that ease symptoms but are hard to follow, and are not meant for long-term use.
For the study, the researchers enrolled patients meeting Rome III IBS criteria who tested negative for common food antigens on immunoglobulin E serology and skin tests. During endoscopy, each patient underwent sequential duodenal challenges with 20-mL suspensions of wheat, yeast, milk, soy, and egg white, followed by CLE with biopsy.
Among 108 patients who finished the study, 76 (70%) were CLE positive. They and their first-degree relatives were significantly more likely to have atopic disorders than were CLE-negative patients (P = .001). The most common allergen was wheat (61% of patients), followed by yeast (20%), milk (9%), soy (7%), and egg white (4%). Also, nine patients reacted to two of the tested food antigens.
Compared with CLE-negative patients or controls, CLE-positive patients also had significantly more intraepithelial lymphocytes (P = .001) and postchallenge expression of claudin-2 (P = .023), which contributes to tight junction permeability and is known to be upregulated in intestinal barrier dysfunction, IBS, and inflammatory bowel disease. Conversely, levels of the tight junction protein occludin were significantly lower in duodenal biopsies from CLE-positive patients versus controls (P = .022). “Levels of mRNAs encoding inflammatory cytokines were unchanged in duodenal tissues after CLE challenge, but eosinophil degranulation increased,” the researchers wrote.
In a double-blind, randomized, crossover study, patients then excluded from their diet the antigen to which they had tested positive or consumed a sham (placebo) diet that excluded only some foods containing the antigen, with a 2-week washout period in between. The CLE-positive patients showed a 70% average improvement in Francis IBS severity score after 3 months of the intervention diet and a 76% improvement at 6 months. Strikingly, 68% of CLE-positive patients showed at least an 80% improvement in symptoms, while only 4% did not respond at all.
“Since we do not observe a histological mast cell/basophil increase or activation, and [we] do not find increased mast cell mediators (tryptase) in the duodenal fluid after positive challenge, we assume a nonclassical or atypical food allergy as cause of the mucosal reaction observed by CLE,” the researchers wrote. Other immune cell parameters remained unchanged, but additional studies are needed to see if these changes are truly absent or occur later after challenge. The researchers are conducting murine studies of eosinophilic food allergy to shed more light on these nonclassical food allergies.
Funders included the Rashid Hussein Charity Trust, the German Research Foundation, and the Leibniz Foundation. The researchers reported having no conflicts of interest.
SOURCE: Fritscher-Ravens A et al. Gastroenterology. 2019 May 14. doi: 10.1053/j.gastro.2019.03.046.
FROM GASTROENTEROLOGY
Algorithm predicts villous atrophy in children with potential celiac disease
A new algorithm may be able to predict which children with potential celiac disease will go on to develop villous atrophy, according to investigators writing in Gastroenterology.
The risk model was developed from the largest cohort of its kind, with the longest follow-up to date, reported lead author Renata Auricchio, MD, PhD, of University Federico II in Naples, Italy, and colleagues. Using the algorithm, which relies most heavily on a baseline number of intraepithelial lymphocytes (IELs) in mucosa, followed by age at diagnosis and genetic profile, clinicians may now consider prescribing gluten-free diets to only the highest-risk patients, instead of all suspected cases, noting that more than half of potential cases do not develop flat mucosa within 12 years.
Development of the algorithm began with enrollment of 340 children aged 2-18 years who were positive for endomysial antibodies immunoglobulin A antibodies and had tested positive twice consecutively for antitissue transglutaminase antibodies. Additionally, children were required to possess HLA DQ2- or DQ8-positive haplotypes and have normal duodenal architecture in five biopsy samples. Because of symptoms suggestive of celiac disease or parental discretion, 60 patients were started on a gluten-free diet and excluded from the study, leaving 280 patients in the final cohort. These patients were kept on a gluten-containing diet and followed for up to 12 years. Every 6 months, the investigators checked antibodies and clinical status, and every 2 years, small bowel biopsy was performed, if symptoms had not necessitated this earlier.
After a median follow-up of 60 months, ranging from 18 months to 12 years, 39 patients (13.9%) developed symptoms of celiac disease and were placed on a gluten-free diet, although they declined confirmatory biopsy, disallowing classification of celiac disease. Another 33 patients (11.7%) were lost to follow-up and 89 (32%) stopped producing antibodies, with none going on to develop villous atrophy. In total, 42 patients (15%) developed flat mucosa during the follow-up period, with an estimated cumulative incidence of 43% at 12 years. The investigators noted that patients most frequently progressed within two time frames; at 24-48 months after enrollment, or at 96-120 months.
