IBD & Intestinal Disorders

For first-line treatment of patients with fecal incontinence, pelvic floor muscle training (PFMT) is superior to attention-control massage, according to investigators.

Source: American Gastroenterological Association

In a study involving 98 patients, those who combined PFMT with biofeedback and conservative therapy were five times as likely to report improved symptoms than those who used attention-control massage and conservative therapy, reported Anja Ussing, MD, of Copenhagen University Hospital in Hvidovre, Denmark, and colleagues. Patients in the PFMT group also had significantly greater reductions in severity of incontinence, based on Vaizey incontinence score.

“Evidence from randomized controlled trials regarding the effect of PFMT for fecal incontinence is lacking,” the investigators wrote in Clinical Gastroenterology and Hepatology. Although previous trials have evaluated PFMT, none controlled for the effect of interactions with care providers. “To evaluate the effect of PFMT, there is a need for a trial that uses a comparator to control for this nonspecific trial effect associated with the attention given by the health care professional.”

To perform such a trial, the investigators recruited 98 patients with a history of fecal incontinence for at least 6 months. Patients were excluded if they had severe neurologic conditions, pregnancy, diarrhea, rectal prolapse, previous radiotherapy or cancer surgery in the lower abdomen, cognitive impairment, inadequate fluency in Danish, or a history of at least two PFMT training sessions within the past year. Enrolled patients were randomized in a 1:1 ratio to receive PFMT with biofeedback and conservative treatment, or attention-control massage training and conservative therapy. The primary outcome was symptom improvement, determined by the Patient Global Impression of Improvement scale at 16 weeks. Secondary outcome measures included the Fecal Incontinence Severity Index, Vaizey score, and Fecal Incontinence Quality of Life Scale.

Patients were predominantly female, with just three men in the PFMT group and six in the attention-control massage group. The PFMT group also had a slightly higher median age, at 65 years, compared with 58 years in the control group.

At 16 weeks, the difference in self-reported symptoms was dramatic, with 74.5% of patients in the PFMT group reporting improvement, compared with 35.5% in the control group, which translated to an unadjusted odds ratio of 5.16 (P = .0002). When symptom improvements were confined to those who reported being “very much better” or “much better,” the disparity between groups still remained strong, with an unadjusted OR of 2.98 (P = .025). Among the three secondary outcomes, only the Vaizey score showed a significant difference between groups. Patients treated with PFMT had a mean difference in Vaizey score change of –1.83 points, using a scale from 0 to 24, with 24 representing complete incontinence (P = .04).

“We were not able to show any differences between groups in the number of fecal incontinence episodes,” the investigators wrote. “We had much missing data in the bowel diaries and we can only guess what the result would have been if the data had been more complete. Electronic assessment of incontinence episodes could be a way to reduce the amount of missing data in future trials.”

Still, the investigators concluded that PFMT was the superior therapy. “Based on the results, PFMT in combination with conservative treatment should be offered as first-line treatment for adults with fecal incontinence.”

They also highlighted the broad applicability of their findings, regardless of facility type.

“In the current trial, more than one-third of patients had sphincter injuries confirmed at endoanal ultrasound, this reflects the tertiary setting of our trial,” they wrote. “However, our results may be highly relevant in a primary setting because there is an unmet need for treatment of fecal incontinence in primary health care, and the interventions do not necessarily need to be conducted at specialized centers.”

The study was funded by the Danish Foundation for Research in Physiotherapy, The Lundbeck Foundation, the Research Foundation at Copenhagen University Hospital, and the Foundation of Aase and Ejnar Danielsen. The investigators reported additional relationships with Medtronic, Helsefonden, Gynzone, and others.

SOURCE: Ussing A et al. Clin Gastroenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.015.

For first-line treatment of patients with fecal incontinence, pelvic floor muscle training (PFMT) is superior to attention-control massage, according to investigators.

Source: American Gastroenterological Association

In a study involving 98 patients, those who combined PFMT with biofeedback and conservative therapy were five times as likely to report improved symptoms than those who used attention-control massage and conservative therapy, reported Anja Ussing, MD, of Copenhagen University Hospital in Hvidovre, Denmark, and colleagues. Patients in the PFMT group also had significantly greater reductions in severity of incontinence, based on Vaizey incontinence score.

“Evidence from randomized controlled trials regarding the effect of PFMT for fecal incontinence is lacking,” the investigators wrote in Clinical Gastroenterology and Hepatology. Although previous trials have evaluated PFMT, none controlled for the effect of interactions with care providers. “To evaluate the effect of PFMT, there is a need for a trial that uses a comparator to control for this nonspecific trial effect associated with the attention given by the health care professional.”

To perform such a trial, the investigators recruited 98 patients with a history of fecal incontinence for at least 6 months. Patients were excluded if they had severe neurologic conditions, pregnancy, diarrhea, rectal prolapse, previous radiotherapy or cancer surgery in the lower abdomen, cognitive impairment, inadequate fluency in Danish, or a history of at least two PFMT training sessions within the past year. Enrolled patients were randomized in a 1:1 ratio to receive PFMT with biofeedback and conservative treatment, or attention-control massage training and conservative therapy. The primary outcome was symptom improvement, determined by the Patient Global Impression of Improvement scale at 16 weeks. Secondary outcome measures included the Fecal Incontinence Severity Index, Vaizey score, and Fecal Incontinence Quality of Life Scale.

Patients were predominantly female, with just three men in the PFMT group and six in the attention-control massage group. The PFMT group also had a slightly higher median age, at 65 years, compared with 58 years in the control group.

At 16 weeks, the difference in self-reported symptoms was dramatic, with 74.5% of patients in the PFMT group reporting improvement, compared with 35.5% in the control group, which translated to an unadjusted odds ratio of 5.16 (P = .0002). When symptom improvements were confined to those who reported being “very much better” or “much better,” the disparity between groups still remained strong, with an unadjusted OR of 2.98 (P = .025). Among the three secondary outcomes, only the Vaizey score showed a significant difference between groups. Patients treated with PFMT had a mean difference in Vaizey score change of –1.83 points, using a scale from 0 to 24, with 24 representing complete incontinence (P = .04).

“We were not able to show any differences between groups in the number of fecal incontinence episodes,” the investigators wrote. “We had much missing data in the bowel diaries and we can only guess what the result would have been if the data had been more complete. Electronic assessment of incontinence episodes could be a way to reduce the amount of missing data in future trials.”

Still, the investigators concluded that PFMT was the superior therapy. “Based on the results, PFMT in combination with conservative treatment should be offered as first-line treatment for adults with fecal incontinence.”

They also highlighted the broad applicability of their findings, regardless of facility type.

“In the current trial, more than one-third of patients had sphincter injuries confirmed at endoanal ultrasound, this reflects the tertiary setting of our trial,” they wrote. “However, our results may be highly relevant in a primary setting because there is an unmet need for treatment of fecal incontinence in primary health care, and the interventions do not necessarily need to be conducted at specialized centers.”

The study was funded by the Danish Foundation for Research in Physiotherapy, The Lundbeck Foundation, the Research Foundation at Copenhagen University Hospital, and the Foundation of Aase and Ejnar Danielsen. The investigators reported additional relationships with Medtronic, Helsefonden, Gynzone, and others.

SOURCE: Ussing A et al. Clin Gastroenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.015.

For first-line treatment of patients with fecal incontinence, pelvic floor muscle training (PFMT) is superior to attention-control massage, according to investigators.

Source: American Gastroenterological Association

In a study involving 98 patients, those who combined PFMT with biofeedback and conservative therapy were five times as likely to report improved symptoms than those who used attention-control massage and conservative therapy, reported Anja Ussing, MD, of Copenhagen University Hospital in Hvidovre, Denmark, and colleagues. Patients in the PFMT group also had significantly greater reductions in severity of incontinence, based on Vaizey incontinence score.

“Evidence from randomized controlled trials regarding the effect of PFMT for fecal incontinence is lacking,” the investigators wrote in Clinical Gastroenterology and Hepatology. Although previous trials have evaluated PFMT, none controlled for the effect of interactions with care providers. “To evaluate the effect of PFMT, there is a need for a trial that uses a comparator to control for this nonspecific trial effect associated with the attention given by the health care professional.”

To perform such a trial, the investigators recruited 98 patients with a history of fecal incontinence for at least 6 months. Patients were excluded if they had severe neurologic conditions, pregnancy, diarrhea, rectal prolapse, previous radiotherapy or cancer surgery in the lower abdomen, cognitive impairment, inadequate fluency in Danish, or a history of at least two PFMT training sessions within the past year. Enrolled patients were randomized in a 1:1 ratio to receive PFMT with biofeedback and conservative treatment, or attention-control massage training and conservative therapy. The primary outcome was symptom improvement, determined by the Patient Global Impression of Improvement scale at 16 weeks. Secondary outcome measures included the Fecal Incontinence Severity Index, Vaizey score, and Fecal Incontinence Quality of Life Scale.

Patients were predominantly female, with just three men in the PFMT group and six in the attention-control massage group. The PFMT group also had a slightly higher median age, at 65 years, compared with 58 years in the control group.

At 16 weeks, the difference in self-reported symptoms was dramatic, with 74.5% of patients in the PFMT group reporting improvement, compared with 35.5% in the control group, which translated to an unadjusted odds ratio of 5.16 (P = .0002). When symptom improvements were confined to those who reported being “very much better” or “much better,” the disparity between groups still remained strong, with an unadjusted OR of 2.98 (P = .025). Among the three secondary outcomes, only the Vaizey score showed a significant difference between groups. Patients treated with PFMT had a mean difference in Vaizey score change of –1.83 points, using a scale from 0 to 24, with 24 representing complete incontinence (P = .04).

“We were not able to show any differences between groups in the number of fecal incontinence episodes,” the investigators wrote. “We had much missing data in the bowel diaries and we can only guess what the result would have been if the data had been more complete. Electronic assessment of incontinence episodes could be a way to reduce the amount of missing data in future trials.”

Still, the investigators concluded that PFMT was the superior therapy. “Based on the results, PFMT in combination with conservative treatment should be offered as first-line treatment for adults with fecal incontinence.”

They also highlighted the broad applicability of their findings, regardless of facility type.

“In the current trial, more than one-third of patients had sphincter injuries confirmed at endoanal ultrasound, this reflects the tertiary setting of our trial,” they wrote. “However, our results may be highly relevant in a primary setting because there is an unmet need for treatment of fecal incontinence in primary health care, and the interventions do not necessarily need to be conducted at specialized centers.”

The study was funded by the Danish Foundation for Research in Physiotherapy, The Lundbeck Foundation, the Research Foundation at Copenhagen University Hospital, and the Foundation of Aase and Ejnar Danielsen. The investigators reported additional relationships with Medtronic, Helsefonden, Gynzone, and others.

SOURCE: Ussing A et al. Clin Gastroenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.015.

Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.

A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.

Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.

“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.

Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1⁺-activated endothelial cells.

This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.