To develop the algorithm, the investigators performed multivariable analysis with several potential risk factors, including age, sex, genetic profile, mucosal characteristics, and concomitant autoimmune diseases. Of these, a high number of IELs upon first biopsy was most highly correlated with progression to celiac disease. Patients who developed villous atrophy had a mean value of 11.9 IELs at first biopsy, compared with 6.44 among those who remained potential (P = .05). The next strongest predictive factors were age and genetic profile. Just 7% of children less than 3 years developed flat mucosa, compared with 51% of patients aged 3-10 years and 55% of those older than 10 years (P = .007). HLA status was predictive in the group aged 3-10 years but not significant in the youngest or oldest patients. Therefore, HLA haplotype was included in the final algorithm, but with smaller contribution than five non-HLA genes, namely, IL12a, SH2B3, RGS1, CCR, and IL2/IL21.
“Combining these risk factors, we set up a model to predict the probability for a patient to evolve from potential celiac disease to villous atrophy,” the investigators wrote. “Overall, the discriminant analysis model allows us to correctly classify, at entry, 80% of the children who will not develop a flat mucosa over follow-up, while approximately 69% of those who will develop flat mucosa are correctly classified by the parameters we analyzed. This system is then more accurate to predict a child who will not develop flat mucosa and then can be monitored on a gluten-containing diet than a child who will become celiac.”
The investigators noted that IEL count may be an uncommon diagnostic; however, they recommended the test, even if it necessitates referral. “The [IEL] count turned out to be crucial for the prediction power of the discriminant analysis,” the investigators wrote.
“The long-term risks of potential celiac disease have never been accurately evaluated. Thus, before adopting a wait-and-see strategy on a gluten-containing diet, a final decision should always be shared with the family.”
Still, the investigators concluded that gluten-free diet “should not be prescribed indistinctly to all patients” with potential celiac disease, as it is a “very heterogenic condition and is not necessarily the first step of overt disease.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Auricchio R et al. Gastroenterology. 2019 Apr 9. doi: 10.1053/j.gastro.2019.04.004.
While the simplification of the diagnostic process for celiac disease (CD), now heavily reliant on CD-specific autoantibodies, has made the life of clinicians easier in many respects, new scenarios also have emerged that are posing new challenges. One of them is that a substantial, growing portion of subjects (who may or may not have symptoms) present with positive CD autoantibodies but a normal duodenal mucosa (“potential celiac patient”). If left on gluten, with time some will develop villous atrophy, but some won’t. What is the clinician supposed to do with them?
The paper by Auricchio et al. addresses this issue in a rigorous, well-structured way by closely prospectively monitoring a large series of pediatric patients. Their conclusions have very useful implications for the clinician. In fact taking into consideration several criteria, they found valuable after a long observation period – such as age of the child, HLA status, persistence of elevated CD-specific autoantibodies, and presence or absence of intraepithelial lymphocytes in the initial biopsy – they concluded that one can correctly identify at the beginning four out of five potential celiac patients who will not develop villous atrophy, and thus do not need to follow a gluten-free diet.
Ultimately, however, let’s not forget that we are still dealing with percentages of risk to develop full-blown CD, not with definitive certainties. Hence, the decision of starting a gluten-free diet or not (and of how often and in which way to monitor those who remain on gluten) remains a mutually agreed upon plan sealed by two actors: on one side the patient (or the patient’s family); and on the other, an experienced health care provider who has clearly explained the facts. In other words, evidence-based criteria, good old medicine, and a grain of salt!
Stefano Guandalini, MD, is a pediatric gastroenterologist at the University of Chicago Medical Center. He has no conflicts of interest.
While the simplification of the diagnostic process for celiac disease (CD), now heavily reliant on CD-specific autoantibodies, has made the life of clinicians easier in many respects, new scenarios also have emerged that are posing new challenges. One of them is that a substantial, growing portion of subjects (who may or may not have symptoms) present with positive CD autoantibodies but a normal duodenal mucosa (“potential celiac patient”). If left on gluten, with time some will develop villous atrophy, but some won’t. What is the clinician supposed to do with them?