“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.

The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.

Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.

They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.

“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”

They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.

“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.

The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.

SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.

Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.

A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.

Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.

“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.

Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1⁺-activated endothelial cells.

This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.

“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.

The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.

Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.

They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.

“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”

They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.

“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.

The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.

SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.

Single-cell sequencing of tissues from patients with Crohn’s disease has revealed a new pathogenic cellular module associated with failure of anti–tumor necrosis factor (TNF) therapy.

A paper published in the Aug. 29 online edition of Cell presented the results of a study that mapped the transcriptome – the RNA activity that reveals the patterns of gene expression for a cell – of lamina propria cells taken from biopsies of uninflamed and inflamed ileal tissues from 11 patients with ileal Crohn’s disease.

Jérôme C. Martin, PharmD, PhD, from the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and coauthors wrote that while genome-wide association studies, tissue analyses, and animal models have revealed much about the immune and inflammatory processes that contribute to inflammatory bowel disease, there still remain unanswered questions about why some patients don’t respond to immune biotherapies.

“Current approaches restricted to well-established antibody panels based on prior knowledge preclude the identification of novel pathogenic cell populations in the diseased intestine,” they wrote.

Analysis of gene expression revealed significant cellular differences in the immune and stromal cells from inflamed compared to uninflamed ileum tissues. Researchers identified a group of cell subtypes that were highly correlated across inflamed ileums, and which included activated dendritic cells, activated fibroblasts, highly activated T cells, IgG plasma cells, inflammatory macrophages, inflammatory mononuclear phagocytes, and atypical chemokine receptor 1⁺-activated endothelial cells.

This so-called GIMATS module was present in only five of the patients, but it was independent of pathology severity, disease duration, and systemic markers of inflammation. The authors suggested that the module was associated with a positive feedback loop that increased the clustering of inflammatory mononuclear phagocytes in inflamed tissues.

“Taken together, our results identified a unique cellular organization in inflamed tissues of a subset of patients, thus revealing different pathogenic responses between patients despite similar pathological severity and systemic inflammatory markers,” the authors wrote.

The authors then looked for GIMATS expression in a larger cohort of 441 patients with ileal Crohn’s disease – including children aged over 2 years but excluding individuals with mutations that are associated with development of anti-TNF–resistant lesions early in life.

Given that 20%-30% of patients with ileal Crohn’s disease never respond to anti-TNF therapy, and require surgical intervention for uncontrolled bowel disease, the authors examined whether the GIMATs module might affect patient response to anti-TNF therapy.

They found that enrichment of this module was evident in the early stages of the disease, before the use of biologics therapy, and there were significant differences between treatment responders and nonresponders in their GIMATS module score at baseline. The authors said this suggested TNF blockade might not be enough to affect the inflammatory response associated with the GIMATS module.

“It is interesting that TNF was produced mainly by T cells in patients with low GIMATS module scores, while it was produced both by T cells and inflammatory [mononuclear phagocytes] in patients with a high module scores,” they wrote. “By providing a comprehensive network of the cellular and molecular basis for resistance to anti-TNF blockade, our study thus opens novel opportunities for therapeutic discoveries tailored for combination with anti-TNF antibody blockade.”

They also found that the GIMATs score did not correlate with disease activity in pediatric patients at diagnosis.

“As was observed in the discovery cohort, patients with high or low GIMATS module score had similar markers of systemic inflammation, indicating that the GIMATS score conveys information regarding response to biologic therapy that is not provided by standard [Crohn’s disease] biomarkers,” they wrote.

The study was partly supported by an author grant from Boehringer Ingelheim. Three authors also declared advisory board positions, consultancies, and research funding from the pharmaceutical industry, including Boehringer Ingelheim. No other conflicts of interest were declared.

SOURCE: Martin J et al. Cell. 2019 Aug 29. doi: 10.1016/j.cell.2019.08.008.

CHICAGO – Several new drugs for the treatment of celiac disease are in development, and existing treatments for other indications are being studied as treatments for celiac disease as well, according to a lecture delivered at the 2019 James W. Freston Conference: Food at the Intersection of Gut Health and Disease.

Home testing services and portable gluten-detection devices enable patients to diagnose and manage themselves without medical supervision, but these strategies raise concerns about accuracy and efficacy, said Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University in New York.
 

Potential treatments on the horizon

The gluten-free diet is the only treatment proven effective for celiac disease, but it can be expensive or unpalatable for some patients. The diet also entails risks of bowel irregularity and weight gain. “The gluten-free diet remains an inadequate treatment for many people with celiac disease,” said Dr. Lebwohl.

Tennyson et al. found that 66% of patients with biopsy-proven celiac disease are interested in nondietary therapy (Therap Adv Gastroenterol. 2013;6[5]:358-64.). Such patients are more likely to be male and older than 50 years.

Latiglutenase, a gluten enzyme derived from bacteria and cereal, is among the pharmacotherapies being investigated as a treatment for nonresponsive celiac disease. It reduces or eliminates the toxicity of gluten. In a recent phase 2b trial, however, the treatment did not achieve the primary outcome measure of histologic improvement (Gastroenterology. 2017;152[4]:787-98.). Compared with placebo, the drug was not associated with significant improvements in histologic and symptom scores.

Another drug in development is the tight-junction modulator larazotide acetate. Studies of zonula occludens toxin and its mammalian analogue zonulin led to the development of larazotide acetate. Leffler et al. found that a 0.5-mg dose of the drug reduced symptoms of nonresponsive celiac disease in patients who were following a gluten-free diet, compared with patients treated with the diet alone (Gastroenterology. 2015;148[7]:1311-9.). Innovate Pharmaceuticals plans to study the drug in phase 3 trials, said Dr. Lebwohl.

ImmunosanT has studied Nexvax2, which promotes gluten peptide desensitization. A phase 2 study examined the drug’s efficacy in reducing symptoms during a masked food challenge. The company discontinued this study when an interim analysis showed that the drug provided no more protection from gluten exposure than placebo. Nexvax2 was safe and well tolerated, and the study revealed no new safety signals.

In addition to newly developed therapies, researchers are studying whether drugs marketed for other indications could be effective treatments for celiac disease. For example, budesonide, a treatment for asthma and chronic obstructive pulmonary disease, is being investigated for nonresponsive celiac disease and refractory celiac disease. Other research is examining whether budesonide could provide effective protection after inadvertent gluten exposure. Systemic steroids, immunosuppressants such as azathioprine, chemotherapeutics such as cladribine, and mesalamine, which is a treatment for inflammatory bowel disease, also are under investigation.

But several questions related to drug development for celiac disease remain unanswered. For example, whether researchers should choose clinical or histologic endpoints for their trials is a subject of debate. “Probably, we’re going to be looking for two endpoints,” said Dr. Lebwohl. No consensus has been established about whether trials should include patients for whom diagnosis is based on a test other than a biopsy. Also, the effect of nondietary therapy on adherence to the gluten-free diet remains to be clarified.
 

Self-management of celiac disease

“We’re in a new era” of self-monitoring and direct-to-consumer advertising aimed at patients with celiac disease, said Dr. Lebwohl. Products and services that enable patients to diagnose and manage themselves independently are broadly available. For example, 23andMe provides at-home testing for HLA-DQ2.5 and HLA-DQ8, which could support a diagnosis of celiac disease. The service does not, however, test for HLA-DQ2.2, which is present in about 5% of patients with celiac disease. This testing consequently has high negative-predictive value, but poor positive-predictive value, said Dr. Lebwohl.

Similarly, ImAware provides blood tests that patients can take at home and send to the company for results. The tests look for antibodies such as tissue transglutaminase immunoglobulin A/immunoglobulin G and deamidated gliadin peptide IgA/IgG. The company advises patients to share their results with a health care professional.

Furthermore, portable devices such as Nima are marketed as gluten detectors. One study of the device included 804 users from all 50 states. The device found gluten in 32% of all restaurant food tested advertised as gluten-free. The interpretation of these results should take into account the fact that the device may detect gluten levels lower than 20 ppm, which generally are safe for patients with celiac disease. Furthermore, the data were uploaded voluntarily by users, and thus are not a random sample (Am J Gastroenterol. 2019;114[5]:792-7.). The device cannot detect certain forms of gluten such as barley malt. Because of limitations like these, the Nima device has “vocal critics,” said Dr. Lebwohl.

A profusion of books that offer dietary advice for patients with celiac disease also has become available. Data from Google Trends indicate that the popularity of the gluten-free diet spread from small pockets of the country in 2006 to most of the states in 2015.

Yet this “do-it-yourself” approach to celiac disease raises several concerns, said Dr. Lebwohl. Patients are at risk of interpreting their test results incorrectly, for example. Failing to consult a dietitian or physician, each of whom could have expertise in the field, entails risks as well. “Knowledgeable and empathetic care-giving is more important than ever,” Dr. Lebwohl concluded.

Dr. Lebwohl is on the medical advisory board of Innovate Biopharmaceuticals, a consultant for Takeda, and an unpaid advisor for the Nima Sensor.

[email protected]

CHICAGO – Several new drugs for the treatment of celiac disease are in development, and existing treatments for other indications are being studied as treatments for celiac disease as well, according to a lecture delivered at the 2019 James W. Freston Conference: Food at the Intersection of Gut Health and Disease.

Home testing services and portable gluten-detection devices enable patients to diagnose and manage themselves without medical supervision, but these strategies raise concerns about accuracy and efficacy, said Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University in New York.
 

Potential treatments on the horizon

The gluten-free diet is the only treatment proven effective for celiac disease, but it can be expensive or unpalatable for some patients. The diet also entails risks of bowel irregularity and weight gain. “The gluten-free diet remains an inadequate treatment for many people with celiac disease,” said Dr. Lebwohl.

Tennyson et al. found that 66% of patients with biopsy-proven celiac disease are interested in nondietary therapy (Therap Adv Gastroenterol. 2013;6[5]:358-64.). Such patients are more likely to be male and older than 50 years.

Latiglutenase, a gluten enzyme derived from bacteria and cereal, is among the pharmacotherapies being investigated as a treatment for nonresponsive celiac disease. It reduces or eliminates the toxicity of gluten. In a recent phase 2b trial, however, the treatment did not achieve the primary outcome measure of histologic improvement (Gastroenterology. 2017;152[4]:787-98.). Compared with placebo, the drug was not associated with significant improvements in histologic and symptom scores.

Another drug in development is the tight-junction modulator larazotide acetate. Studies of zonula occludens toxin and its mammalian analogue zonulin led to the development of larazotide acetate. Leffler et al. found that a 0.5-mg dose of the drug reduced symptoms of nonresponsive celiac disease in patients who were following a gluten-free diet, compared with patients treated with the diet alone (Gastroenterology. 2015;148[7]:1311-9.). Innovate Pharmaceuticals plans to study the drug in phase 3 trials, said Dr. Lebwohl.