The paper by Auricchio et al. addresses this issue in a rigorous, well-structured way by closely prospectively monitoring a large series of pediatric patients. Their conclusions have very useful implications for the clinician. In fact taking into consideration several criteria, they found valuable after a long observation period – such as age of the child, HLA status, persistence of elevated CD-specific autoantibodies, and presence or absence of intraepithelial lymphocytes in the initial biopsy – they concluded that one can correctly identify at the beginning four out of five potential celiac patients who will not develop villous atrophy, and thus do not need to follow a gluten-free diet.
Ultimately, however, let’s not forget that we are still dealing with percentages of risk to develop full-blown CD, not with definitive certainties. Hence, the decision of starting a gluten-free diet or not (and of how often and in which way to monitor those who remain on gluten) remains a mutually agreed upon plan sealed by two actors: on one side the patient (or the patient’s family); and on the other, an experienced health care provider who has clearly explained the facts. In other words, evidence-based criteria, good old medicine, and a grain of salt!
Stefano Guandalini, MD, is a pediatric gastroenterologist at the University of Chicago Medical Center. He has no conflicts of interest.
While the simplification of the diagnostic process for celiac disease (CD), now heavily reliant on CD-specific autoantibodies, has made the life of clinicians easier in many respects, new scenarios also have emerged that are posing new challenges. One of them is that a substantial, growing portion of subjects (who may or may not have symptoms) present with positive CD autoantibodies but a normal duodenal mucosa (“potential celiac patient”). If left on gluten, with time some will develop villous atrophy, but some won’t. What is the clinician supposed to do with them?
The paper by Auricchio et al. addresses this issue in a rigorous, well-structured way by closely prospectively monitoring a large series of pediatric patients. Their conclusions have very useful implications for the clinician. In fact taking into consideration several criteria, they found valuable after a long observation period – such as age of the child, HLA status, persistence of elevated CD-specific autoantibodies, and presence or absence of intraepithelial lymphocytes in the initial biopsy – they concluded that one can correctly identify at the beginning four out of five potential celiac patients who will not develop villous atrophy, and thus do not need to follow a gluten-free diet.
Ultimately, however, let’s not forget that we are still dealing with percentages of risk to develop full-blown CD, not with definitive certainties. Hence, the decision of starting a gluten-free diet or not (and of how often and in which way to monitor those who remain on gluten) remains a mutually agreed upon plan sealed by two actors: on one side the patient (or the patient’s family); and on the other, an experienced health care provider who has clearly explained the facts. In other words, evidence-based criteria, good old medicine, and a grain of salt!
Stefano Guandalini, MD, is a pediatric gastroenterologist at the University of Chicago Medical Center. He has no conflicts of interest.
A new algorithm may be able to predict which children with potential celiac disease will go on to develop villous atrophy, according to investigators writing in Gastroenterology.
The risk model was developed from the largest cohort of its kind, with the longest follow-up to date, reported lead author Renata Auricchio, MD, PhD, of University Federico II in Naples, Italy, and colleagues. Using the algorithm, which relies most heavily on a baseline number of intraepithelial lymphocytes (IELs) in mucosa, followed by age at diagnosis and genetic profile, clinicians may now consider prescribing gluten-free diets to only the highest-risk patients, instead of all suspected cases, noting that more than half of potential cases do not develop flat mucosa within 12 years.
Development of the algorithm began with enrollment of 340 children aged 2-18 years who were positive for endomysial antibodies immunoglobulin A antibodies and had tested positive twice consecutively for antitissue transglutaminase antibodies. Additionally, children were required to possess HLA DQ2- or DQ8-positive haplotypes and have normal duodenal architecture in five biopsy samples. Because of symptoms suggestive of celiac disease or parental discretion, 60 patients were started on a gluten-free diet and excluded from the study, leaving 280 patients in the final cohort. These patients were kept on a gluten-containing diet and followed for up to 12 years. Every 6 months, the investigators checked antibodies and clinical status, and every 2 years, small bowel biopsy was performed, if symptoms had not necessitated this earlier.
After a median follow-up of 60 months, ranging from 18 months to 12 years, 39 patients (13.9%) developed symptoms of celiac disease and were placed on a gluten-free diet, although they declined confirmatory biopsy, disallowing classification of celiac disease. Another 33 patients (11.7%) were lost to follow-up and 89 (32%) stopped producing antibodies, with none going on to develop villous atrophy. In total, 42 patients (15%) developed flat mucosa during the follow-up period, with an estimated cumulative incidence of 43% at 12 years. The investigators noted that patients most frequently progressed within two time frames; at 24-48 months after enrollment, or at 96-120 months.
To develop the algorithm, the investigators performed multivariable analysis with several potential risk factors, including age, sex, genetic profile, mucosal characteristics, and concomitant autoimmune diseases. Of these, a high number of IELs upon first biopsy was most highly correlated with progression to celiac disease. Patients who developed villous atrophy had a mean value of 11.9 IELs at first biopsy, compared with 6.44 among those who remained potential (P = .05). The next strongest predictive factors were age and genetic profile. Just 7% of children less than 3 years developed flat mucosa, compared with 51% of patients aged 3-10 years and 55% of those older than 10 years (P = .007). HLA status was predictive in the group aged 3-10 years but not significant in the youngest or oldest patients. Therefore, HLA haplotype was included in the final algorithm, but with smaller contribution than five non-HLA genes, namely, IL12a, SH2B3, RGS1, CCR, and IL2/IL21.
“Combining these risk factors, we set up a model to predict the probability for a patient to evolve from potential celiac disease to villous atrophy,” the investigators wrote. “Overall, the discriminant analysis model allows us to correctly classify, at entry, 80% of the children who will not develop a flat mucosa over follow-up, while approximately 69% of those who will develop flat mucosa are correctly classified by the parameters we analyzed. This system is then more accurate to predict a child who will not develop flat mucosa and then can be monitored on a gluten-containing diet than a child who will become celiac.”
The investigators noted that IEL count may be an uncommon diagnostic; however, they recommended the test, even if it necessitates referral. “The [IEL] count turned out to be crucial for the prediction power of the discriminant analysis,” the investigators wrote.
“The long-term risks of potential celiac disease have never been accurately evaluated. Thus, before adopting a wait-and-see strategy on a gluten-containing diet, a final decision should always be shared with the family.”
Still, the investigators concluded that gluten-free diet “should not be prescribed indistinctly to all patients” with potential celiac disease, as it is a “very heterogenic condition and is not necessarily the first step of overt disease.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Auricchio R et al. Gastroenterology. 2019 Apr 9. doi: 10.1053/j.gastro.2019.04.004.
A new algorithm may be able to predict which children with potential celiac disease will go on to develop villous atrophy, according to investigators writing in Gastroenterology.
The risk model was developed from the largest cohort of its kind, with the longest follow-up to date, reported lead author Renata Auricchio, MD, PhD, of University Federico II in Naples, Italy, and colleagues. Using the algorithm, which relies most heavily on a baseline number of intraepithelial lymphocytes (IELs) in mucosa, followed by age at diagnosis and genetic profile, clinicians may now consider prescribing gluten-free diets to only the highest-risk patients, instead of all suspected cases, noting that more than half of potential cases do not develop flat mucosa within 12 years.
Development of the algorithm began with enrollment of 340 children aged 2-18 years who were positive for endomysial antibodies immunoglobulin A antibodies and had tested positive twice consecutively for antitissue transglutaminase antibodies. Additionally, children were required to possess HLA DQ2- or DQ8-positive haplotypes and have normal duodenal architecture in five biopsy samples. Because of symptoms suggestive of celiac disease or parental discretion, 60 patients were started on a gluten-free diet and excluded from the study, leaving 280 patients in the final cohort. These patients were kept on a gluten-containing diet and followed for up to 12 years. Every 6 months, the investigators checked antibodies and clinical status, and every 2 years, small bowel biopsy was performed, if symptoms had not necessitated this earlier.
After a median follow-up of 60 months, ranging from 18 months to 12 years, 39 patients (13.9%) developed symptoms of celiac disease and were placed on a gluten-free diet, although they declined confirmatory biopsy, disallowing classification of celiac disease. Another 33 patients (11.7%) were lost to follow-up and 89 (32%) stopped producing antibodies, with none going on to develop villous atrophy. In total, 42 patients (15%) developed flat mucosa during the follow-up period, with an estimated cumulative incidence of 43% at 12 years. The investigators noted that patients most frequently progressed within two time frames; at 24-48 months after enrollment, or at 96-120 months.