ImmunosanT has studied Nexvax2, which promotes gluten peptide desensitization. A phase 2 study examined the drug’s efficacy in reducing symptoms during a masked food challenge. The company discontinued this study when an interim analysis showed that the drug provided no more protection from gluten exposure than placebo. Nexvax2 was safe and well tolerated, and the study revealed no new safety signals.

In addition to newly developed therapies, researchers are studying whether drugs marketed for other indications could be effective treatments for celiac disease. For example, budesonide, a treatment for asthma and chronic obstructive pulmonary disease, is being investigated for nonresponsive celiac disease and refractory celiac disease. Other research is examining whether budesonide could provide effective protection after inadvertent gluten exposure. Systemic steroids, immunosuppressants such as azathioprine, chemotherapeutics such as cladribine, and mesalamine, which is a treatment for inflammatory bowel disease, also are under investigation.

But several questions related to drug development for celiac disease remain unanswered. For example, whether researchers should choose clinical or histologic endpoints for their trials is a subject of debate. “Probably, we’re going to be looking for two endpoints,” said Dr. Lebwohl. No consensus has been established about whether trials should include patients for whom diagnosis is based on a test other than a biopsy. Also, the effect of nondietary therapy on adherence to the gluten-free diet remains to be clarified.
 

Self-management of celiac disease

“We’re in a new era” of self-monitoring and direct-to-consumer advertising aimed at patients with celiac disease, said Dr. Lebwohl. Products and services that enable patients to diagnose and manage themselves independently are broadly available. For example, 23andMe provides at-home testing for HLA-DQ2.5 and HLA-DQ8, which could support a diagnosis of celiac disease. The service does not, however, test for HLA-DQ2.2, which is present in about 5% of patients with celiac disease. This testing consequently has high negative-predictive value, but poor positive-predictive value, said Dr. Lebwohl.

Similarly, ImAware provides blood tests that patients can take at home and send to the company for results. The tests look for antibodies such as tissue transglutaminase immunoglobulin A/immunoglobulin G and deamidated gliadin peptide IgA/IgG. The company advises patients to share their results with a health care professional.

Furthermore, portable devices such as Nima are marketed as gluten detectors. One study of the device included 804 users from all 50 states. The device found gluten in 32% of all restaurant food tested advertised as gluten-free. The interpretation of these results should take into account the fact that the device may detect gluten levels lower than 20 ppm, which generally are safe for patients with celiac disease. Furthermore, the data were uploaded voluntarily by users, and thus are not a random sample (Am J Gastroenterol. 2019;114[5]:792-7.). The device cannot detect certain forms of gluten such as barley malt. Because of limitations like these, the Nima device has “vocal critics,” said Dr. Lebwohl.

A profusion of books that offer dietary advice for patients with celiac disease also has become available. Data from Google Trends indicate that the popularity of the gluten-free diet spread from small pockets of the country in 2006 to most of the states in 2015.

Yet this “do-it-yourself” approach to celiac disease raises several concerns, said Dr. Lebwohl. Patients are at risk of interpreting their test results incorrectly, for example. Failing to consult a dietitian or physician, each of whom could have expertise in the field, entails risks as well. “Knowledgeable and empathetic care-giving is more important than ever,” Dr. Lebwohl concluded.

Dr. Lebwohl is on the medical advisory board of Innovate Biopharmaceuticals, a consultant for Takeda, and an unpaid advisor for the Nima Sensor.

[email protected]

CHICAGO – Several new drugs for the treatment of celiac disease are in development, and existing treatments for other indications are being studied as treatments for celiac disease as well, according to a lecture delivered at the 2019 James W. Freston Conference: Food at the Intersection of Gut Health and Disease.

Home testing services and portable gluten-detection devices enable patients to diagnose and manage themselves without medical supervision, but these strategies raise concerns about accuracy and efficacy, said Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University in New York.
 

Potential treatments on the horizon

The gluten-free diet is the only treatment proven effective for celiac disease, but it can be expensive or unpalatable for some patients. The diet also entails risks of bowel irregularity and weight gain. “The gluten-free diet remains an inadequate treatment for many people with celiac disease,” said Dr. Lebwohl.

Tennyson et al. found that 66% of patients with biopsy-proven celiac disease are interested in nondietary therapy (Therap Adv Gastroenterol. 2013;6[5]:358-64.). Such patients are more likely to be male and older than 50 years.

Latiglutenase, a gluten enzyme derived from bacteria and cereal, is among the pharmacotherapies being investigated as a treatment for nonresponsive celiac disease. It reduces or eliminates the toxicity of gluten. In a recent phase 2b trial, however, the treatment did not achieve the primary outcome measure of histologic improvement (Gastroenterology. 2017;152[4]:787-98.). Compared with placebo, the drug was not associated with significant improvements in histologic and symptom scores.

Another drug in development is the tight-junction modulator larazotide acetate. Studies of zonula occludens toxin and its mammalian analogue zonulin led to the development of larazotide acetate. Leffler et al. found that a 0.5-mg dose of the drug reduced symptoms of nonresponsive celiac disease in patients who were following a gluten-free diet, compared with patients treated with the diet alone (Gastroenterology. 2015;148[7]:1311-9.). Innovate Pharmaceuticals plans to study the drug in phase 3 trials, said Dr. Lebwohl.

ImmunosanT has studied Nexvax2, which promotes gluten peptide desensitization. A phase 2 study examined the drug’s efficacy in reducing symptoms during a masked food challenge. The company discontinued this study when an interim analysis showed that the drug provided no more protection from gluten exposure than placebo. Nexvax2 was safe and well tolerated, and the study revealed no new safety signals.

In addition to newly developed therapies, researchers are studying whether drugs marketed for other indications could be effective treatments for celiac disease. For example, budesonide, a treatment for asthma and chronic obstructive pulmonary disease, is being investigated for nonresponsive celiac disease and refractory celiac disease. Other research is examining whether budesonide could provide effective protection after inadvertent gluten exposure. Systemic steroids, immunosuppressants such as azathioprine, chemotherapeutics such as cladribine, and mesalamine, which is a treatment for inflammatory bowel disease, also are under investigation.

But several questions related to drug development for celiac disease remain unanswered. For example, whether researchers should choose clinical or histologic endpoints for their trials is a subject of debate. “Probably, we’re going to be looking for two endpoints,” said Dr. Lebwohl. No consensus has been established about whether trials should include patients for whom diagnosis is based on a test other than a biopsy. Also, the effect of nondietary therapy on adherence to the gluten-free diet remains to be clarified.
 

Self-management of celiac disease

“We’re in a new era” of self-monitoring and direct-to-consumer advertising aimed at patients with celiac disease, said Dr. Lebwohl. Products and services that enable patients to diagnose and manage themselves independently are broadly available. For example, 23andMe provides at-home testing for HLA-DQ2.5 and HLA-DQ8, which could support a diagnosis of celiac disease. The service does not, however, test for HLA-DQ2.2, which is present in about 5% of patients with celiac disease. This testing consequently has high negative-predictive value, but poor positive-predictive value, said Dr. Lebwohl.

Similarly, ImAware provides blood tests that patients can take at home and send to the company for results. The tests look for antibodies such as tissue transglutaminase immunoglobulin A/immunoglobulin G and deamidated gliadin peptide IgA/IgG. The company advises patients to share their results with a health care professional.

Furthermore, portable devices such as Nima are marketed as gluten detectors. One study of the device included 804 users from all 50 states. The device found gluten in 32% of all restaurant food tested advertised as gluten-free. The interpretation of these results should take into account the fact that the device may detect gluten levels lower than 20 ppm, which generally are safe for patients with celiac disease. Furthermore, the data were uploaded voluntarily by users, and thus are not a random sample (Am J Gastroenterol. 2019;114[5]:792-7.). The device cannot detect certain forms of gluten such as barley malt. Because of limitations like these, the Nima device has “vocal critics,” said Dr. Lebwohl.

A profusion of books that offer dietary advice for patients with celiac disease also has become available. Data from Google Trends indicate that the popularity of the gluten-free diet spread from small pockets of the country in 2006 to most of the states in 2015.

Yet this “do-it-yourself” approach to celiac disease raises several concerns, said Dr. Lebwohl. Patients are at risk of interpreting their test results incorrectly, for example. Failing to consult a dietitian or physician, each of whom could have expertise in the field, entails risks as well. “Knowledgeable and empathetic care-giving is more important than ever,” Dr. Lebwohl concluded.

Dr. Lebwohl is on the medical advisory board of Innovate Biopharmaceuticals, a consultant for Takeda, and an unpaid advisor for the Nima Sensor.

[email protected]

In the upper GI section of the Postgraduate course program, Ikuo Hirano, MD, educated us on the refractory patient with eosinophilic esophagitis, reinforcing the need for chronic maintenance treatment and the complementary role of dilation. Gregory Ginsberg, MD, elucidated the specific strategies needed for gastric polyps with advice on which to leave and which to resect. Sachin Wani, MD, carefully outlined the changing landscape of Barrett’s esophagus with emphasis on our move to ablate rather than observe low-grade dysplasia. In the difficult area of treating gastroparesis, Linda Nguyen, MD, acquainted us with some of the newer medications for this disorder and discussed the emerging role of endoscopic pyloromyotomy. Michael Camilleri, MD, delivered a thorough analysis on the concept of leaky gut with data-driven recommendations on testing and the lack of adequate treatment. Finally, William Chey, MD, gave perspective to diagnosis and treatment of small-bowel bacterial overgrowth, particularly with its role in irritable bowel syndrome.

In the lower GI section of the course, Sunanda Kane, MD, gave a wonderful overview the present and emerging biologics for treatment of inflammatory bowel disease (IBD). David Rubin, MD, shared his expertise and vast experience for best management of ulcerative colitis while Edward Loftus Jr., MD, discussed the fact and fiction of diet-based therapy in IBD. This was followed by a timely lecture by Christina Ha, MD, on the need to think well outside the GI tract in IBD, discussing infections, cancers, and vaccinations in patients with IBD. The IBD section finished with an erudite and timely lecture by Marla Dubinsky, MD, evaluating the controversy over use of biosimilars in our clinical practice. The remainder of the lower GI section started with AGA President David Lieberman, MD, analyzing recent data on the need to move the colonic cancer screening age to 45 years, particularly in African Americans. Following this was a timely talk by Xavie Llor, MD, PhD, on when to suspect and how to test for the expanding definition of Lynch syndrome. Lin Chang, MD, delivered the penultimate clinical lecture on management of irritable bowel syndrome based on her many years of clinical expertise in this area. Finally, Gail Hecht, MD, AGAF, a former AGA president, summarized the exciting world of microbiome research from the recent annual Gut Microbiota for Health World Summit. All in all it was considered one of the best AGA Postgraduate courses by many and we look forward to even greater improvements for 2020.

This is a summary provided by the moderator of one of the AGA Postgraduate Course sessions held at DDW 2019. Dr. Katzka is professor of medicine and head of the Esophageal Interest Group at the Mayo Clinic in Rochester, Minn. He is on the advisory boards for Shire and Celgene.