To develop the algorithm, the investigators performed multivariable analysis with several potential risk factors, including age, sex, genetic profile, mucosal characteristics, and concomitant autoimmune diseases. Of these, a high number of IELs upon first biopsy was most highly correlated with progression to celiac disease. Patients who developed villous atrophy had a mean value of 11.9 IELs at first biopsy, compared with 6.44 among those who remained potential (P = .05). The next strongest predictive factors were age and genetic profile. Just 7% of children less than 3 years developed flat mucosa, compared with 51% of patients aged 3-10 years and 55% of those older than 10 years (P = .007). HLA status was predictive in the group aged 3-10 years but not significant in the youngest or oldest patients. Therefore, HLA haplotype was included in the final algorithm, but with smaller contribution than five non-HLA genes, namely, IL12a, SH2B3, RGS1, CCR, and IL2/IL21.
“Combining these risk factors, we set up a model to predict the probability for a patient to evolve from potential celiac disease to villous atrophy,” the investigators wrote. “Overall, the discriminant analysis model allows us to correctly classify, at entry, 80% of the children who will not develop a flat mucosa over follow-up, while approximately 69% of those who will develop flat mucosa are correctly classified by the parameters we analyzed. This system is then more accurate to predict a child who will not develop flat mucosa and then can be monitored on a gluten-containing diet than a child who will become celiac.”
The investigators noted that IEL count may be an uncommon diagnostic; however, they recommended the test, even if it necessitates referral. “The [IEL] count turned out to be crucial for the prediction power of the discriminant analysis,” the investigators wrote.
“The long-term risks of potential celiac disease have never been accurately evaluated. Thus, before adopting a wait-and-see strategy on a gluten-containing diet, a final decision should always be shared with the family.”
Still, the investigators concluded that gluten-free diet “should not be prescribed indistinctly to all patients” with potential celiac disease, as it is a “very heterogenic condition and is not necessarily the first step of overt disease.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Auricchio R et al. Gastroenterology. 2019 Apr 9. doi: 10.1053/j.gastro.2019.04.004.
FROM GASTROENTEROLOGY
Immune modulators help anti-TNF agents battle Crohn’s disease, but not UC
Adding an immune modulator (IM) to anti–tumor necrosis factor (anti-TNF) initiation therapy benefits patients with Crohn’s disease (CD) but not those with ulcerative colitis (UC), according to a recent retrospective look at more than 1,000 cases.
The study showed that patients with CD who started combination therapy instead of monotherapy had lower rates of treatment ineffectiveness, experienced longer delays until hospitalization, and less often needed to switch their anti-TNF agent, reported lead author Laura E. Targownik, MD, of the University of Manitoba, in Winnipeg, Canada, and colleagues.
“Current guidelines on the medical management of IBD strongly support the use of IMs and anti-TNFs in combination over anti-TNF monotherapy,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, there is a sparsity of real-world data demonstrating the incremental benefits of combination therapy.”
The investigators noted that the SONIC trial, conducted in 2010, showed that patients treated with combination therapy were more likely to achieve corticosteroid-free remission at weeks 26 and 50; this became the basis of evidence leading multiple clinical guidelines to recommend combination therapy for patients with CD.
The present study involved 852 patients with CD and 303 with UC who began treatment with an anti-TNF agent during 2001-2016. Data were drawn from the Manitoba Inflammatory Bowel Disease (IBD) Epidemiology database.
The main outcome of interest was treatment ineffectiveness, which was defined by any of the following four events: acute, IBD-related hospital admission for more than 48 hours; resective intestinal surgery; corticosteroid use at least 14 days after initiating anti-TNF therapy, or, if corticosteroids were used within 16 weeks of anti-TNF initiation, then subsequent corticosteroid use occurring at least 16 weeks after initiation; or switching to a different anti-TNF agent. The investigators also looked for differences in effectiveness between two agents from each class: anti-TNF agents infliximab and adalimumab, and immunomodulators methotrexate and azathioprine.
Results showed that patients with CD had higher rates of ineffectiveness-free survival when treated with combination therapy instead of monotherapy at 1 year (74.2% vs. 68.6%) and 2 years (64.0% vs. 54.5%). Using a Cox proportional hazards model, this translated to a 38% reduced risk of treatment ineffectiveness (adjusted hazard ratio, 0.62).
“This suggests that the findings of the SONIC trial may extend to real-world clinical practice, even in patients who had previous IM exposure,” the investigators noted.
Combination therapy was also significantly associated with longer time to first IBD-related hospitalization (HR, 0.53) and the need to switch anti-TNF agent (HR, 0.63). However, no such relationships were found for time to resective surgery or corticosteroid use. Although combination therapy had no impact on the rate of primary treatment ineffectiveness in multivariable logistic regression, those who received anti-TNF therapy for more than 90 days had delayed secondary treatment ineffectiveness and fewer IBD-related hospitalizations. Choice of agent from either class had no influence on effectiveness of combination therapy.
In contrast with the above findings, combination therapy in patients with UC was less promising, which aligns with previous studies.
“[W]e were not able to demonstrate a significant advantage to combination therapy in persons with UC,” the investigators wrote. “In addition, all published cohort studies to date have not been able to confirm a significant benefit to combination therapy in UC. ... In light of the lower quality of prior evidence, combined with the results from our study, the indication for combination therapy in UC would appear to be weaker.”
“Further analyses in larger cohorts may clarify whether there is a clinically relevant benefit of combination therapy in persons with UC,” the investigators concluded. “Because of the discrepancy between our findings and those of a meta-analysis of cohort studies previously published on this topic, confirmation of our results is required in future studies.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Targownik LE et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.003.
Twenty years after the approval of the first anti–tumor necrosis factor (TNF) biologic agent for the treatment of inflammatory bowel disease (IBD), patients and providers are still learning how to optimize these medications. One optimization is the use of combination therapy (immunomodulator and anti-TNF). Immunomodulators are used independently for maintenance of remission of IBD, and they have been shown to reduce immunogenicity and improve efficacy when used in combination with an anti-TNF agent in prior short-term randomized controlled trials. However, use of combination therapy in the real-world is not universally practiced. Data are lacking on the risks and benefits of long-term use of these agents. Therefore, this article by Targownik et al. is very timely.
Importantly, a mixed group of patients who had previously been on azathioprine monotherapy and those newly starting this therapy at the time of anti-TNF initiation were included in this cohort (a group similar to what we see in real-world practice). Data on risk factors for disease complications, such as disease phenotype or severity, were not available. By contrast, none of the efficacy associations were improved in the smaller group of patients with ulcerative colitis on combination therapy.
As providers counsel patients on the benefits and risks of various IBD treatment choices, these data by Targownik et al. will inform decisions. Future research should incorporate additional means of biologic optimization, such as the use of therapeutic drug monitoring and/or risk factor–based selection of therapeutic agents, to better inform individualized treatment choices.
Millie D. Long MD, MPH, is an associate professor of medicine in the division of gastroenterology and hepatology; Inflammatory Bowel Diseases Center; vice chief for education; director, Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill. She has the following conflicts of interest: AbbVie, Takeda, Pfizer, UCB, Janssen, Salix, Prometheus, Target Pharmasolutions, and Valeant.
Twenty years after the approval of the first anti–tumor necrosis factor (TNF) biologic agent for the treatment of inflammatory bowel disease (IBD), patients and providers are still learning how to optimize these medications. One optimization is the use of combination therapy (immunomodulator and anti-TNF). Immunomodulators are used independently for maintenance of remission of IBD, and they have been shown to reduce immunogenicity and improve efficacy when used in combination with an anti-TNF agent in prior short-term randomized controlled trials. However, use of combination therapy in the real-world is not universally practiced. Data are lacking on the risks and benefits of long-term use of these agents. Therefore, this article by Targownik et al. is very timely.
Importantly, a mixed group of patients who had previously been on azathioprine monotherapy and those newly starting this therapy at the time of anti-TNF initiation were included in this cohort (a group similar to what we see in real-world practice). Data on risk factors for disease complications, such as disease phenotype or severity, were not available. By contrast, none of the efficacy associations were improved in the smaller group of patients with ulcerative colitis on combination therapy.
As providers counsel patients on the benefits and risks of various IBD treatment choices, these data by Targownik et al. will inform decisions. Future research should incorporate additional means of biologic optimization, such as the use of therapeutic drug monitoring and/or risk factor–based selection of therapeutic agents, to better inform individualized treatment choices.
Millie D. Long MD, MPH, is an associate professor of medicine in the division of gastroenterology and hepatology; Inflammatory Bowel Diseases Center; vice chief for education; director, Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill. She has the following conflicts of interest: AbbVie, Takeda, Pfizer, UCB, Janssen, Salix, Prometheus, Target Pharmasolutions, and Valeant.