In the upper GI section of the Postgraduate course program, Ikuo Hirano, MD, educated us on the refractory patient with eosinophilic esophagitis, reinforcing the need for chronic maintenance treatment and the complementary role of dilation. Gregory Ginsberg, MD, elucidated the specific strategies needed for gastric polyps with advice on which to leave and which to resect. Sachin Wani, MD, carefully outlined the changing landscape of Barrett’s esophagus with emphasis on our move to ablate rather than observe low-grade dysplasia. In the difficult area of treating gastroparesis, Linda Nguyen, MD, acquainted us with some of the newer medications for this disorder and discussed the emerging role of endoscopic pyloromyotomy. Michael Camilleri, MD, delivered a thorough analysis on the concept of leaky gut with data-driven recommendations on testing and the lack of adequate treatment. Finally, William Chey, MD, gave perspective to diagnosis and treatment of small-bowel bacterial overgrowth, particularly with its role in irritable bowel syndrome.

In the lower GI section of the course, Sunanda Kane, MD, gave a wonderful overview the present and emerging biologics for treatment of inflammatory bowel disease (IBD). David Rubin, MD, shared his expertise and vast experience for best management of ulcerative colitis while Edward Loftus Jr., MD, discussed the fact and fiction of diet-based therapy in IBD. This was followed by a timely lecture by Christina Ha, MD, on the need to think well outside the GI tract in IBD, discussing infections, cancers, and vaccinations in patients with IBD. The IBD section finished with an erudite and timely lecture by Marla Dubinsky, MD, evaluating the controversy over use of biosimilars in our clinical practice. The remainder of the lower GI section started with AGA President David Lieberman, MD, analyzing recent data on the need to move the colonic cancer screening age to 45 years, particularly in African Americans. Following this was a timely talk by Xavie Llor, MD, PhD, on when to suspect and how to test for the expanding definition of Lynch syndrome. Lin Chang, MD, delivered the penultimate clinical lecture on management of irritable bowel syndrome based on her many years of clinical expertise in this area. Finally, Gail Hecht, MD, AGAF, a former AGA president, summarized the exciting world of microbiome research from the recent annual Gut Microbiota for Health World Summit. All in all it was considered one of the best AGA Postgraduate courses by many and we look forward to even greater improvements for 2020.

This is a summary provided by the moderator of one of the AGA Postgraduate Course sessions held at DDW 2019. Dr. Katzka is professor of medicine and head of the Esophageal Interest Group at the Mayo Clinic in Rochester, Minn. He is on the advisory boards for Shire and Celgene.

In the upper GI section of the Postgraduate course program, Ikuo Hirano, MD, educated us on the refractory patient with eosinophilic esophagitis, reinforcing the need for chronic maintenance treatment and the complementary role of dilation. Gregory Ginsberg, MD, elucidated the specific strategies needed for gastric polyps with advice on which to leave and which to resect. Sachin Wani, MD, carefully outlined the changing landscape of Barrett’s esophagus with emphasis on our move to ablate rather than observe low-grade dysplasia. In the difficult area of treating gastroparesis, Linda Nguyen, MD, acquainted us with some of the newer medications for this disorder and discussed the emerging role of endoscopic pyloromyotomy. Michael Camilleri, MD, delivered a thorough analysis on the concept of leaky gut with data-driven recommendations on testing and the lack of adequate treatment. Finally, William Chey, MD, gave perspective to diagnosis and treatment of small-bowel bacterial overgrowth, particularly with its role in irritable bowel syndrome.

In the lower GI section of the course, Sunanda Kane, MD, gave a wonderful overview the present and emerging biologics for treatment of inflammatory bowel disease (IBD). David Rubin, MD, shared his expertise and vast experience for best management of ulcerative colitis while Edward Loftus Jr., MD, discussed the fact and fiction of diet-based therapy in IBD. This was followed by a timely lecture by Christina Ha, MD, on the need to think well outside the GI tract in IBD, discussing infections, cancers, and vaccinations in patients with IBD. The IBD section finished with an erudite and timely lecture by Marla Dubinsky, MD, evaluating the controversy over use of biosimilars in our clinical practice. The remainder of the lower GI section started with AGA President David Lieberman, MD, analyzing recent data on the need to move the colonic cancer screening age to 45 years, particularly in African Americans. Following this was a timely talk by Xavie Llor, MD, PhD, on when to suspect and how to test for the expanding definition of Lynch syndrome. Lin Chang, MD, delivered the penultimate clinical lecture on management of irritable bowel syndrome based on her many years of clinical expertise in this area. Finally, Gail Hecht, MD, AGAF, a former AGA president, summarized the exciting world of microbiome research from the recent annual Gut Microbiota for Health World Summit. All in all it was considered one of the best AGA Postgraduate courses by many and we look forward to even greater improvements for 2020.

This is a summary provided by the moderator of one of the AGA Postgraduate Course sessions held at DDW 2019. Dr. Katzka is professor of medicine and head of the Esophageal Interest Group at the Mayo Clinic in Rochester, Minn. He is on the advisory boards for Shire and Celgene.

CD4+ T-cell reactivation and interleukin (IL)–2 release are responsible for acute gastrointestinal symptoms when patients with celiac disease are exposed to gluten, according to investigators.

designer491/Thinkstock

Although T cells have been well studied in previous celiac disease research, clinical symptoms after acute gluten exposure have never been linked with specific cytokine changes, reported lead author Gautam Goel, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“If treated [celiac disease] patients, i.e., those following a strict [gluten-free diet], are exposed to gluten-containing food, they typically suffer from gastrointestinal reactions occurring 1 to 2 hours after the gluten exposure,” the investigators wrote in Science Advances. “There is currently no explanation for the acute gluten-induced symptoms seen in treated [celiac disease] patients.”

The current study was prompted by two phase 1 trials involving the therapeutic vaccine Nexvax2, which uses peptide fragments of gluten proteins to desensitize celiac patients to gluten, the investigators explained. During those trials, intradermal injections of Nexvax2 above a certain dose threshold led to gastrointestinal symptoms within 2-5 hours, but not injection site reactions, which would have been indicative of a cutaneous response to recall antigen.

“Our observations from these phase 1 studies led us to hypothesize that cytokine release occurs following natural gluten exposure and could be used to implicate which arms of the immune system drive early symptoms.”

Of the 28 patients in the two trials, all underwent intradermal testing, while 19 also participated in an oral gluten challenge. Following intradermal injection of gluten peptides, patients exhibited gastrointestinal symptoms, along with coordinated elevations of least 15 plasma cytokines; most significantly IL-2, MCP-1, IL-8, IL-10, MIP-1beta, IP-10, and eotaxin. The first cytokines to respond to injection were IL-2 and IL-8, rising within 2 hours, prior to symptoms. At 4 hours, when symptoms were present, peak IL-2 elevations were most dramatic, with a 272-fold elevation, followed by IL-8 (11-fold) and IL-10 (1.2-fold).

“IL-2 is both the earliest and most sensitive marker for the coordinated cytokine release that was almost universal in HLA-DQ2.5 + [celiac disease] patients administered gluten peptides,” the investigators wrote.

Similar to intradermal testing, oral challenge with gluten caused IL-2, IL-8, and IL-10 to elevate within 2 hours, and peak within 4-6 hours. Again, IL-2 was most sensitive, with a 15-fold increase at 4 hours. This increase in IL-2 correlated with IL-8 and IL-10 elevations, although IL-2 increases were at least six times greater than the other two cytokines.

“Together, the serum cytokine profile following gluten ingestion is less prominent but qualitatively similar and over a corresponding time course to that after injecting gluten peptides, which is consistent with activated CD4+ T cells being the driver of cytokine release in both scenarios,” the investigators wrote.

Further testing showed that, after gluten challenge, plasma levels of IL-2, IL-8, and IL-10 negatively correlated with duodenal villous height-to-crypt depth ratios. In addition, high levels of IL-2 correlated with severe nausea and vomiting, adding to the evidence that celiac symptoms were linked with specific cytokine elevations.

“The link between immune activation and symptoms was further strengthened by showing that postdose symptoms and cytokine release were both lessened after three weekly doses and absent after 16 twice-weekly injections of gluten peptides,” the investigators wrote. “These findings are consistent with the difference in severity of symptoms after gluten ingestion compared to gluten peptide injection being related to potency of the antigen challenge and T-cell activation measured by circulating IL-2 concentration at 4 hours.”

Even though IL-2 elevations appeared to drive celiac symptoms, the source of IL-2 was initially unknown. “Activated T cells are the primary source of IL-2, but [dendritic cells] can also secrete IL-2 following ligation of specific pathogen recognition receptors; mast cells also secrete IL-2 following exposure to IL-33 or IL-9,” the investigators explained. Still, CD4+ T cells are known to be key players in celiac disease, and the timing and magnitude of IL-2 release made T cells the most likely candidates. To test this hypothesis, the investigators collected blood from patients 6 days after gluten food challenge and incubated these samples for 24 hours with gluten peptides. Results of this test suggested that gluten-specific CD4+ T cells were the most likely source of IL-2.

The connection between particular cytokines and gastrointestinal symptoms is now supported with evidence; however, the investigators pointed out that a relationship between cytokines and other symptoms of celiac disease remains to be seen. “Whether cytokines elevated in blood after injecting gluten peptides or ingesting gluten have any direct extraintestinal effects is unclear,” the investigators wrote. “Fatigue, headache, and ‘brain fog’ are the commonly reported extraintestinal symptoms in [celiac disease] patients. However, symptoms being focused on the upper gastrointestinal tract suggest that cytokines increased in blood have clinical and immunological effects that selectively affect the tissue from which they originate.”

“Future studies should test whether cytokine concentrations are substantially higher in gut mucosal tissue than in blood after gluten challenge or injection of gluten peptides and determine whether alterations in local cytokine levels are matched by immune and inflammatory cell infiltration,” the investigators wrote.

The study was supported by the University of Chicago Celiac Disease Center and the University of Oslo KG Jebsen Coeliac Disease Research Centre. The investigators reported additional relationships The investigators reported additional relationships with several government and nonprofit organizations. Multiple investigators are employees of ImmusanT, which is developing Nexvax2.

SOURCE: Goel G et al. Science Advances. 2019 Aug 7. doi: 10.1126/sciadv.aaw7756.

CD4+ T-cell reactivation and interleukin (IL)–2 release are responsible for acute gastrointestinal symptoms when patients with celiac disease are exposed to gluten, according to investigators.

designer491/Thinkstock

Although T cells have been well studied in previous celiac disease research, clinical symptoms after acute gluten exposure have never been linked with specific cytokine changes, reported lead author Gautam Goel, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“If treated [celiac disease] patients, i.e., those following a strict [gluten-free diet], are exposed to gluten-containing food, they typically suffer from gastrointestinal reactions occurring 1 to 2 hours after the gluten exposure,” the investigators wrote in Science Advances. “There is currently no explanation for the acute gluten-induced symptoms seen in treated [celiac disease] patients.”

The current study was prompted by two phase 1 trials involving the therapeutic vaccine Nexvax2, which uses peptide fragments of gluten proteins to desensitize celiac patients to gluten, the investigators explained. During those trials, intradermal injections of Nexvax2 above a certain dose threshold led to gastrointestinal symptoms within 2-5 hours, but not injection site reactions, which would have been indicative of a cutaneous response to recall antigen.

“Our observations from these phase 1 studies led us to hypothesize that cytokine release occurs following natural gluten exposure and could be used to implicate which arms of the immune system drive early symptoms.”

Of the 28 patients in the two trials, all underwent intradermal testing, while 19 also participated in an oral gluten challenge. Following intradermal injection of gluten peptides, patients exhibited gastrointestinal symptoms, along with coordinated elevations of least 15 plasma cytokines; most significantly IL-2, MCP-1, IL-8, IL-10, MIP-1beta, IP-10, and eotaxin. The first cytokines to respond to injection were IL-2 and IL-8, rising within 2 hours, prior to symptoms. At 4 hours, when symptoms were present, peak IL-2 elevations were most dramatic, with a 272-fold elevation, followed by IL-8 (11-fold) and IL-10 (1.2-fold).

“IL-2 is both the earliest and most sensitive marker for the coordinated cytokine release that was almost universal in HLA-DQ2.5 + [celiac disease] patients administered gluten peptides,” the investigators wrote.

Similar to intradermal testing, oral challenge with gluten caused IL-2, IL-8, and IL-10 to elevate within 2 hours, and peak within 4-6 hours. Again, IL-2 was most sensitive, with a 15-fold increase at 4 hours. This increase in IL-2 correlated with IL-8 and IL-10 elevations, although IL-2 increases were at least six times greater than the other two cytokines.

“Together, the serum cytokine profile following gluten ingestion is less prominent but qualitatively similar and over a corresponding time course to that after injecting gluten peptides, which is consistent with activated CD4+ T cells being the driver of cytokine release in both scenarios,” the investigators wrote.

Further testing showed that, after gluten challenge, plasma levels of IL-2, IL-8, and IL-10 negatively correlated with duodenal villous height-to-crypt depth ratios. In addition, high levels of IL-2 correlated with severe nausea and vomiting, adding to the evidence that celiac symptoms were linked with specific cytokine elevations.

“The link between immune activation and symptoms was further strengthened by showing that postdose symptoms and cytokine release were both lessened after three weekly doses and absent after 16 twice-weekly injections of gluten peptides,” the investigators wrote. “These findings are consistent with the difference in severity of symptoms after gluten ingestion compared to gluten peptide injection being related to potency of the antigen challenge and T-cell activation measured by circulating IL-2 concentration at 4 hours.”

Even though IL-2 elevations appeared to drive celiac symptoms, the source of IL-2 was initially unknown. “Activated T cells are the primary source of IL-2, but [dendritic cells] can also secrete IL-2 following ligation of specific pathogen recognition receptors; mast cells also secrete IL-2 following exposure to IL-33 or IL-9,” the investigators explained. Still, CD4+ T cells are known to be key players in celiac disease, and the timing and magnitude of IL-2 release made T cells the most likely candidates. To test this hypothesis, the investigators collected blood from patients 6 days after gluten food challenge and incubated these samples for 24 hours with gluten peptides. Results of this test suggested that gluten-specific CD4+ T cells were the most likely source of IL-2.

The connection between particular cytokines and gastrointestinal symptoms is now supported with evidence; however, the investigators pointed out that a relationship between cytokines and other symptoms of celiac disease remains to be seen. “Whether cytokines elevated in blood after injecting gluten peptides or ingesting gluten have any direct extraintestinal effects is unclear,” the investigators wrote. “Fatigue, headache, and ‘brain fog’ are the commonly reported extraintestinal symptoms in [celiac disease] patients. However, symptoms being focused on the upper gastrointestinal tract suggest that cytokines increased in blood have clinical and immunological effects that selectively affect the tissue from which they originate.”

“Future studies should test whether cytokine concentrations are substantially higher in gut mucosal tissue than in blood after gluten challenge or injection of gluten peptides and determine whether alterations in local cytokine levels are matched by immune and inflammatory cell infiltration,” the investigators wrote.

The study was supported by the University of Chicago Celiac Disease Center and the University of Oslo KG Jebsen Coeliac Disease Research Centre. The investigators reported additional relationships The investigators reported additional relationships with several government and nonprofit organizations. Multiple investigators are employees of ImmusanT, which is developing Nexvax2.

SOURCE: Goel G et al. Science Advances. 2019 Aug 7. doi: 10.1126/sciadv.aaw7756.

CD4+ T-cell reactivation and interleukin (IL)–2 release are responsible for acute gastrointestinal symptoms when patients with celiac disease are exposed to gluten, according to investigators.

designer491/Thinkstock

Although T cells have been well studied in previous celiac disease research, clinical symptoms after acute gluten exposure have never been linked with specific cytokine changes, reported lead author Gautam Goel, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“If treated [celiac disease] patients, i.e., those following a strict [gluten-free diet], are exposed to gluten-containing food, they typically suffer from gastrointestinal reactions occurring 1 to 2 hours after the gluten exposure,” the investigators wrote in Science Advances. “There is currently no explanation for the acute gluten-induced symptoms seen in treated [celiac disease] patients.”

The current study was prompted by two phase 1 trials involving the therapeutic vaccine Nexvax2, which uses peptide fragments of gluten proteins to desensitize celiac patients to gluten, the investigators explained. During those trials, intradermal injections of Nexvax2 above a certain dose threshold led to gastrointestinal symptoms within 2-5 hours, but not injection site reactions, which would have been indicative of a cutaneous response to recall antigen.

“Our observations from these phase 1 studies led us to hypothesize that cytokine release occurs following natural gluten exposure and could be used to implicate which arms of the immune system drive early symptoms.”

Of the 28 patients in the two trials, all underwent intradermal testing, while 19 also participated in an oral gluten challenge. Following intradermal injection of gluten peptides, patients exhibited gastrointestinal symptoms, along with coordinated elevations of least 15 plasma cytokines; most significantly IL-2, MCP-1, IL-8, IL-10, MIP-1beta, IP-10, and eotaxin. The first cytokines to respond to injection were IL-2 and IL-8, rising within 2 hours, prior to symptoms. At 4 hours, when symptoms were present, peak IL-2 elevations were most dramatic, with a 272-fold elevation, followed by IL-8 (11-fold) and IL-10 (1.2-fold).

“IL-2 is both the earliest and most sensitive marker for the coordinated cytokine release that was almost universal in HLA-DQ2.5 + [celiac disease] patients administered gluten peptides,” the investigators wrote.

Similar to intradermal testing, oral challenge with gluten caused IL-2, IL-8, and IL-10 to elevate within 2 hours, and peak within 4-6 hours. Again, IL-2 was most sensitive, with a 15-fold increase at 4 hours. This increase in IL-2 correlated with IL-8 and IL-10 elevations, although IL-2 increases were at least six times greater than the other two cytokines.

“Together, the serum cytokine profile following gluten ingestion is less prominent but qualitatively similar and over a corresponding time course to that after injecting gluten peptides, which is consistent with activated CD4+ T cells being the driver of cytokine release in both scenarios,” the investigators wrote.

Further testing showed that, after gluten challenge, plasma levels of IL-2, IL-8, and IL-10 negatively correlated with duodenal villous height-to-crypt depth ratios. In addition, high levels of IL-2 correlated with severe nausea and vomiting, adding to the evidence that celiac symptoms were linked with specific cytokine elevations.

“The link between immune activation and symptoms was further strengthened by showing that postdose symptoms and cytokine release were both lessened after three weekly doses and absent after 16 twice-weekly injections of gluten peptides,” the investigators wrote. “These findings are consistent with the difference in severity of symptoms after gluten ingestion compared to gluten peptide injection being related to potency of the antigen challenge and T-cell activation measured by circulating IL-2 concentration at 4 hours.”

Even though IL-2 elevations appeared to drive celiac symptoms, the source of IL-2 was initially unknown. “Activated T cells are the primary source of IL-2, but [dendritic cells] can also secrete IL-2 following ligation of specific pathogen recognition receptors; mast cells also secrete IL-2 following exposure to IL-33 or IL-9,” the investigators explained. Still, CD4+ T cells are known to be key players in celiac disease, and the timing and magnitude of IL-2 release made T cells the most likely candidates. To test this hypothesis, the investigators collected blood from patients 6 days after gluten food challenge and incubated these samples for 24 hours with gluten peptides. Results of this test suggested that gluten-specific CD4+ T cells were the most likely source of IL-2.

The connection between particular cytokines and gastrointestinal symptoms is now supported with evidence; however, the investigators pointed out that a relationship between cytokines and other symptoms of celiac disease remains to be seen. “Whether cytokines elevated in blood after injecting gluten peptides or ingesting gluten have any direct extraintestinal effects is unclear,” the investigators wrote. “Fatigue, headache, and ‘brain fog’ are the commonly reported extraintestinal symptoms in [celiac disease] patients. However, symptoms being focused on the upper gastrointestinal tract suggest that cytokines increased in blood have clinical and immunological effects that selectively affect the tissue from which they originate.”

“Future studies should test whether cytokine concentrations are substantially higher in gut mucosal tissue than in blood after gluten challenge or injection of gluten peptides and determine whether alterations in local cytokine levels are matched by immune and inflammatory cell infiltration,” the investigators wrote.

The study was supported by the University of Chicago Celiac Disease Center and the University of Oslo KG Jebsen Coeliac Disease Research Centre. The investigators reported additional relationships The investigators reported additional relationships with several government and nonprofit organizations. Multiple investigators are employees of ImmusanT, which is developing Nexvax2.

SOURCE: Goel G et al. Science Advances. 2019 Aug 7. doi: 10.1126/sciadv.aaw7756.

Vitamin D supplementation may lead to significant improvements in ulcerative colitis (UC), based on a placebo-controlled trial involving 60 patients with active disease.

Those who achieved vitamin D levels greater than 40 ng/mL were most likely to benefit, reported lead author Rizwan Ahamed Z, MD, of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues. They noted that the findings contribute much-needed clinical data to a largely theoretical subject area.

“[T]he discovery of vitamin D receptors on lymphocytes, monocytes, and dendritic cells initiated various studies which have highlighted the role of vitamin D in regulating gut mucosal immunity and gut barrier,” the investigators wrote in Journal of Clinical Gastroenterology. “In experimental interleukin (IL)-10 knockout mice models, vitamin D deficiency was found to result in severe colitis, progressive wasting, and high mortality. However, vitamin D supplementation not only prevented but also ameliorated symptoms of colitis in the mice model.”

Human studies have revealed similar associations between vitamin D supplementation and inflammatory bowel disease, such as a study by Jørgensen and colleagues that found a lower risk of relapse in Crohn’s disease, and another by Sharifi and colleagues that showed injectable vitamin D could reduce erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with UC. Still, the investigators suggested that more clinical data are needed, particularly for outcomes after vitamin D therapy. In addition to providing such data, the present trial was also the first of its kind to test oral nano vitamin D₃, which may have better bioavailability than conventional supplements.

The investigators initially recruited 110 patients with active UC who had an ulcerative colitis disease activity index (UCDAI) of at least 3. After screening, 50 patients were excluded because they had vitamin D levels greater than 40 ng/mL, were already taking a vitamin D supplement, had severe UC requiring hospitalization, or exhibited severe systemic illness. The remaining 60 patients were randomized in a 1:1 ratio to receive either 60,000 IU nano vitamin D₃ once daily for 8 days, or placebo. Disease parameters, which were measured at baseline and then again at 4 weeks, included UCDAI, ESR, CRP, and fecal calprotectin. The primary outcome was response, defined as a UCDAI reduction of at least 3 points. Secondary outcome measures included stool frequency, stool consistency, and remission (UCDAI less than 3); in addition, the investigators evaluated histologic, endoscopic, fecal, and serum inflammatory markers.

The majority of patients in the study were men (60%), with a mean age of 36 years. Most patients had moderate UC (73.3%), while smaller proportions had severe (18%) or mild (8%) disease. All patients were taking a 5-aminosalicylic acid oral compound and some (16.6%) were also taking azathioprine. At baseline, the mean vitamin D level was 14 ng/mL. Most patients (70%) were diagnosed with vitamin D deficiency, based on measurements below 20 ng/mL. The remaining patients were diagnosed with insufficiency (13%; 20-30 ng/mL) or suboptimal levels (17%; 30-40 ng/mL).

From baseline to 4-week follow-up, median vitamin D level in the supplement group increased from 15.4 to 40.83 ng/mL, compared with a much smaller increase in the placebo group, from 13.45 to 18.85 ng/mL. Compared with the placebo group, significantly more patients given nano vitamin D₃ achieved a UCDAI 3-point reduction (53% vs 13%; P = .001); this translated to a Pearson correlation coefficient (rho) of –0.713, between vitamin D level and UCDAI. Similar, albeit less strong, inverse relationships were detected between vitamin D level and CRP (rho = −0.603) and calprotectin (rho = −0.368).

Benefits observed in the supplement group also extended to stool frequency, stool consistency, and histologic measures. Those who achieved a vitamin D level greater than 40 ng/mL were 4 times more likely to have a UCDAI 3-point reduction than those who did not meet the same criteria (80% vs 20%; P = .038). Independent predictors of response included baseline histologic activity (odds ratio, 1.92), and to a greater extent, vitamin D supplementation (OR, 9.17). No patients achieved remission, which the investigators attributed to the relatively short study duration.

Minor, self-limiting side effects occurred in 13.3% and 10% of patients given the vitamin D supplement and placebo, respectively.

“[T]he present study showed significant improvement in all inflammatory parameters of the disease including clinical, endoscopic, histopathologic, and serum and fecal markers of inflammation, all of which paralleled each other in showing [the benefit of] oral nano vitamin D supplementation,” the investigators concluded. They advised that larger, longer-term studies are needed before the findings can be generalized to all patients with active UC.

The investigators disclosed no external funding or conflicts of interest.

SOURCE: Ahamed R et al. J Clin Gastroenterol. 2019 Jul 24. doi: 10.1097/MCG.0000000000001233.

Vitamin D supplementation may lead to significant improvements in ulcerative colitis (UC), based on a placebo-controlled trial involving 60 patients with active disease.

Those who achieved vitamin D levels greater than 40 ng/mL were most likely to benefit, reported lead author Rizwan Ahamed Z, MD, of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues. They noted that the findings contribute much-needed clinical data to a largely theoretical subject area.

“[T]he discovery of vitamin D receptors on lymphocytes, monocytes, and dendritic cells initiated various studies which have highlighted the role of vitamin D in regulating gut mucosal immunity and gut barrier,” the investigators wrote in Journal of Clinical Gastroenterology. “In experimental interleukin (IL)-10 knockout mice models, vitamin D deficiency was found to result in severe colitis, progressive wasting, and high mortality. However, vitamin D supplementation not only prevented but also ameliorated symptoms of colitis in the mice model.”

Human studies have revealed similar associations between vitamin D supplementation and inflammatory bowel disease, such as a study by Jørgensen and colleagues that found a lower risk of relapse in Crohn’s disease, and another by Sharifi and colleagues that showed injectable vitamin D could reduce erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with UC. Still, the investigators suggested that more clinical data are needed, particularly for outcomes after vitamin D therapy. In addition to providing such data, the present trial was also the first of its kind to test oral nano vitamin D₃, which may have better bioavailability than conventional supplements.

The investigators initially recruited 110 patients with active UC who had an ulcerative colitis disease activity index (UCDAI) of at least 3. After screening, 50 patients were excluded because they had vitamin D levels greater than 40 ng/mL, were already taking a vitamin D supplement, had severe UC requiring hospitalization, or exhibited severe systemic illness. The remaining 60 patients were randomized in a 1:1 ratio to receive either 60,000 IU nano vitamin D₃ once daily for 8 days, or placebo. Disease parameters, which were measured at baseline and then again at 4 weeks, included UCDAI, ESR, CRP, and fecal calprotectin. The primary outcome was response, defined as a UCDAI reduction of at least 3 points. Secondary outcome measures included stool frequency, stool consistency, and remission (UCDAI less than 3); in addition, the investigators evaluated histologic, endoscopic, fecal, and serum inflammatory markers.

The majority of patients in the study were men (60%), with a mean age of 36 years. Most patients had moderate UC (73.3%), while smaller proportions had severe (18%) or mild (8%) disease. All patients were taking a 5-aminosalicylic acid oral compound and some (16.6%) were also taking azathioprine. At baseline, the mean vitamin D level was 14 ng/mL. Most patients (70%) were diagnosed with vitamin D deficiency, based on measurements below 20 ng/mL. The remaining patients were diagnosed with insufficiency (13%; 20-30 ng/mL) or suboptimal levels (17%; 30-40 ng/mL).

From baseline to 4-week follow-up, median vitamin D level in the supplement group increased from 15.4 to 40.83 ng/mL, compared with a much smaller increase in the placebo group, from 13.45 to 18.85 ng/mL. Compared with the placebo group, significantly more patients given nano vitamin D₃ achieved a UCDAI 3-point reduction (53% vs 13%; P = .001); this translated to a Pearson correlation coefficient (rho) of –0.713, between vitamin D level and UCDAI. Similar, albeit less strong, inverse relationships were detected between vitamin D level and CRP (rho = −0.603) and calprotectin (rho = −0.368).

Benefits observed in the supplement group also extended to stool frequency, stool consistency, and histologic measures. Those who achieved a vitamin D level greater than 40 ng/mL were 4 times more likely to have a UCDAI 3-point reduction than those who did not meet the same criteria (80% vs 20%; P = .038). Independent predictors of response included baseline histologic activity (odds ratio, 1.92), and to a greater extent, vitamin D supplementation (OR, 9.17). No patients achieved remission, which the investigators attributed to the relatively short study duration.

Minor, self-limiting side effects occurred in 13.3% and 10% of patients given the vitamin D supplement and placebo, respectively.

“[T]he present study showed significant improvement in all inflammatory parameters of the disease including clinical, endoscopic, histopathologic, and serum and fecal markers of inflammation, all of which paralleled each other in showing [the benefit of] oral nano vitamin D supplementation,” the investigators concluded. They advised that larger, longer-term studies are needed before the findings can be generalized to all patients with active UC.

The investigators disclosed no external funding or conflicts of interest.

SOURCE: Ahamed R et al. J Clin Gastroenterol. 2019 Jul 24. doi: 10.1097/MCG.0000000000001233.

Vitamin D supplementation may lead to significant improvements in ulcerative colitis (UC), based on a placebo-controlled trial involving 60 patients with active disease.

Those who achieved vitamin D levels greater than 40 ng/mL were most likely to benefit, reported lead author Rizwan Ahamed Z, MD, of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues. They noted that the findings contribute much-needed clinical data to a largely theoretical subject area.

“[T]he discovery of vitamin D receptors on lymphocytes, monocytes, and dendritic cells initiated various studies which have highlighted the role of vitamin D in regulating gut mucosal immunity and gut barrier,” the investigators wrote in Journal of Clinical Gastroenterology. “In experimental interleukin (IL)-10 knockout mice models, vitamin D deficiency was found to result in severe colitis, progressive wasting, and high mortality. However, vitamin D supplementation not only prevented but also ameliorated symptoms of colitis in the mice model.”

Human studies have revealed similar associations between vitamin D supplementation and inflammatory bowel disease, such as a study by Jørgensen and colleagues that found a lower risk of relapse in Crohn’s disease, and another by Sharifi and colleagues that showed injectable vitamin D could reduce erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with UC. Still, the investigators suggested that more clinical data are needed, particularly for outcomes after vitamin D therapy. In addition to providing such data, the present trial was also the first of its kind to test oral nano vitamin D₃, which may have better bioavailability than conventional supplements.

The investigators initially recruited 110 patients with active UC who had an ulcerative colitis disease activity index (UCDAI) of at least 3. After screening, 50 patients were excluded because they had vitamin D levels greater than 40 ng/mL, were already taking a vitamin D supplement, had severe UC requiring hospitalization, or exhibited severe systemic illness. The remaining 60 patients were randomized in a 1:1 ratio to receive either 60,000 IU nano vitamin D₃ once daily for 8 days, or placebo. Disease parameters, which were measured at baseline and then again at 4 weeks, included UCDAI, ESR, CRP, and fecal calprotectin. The primary outcome was response, defined as a UCDAI reduction of at least 3 points. Secondary outcome measures included stool frequency, stool consistency, and remission (UCDAI less than 3); in addition, the investigators evaluated histologic, endoscopic, fecal, and serum inflammatory markers.

The majority of patients in the study were men (60%), with a mean age of 36 years. Most patients had moderate UC (73.3%), while smaller proportions had severe (18%) or mild (8%) disease. All patients were taking a 5-aminosalicylic acid oral compound and some (16.6%) were also taking azathioprine. At baseline, the mean vitamin D level was 14 ng/mL. Most patients (70%) were diagnosed with vitamin D deficiency, based on measurements below 20 ng/mL. The remaining patients were diagnosed with insufficiency (13%; 20-30 ng/mL) or suboptimal levels (17%; 30-40 ng/mL).

From baseline to 4-week follow-up, median vitamin D level in the supplement group increased from 15.4 to 40.83 ng/mL, compared with a much smaller increase in the placebo group, from 13.45 to 18.85 ng/mL. Compared with the placebo group, significantly more patients given nano vitamin D₃ achieved a UCDAI 3-point reduction (53% vs 13%; P = .001); this translated to a Pearson correlation coefficient (rho) of –0.713, between vitamin D level and UCDAI. Similar, albeit less strong, inverse relationships were detected between vitamin D level and CRP (rho = −0.603) and calprotectin (rho = −0.368).

Benefits observed in the supplement group also extended to stool frequency, stool consistency, and histologic measures. Those who achieved a vitamin D level greater than 40 ng/mL were 4 times more likely to have a UCDAI 3-point reduction than those who did not meet the same criteria (80% vs 20%; P = .038). Independent predictors of response included baseline histologic activity (odds ratio, 1.92), and to a greater extent, vitamin D supplementation (OR, 9.17). No patients achieved remission, which the investigators attributed to the relatively short study duration.

Minor, self-limiting side effects occurred in 13.3% and 10% of patients given the vitamin D supplement and placebo, respectively.

“[T]he present study showed significant improvement in all inflammatory parameters of the disease including clinical, endoscopic, histopathologic, and serum and fecal markers of inflammation, all of which paralleled each other in showing [the benefit of] oral nano vitamin D supplementation,” the investigators concluded. They advised that larger, longer-term studies are needed before the findings can be generalized to all patients with active UC.

The investigators disclosed no external funding or conflicts of interest.

SOURCE: Ahamed R et al. J Clin Gastroenterol. 2019 Jul 24. doi: 10.1097/MCG.0000000000001233.

A new clinical practice guideline for the treatment of luminal Crohn’s disease (CD) in children has been released by the Canadian Association of Gastroenterology (CAG).

The new guideline provides evidence-based recommendations regarding optimal medical treatment strategies for achieving clinical remission based on a multi-item assessment of disease activity in pediatric patients with luminal CD. The guideline does not address surgical management, diagnosis, psychosocial therapies, preventative health considerations, or growth monitoring.

“The implications of inadequately treated CD are of particular importance in children because of the potentially serious and irreversible consequences,” wrote David R. Mack, MD, of the University of Ottawa and associates. Dr. Mack is the lead author of the pediatric practice guideline copublished in Gastroenterology and the Journal of the Canadian Association of Gastroenterology.

The consensus group reached its recommendations based on a systematic review of the literature for studies related to the medical treatment of pediatric CD. The majority of studies were randomized trials conducted in adults with CD.

“Evidence of efficacy of specific treatments in achieving mucosal healing is limited; therefore, “complete” or “deep” remission (clinical remission plus mucosal healing) was not the chosen primary outcome,” the guideline authors wrote.

The panel recommended that corticosteroids can be used as induction therapy in children with moderate to severe disease. Moreover, budesonide may be an appropriate alternative for induction therapy in patients with mild to moderate CD.

In contrast, the group recommended against the use of corticosteroids as maintenance therapy, largely because of adverse events reported with long-term use.

At diagnosis or initial stages of severe disease, as well as in patients who have failed with immunosuppressant and corticosteroid induction strategies, enteral nutrition should be used exclusively for induction therapy. In addition, anti–tumor necrosis factor biologics are an appropriate option for induction and maintenance therapy in these patients, according to the guideline.

“The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy,” they wrote.

With respect to cannabis-based products, the panel made a strong recommendation against the use of these agents in all pediatric patients.

In terms of assessment, the team recommended that patients in clinical remission receiving methotrexate or a thiopurine agent as maintenance therapy should be evaluated for mucosal healing within 1 year of therapy initiation.

No consensus was reached on the adjuvant use of immunosuppressants during initiation therapy with a biologic drug, but the consensus panel recommended against the use of thiopurine combinations in male patients. Furthermore, no consensus was reached on the role of vedolizumab or antibiotics for induction or maintenance therapy, methotrexate for induction therapy, and the function of aminosalicylates in patients with mild CD.

The panel highlighted the importance of incorporating patient perspectives into treatment decision making.

“It is hoped that the available information will enhance the discussion between the clinician and the patient and enable the patient to make an evidence-based informed decision.”

The expert consensus was made up of 15 voting members that consisted of pediatric gastroenterologists throughout the United States and Canada, with expertise in several domains, including clinical epidemiology, nutrition, health services research, and patient engagement.

Quality of evidence and risk of bias was assessed using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) criteria. The quality of evidence for each consensus statement was denoted as either high, moderate, low, or very low, based on the criteria.

The consensus statements were finalized at an in-person meeting conducted in Toronto in October 2017.

The guideline was supported through grant funding provided by AbbVie and Takeda. The authors reported financial affiliations with AbbVie and Takeda, as well as Janssen, Nestle Health Sciences, Shire, and several others.

SOURCE: Mack DR et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.022.

A new clinical practice guideline for the treatment of luminal Crohn’s disease (CD) in children has been released by the Canadian Association of Gastroenterology (CAG).

The new guideline provides evidence-based recommendations regarding optimal medical treatment strategies for achieving clinical remission based on a multi-item assessment of disease activity in pediatric patients with luminal CD. The guideline does not address surgical management, diagnosis, psychosocial therapies, preventative health considerations, or growth monitoring.

“The implications of inadequately treated CD are of particular importance in children because of the potentially serious and irreversible consequences,” wrote David R. Mack, MD, of the University of Ottawa and associates. Dr. Mack is the lead author of the pediatric practice guideline copublished in Gastroenterology and the Journal of the Canadian Association of Gastroenterology.

The consensus group reached its recommendations based on a systematic review of the literature for studies related to the medical treatment of pediatric CD. The majority of studies were randomized trials conducted in adults with CD.

“Evidence of efficacy of specific treatments in achieving mucosal healing is limited; therefore, “complete” or “deep” remission (clinical remission plus mucosal healing) was not the chosen primary outcome,” the guideline authors wrote.

The panel recommended that corticosteroids can be used as induction therapy in children with moderate to severe disease. Moreover, budesonide may be an appropriate alternative for induction therapy in patients with mild to moderate CD.

In contrast, the group recommended against the use of corticosteroids as maintenance therapy, largely because of adverse events reported with long-term use.

At diagnosis or initial stages of severe disease, as well as in patients who have failed with immunosuppressant and corticosteroid induction strategies, enteral nutrition should be used exclusively for induction therapy. In addition, anti–tumor necrosis factor biologics are an appropriate option for induction and maintenance therapy in these patients, according to the guideline.

“The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy,” they wrote.

With respect to cannabis-based products, the panel made a strong recommendation against the use of these agents in all pediatric patients.

In terms of assessment, the team recommended that patients in clinical remission receiving methotrexate or a thiopurine agent as maintenance therapy should be evaluated for mucosal healing within 1 year of therapy initiation.

No consensus was reached on the adjuvant use of immunosuppressants during initiation therapy with a biologic drug, but the consensus panel recommended against the use of thiopurine combinations in male patients. Furthermore, no consensus was reached on the role of vedolizumab or antibiotics for induction or maintenance therapy, methotrexate for induction therapy, and the function of aminosalicylates in patients with mild CD.

The panel highlighted the importance of incorporating patient perspectives into treatment decision making.

“It is hoped that the available information will enhance the discussion between the clinician and the patient and enable the patient to make an evidence-based informed decision.”

The expert consensus was made up of 15 voting members that consisted of pediatric gastroenterologists throughout the United States and Canada, with expertise in several domains, including clinical epidemiology, nutrition, health services research, and patient engagement.

Quality of evidence and risk of bias was assessed using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) criteria. The quality of evidence for each consensus statement was denoted as either high, moderate, low, or very low, based on the criteria.

The consensus statements were finalized at an in-person meeting conducted in Toronto in October 2017.

The guideline was supported through grant funding provided by AbbVie and Takeda. The authors reported financial affiliations with AbbVie and Takeda, as well as Janssen, Nestle Health Sciences, Shire, and several others.

SOURCE: Mack DR et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.022.

A new clinical practice guideline for the treatment of luminal Crohn’s disease (CD) in children has been released by the Canadian Association of Gastroenterology (CAG).

The new guideline provides evidence-based recommendations regarding optimal medical treatment strategies for achieving clinical remission based on a multi-item assessment of disease activity in pediatric patients with luminal CD. The guideline does not address surgical management, diagnosis, psychosocial therapies, preventative health considerations, or growth monitoring.

“The implications of inadequately treated CD are of particular importance in children because of the potentially serious and irreversible consequences,” wrote David R. Mack, MD, of the University of Ottawa and associates. Dr. Mack is the lead author of the pediatric practice guideline copublished in Gastroenterology and the Journal of the Canadian Association of Gastroenterology.

The consensus group reached its recommendations based on a systematic review of the literature for studies related to the medical treatment of pediatric CD. The majority of studies were randomized trials conducted in adults with CD.

“Evidence of efficacy of specific treatments in achieving mucosal healing is limited; therefore, “complete” or “deep” remission (clinical remission plus mucosal healing) was not the chosen primary outcome,” the guideline authors wrote.

The panel recommended that corticosteroids can be used as induction therapy in children with moderate to severe disease. Moreover, budesonide may be an appropriate alternative for induction therapy in patients with mild to moderate CD.

In contrast, the group recommended against the use of corticosteroids as maintenance therapy, largely because of adverse events reported with long-term use.

At diagnosis or initial stages of severe disease, as well as in patients who have failed with immunosuppressant and corticosteroid induction strategies, enteral nutrition should be used exclusively for induction therapy. In addition, anti–tumor necrosis factor biologics are an appropriate option for induction and maintenance therapy in these patients, according to the guideline.

“The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy,” they wrote.

With respect to cannabis-based products, the panel made a strong recommendation against the use of these agents in all pediatric patients.

In terms of assessment, the team recommended that patients in clinical remission receiving methotrexate or a thiopurine agent as maintenance therapy should be evaluated for mucosal healing within 1 year of therapy initiation.

No consensus was reached on the adjuvant use of immunosuppressants during initiation therapy with a biologic drug, but the consensus panel recommended against the use of thiopurine combinations in male patients. Furthermore, no consensus was reached on the role of vedolizumab or antibiotics for induction or maintenance therapy, methotrexate for induction therapy, and the function of aminosalicylates in patients with mild CD.

The panel highlighted the importance of incorporating patient perspectives into treatment decision making.

“It is hoped that the available information will enhance the discussion between the clinician and the patient and enable the patient to make an evidence-based informed decision.”

The expert consensus was made up of 15 voting members that consisted of pediatric gastroenterologists throughout the United States and Canada, with expertise in several domains, including clinical epidemiology, nutrition, health services research, and patient engagement.

Quality of evidence and risk of bias was assessed using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) criteria. The quality of evidence for each consensus statement was denoted as either high, moderate, low, or very low, based on the criteria.

The consensus statements were finalized at an in-person meeting conducted in Toronto in October 2017.

The guideline was supported through grant funding provided by AbbVie and Takeda. The authors reported financial affiliations with AbbVie and Takeda, as well as Janssen, Nestle Health Sciences, Shire, and several others.

SOURCE: Mack DR et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.022.

The Canadian Association of Gastroenterology has released a new clinical practice guideline for the treatment of luminal Crohn’s disease (CD) in adults.

“In the last decade, treatment paradigms have changed, recognizing that certain clinical parameters carry an increased risk of progressive and disabling disease,” wrote Remo Panaccione, MD, of the University of Calgary (Canada) and collaborators. Dr. Panaccione is the lead author of this practice guideline copublished in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.

The expert consensus panel consisted of 20 voting members, including both academic and community gastroenterologists, in addition to a specialist nurse practitioner. Other nonvoting members included two GRADE experts, lay observers, and a patient representative.

The panel systematically reviewed the body of literature for studies related to the management of CD in adults. After applying the search criteria, the team found that the majority of evidence was extracted from systematic reviews and meta-analyses of randomized trials.

Quality of evidence and risk of bias was assessed using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) methodology. The quality of evidence for each consensus statement was classified as either high, moderate, low, or very low, based on the methodology’s criteria.

The consensus statements were finalized at a face-to-face meeting in Toronto held in September 2016. Prior to completion, a web-based system was used to allow for anonymous voting on level of agreement for each consensus statement.

The new guideline provides evidence-based recommendations about optimal treatment approaches for patients with mild to severe active luminal CD in an ambulatory setting, with particular focus on six major drug classes, including corticosteroids, biologic therapies, immunosuppressants, 5-aminosalicylate, antibiotics, and other therapies.

The consensus group recommended against the use of 5-aminosalicylate or antibiotics as induction or maintenance treatment strategies. Alternatively, they suggested that corticosteroids, including budesonide, could be used as induction therapy, but not as maintenance therapy.

“Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD,” they wrote.

With respect to immunosuppressive therapy, thiopurine agents could be an appropriate option for maintenance therapy in certain low-risk patients, but were not recommended as induction therapy, according to the guideline.

In patients who fail with conventional induction therapies, Dr. Panaccione and colleagues recommended that biological treatments, including ustekinumab, vedolizumab, and anti–tumor necrosis factor agents, could be used. No consensus was reached on the concomitant use of immunosuppressants and biologics.

In recent years, an increasing amount of evidence has emphasized the importance of mucosal healing as a key goal of therapy. In particular, the use of some therapies can result in mucosal healing and symptomatic improvement in certain patients with luminal CD.

In addition, the authors explained that mucosal healing has been linked to better clinical outcomes over the short and long term. As a result, the recommendations in the guideline target complete remission, defined as both endoscopic and symptomatic remission.

“The outcome assessed in most randomized controlled trials (RCTs) has been either symptomatic remission or symptomatic response, with only more contemporary clinical trials including endoscopic outcomes,” the guideline authors wrote.

For this reason, the GRADE criteria–based quality of evidence for some of the consensus statements had to be lowered, they noted.

The panel acknowledged the importance of incorporating patient perspectives into treatment decision making; however, they reported that many gaps in clinical practice still remain.

“In many instances, factors that influence patient decisions relating to therapy choice and goals of therapy are not the same as those of the treating clinician,” they wrote. “[Current] surveys indicate a discrepancy between patient and physician treatment goals.”

In response, the guideline authors highlighted the importance of improved patient-physician collaboration and patient education.

The guideline was supported through grant funding provided by AbbVie, Janssen, Pfizer, and Takeda. The authors reported financial affiliations with AbbVie, Amgen, Baxter, Janssen, Shire, Takeda, and several others.
 

SOURCE: Panaccione R et al. Clin Gastroenterol Hepatol. 2019 Mar 7. doi: 10.1016/j.cgh.2019.02.043.

The Canadian Association of Gastroenterology has released a new clinical practice guideline for the treatment of luminal Crohn’s disease (CD) in adults.

“In the last decade, treatment paradigms have changed, recognizing that certain clinical parameters carry an increased risk of progressive and disabling disease,” wrote Remo Panaccione, MD, of the University of Calgary (Canada) and collaborators. Dr. Panaccione is the lead author of this practice guideline copublished in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.

The expert consensus panel consisted of 20 voting members, including both academic and community gastroenterologists, in addition to a specialist nurse practitioner. Other nonvoting members included two GRADE experts, lay observers, and a patient representative.

The panel systematically reviewed the body of literature for studies related to the management of CD in adults. After applying the search criteria, the team found that the majority of evidence was extracted from systematic reviews and meta-analyses of randomized trials.

Quality of evidence and risk of bias was assessed using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) methodology. The quality of evidence for each consensus statement was classified as either high, moderate, low, or very low, based on the methodology’s criteria.

The consensus statements were finalized at a face-to-face meeting in Toronto held in September 2016. Prior to completion, a web-based system was used to allow for anonymous voting on level of agreement for each consensus statement.

The new guideline provides evidence-based recommendations about optimal treatment approaches for patients with mild to severe active luminal CD in an ambulatory setting, with particular focus on six major drug classes, including corticosteroids, biologic therapies, immunosuppressants, 5-aminosalicylate, antibiotics, and other therapies.

The consensus group recommended against the use of 5-aminosalicylate or antibiotics as induction or maintenance treatment strategies. Alternatively, they suggested that corticosteroids, including budesonide, could be used as induction therapy, but not as maintenance therapy.

“Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD,” they wrote.

With respect to immunosuppressive therapy, thiopurine agents could be an appropriate option for maintenance therapy in certain low-risk patients, but were not recommended as induction therapy, according to the guideline.

In patients who fail with conventional induction therapies, Dr. Panaccione and colleagues recommended that biological treatments, including ustekinumab, vedolizumab, and anti–tumor necrosis factor agents, could be used. No consensus was reached on the concomitant use of immunosuppressants and biologics.

In recent years, an increasing amount of evidence has emphasized the importance of mucosal healing as a key goal of therapy. In particular, the use of some therapies can result in mucosal healing and symptomatic improvement in certain patients with luminal CD.

In addition, the authors explained that mucosal healing has been linked to better clinical outcomes over the short and long term. As a result, the recommendations in the guideline target complete remission, defined as both endoscopic and symptomatic remission.

“The outcome assessed in most randomized controlled trials (RCTs) has been either symptomatic remission or symptomatic response, with only more contemporary clinical trials including endoscopic outcomes,” the guideline authors wrote.

For this reason, the GRADE criteria–based quality of evidence for some of the consensus statements had to be lowered, they noted.

The panel acknowledged the importance of incorporating patient perspectives into treatment decision making; however, they reported that many gaps in clinical practice still remain.

“In many instances, factors that influence patient decisions relating to therapy choice and goals of therapy are not the same as those of the treating clinician,” they wrote. “[Current] surveys indicate a discrepancy between patient and physician treatment goals.”

In response, the guideline authors highlighted the importance of improved patient-physician collaboration and patient education.

The guideline was supported through grant funding provided by AbbVie, Janssen, Pfizer, and Takeda. The authors reported financial affiliations with AbbVie, Amgen, Baxter, Janssen, Shire, Takeda, and several others.
 

SOURCE: Panaccione R et al. Clin Gastroenterol Hepatol. 2019 Mar 7. doi: 10.1016/j.cgh.2019.02.043.

The Canadian Association of Gastroenterology has released a new clinical practice guideline for the treatment of luminal Crohn’s disease (CD) in adults.

“In the last decade, treatment paradigms have changed, recognizing that certain clinical parameters carry an increased risk of progressive and disabling disease,” wrote Remo Panaccione, MD, of the University of Calgary (Canada) and collaborators. Dr. Panaccione is the lead author of this practice guideline copublished in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.

The expert consensus panel consisted of 20 voting members, including both academic and community gastroenterologists, in addition to a specialist nurse practitioner. Other nonvoting members included two GRADE experts, lay observers, and a patient representative.

The panel systematically reviewed the body of literature for studies related to the management of CD in adults. After applying the search criteria, the team found that the majority of evidence was extracted from systematic reviews and meta-analyses of randomized trials.

Quality of evidence and risk of bias was assessed using the GRADE (Grading of Recommendation Assessment, Development and Evaluation) methodology. The quality of evidence for each consensus statement was classified as either high, moderate, low, or very low, based on the methodology’s criteria.

The consensus statements were finalized at a face-to-face meeting in Toronto held in September 2016. Prior to completion, a web-based system was used to allow for anonymous voting on level of agreement for each consensus statement.

The new guideline provides evidence-based recommendations about optimal treatment approaches for patients with mild to severe active luminal CD in an ambulatory setting, with particular focus on six major drug classes, including corticosteroids, biologic therapies, immunosuppressants, 5-aminosalicylate, antibiotics, and other therapies.

The consensus group recommended against the use of 5-aminosalicylate or antibiotics as induction or maintenance treatment strategies. Alternatively, they suggested that corticosteroids, including budesonide, could be used as induction therapy, but not as maintenance therapy.

“Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD,” they wrote.

With respect to immunosuppressive therapy, thiopurine agents could be an appropriate option for maintenance therapy in certain low-risk patients, but were not recommended as induction therapy, according to the guideline.

In patients who fail with conventional induction therapies, Dr. Panaccione and colleagues recommended that biological treatments, including ustekinumab, vedolizumab, and anti–tumor necrosis factor agents, could be used. No consensus was reached on the concomitant use of immunosuppressants and biologics.

In recent years, an increasing amount of evidence has emphasized the importance of mucosal healing as a key goal of therapy. In particular, the use of some therapies can result in mucosal healing and symptomatic improvement in certain patients with luminal CD.

In addition, the authors explained that mucosal healing has been linked to better clinical outcomes over the short and long term. As a result, the recommendations in the guideline target complete remission, defined as both endoscopic and symptomatic remission.

“The outcome assessed in most randomized controlled trials (RCTs) has been either symptomatic remission or symptomatic response, with only more contemporary clinical trials including endoscopic outcomes,” the guideline authors wrote.

For this reason, the GRADE criteria–based quality of evidence for some of the consensus statements had to be lowered, they noted.

The panel acknowledged the importance of incorporating patient perspectives into treatment decision making; however, they reported that many gaps in clinical practice still remain.

“In many instances, factors that influence patient decisions relating to therapy choice and goals of therapy are not the same as those of the treating clinician,” they wrote. “[Current] surveys indicate a discrepancy between patient and physician treatment goals.”

In response, the guideline authors highlighted the importance of improved patient-physician collaboration and patient education.

The guideline was supported through grant funding provided by AbbVie, Janssen, Pfizer, and Takeda. The authors reported financial affiliations with AbbVie, Amgen, Baxter, Janssen, Shire, Takeda, and several others.
 

SOURCE: Panaccione R et al. Clin Gastroenterol Hepatol. 2019 Mar 7. doi: 10.1016/j.cgh.2019.02.043.

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.

Wikimedia Commons/FitzColinGerald/Creative Commons License

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.

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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.

Wikimedia Commons/FitzColinGerald/Creative Commons License

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.

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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.

Wikimedia Commons/FitzColinGerald/Creative Commons License

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.

[email protected]

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

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.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

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.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

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.