Twenty years after the approval of the first anti–tumor necrosis factor (TNF) biologic agent for the treatment of inflammatory bowel disease (IBD), patients and providers are still learning how to optimize these medications. One optimization is the use of combination therapy (immunomodulator and anti-TNF). Immunomodulators are used independently for maintenance of remission of IBD, and they have been shown to reduce immunogenicity and improve efficacy when used in combination with an anti-TNF agent in prior short-term randomized controlled trials. However, use of combination therapy in the real-world is not universally practiced. Data are lacking on the risks and benefits of long-term use of these agents. Therefore, this article by Targownik et al. is very timely.
Importantly, a mixed group of patients who had previously been on azathioprine monotherapy and those newly starting this therapy at the time of anti-TNF initiation were included in this cohort (a group similar to what we see in real-world practice). Data on risk factors for disease complications, such as disease phenotype or severity, were not available. By contrast, none of the efficacy associations were improved in the smaller group of patients with ulcerative colitis on combination therapy.
As providers counsel patients on the benefits and risks of various IBD treatment choices, these data by Targownik et al. will inform decisions. Future research should incorporate additional means of biologic optimization, such as the use of therapeutic drug monitoring and/or risk factor–based selection of therapeutic agents, to better inform individualized treatment choices.
Millie D. Long MD, MPH, is an associate professor of medicine in the division of gastroenterology and hepatology; Inflammatory Bowel Diseases Center; vice chief for education; director, Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill. She has the following conflicts of interest: AbbVie, Takeda, Pfizer, UCB, Janssen, Salix, Prometheus, Target Pharmasolutions, and Valeant.
Adding an immune modulator (IM) to anti–tumor necrosis factor (anti-TNF) initiation therapy benefits patients with Crohn’s disease (CD) but not those with ulcerative colitis (UC), according to a recent retrospective look at more than 1,000 cases.
The study showed that patients with CD who started combination therapy instead of monotherapy had lower rates of treatment ineffectiveness, experienced longer delays until hospitalization, and less often needed to switch their anti-TNF agent, reported lead author Laura E. Targownik, MD, of the University of Manitoba, in Winnipeg, Canada, and colleagues.
“Current guidelines on the medical management of IBD strongly support the use of IMs and anti-TNFs in combination over anti-TNF monotherapy,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, there is a sparsity of real-world data demonstrating the incremental benefits of combination therapy.”
The investigators noted that the SONIC trial, conducted in 2010, showed that patients treated with combination therapy were more likely to achieve corticosteroid-free remission at weeks 26 and 50; this became the basis of evidence leading multiple clinical guidelines to recommend combination therapy for patients with CD.
The present study involved 852 patients with CD and 303 with UC who began treatment with an anti-TNF agent during 2001-2016. Data were drawn from the Manitoba Inflammatory Bowel Disease (IBD) Epidemiology database.
The main outcome of interest was treatment ineffectiveness, which was defined by any of the following four events: acute, IBD-related hospital admission for more than 48 hours; resective intestinal surgery; corticosteroid use at least 14 days after initiating anti-TNF therapy, or, if corticosteroids were used within 16 weeks of anti-TNF initiation, then subsequent corticosteroid use occurring at least 16 weeks after initiation; or switching to a different anti-TNF agent. The investigators also looked for differences in effectiveness between two agents from each class: anti-TNF agents infliximab and adalimumab, and immunomodulators methotrexate and azathioprine.
Results showed that patients with CD had higher rates of ineffectiveness-free survival when treated with combination therapy instead of monotherapy at 1 year (74.2% vs. 68.6%) and 2 years (64.0% vs. 54.5%). Using a Cox proportional hazards model, this translated to a 38% reduced risk of treatment ineffectiveness (adjusted hazard ratio, 0.62).
“This suggests that the findings of the SONIC trial may extend to real-world clinical practice, even in patients who had previous IM exposure,” the investigators noted.
Combination therapy was also significantly associated with longer time to first IBD-related hospitalization (HR, 0.53) and the need to switch anti-TNF agent (HR, 0.63). However, no such relationships were found for time to resective surgery or corticosteroid use. Although combination therapy had no impact on the rate of primary treatment ineffectiveness in multivariable logistic regression, those who received anti-TNF therapy for more than 90 days had delayed secondary treatment ineffectiveness and fewer IBD-related hospitalizations. Choice of agent from either class had no influence on effectiveness of combination therapy.
In contrast with the above findings, combination therapy in patients with UC was less promising, which aligns with previous studies.
“[W]e were not able to demonstrate a significant advantage to combination therapy in persons with UC,” the investigators wrote. “In addition, all published cohort studies to date have not been able to confirm a significant benefit to combination therapy in UC. ... In light of the lower quality of prior evidence, combined with the results from our study, the indication for combination therapy in UC would appear to be weaker.”
“Further analyses in larger cohorts may clarify whether there is a clinically relevant benefit of combination therapy in persons with UC,” the investigators concluded. “Because of the discrepancy between our findings and those of a meta-analysis of cohort studies previously published on this topic, confirmation of our results is required in future studies.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Targownik LE et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.003.
Adding an immune modulator (IM) to anti–tumor necrosis factor (anti-TNF) initiation therapy benefits patients with Crohn’s disease (CD) but not those with ulcerative colitis (UC), according to a recent retrospective look at more than 1,000 cases.
The study showed that patients with CD who started combination therapy instead of monotherapy had lower rates of treatment ineffectiveness, experienced longer delays until hospitalization, and less often needed to switch their anti-TNF agent, reported lead author Laura E. Targownik, MD, of the University of Manitoba, in Winnipeg, Canada, and colleagues.
“Current guidelines on the medical management of IBD strongly support the use of IMs and anti-TNFs in combination over anti-TNF monotherapy,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, there is a sparsity of real-world data demonstrating the incremental benefits of combination therapy.”
The investigators noted that the SONIC trial, conducted in 2010, showed that patients treated with combination therapy were more likely to achieve corticosteroid-free remission at weeks 26 and 50; this became the basis of evidence leading multiple clinical guidelines to recommend combination therapy for patients with CD.
The present study involved 852 patients with CD and 303 with UC who began treatment with an anti-TNF agent during 2001-2016. Data were drawn from the Manitoba Inflammatory Bowel Disease (IBD) Epidemiology database.
The main outcome of interest was treatment ineffectiveness, which was defined by any of the following four events: acute, IBD-related hospital admission for more than 48 hours; resective intestinal surgery; corticosteroid use at least 14 days after initiating anti-TNF therapy, or, if corticosteroids were used within 16 weeks of anti-TNF initiation, then subsequent corticosteroid use occurring at least 16 weeks after initiation; or switching to a different anti-TNF agent. The investigators also looked for differences in effectiveness between two agents from each class: anti-TNF agents infliximab and adalimumab, and immunomodulators methotrexate and azathioprine.
Results showed that patients with CD had higher rates of ineffectiveness-free survival when treated with combination therapy instead of monotherapy at 1 year (74.2% vs. 68.6%) and 2 years (64.0% vs. 54.5%). Using a Cox proportional hazards model, this translated to a 38% reduced risk of treatment ineffectiveness (adjusted hazard ratio, 0.62).
“This suggests that the findings of the SONIC trial may extend to real-world clinical practice, even in patients who had previous IM exposure,” the investigators noted.
Combination therapy was also significantly associated with longer time to first IBD-related hospitalization (HR, 0.53) and the need to switch anti-TNF agent (HR, 0.63). However, no such relationships were found for time to resective surgery or corticosteroid use. Although combination therapy had no impact on the rate of primary treatment ineffectiveness in multivariable logistic regression, those who received anti-TNF therapy for more than 90 days had delayed secondary treatment ineffectiveness and fewer IBD-related hospitalizations. Choice of agent from either class had no influence on effectiveness of combination therapy.
In contrast with the above findings, combination therapy in patients with UC was less promising, which aligns with previous studies.
“[W]e were not able to demonstrate a significant advantage to combination therapy in persons with UC,” the investigators wrote. “In addition, all published cohort studies to date have not been able to confirm a significant benefit to combination therapy in UC. ... In light of the lower quality of prior evidence, combined with the results from our study, the indication for combination therapy in UC would appear to be weaker.”
“Further analyses in larger cohorts may clarify whether there is a clinically relevant benefit of combination therapy in persons with UC,” the investigators concluded. “Because of the discrepancy between our findings and those of a meta-analysis of cohort studies previously published on this topic, confirmation of our results is required in future studies.”
The investigators disclosed no funding or conflicts of interest.
SOURCE: Targownik LE et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.003.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY