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AI-guided colonoscopy results in more small adenomas detected
according to results from a large meta-analysis of randomized controlled trials.
But while adenoma detection rates increased by nearly 25%, compared with conventional care, the AI-guided procedures were also associated with an increase in unnecessary removal of non-neoplastic polyps. Little effect was seen on the detection of larger, advanced lesions.
The findings, published in Annals of Internal Medicine, are likely to change clinical guidelines in favor of AI-assisted procedures, said Cesare Hassan, MD, PhD, of Humanitas Research Hospital and University in Milan, Italy.
For their research, Dr. Hassan and his colleagues looked at results from 21 trials randomizing more than 18,000 patients to colonoscopy with computer-aided detection (CADe) or standard colonoscopy. Colonoscopy could be carried out for screening, surveillance, or diagnostic purposes. The included trials, which were all published in 2019 or later, took place in Asia, North America, and Europe. In most of the studies endoscopists were not blinded to treatment allocation.
The adenoma detection rate, or the proportion of individuals undergoing colonoscopy who had at least one adenoma detected and removed, was 44% in the CADe arms, compared with 35.9% assigned to standard care (relative risk [RR], 1.24; 95% CI, 1.16-1.33). The CADe patients also saw more non-neoplastic polyps removed: 0.52 per colonoscopy, compared with 0.34 for standard care. The increased adenoma detection rate appeared to be driven by a 55% decrease in the error or miss rate of adenomas at per-polyp analysis, the investigators wrote in their paper.
CADe did not increase the number of advanced adenomas (defined as greater than 10 mm, with high-grade dysplasia and villous histology) detected per colonoscopy. Rather, the benefit was “mainly limited to increased detection of diminutive (≤5 mm) adenomas,” the investigators wrote. Dr. Hassan commented that the lack of benefit for detecting larger adenomas was expected, as these are easier for endoscopists to identify visually.
The key limitation of the meta-analysis, Dr. Hassan said, was the fact that endoscopists in the studies could not be blinded. “We can assume there is a risk of bias in our estimates — that is why we describe the quality of evidence as low or moderate, never high. Through randomization we can control other aspects, especially the prevalence of disease, which avoids a scenario in which the endoscopist opts to treat riskier patients with CADe.” But the possibility of a change in the endoscopist’s performance when using these systems cannot be excluded.
Dr. Hassan commented that quantifying the risks, and costs, of overtreatment linked to CADe would require more investigation. “Any time I remove a polyp there’s a risk of perforation and bleeding,” he noted, though most of the unnecessary resections seen in the meta-analysis were of small hyperplastic polyps considered to be low risk for complications. Use of CADe was associated with only slight increases in procedure time, the investigators found.
In a multicenter Spanish study also published in Annals of Internal Medicine, Carolina Mangas-Sanjuan, MD, PhD, of the Hospital General Universitario Dr. Balmis, Alicante, Spain, and her colleagues looked at computer-aided detection of advanced colorectal neoplasias in a higher-risk cohort and saw little advantage over standard colonoscopy.
This study, which randomized 3,213 subjects, is the largest to date aimed at learning whether AI can improve the detection of advanced lesions. As in Dr. Hassan’s meta-analysis, the researchers did not see significant differences in the rates of detection for these larger lesions. Nor, in this study, did CADe did improve the global adenoma detection rate among the FIT positive individuals undergoing screening.
The detection rate of advanced colorectal neoplasias (advanced adenoma or advanced serrated polyp) was 34.8% with CADe (95% CI, 32.5%-37.2%) and 34.6% for standard colonoscopy (95% CI, 32.2%-36.9%); adjusted risk ratio, 1.01 [95% CI, 0.92-1.10]. The mean number of advanced colorectal neoplasias detected per colonoscopy was 0.54 for the intervention group, compared with 0.52 for standard care. For all adenomas, the detection rate was 64.2% with CADe vs 62% for controls.
Dr. Rodrigo Jover of the Hospital General Universitario Dr. Balmis, the study’s corresponding author, commented to this news organization that “while CADe systems are able to improve detection of small low-risk lesions, these devices are not yet able to detect more significant high-risk lesions. Therefore, there is still room for improvement if these systems are adequately trained with datasets of large, difficult-to-detect lesions.”
In an editorial comment on the Spanish and Italian studies Dennis Shung, MD, PhD of Yale University in New Haven, Connecticut, concluded that “this recent evidence suggests that CADe systems do not meaningfully improve the detection of larger (≥10 mm) clinically significant polyps. This tempers enthusiasm for CADe but does not negate the clear performance benefit for detecting adenomas of all sizes.”
How to integrate the AI systems into real-world practice is the real challenge ahead, Dr. Shung argued, noting that, in contrast to randomized trials, “several recent real-world studies have found no improvement in [adenoma detection rate] when CADe is deployed.” Lower trust in the systems can result in their underutilization, Dr. Shung argued, while higher trust can lead to overreliance. “How lgorithmic systems partner with clinicians and how these should be designed and refined across heterogeneous systems and contexts are necessary questions that must be explored to minimize disruption and lead to real-world effectiveness.”
Dr. Mangas-Sanjuan’s study was funded by a grant from Medtronic; Part of Dr. Hassan’s meta-analysis was supported by a European Commission grant to one co-author. Drs. Shung, Hassan, Manguas-Sanjuan, and Jover declared no financial conflicts of interest.
according to results from a large meta-analysis of randomized controlled trials.
But while adenoma detection rates increased by nearly 25%, compared with conventional care, the AI-guided procedures were also associated with an increase in unnecessary removal of non-neoplastic polyps. Little effect was seen on the detection of larger, advanced lesions.
The findings, published in Annals of Internal Medicine, are likely to change clinical guidelines in favor of AI-assisted procedures, said Cesare Hassan, MD, PhD, of Humanitas Research Hospital and University in Milan, Italy.
For their research, Dr. Hassan and his colleagues looked at results from 21 trials randomizing more than 18,000 patients to colonoscopy with computer-aided detection (CADe) or standard colonoscopy. Colonoscopy could be carried out for screening, surveillance, or diagnostic purposes. The included trials, which were all published in 2019 or later, took place in Asia, North America, and Europe. In most of the studies endoscopists were not blinded to treatment allocation.
The adenoma detection rate, or the proportion of individuals undergoing colonoscopy who had at least one adenoma detected and removed, was 44% in the CADe arms, compared with 35.9% assigned to standard care (relative risk [RR], 1.24; 95% CI, 1.16-1.33). The CADe patients also saw more non-neoplastic polyps removed: 0.52 per colonoscopy, compared with 0.34 for standard care. The increased adenoma detection rate appeared to be driven by a 55% decrease in the error or miss rate of adenomas at per-polyp analysis, the investigators wrote in their paper.
CADe did not increase the number of advanced adenomas (defined as greater than 10 mm, with high-grade dysplasia and villous histology) detected per colonoscopy. Rather, the benefit was “mainly limited to increased detection of diminutive (≤5 mm) adenomas,” the investigators wrote. Dr. Hassan commented that the lack of benefit for detecting larger adenomas was expected, as these are easier for endoscopists to identify visually.
The key limitation of the meta-analysis, Dr. Hassan said, was the fact that endoscopists in the studies could not be blinded. “We can assume there is a risk of bias in our estimates — that is why we describe the quality of evidence as low or moderate, never high. Through randomization we can control other aspects, especially the prevalence of disease, which avoids a scenario in which the endoscopist opts to treat riskier patients with CADe.” But the possibility of a change in the endoscopist’s performance when using these systems cannot be excluded.
Dr. Hassan commented that quantifying the risks, and costs, of overtreatment linked to CADe would require more investigation. “Any time I remove a polyp there’s a risk of perforation and bleeding,” he noted, though most of the unnecessary resections seen in the meta-analysis were of small hyperplastic polyps considered to be low risk for complications. Use of CADe was associated with only slight increases in procedure time, the investigators found.
In a multicenter Spanish study also published in Annals of Internal Medicine, Carolina Mangas-Sanjuan, MD, PhD, of the Hospital General Universitario Dr. Balmis, Alicante, Spain, and her colleagues looked at computer-aided detection of advanced colorectal neoplasias in a higher-risk cohort and saw little advantage over standard colonoscopy.
This study, which randomized 3,213 subjects, is the largest to date aimed at learning whether AI can improve the detection of advanced lesions. As in Dr. Hassan’s meta-analysis, the researchers did not see significant differences in the rates of detection for these larger lesions. Nor, in this study, did CADe did improve the global adenoma detection rate among the FIT positive individuals undergoing screening.
The detection rate of advanced colorectal neoplasias (advanced adenoma or advanced serrated polyp) was 34.8% with CADe (95% CI, 32.5%-37.2%) and 34.6% for standard colonoscopy (95% CI, 32.2%-36.9%); adjusted risk ratio, 1.01 [95% CI, 0.92-1.10]. The mean number of advanced colorectal neoplasias detected per colonoscopy was 0.54 for the intervention group, compared with 0.52 for standard care. For all adenomas, the detection rate was 64.2% with CADe vs 62% for controls.
Dr. Rodrigo Jover of the Hospital General Universitario Dr. Balmis, the study’s corresponding author, commented to this news organization that “while CADe systems are able to improve detection of small low-risk lesions, these devices are not yet able to detect more significant high-risk lesions. Therefore, there is still room for improvement if these systems are adequately trained with datasets of large, difficult-to-detect lesions.”
In an editorial comment on the Spanish and Italian studies Dennis Shung, MD, PhD of Yale University in New Haven, Connecticut, concluded that “this recent evidence suggests that CADe systems do not meaningfully improve the detection of larger (≥10 mm) clinically significant polyps. This tempers enthusiasm for CADe but does not negate the clear performance benefit for detecting adenomas of all sizes.”
How to integrate the AI systems into real-world practice is the real challenge ahead, Dr. Shung argued, noting that, in contrast to randomized trials, “several recent real-world studies have found no improvement in [adenoma detection rate] when CADe is deployed.” Lower trust in the systems can result in their underutilization, Dr. Shung argued, while higher trust can lead to overreliance. “How lgorithmic systems partner with clinicians and how these should be designed and refined across heterogeneous systems and contexts are necessary questions that must be explored to minimize disruption and lead to real-world effectiveness.”
Dr. Mangas-Sanjuan’s study was funded by a grant from Medtronic; Part of Dr. Hassan’s meta-analysis was supported by a European Commission grant to one co-author. Drs. Shung, Hassan, Manguas-Sanjuan, and Jover declared no financial conflicts of interest.
according to results from a large meta-analysis of randomized controlled trials.
But while adenoma detection rates increased by nearly 25%, compared with conventional care, the AI-guided procedures were also associated with an increase in unnecessary removal of non-neoplastic polyps. Little effect was seen on the detection of larger, advanced lesions.
The findings, published in Annals of Internal Medicine, are likely to change clinical guidelines in favor of AI-assisted procedures, said Cesare Hassan, MD, PhD, of Humanitas Research Hospital and University in Milan, Italy.
For their research, Dr. Hassan and his colleagues looked at results from 21 trials randomizing more than 18,000 patients to colonoscopy with computer-aided detection (CADe) or standard colonoscopy. Colonoscopy could be carried out for screening, surveillance, or diagnostic purposes. The included trials, which were all published in 2019 or later, took place in Asia, North America, and Europe. In most of the studies endoscopists were not blinded to treatment allocation.
The adenoma detection rate, or the proportion of individuals undergoing colonoscopy who had at least one adenoma detected and removed, was 44% in the CADe arms, compared with 35.9% assigned to standard care (relative risk [RR], 1.24; 95% CI, 1.16-1.33). The CADe patients also saw more non-neoplastic polyps removed: 0.52 per colonoscopy, compared with 0.34 for standard care. The increased adenoma detection rate appeared to be driven by a 55% decrease in the error or miss rate of adenomas at per-polyp analysis, the investigators wrote in their paper.
CADe did not increase the number of advanced adenomas (defined as greater than 10 mm, with high-grade dysplasia and villous histology) detected per colonoscopy. Rather, the benefit was “mainly limited to increased detection of diminutive (≤5 mm) adenomas,” the investigators wrote. Dr. Hassan commented that the lack of benefit for detecting larger adenomas was expected, as these are easier for endoscopists to identify visually.
The key limitation of the meta-analysis, Dr. Hassan said, was the fact that endoscopists in the studies could not be blinded. “We can assume there is a risk of bias in our estimates — that is why we describe the quality of evidence as low or moderate, never high. Through randomization we can control other aspects, especially the prevalence of disease, which avoids a scenario in which the endoscopist opts to treat riskier patients with CADe.” But the possibility of a change in the endoscopist’s performance when using these systems cannot be excluded.
Dr. Hassan commented that quantifying the risks, and costs, of overtreatment linked to CADe would require more investigation. “Any time I remove a polyp there’s a risk of perforation and bleeding,” he noted, though most of the unnecessary resections seen in the meta-analysis were of small hyperplastic polyps considered to be low risk for complications. Use of CADe was associated with only slight increases in procedure time, the investigators found.
In a multicenter Spanish study also published in Annals of Internal Medicine, Carolina Mangas-Sanjuan, MD, PhD, of the Hospital General Universitario Dr. Balmis, Alicante, Spain, and her colleagues looked at computer-aided detection of advanced colorectal neoplasias in a higher-risk cohort and saw little advantage over standard colonoscopy.
This study, which randomized 3,213 subjects, is the largest to date aimed at learning whether AI can improve the detection of advanced lesions. As in Dr. Hassan’s meta-analysis, the researchers did not see significant differences in the rates of detection for these larger lesions. Nor, in this study, did CADe did improve the global adenoma detection rate among the FIT positive individuals undergoing screening.
The detection rate of advanced colorectal neoplasias (advanced adenoma or advanced serrated polyp) was 34.8% with CADe (95% CI, 32.5%-37.2%) and 34.6% for standard colonoscopy (95% CI, 32.2%-36.9%); adjusted risk ratio, 1.01 [95% CI, 0.92-1.10]. The mean number of advanced colorectal neoplasias detected per colonoscopy was 0.54 for the intervention group, compared with 0.52 for standard care. For all adenomas, the detection rate was 64.2% with CADe vs 62% for controls.
Dr. Rodrigo Jover of the Hospital General Universitario Dr. Balmis, the study’s corresponding author, commented to this news organization that “while CADe systems are able to improve detection of small low-risk lesions, these devices are not yet able to detect more significant high-risk lesions. Therefore, there is still room for improvement if these systems are adequately trained with datasets of large, difficult-to-detect lesions.”
In an editorial comment on the Spanish and Italian studies Dennis Shung, MD, PhD of Yale University in New Haven, Connecticut, concluded that “this recent evidence suggests that CADe systems do not meaningfully improve the detection of larger (≥10 mm) clinically significant polyps. This tempers enthusiasm for CADe but does not negate the clear performance benefit for detecting adenomas of all sizes.”
How to integrate the AI systems into real-world practice is the real challenge ahead, Dr. Shung argued, noting that, in contrast to randomized trials, “several recent real-world studies have found no improvement in [adenoma detection rate] when CADe is deployed.” Lower trust in the systems can result in their underutilization, Dr. Shung argued, while higher trust can lead to overreliance. “How lgorithmic systems partner with clinicians and how these should be designed and refined across heterogeneous systems and contexts are necessary questions that must be explored to minimize disruption and lead to real-world effectiveness.”
Dr. Mangas-Sanjuan’s study was funded by a grant from Medtronic; Part of Dr. Hassan’s meta-analysis was supported by a European Commission grant to one co-author. Drs. Shung, Hassan, Manguas-Sanjuan, and Jover declared no financial conflicts of interest.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Artificial intelligence technologies significantly improved detection of precancerous polyps during colonoscopy,</metaDescription> <articlePDF/> <teaserImage/> <teaser>Use of the technology increased detection rates, but overtreatment was common, and detection of larger advanced neoplasias was little affected, according to results from a meta-analysis and randomized trial.</teaser> <title>AI-guided colonoscopy results in more small adenomas detected</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gih</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">17</term> </publications> <sections> <term canonical="true">27970</term> <term>39313</term> </sections> <topics> <term canonical="true">344</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>AI-guided colonoscopy results in more small adenomas detected</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">Artificial intelligence technologies significantly improved detection of precancerous polyps during colonoscopy,</span> according to results from a large meta-analysis of randomized controlled trials. </p> <p>But while adenoma detection rates increased by nearly 25%, compared with conventional care, the AI-guided procedures were also associated with an increase in unnecessary removal of non-neoplastic polyps. Little effect was seen on the detection of larger, advanced lesions. <br/><br/>The findings, <span class="Hyperlink"><a href="https://doi.org/10.7326/M22-3678">published</a></span> in Annals of Internal Medicine, are likely to change clinical guidelines in favor of AI-assisted procedures, said Cesare Hassan, MD, PhD, of Humanitas Research Hospital and University in Milan, Italy. <br/><br/>For their research, Dr. Hassan and his colleagues looked at results from 21 trials randomizing more than 18,000 patients to colonoscopy with computer-aided detection (CADe) or standard colonoscopy. Colonoscopy could be carried out for screening, surveillance, or diagnostic purposes. The included trials, which were all published in 2019 or later, took place in Asia, North America, and Europe. In most of the studies endoscopists were not blinded to treatment allocation.<br/><br/>The adenoma detection rate, or the proportion of individuals undergoing colonoscopy who had at least one adenoma detected and removed, was 44% in the CADe arms, compared with 35.9% assigned to standard care (relative risk [RR], 1.24; 95% CI, 1.16-1.33). The CADe patients also saw more non-neoplastic polyps removed: 0.52 per colonoscopy, compared with 0.34 for standard care. The increased adenoma detection rate appeared to be driven by a 55% decrease in the error or miss rate of adenomas at per-polyp analysis, the investigators wrote in their paper. <br/><br/>CADe did not increase the number of advanced adenomas (defined as greater than 10 mm, with high-grade dysplasia and villous histology) detected per colonoscopy. Rather, the benefit was “mainly limited to increased detection of diminutive (≤5 mm) adenomas,” the investigators wrote. Dr. Hassan commented that the lack of benefit for detecting larger adenomas was expected, as these are easier for endoscopists to identify visually. <br/><br/>The key limitation of the meta-analysis, Dr. Hassan said, was the fact that endoscopists in the studies could not be blinded. “We can assume there is a risk of bias in our estimates — that is why we describe the quality of evidence as low or moderate, never high. Through randomization we can control other aspects, especially the prevalence of disease, which avoids a scenario in which the endoscopist opts to treat riskier patients with CADe.” But the possibility of a change in the endoscopist’s performance when using these systems cannot be excluded. <br/><br/>Dr. Hassan commented that quantifying the risks, and costs, of overtreatment linked to CADe would require more investigation. “Any time I remove a polyp there’s a risk of perforation and bleeding,” he noted, though most of the unnecessary resections seen in the meta-analysis were of small hyperplastic polyps considered to be low risk for complications. Use of CADe was associated with only slight increases in procedure time, the investigators found. <br/><br/>In a multicenter Spanish study also <span class="Hyperlink"><a href="http://">published</a></span> in Annals of Internal Medicine, Carolina Mangas-Sanjuan, MD, PhD, of the Hospital General Universitario Dr. Balmis, Alicante, Spain, and her colleagues looked at computer-aided detection of advanced colorectal neoplasias in a higher-risk cohort and saw little advantage over standard colonoscopy. <br/><br/>This study, which randomized 3,213 subjects, is the largest to date aimed at learning whether AI can improve the detection of advanced lesions. As in Dr. Hassan’s meta-analysis, the researchers did not see significant differences in the rates of detection for these larger lesions. Nor, in this study, did CADe did improve the global adenoma detection rate among the FIT positive individuals undergoing screening.<br/><br/>The detection rate of advanced colorectal neoplasias (advanced adenoma or advanced serrated polyp) was 34.8% with CADe (95% CI, 32.5%-37.2%) and 34.6% for standard colonoscopy (95% CI, 32.2%-36.9%); adjusted risk ratio, 1.01 [95% CI, 0.92-1.10]. The mean number of advanced colorectal neoplasias detected per colonoscopy was 0.54 for the intervention group, compared with 0.52 for standard care. For all adenomas, the detection rate was 64.2% with CADe vs 62% for controls. <br/><br/>Dr. Rodrigo Jover of the Hospital General Universitario Dr. Balmis, the study’s corresponding author, commented to this news organization that “while CADe systems are able to improve detection of small low-risk lesions, these devices are not yet able to detect more significant high-risk lesions. Therefore, there is still room for improvement if these systems are adequately trained with datasets of large, difficult-to-detect lesions.”<br/><br/>In an editorial comment on the Spanish and Italian studies Dennis Shung, MD, PhD of Yale University in New Haven, Connecticut, concluded that “this recent evidence suggests that CADe systems do not meaningfully improve the detection of larger (≥10 mm) clinically significant polyps. This tempers enthusiasm for CADe but does not negate the clear performance benefit for detecting adenomas of all sizes.”<br/><br/>How to integrate the AI systems into real-world practice is the real challenge ahead, Dr. Shung argued, noting that, in contrast to randomized trials, “several recent real-world studies have found no improvement in [adenoma detection rate] when CADe is deployed.” Lower trust in the systems can result in their underutilization, Dr. Shung argued, while higher trust can lead to overreliance. “How lgorithmic systems partner with clinicians and how these should be designed and refined across heterogeneous systems and contexts are necessary questions that must be explored to minimize disruption and lead to real-world effectiveness.” <br/><br/>Dr. Mangas-Sanjuan’s study was funded by a grant from Medtronic; Part of Dr. Hassan’s meta-analysis was supported by a European Commission grant to one co-author. Drs. Shung, Hassan, Manguas-Sanjuan, and Jover declared no financial conflicts of interest.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM ANNALS OF INTERNAL MEDICINE
AGA clinical practice guideline affirms role of biomarkers in Crohn’s disease management
, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity.
Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was published online Nov. 17 in Gastroenterology.
“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”
Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed Clinical Decision Support Tool, include the following:
For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment.
For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population.
For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity.
For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment.
For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment.
All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI).
Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity.
As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.”
The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.
, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity.
Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was published online Nov. 17 in Gastroenterology.
“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”
Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed Clinical Decision Support Tool, include the following:
For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment.
For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population.
For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity.
For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment.
For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment.
All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI).
Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity.
As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.”
The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.
, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity.
Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was published online Nov. 17 in Gastroenterology.
“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”
Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed Clinical Decision Support Tool, include the following:
For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment.
For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population.
For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity.
For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment.
For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment.
All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI).
Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity.
As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.”
The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.
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This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>A new Clinical Practice Guideline from American Gastroenterological Association points to a stronger and better defined role for fecal and blood biomarkers in t</metaDescription> <articlePDF/> <teaserImage/> <teaser>Routine endoscopy can be avoided in asymptomatic patients with normal FCP and CRP, while in patients with severe symptoms, elevated levels of these biomarkers may stand in for endoscopy to guide treatment adjustments</teaser> <title>AGA Clinical Practice Guideline Affirms Role of Biomarkers in Crohn’s Disease Management</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gih</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term>17</term> <term canonical="true">21</term> </publications> <sections> <term canonical="true">69</term> <term>39313</term> <term>75</term> </sections> <topics> <term canonical="true">345</term> <term>213</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>AGA Clinical Practice Guideline Affirms Role of Biomarkers in Crohn’s Disease Management</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">A new Clinical Practice Guideline from American Gastroenterological Association points to a stronger and better defined role for fecal and blood biomarkers in the management of Crohn’s disease</span>, offering the most specific evidence-based recommendations yet for the use of fecal calprotectin (FCP) and serum C-reactive protein (CRP) in assessing disease activity. </p> <p>Repeated monitoring with endoscopy allows for an objective assessment of inflammation and mucosal healing compared with symptoms alone. However, relying solely on endoscopy to guide management is an approach “limited by cost and resource utilization, invasiveness, and reduced patient acceptability,” wrote guideline authors on behalf of the AGA Clinical Guidelines Committee. The guideline was <span class="Hyperlink"><a href="https://www.gastrojournal.org/article/S0016-5085(23)05064-3/fulltext">published online</a></span> Nov. 17 in Gastroenterology. <br/><br/>“Use of biomarkers is no longer considered experimental and should be an integral part of IBD care and monitoring,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist with Massachusetts General Hospital in Boston and first author of the guideline. “We need further studies to define their optimal longitudinal use, but at a given time point, there is now abundant evidence that biomarkers provide significant incremental benefit over symptoms alone in assessing a patient’s status.”<br/><br/>Using evidence from randomized controlled trials and observational studies, and applying it to common clinical scenarios, there are conditional recommendations on the use of biomarkers in patients with established, diagnosed disease who were asymptomatic, symptomatic, or in surgically induced remission. Those recommendations, laid out in a detailed <span class="Hyperlink"><a href="https://www.gastrojournal.org/article/S0016-5085(23)05153-3/fulltext">Clinical Decision Support Tool</a></span>, include the following:<br/><br/>For asymptomatic patients: Check CRP and FCP every 6-12 months. Patients with normal levels, and who have endoscopically confirmed remission within the last 3 years without any subsequent change in symptoms or treatment, need not undergo endoscopy and can be followed with biomarker and clinical checks alone. If CRP or FCP are elevated (defined as CRP ≥ 5 mg/L, FCP ≥ 150 mcg/g), consider repeating biomarkers and/or performing endoscopic assessment of disease activity before adjusting treatment. <br/><br/>For mildly symptomatic patients: Role of biomarker testing may be limited and endoscopic or radiologic assessment may be required to assess active inflammation given the higher rate of false positive and false negative results with biomarkers in this population. <br/><br/>For patients with more severe symptoms: Elevated CRP or FCP can be used to guide treatment adjustment without endoscopic confirmation in certain situations. Normal levels may be false negative and should be confirmed by endoscopic assessment of disease activity. <br/><br/>For patients in surgically induced remission with a low likelihood of recurrence: FCP levels below 50 mcg/g can be used in lieu of routine endoscopic assessment within the first year after surgery. Higher FCP levels should prompt endoscopic assessment. <br/><br/>For patients in surgically induced remission with a high risk of recurrence: Do not rely on biomarkers. Perform endoscopic assessment. <br/><br/>All recommendations were deemed of low to moderate certainty based on results from randomized clinical trials and observational studies that utilized these biomarkers in patients with Crohn’s disease. Citing a dearth of quality evidence, the guideline authors determined they could not make recommendations on the use of a third proprietary biomarker — the endoscopic healing index (EHI). <br/><br/>Recent AGA Clinical Practice Guidelines on the role of biomarkers in ulcerative colitis, published in March, also support a strong role for fecal and blood biomarkers, determining when these can be used to avoid unneeded endoscopic assessments. However, in patients with Crohn’s disease, symptoms correlate less well with endoscopic activity. <br/><br/>As a result, “biomarker performance was acceptable only in asymptomatic individuals who had recently confirmed endoscopic remission; in those without recent endoscopic assessment, test performance was suboptimal.” In addition, the weaker correlation between symptoms and endoscopic activity in Crohn’s “reduced the utility of biomarker measurement to infer disease activity in those with mild symptoms.” <br/><br/>The guidelines were fully funded by the AGA Institute. The authors disclosed a number of potential conflicts of interest, including receiving research grants, as well as consulting and speaking fees, from pharmaceutical companies.</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM GASTROENTEROLOGY
From failure to hope: Tracking the changing landscape of Alzheimer’s therapies
In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.
Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.
His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.
Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.
Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.
Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
How did all this begin?
Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.
How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?
We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.
We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
Are you able to capture every Alzheimer’s drug in development globally?
If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.
Who are the report’s main readers?
Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.
It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
What about patients and families? Are they able to use the report as well?
One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.
Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?
My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.
What other approaches are interesting to you?
We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.
Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?
That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.
What about other therapy classes?
We aim to be more serious about devices.
What will you call the database?
The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.
The annual pipeline report is very much associated with you. Is the database going to be different?
Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.
Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.
We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.
Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.
In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.
Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.
His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.
Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.
Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.
Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
How did all this begin?
Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.
How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?
We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.
We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
Are you able to capture every Alzheimer’s drug in development globally?
If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.
Who are the report’s main readers?
Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.
It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
What about patients and families? Are they able to use the report as well?
One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.
Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?
My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.
What other approaches are interesting to you?
We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.
Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?
That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.
What about other therapy classes?
We aim to be more serious about devices.
What will you call the database?
The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.
The annual pipeline report is very much associated with you. Is the database going to be different?
Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.
Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.
We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.
Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.
In 2014 neurologist Jeffrey L. Cummings, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development.
Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “99% paper,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way.
His “Alzheimer’s Drug Development Pipeline” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process.
Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory.
Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end.
Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years.
How did all this begin?
Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually.
How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms?
We capture information available on clinicaltrials.gov. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated.
We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is CADRO, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.
Are you able to capture every Alzheimer’s drug in development globally?
If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive.
Who are the report’s main readers?
Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a PDE-5 inhibitor for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes.
It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year.
What about patients and families? Are they able to use the report as well?
One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore.
Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge?
My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated.
What other approaches are interesting to you?
We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions.
Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?
That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set.
What about other therapy classes?
We aim to be more serious about devices.
What will you call the database?
The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by Feixiong Cheng, PhD.
The annual pipeline report is very much associated with you. Is the database going to be different?
Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.
Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different.
We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource.
Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development th</metaDescription> <articlePDF/> <teaserImage>276466</teaserImage> <title>From failure to hope: Tracking the changing landscape of Alzheimer’s therapies</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2023</pubPubdateYear> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName>January 2021</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> </publications_g> <publications> <term canonical="true">22</term> </publications> <sections> <term canonical="true">73751</term> <term>39313</term> <term>62</term> </sections> <topics> <term canonical="true">180</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/2400facc.jpg</altRep> <description role="drol:caption">Dr. Jeffrey L. Cummings</description> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>From failure to hope: Tracking the changing landscape of Alzheimer’s therapies</title> <deck/> </itemMeta> <itemContent> <p>In 2014 neurologist <span class="Hyperlink"><a href="https://www.unlv.edu/news/expert/dr-jeffrey-l-cummings">Jeffrey L. Cummings</a></span>, MD, startled the Alzheimer’s disease research world with a paper that laid bare the alarmingly high failure rate of Alzheimer’s disease therapies in development. </p> <p>Publishing in the journal Alzheimer’s Research & Therapy, Dr. Cummings and his colleagues determined that 99.6% of all therapies tested between 2002 and 2012 had failed. Since downloaded some 75,000 times, Dr. Cumming’s “<span class="Hyperlink"><a href="https://alzres.biomedcentral.com/articles/10.1186/alzrt269">99% paper</a></span>,” as it came to be nicknamed, led him to look more deeply and thoroughly at Alzheimer’s disease drugs in the pipeline, and describe them in a readable, user-friendly way. <br/><br/><span class="tag metaDescription">Every year since 2016, Dr. Cummings, of the University of Nevada, Las Vegas, and his colleagues, have published an update of Alzheimer’s drugs in development that offers a concise, graphic, all-in-one overview.</span> His “<span class="Hyperlink"><a href="https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.12385">Alzheimer’s Drug Development Pipeline</a></span>” report, in the journal Alzheimer’s & Dementia, classifies therapies by their targets, their mechanisms of action, and where they stand in the development process. <br/><br/>[[{"fid":"276466","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Jeffrey Cummings, MD, is Research Professor, Department of Brain Health at the University of Nevada, Las Vegas (UNLV), and Director, Chambers-Grundy Center for Transformative Neuroscience at UNLV.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Jeffrey L. Cummings"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]Heavy on color-coded visuals, this snapshot of Alzheimer’s disease therapies is widely consulted by industry, researchers, and clinicians. Over time this report – which first documented a crisis – has come to show something more optimistic: an increasingly crowded pipeline reflecting a broad array of treatment approaches. Dr. Cummings wants more people to know that Alzheimer’s disease drug research, which now includes the first two Food and Drug Administration–approved monoclonal antibodies against amyloid-beta, is not the bleak landscape that it was in recent memory. <br/><br/>Lately, with the help of a grant from the National Institute on Aging, Dr. Cummings and his group have been working to expand on their reports to build an even more user-friendly database that can be searched by people in all corners of the neurodegenerative disease world. Dr. Cummings says he plans for this public-facing database to be up and running by year end. <br/><br/>Neurology Reviews spoke with Dr. Cummings, who is a member of the publication’s Editorial Advisory Board, about the genesis of his influential drug-tracking effort, how it has evolved, and what has been learned from it over the years. <br/><br/></p> <p><strong>How did all this begin?<br/><br/></strong>Already in 2014 there was a dialogue going on was about the high failure rate for Alzheimer’s drugs. And I thought: “there’s probably a number that can be assigned to that.” And when it turned out to be 99.6%, that generated a huge amount of interest. That’s when I realized what interests me also interests the world. And that I was uniquely positioned after that point to do something annually. </p> <p><strong>How do you create your annual report, and how do you classify the drugs in it when some might act on little-understood pathways or mechanisms? <br/><br/></strong>We capture information available on <span class="Hyperlink"><a href="http://clinicaltrials.gov">clinicaltrials.gov</a></span>. We are notified immediately of any new Alzheimer-related trials, and we automate everything that is possible to automate. But there is still some human curation required. Most of that is around mechanisms. If it’s a monoclonal antibody directed at amyloid-beta, that’s not difficult to categorize. But with the small molecules especially, it can be more complicated. </p> <p>We often look to see how the sponsor describes the drug and what their perception of the primary target is. A resource of great importance to us is <span class="Hyperlink"><a href="https://iadrp.nia.nih.gov/about/cadro">CADRO</a></span>, Common Alzheimer’s and Related Dementias Disease Research Ontology, which describes about 20 mechanisms that a group of scientists sponsored by the National Institutes of Health and the Alzheimer’s Association have agreed on. Inflammation, epigenetics, and oxidation are just a few that most people know. CADRO is organized in a very specific way that allows us to go to the mechanism and relate it to the target. But we do try to be humble and acknowledge we probably make some errors in this.<br/><br/></p> <p><strong>Are you able to capture every Alzheimer’s drug in development globally? <br/><br/></strong>If they’re on clinicaltrials.gov, they’re in our database. But we think there’s about 15% of drugs in the world that aren’t for some reason on clinicaltrials.gov – so we know we are comprehensive, but not quite exhaustive. I’m in kind of quandary about whether to search for that other 15%. But we do always acknowledge that we’re not 100% exhaustive. </p> <p><strong>Who are the report’s main readers?<br/><br/></strong>Drug developers use it for investor discussions, and also to understand the competition and the landscape. The competition might be a drug with the same mechanism, and the landscape might be drugs coming into the Alzheimer’s disease world. So if someone is developing a <span class="Hyperlink">PDE-5 inhibitor</span> for mild dementia, for example, they can see that other people are working on a PDE-5 inhibitor for moderate dementia, and there’s no overlap. Investors use the report to make decisions about which horse in the race to bet on. And of course it’s used by academics and clinicians to learn which are the new drugs in the pipeline, which drugs have fallen out of the pipeline, how are biomarkers changing trials, what are the new outcomes. </p> <p>It’s really become a community project. Investigators will email me and say “Jeff, we’re in phase 1, make sure it’s on your map.” Or, “you forgot our agent! We’re disappointed.” When that occurs it’s because they were not in a trial on the index date – the 1 day in our publication when everything we say in the paper is true. A trial initiated 1 day later won’t make the report for that year. <br/><br/></p> <p><strong>What about patients and families? Are they able to use the report as well?<br/><br/></strong>One of the things we want to expand with the new database is its usefulness for patients. Among the new data display approaches that we have is a world map where you can go click on a dot near your home and find active trials. That’s something patients and families want to know, right? There’s 140 drugs in clinical trials, there must be one for me, how would I get to it? Soon we will have quite a good public portal so if you want to go in and see what new monoclonal antibodies are in phase 2, you can do that with drop-down menus. It’s a very easy to use site that anyone can explore. </p> <p><strong>Looking back at your last decade tracking drugs, what are some lessons learned and what are some of the more exciting drug categories to emerge? <br/><br/></strong>My answer to this question is: Biologics rule. The main successes have been in biologics, in the monoclonal antibodies against amyloid, like the two FDA-approved agents lecanemab and aducanumab. But I think that the monoclonals, while I’m really happy to have them, are a first step. If you look back at tacrine, the first drug approved in 1993 for Alzheimer’s disease, it was a very difficult drug with lots of side effects. But then within 3 years we had donepezil, which was a very benign drug. I feel that a similar evolution is likely with regard to these antibodies. The first ones, we know, have big challenges, and you learn from those challenges and you just keep improving them. But you have to start somewhere, and you have to validate that target. Now I think that amyloid is validated. </p> <p><strong>What other approaches are interesting to you?<br/><br/></strong>We have seen dramatic imaging results with marked reductions in neurofibrillary tangles from an antisense oligonucleotide aimed at tau protein. And there are two very active areas in the pipeline: inflammation and synaptic plasticity. Each has roughly 20 drugs apiece in development across all phases. And as you know, both synaptic plasticity and inflammation are represented across neurodegenerative conditions. </p> <p><strong>Your annual report has always focused on drugs to treat Alzheimer’s disease. Will the new database cover other types of dementia and neurodegenerative diseases?</strong><br/><br/>That’s an obvious next step. I’m hoping that late this year we will have funding to expand the database into frontotemporal lobar degenerations, which will include all the tauopathies. And there’s also an overlap with TDP-43 diseases, so we’ll bring all of that in too. We have a new initiative on Parkinson’s disease and dementia with Lewy bodies that I hope will materialize by next year. My goal is that this will eventually become a neurodegenerative disease therapies database. The really interesting drugs right now are being tested in more than one neurodegenerative disease, and we should look at those more carefully. It will be more feasible to do that if they’re on the same data set. </p> <p><strong>What about other therapy classes?<br/><br/></strong>We aim to be more serious about devices. </p> <p><strong>What will you call the database?<br/><br/></strong>The Clinical Trial Observatory. We may start by calling it the Alzheimer’s Disease Clinical Trial Observatory. But the intention, obviously, is to go way beyond Alzheimer’s disease. The database is managed by a terrific team of data scientists at Cleveland Clinic, led by <span class="Hyperlink"><a href="https://www.lerner.ccf.org/genomic-medicine/cheng/">Feixiong Cheng, PhD</a>. </span></p> <p><strong>The annual pipeline report is very much associated with you. Is the database going to be different? <br/><br/></strong>Right now, I’m like the grandfather of this project. I won’t be around forever. This will have to pass on, and we’re already talking about succession. We’re thinking about how to make sure this community resource continues to be a community resource. Also, over all these years the annual report reflected my perspective. But with a database, many more people will be able to share their perspectives. I happen to think that “biologics rule,” but others might look at the data, see different scientific currents, and draw different conclusions. That will create a rich dialogue.</p> <p><strong>Do you think your reports have changed people’s perspectives on Alzheimer’s disease therapies? There’s a widely held idea that the field is exclusively focused on amyloid, or even dead-ended, but the papers seem to show something different. <br/><br/></strong>We think this effort has helped, and will continue to help and foster investment and growth in treatments for our patients. It really does show how diverse the clinical trials landscape is now. People are surprised to learn of the number and diversity of approaches. Just last week I was presenting at the Center for Brain Health in Dallas and there was a doctor in the audience who was a caregiver to his wife with Alzheimer’s disease. He came up afterwards and said, “I had no idea there were so many drugs in clinical trials,” because there’s no way to find out if you don’t know about this resource. </p> <p>Dr. Cummings discloses consulting for a range of companies working in Alzheimer’s therapies and diagnostics, including Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI. He has received several grants from the National Institute on Aging.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>The Alzheimer’s Drug Development Pipeline report, updated annually since 2016, classifies Alzheimer’s therapies by their targets, their mechanisms of action, and where they stand in the development process.</p> </itemContent> </newsItem> </itemSet></root>
A new chapter for research on treating Huntington’s disease
The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.
DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
References
1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.
2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.
3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.
4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.
5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.
7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.
The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.
DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
References
1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.
2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.
3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.
4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.
5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.
7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.
The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies.
What is Huntington’s disease?
Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course.
Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death.
Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.
Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:
Reduce levels of mutant HTT protein, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.1 Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable.
Modify the length of CAG repeats, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored.
Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research.
The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease.
“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”
Tackling a tricky protein
Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT.
Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.
“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen.
Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein.
“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”
Allele-specific therapy. A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.”
Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.2 A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.2
Other strategies have yielded disappointing or mixed results:
A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.3 Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease.
Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.4
In neither case was excess protein-lowering thought to be the cause of safety problems.
DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.
References
1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-.
2. Wave Life Sciences. Defining a new era of oligonucleotides. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select.
3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf.
4. UniQure. Second Quarter 2022 Financial Results. https://uniqure.gcs-web.com/node/10856/pdf.
5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. doi: 10.1016/S1474-4422(17)30161-8.
7. CHDI Foundation. Postcard from Dubrovnik 2023. https://chdifoundation.org/postcard-from-dubrovnik-2023/.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>165174_web</fileName> <TBEID>0C04C993.SIG</TBEID> <TBUniqueIdentifier>MD_0C04C993</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname/> <articleType>2</articleType> <TBLocation>Inbox-All Pubs</TBLocation> <QCDate/> <firstPublished>20231010T211241</firstPublished> <LastPublished>20231010T211241</LastPublished> <pubStatus qcode="stat:"/> <embargoDate>20231013T000100</embargoDate> <killDate/> <CMSDate>20231013T000100</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText/> <bylineFull/> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. 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This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>BY JENNIE SMITHThe past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fa</metaDescription> <articlePDF/> <teaserImage>297680</teaserImage> <title>A new chapter for research on treating Huntington’s disease</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> </publications_g> <publications> <term canonical="true">22</term> </publications> <sections> <term canonical="true">75329</term> </sections> <topics> <term>249</term> <term canonical="true">285</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012234.jpg</altRep> <description role="drol:caption">Dr. Cristina Sampaio</description> <description role="drol:credit"/> </link> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012233.jpg</altRep> <description role="drol:caption">Dr. Sarah Tabrizi</description> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>A new chapter for research on treating Huntington’s disease</title> <deck/> </itemMeta> <itemContent> <p><br/><br/>BY JENNIE SMITH<br/><br/>The past decade has been a contradictory one for research on Huntington’s disease, marked by breakthroughs in the biology and genetics of this fatal neurodegenerative disease and painful disappointments in trials of novel therapies. <br/><br/></p> <h2>What is Huntington’s disease?</h2> <p>Huntington’s disease is caused by a trinucleotide repeat mutation in the huntingtin gene (HTT) and follows an autosomal dominant pattern of inheritance. In people with more than 39 copies of this CAG repeat tract expansion, the HTT protein misfolds to become toxic, with more repeats linked to earlier disease onset and a more severe course. </p> <p>Huntington’s disease causes loss of neurons in the striatum and disrupts the cortical-striatal-thalamic pathway, a brain circuit that governs movement. Although behavioral symptoms can emerge earlier, signature symptoms – chorea, dystonia, and cognitive abnormalities – usually present at midlife and progress until the patient’s death. <br/><br/>[[{"fid":"297680","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Cristina Sampaio, chief medical officer of CHDI Management, Princeton, N.J.","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Cristina Sampaio"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]Huntington’s disease affects an estimated 30,000 people in the United States, and an estimated 10-12 people for every 100,000 worldwide – making it rare enough that neurologists who do not specialize in movement disorders might never treat a Huntington’s patient. Yet Huntington’s disease is sufficiently prevalent to attract robust research interest and sustain large registries, which have led to remarkable findings with implications not just for Huntington’s disease but for other diseases as well.<br/><br/>Right now, the only Food and Drug Administration–approved treatments for Huntington’s disease are symptomatic therapies to help temper disturbances of movement, sleep, and emotions. There are two major avenues of investigation into Huntington’s disease modification:<br/><br/><em>Reduce levels of mutant HTT protein</em>, whether through small molecules, gene therapies, or antisense oligonucleotides (ASOs) that modulate RNA processing. In March 2021, Roche announced the suspension of its phase 3 trial of tominersen, an ASO.<sup>1</sup> Trials of other protein-lowering agents were canceled for lack of target engagement or over safety concerns, in 2021 and 2022, although this approach is still considered viable. <br/><br/><em>Modify the length of CAG repeats</em>, which involves a more recently encountered mechanism in Huntington’s disease. The strategy is at the preclinical stage. In 2015, a group of scientists reported the game-changing discovery that a large number of genes, associated with some of the same DNA-mismatch repair pathways implicated in cancer, can modify the length of CAG repeats in cells. This gave rise to a new set of therapeutic targets, now being explored. <br/><br/>Neurology Reviews 2023 Rare Neurological Disease Special Report spoke with two frequently collaborating researchers at the forefront of Huntington’s disease science – Cristina Sampaio, MD, PhD, chief medical officer of CHDI Management, Princeton, N.J., and Sarah Tabrizi, MD, PhD, from University College London – about lessons learned from the past several years of Huntington’s disease drug research. <br/><br/>The CHDI Foundation, a nonprofit research organization, was founded in 2003 to facilitate development of Huntington’s disease therapies. Its clinical research platform, Enroll-HD, includes a global registry of some 28,000 patients and a biobank to facilitate biomarker discovery and validation. Dr. Tabrizi’s lab explores Huntington’s disease drug targets in both HTT and DNA mismatch repair, and led two CHDI-funded observational studies, TRACK-HD and TrackOn-HD, to characterize disease progression in people with Huntington’s disease. In 2022, Dr. Tabrizi and Dr. Sampaio were coauthors of a comprehensive review of Huntington’s disease drug development and published a new disease-staging system to help enable trials in presymptomatic Huntington’s disease. <br/><br/>“The story of Huntington’s therapeutics is very informative,” Dr. Sampaio said. “Understanding these mechanisms is relevant for any neurologist – not only for Huntington’s but because they represent a prototype development for a big group of therapies and make us better equipped to think about everything else that is happening in neurology. They’re giving us an understanding of where neurology is going.”<br/><br/></p> <h2>Tackling a tricky protein</h2> <p>Most Huntington’s disease research has focused on ways to attack or lower mutant HTT protein. But HTT has proven a tricky target: HTT is a large protein, present in all cells, and known to interact with more than 100 genes. Healthy HTT is critical to fetal development, but its functions in the adult body remain something of a mystery. Almost all people with Huntington’s disease have both wild-type and mutant HTT. </p> <p>Tominersen, the investigative ASO developed by Roche, works to block translation of the HTT message, leading to a reduction in both healthy and mutant HTT protein. It is delivered by lumbar injection to reach the brain. Upon halting its phase 3 trial of tominersen in 2021, Roche reported that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect. The tominersen program was the first to clearly show that it is possible to lower HTT with an intervention – a critical first step in the development of this class of drugs.<br/><br/>[[{"fid":"297679","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Sarah Tabrizi, University College London","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Sarah Tabrizi"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]“I think the problem with the trial was the aggressive loading doses plus exposure-related toxicity,” Dr. Tabrizi said. “Whether that exposure-related toxicity was related to too much wild-type HTT lowering or the proinflammatory effects of the ASO, you can’t yet disentangle.” Roche has not given up: The company is now seeking to test lower dosages of tominersen on a younger subgroup of patients who have fewer CAG repeats, in whom a benefit of protein lowering might be more clearly seen. <br/><br/>Small molecules and gene therapies have also been developed to reduce mutant HTT, although most, as is the case with tominersen, will also reduce healthy protein. <br/><br/>“There is a long and complex debate about how much [lowering] is too much and how much is enough,” Dr. Sampaio said. “And this is a problem that has not been solved.”<br/><br/><strong>Allele-specific therapy. </strong>A different class of investigative drugs, called allele-specific therapies, target only mutant HTT, sparing healthy protein. The drugs are tailored to genetic markers, or single-nucleotide polymorphisms (SNPs), that are present in different Huntington’s disease populations worldwide. Because treatments based on SNPs are highly tailored, “you need a new drug for each SNP to cover the global Huntington’s disease population,” Dr. Sampaio said. “This presents challenges from a regulatory perspective, as each drug would have to be evaluated separately.” <br/><br/>Two SNP-based therapies failed clinical trials in 2021, when they did not engage their targets.<sup>2 </sup>A third trial succeeded in lowering mutant HTT while preserving healthy protein and is being evaluated further in the clinic.<sup>2</sup> <br/><br/>Other strategies have yielded disappointing or mixed results:<br/><br/>A trial of branaplam, a small molecule, was stopped late in 2022 after patients developed peripheral neuropathy.<sup>3</sup> Novartis, the drug’s manufacturer, said it would no longer investigate branaplam for Huntington’s disease. <br/><br/>Months earlier, in August 2022, a trial of a gene therapy to lower HTT protein – injected directly into the striatum of the brain – was halted because of adverse events in its high-dosage arm but has since resumed, with some changes to protocol.<sup>4</sup><br/><br/>In neither case was excess protein-lowering thought to be the cause of safety problems.</p> <h2>DNA repair emerges as a promising target</h2> <p>Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.</p> <p>Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain. <br/><br/>The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.<sup>5</sup> As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer. <br/><br/>DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.<br/><br/>In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs. <br/><br/>After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said. <br/><br/>In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.<sup>6 </sup>“I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said. <br/><br/>At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.<sup>7</sup> (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said. <br/><br/>“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT. <br/><br/>Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias. <br/><br/>“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.” <br/><br/>Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases. <br/><br/>Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.” <br/><br/>Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.<br/><br/></p> <h2>References</h2> <p> 1. Genentech. Genentech Provides Update on Tominersen Program in Manifest Huntington’s Disease. <a href="https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-">https://www.gene.com/media/press-releases/14902/2021-03-22/genentech-provides-update-on-tominersen-</a>.<br/><br/> 2. Wave Life Sciences. Defining a new era of oligonucleotides. <a href="https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select">https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-phase-1b2a-select</a>.<br/><br/> 3. Novartis. Community update: Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. <a href="https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf">https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pdf</a>.<br/><br/> 4. UniQure. Second Quarter 2022 Financial Results. <a href="https://uniqure.gcs-web.com/node/10856/pdf">https://uniqure.gcs-web.com/node/10856/pdf</a>.<br/><br/> 5. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. <a href="https://www.cell.com/cell/fulltext/S0092-8674(15)00840-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867415008405%3Fshowall%3Dtrue">doi: 10.1016/j.cell.2015.07.003</a>.<br/><br/> 6. Moss DJH et al. Lancet Neurol. 2017 Sep;16(9):701-11. <a href="https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30161-8/fulltext">doi: 10.1016/S1474-4422(17)30161-8</a>.<br/><br/> 7. CHDI Foundation. Postcard from Dubrovnik 2023. <a href="https://chdifoundation.org/postcard-from-dubrovnik-2023/">https://chdifoundation.org/postcard-from-dubrovnik-2023/</a>.</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>Setbacks in trials of protein-lowering therapies – mostly over their safety – mask a story of rapid advances and a more recently discovered treatment pathway that also offers promise for other diseases.</p> </itemContent> </newsItem> </itemSet></root>
AGA CPU stresses brain-gut aspects of bloating, distention and belching
A new Clinical Practice Update from the AGA on belching, abdominal bloating, and distention offers practical management strategies for a class of disorders that, while highly prevalent, can be confusing to clinicians because of their nonspecific and overlapping symptomatology and wide range of possible causes.
The expert review, published online in Gastroenterology, is dedicated to these specific disorders, which, when not caused by bacteria, food intolerance, or autoimmune disease, are increasingly viewed as stemming from dysregulation of the brain-gut axis, and therefore responsive to interventions such as biofeedback therapy and central nervous system modulators, including antidepressants referred to as neuromodulators due to their pain modulating effects in the gut.
Baharak Moshiree, MD, of Atrium Health, Wake Forest Medical University, Charlotte, N.C., the lead author, said the guidance is aimed at GI specialists as much as primary care physicians and other providers who treat patients with these disorders.
Clinicians may not always know which diagnostic studies to order for a patient with bloating, distention, or belching, Dr. Moshiree said, and since large randomized controlled trials in these patient groups are not available, making evidence-based treatment recommendations is challenging. Because the disorders are ubiquitous, “there’s a lot of social media attention around them, and these include fad diets and drugs labeled as medical foods, like probiotics, that patients will often try.”
The guidance includes 15 best practice advice statements along with two diagnostic and treatment algorithms, one for belching and the other for bloating and distention.
For belching, the authors stress discerning between gastric and supragastric belching using clinical history and examination, and if needed, impedance Ph monitoring. For supragastric belching, or esophageal belching, treatment considerations may include cognitive behavioral therapy, biofeedback training, and neuromodulator (antidepressant) drugs either alone or combined with psychological therapies.
Abdominal bloating and distention should be diagnosed using the Rome IV criteria, and in patients with suspected carbohydrate enzyme deficiencies, dietary restriction of potentially problematic carbohydrates or breath testing may be used to rule out intolerance. In a subset of at-risk patients, “small bowel aspiration and glucose- or lactulose-based hydrogen breath testing may be used to evaluate for small intestinal bacterial overgrowth,” the guidance says. Blood testing may be used to rule out celiac disease, and, if positive, a definitive diagnosis should be confirmed with small bowel tissue biopsy obtained during an upper endoscopy, Dr. Moshiree and her colleagues wrote.
Endoscopy and imaging should be restricted to patients with alarm features such as vomiting or weight loss, rapid worsening of symptoms, or an abnormal physical exam. Tests such as gastric emptying transit studies should not be routinely ordered unless nausea and vomiting are present. Similarly, whole-gut motility studies should be ordered only if there are symptoms suggestive of motility disorders, with testing carried out at specialized centers.
When constipation occurs with bloating, clinicians should use anorectal physiology testing to rule out a pelvic-floor disorder, which, if present, can be treated with pelvic floor biofeedback training. Constipation in the context of bloating may also be treated with laxatives. Probiotics are not advised as treatment for bloating and distention in this guidance, given a lack of robust studies. However, neuromodulators may help reduce visceral or gut hypersensitivity and improve psychological comorbidities if these are present, the authors wrote.
Conditions treated with dietary modifications should be overseen by dietitians, and diaphragmatic breathing and neuromodulators can be used to treat a condition called abdominophrenic dyssynergia, the guidance says.
“We tried to make it clinically useful,” Dr. Moshiree said of the practice update, which was not the result of systematic reviews or meta-analyses of multicenter randomized controlled trials. The update contains no ratings on its recommendations and does not grade the evidence used. Rather, the three coauthors looked to results from published randomized trials and observational studies, along with their own expert opinion.
For example, the guidance’s best practice advice on abdominophrenic dyssynergia came from single center studies in Italy where bloating improved with use of biofeedback therapy for this condition. Although this was a single center study, experts have found that biofeedback therapy is helpful for relaxing the pelvic floor muscles which can help bloating and distension symptoms.
Dr. Moshiree also pointed to a 2021 narrative review by Brian E. Lacy, MD. and David Cangemi, MD, of the Mayo Clinic in Jacksonville, Fla., that helped inform the framework for this clinical practice update.
Dr. Moshiree disclosed financial relationships with several pharmaceutical companies including Salix, AbbVie, Medtronic, and Takeda. Her two coauthors, Douglas Drossman, MD, of the Rome Foundation and the University of North Carolina, Chapel Hill, and Aasma Shaukat, MD, of New York University, also disclosed industry support.
A new Clinical Practice Update from the AGA on belching, abdominal bloating, and distention offers practical management strategies for a class of disorders that, while highly prevalent, can be confusing to clinicians because of their nonspecific and overlapping symptomatology and wide range of possible causes.
The expert review, published online in Gastroenterology, is dedicated to these specific disorders, which, when not caused by bacteria, food intolerance, or autoimmune disease, are increasingly viewed as stemming from dysregulation of the brain-gut axis, and therefore responsive to interventions such as biofeedback therapy and central nervous system modulators, including antidepressants referred to as neuromodulators due to their pain modulating effects in the gut.
Baharak Moshiree, MD, of Atrium Health, Wake Forest Medical University, Charlotte, N.C., the lead author, said the guidance is aimed at GI specialists as much as primary care physicians and other providers who treat patients with these disorders.
Clinicians may not always know which diagnostic studies to order for a patient with bloating, distention, or belching, Dr. Moshiree said, and since large randomized controlled trials in these patient groups are not available, making evidence-based treatment recommendations is challenging. Because the disorders are ubiquitous, “there’s a lot of social media attention around them, and these include fad diets and drugs labeled as medical foods, like probiotics, that patients will often try.”
The guidance includes 15 best practice advice statements along with two diagnostic and treatment algorithms, one for belching and the other for bloating and distention.
For belching, the authors stress discerning between gastric and supragastric belching using clinical history and examination, and if needed, impedance Ph monitoring. For supragastric belching, or esophageal belching, treatment considerations may include cognitive behavioral therapy, biofeedback training, and neuromodulator (antidepressant) drugs either alone or combined with psychological therapies.
Abdominal bloating and distention should be diagnosed using the Rome IV criteria, and in patients with suspected carbohydrate enzyme deficiencies, dietary restriction of potentially problematic carbohydrates or breath testing may be used to rule out intolerance. In a subset of at-risk patients, “small bowel aspiration and glucose- or lactulose-based hydrogen breath testing may be used to evaluate for small intestinal bacterial overgrowth,” the guidance says. Blood testing may be used to rule out celiac disease, and, if positive, a definitive diagnosis should be confirmed with small bowel tissue biopsy obtained during an upper endoscopy, Dr. Moshiree and her colleagues wrote.
Endoscopy and imaging should be restricted to patients with alarm features such as vomiting or weight loss, rapid worsening of symptoms, or an abnormal physical exam. Tests such as gastric emptying transit studies should not be routinely ordered unless nausea and vomiting are present. Similarly, whole-gut motility studies should be ordered only if there are symptoms suggestive of motility disorders, with testing carried out at specialized centers.
When constipation occurs with bloating, clinicians should use anorectal physiology testing to rule out a pelvic-floor disorder, which, if present, can be treated with pelvic floor biofeedback training. Constipation in the context of bloating may also be treated with laxatives. Probiotics are not advised as treatment for bloating and distention in this guidance, given a lack of robust studies. However, neuromodulators may help reduce visceral or gut hypersensitivity and improve psychological comorbidities if these are present, the authors wrote.
Conditions treated with dietary modifications should be overseen by dietitians, and diaphragmatic breathing and neuromodulators can be used to treat a condition called abdominophrenic dyssynergia, the guidance says.
“We tried to make it clinically useful,” Dr. Moshiree said of the practice update, which was not the result of systematic reviews or meta-analyses of multicenter randomized controlled trials. The update contains no ratings on its recommendations and does not grade the evidence used. Rather, the three coauthors looked to results from published randomized trials and observational studies, along with their own expert opinion.
For example, the guidance’s best practice advice on abdominophrenic dyssynergia came from single center studies in Italy where bloating improved with use of biofeedback therapy for this condition. Although this was a single center study, experts have found that biofeedback therapy is helpful for relaxing the pelvic floor muscles which can help bloating and distension symptoms.
Dr. Moshiree also pointed to a 2021 narrative review by Brian E. Lacy, MD. and David Cangemi, MD, of the Mayo Clinic in Jacksonville, Fla., that helped inform the framework for this clinical practice update.
Dr. Moshiree disclosed financial relationships with several pharmaceutical companies including Salix, AbbVie, Medtronic, and Takeda. Her two coauthors, Douglas Drossman, MD, of the Rome Foundation and the University of North Carolina, Chapel Hill, and Aasma Shaukat, MD, of New York University, also disclosed industry support.
A new Clinical Practice Update from the AGA on belching, abdominal bloating, and distention offers practical management strategies for a class of disorders that, while highly prevalent, can be confusing to clinicians because of their nonspecific and overlapping symptomatology and wide range of possible causes.
The expert review, published online in Gastroenterology, is dedicated to these specific disorders, which, when not caused by bacteria, food intolerance, or autoimmune disease, are increasingly viewed as stemming from dysregulation of the brain-gut axis, and therefore responsive to interventions such as biofeedback therapy and central nervous system modulators, including antidepressants referred to as neuromodulators due to their pain modulating effects in the gut.
Baharak Moshiree, MD, of Atrium Health, Wake Forest Medical University, Charlotte, N.C., the lead author, said the guidance is aimed at GI specialists as much as primary care physicians and other providers who treat patients with these disorders.
Clinicians may not always know which diagnostic studies to order for a patient with bloating, distention, or belching, Dr. Moshiree said, and since large randomized controlled trials in these patient groups are not available, making evidence-based treatment recommendations is challenging. Because the disorders are ubiquitous, “there’s a lot of social media attention around them, and these include fad diets and drugs labeled as medical foods, like probiotics, that patients will often try.”
The guidance includes 15 best practice advice statements along with two diagnostic and treatment algorithms, one for belching and the other for bloating and distention.
For belching, the authors stress discerning between gastric and supragastric belching using clinical history and examination, and if needed, impedance Ph monitoring. For supragastric belching, or esophageal belching, treatment considerations may include cognitive behavioral therapy, biofeedback training, and neuromodulator (antidepressant) drugs either alone or combined with psychological therapies.
Abdominal bloating and distention should be diagnosed using the Rome IV criteria, and in patients with suspected carbohydrate enzyme deficiencies, dietary restriction of potentially problematic carbohydrates or breath testing may be used to rule out intolerance. In a subset of at-risk patients, “small bowel aspiration and glucose- or lactulose-based hydrogen breath testing may be used to evaluate for small intestinal bacterial overgrowth,” the guidance says. Blood testing may be used to rule out celiac disease, and, if positive, a definitive diagnosis should be confirmed with small bowel tissue biopsy obtained during an upper endoscopy, Dr. Moshiree and her colleagues wrote.
Endoscopy and imaging should be restricted to patients with alarm features such as vomiting or weight loss, rapid worsening of symptoms, or an abnormal physical exam. Tests such as gastric emptying transit studies should not be routinely ordered unless nausea and vomiting are present. Similarly, whole-gut motility studies should be ordered only if there are symptoms suggestive of motility disorders, with testing carried out at specialized centers.
When constipation occurs with bloating, clinicians should use anorectal physiology testing to rule out a pelvic-floor disorder, which, if present, can be treated with pelvic floor biofeedback training. Constipation in the context of bloating may also be treated with laxatives. Probiotics are not advised as treatment for bloating and distention in this guidance, given a lack of robust studies. However, neuromodulators may help reduce visceral or gut hypersensitivity and improve psychological comorbidities if these are present, the authors wrote.
Conditions treated with dietary modifications should be overseen by dietitians, and diaphragmatic breathing and neuromodulators can be used to treat a condition called abdominophrenic dyssynergia, the guidance says.
“We tried to make it clinically useful,” Dr. Moshiree said of the practice update, which was not the result of systematic reviews or meta-analyses of multicenter randomized controlled trials. The update contains no ratings on its recommendations and does not grade the evidence used. Rather, the three coauthors looked to results from published randomized trials and observational studies, along with their own expert opinion.
For example, the guidance’s best practice advice on abdominophrenic dyssynergia came from single center studies in Italy where bloating improved with use of biofeedback therapy for this condition. Although this was a single center study, experts have found that biofeedback therapy is helpful for relaxing the pelvic floor muscles which can help bloating and distension symptoms.
Dr. Moshiree also pointed to a 2021 narrative review by Brian E. Lacy, MD. and David Cangemi, MD, of the Mayo Clinic in Jacksonville, Fla., that helped inform the framework for this clinical practice update.
Dr. Moshiree disclosed financial relationships with several pharmaceutical companies including Salix, AbbVie, Medtronic, and Takeda. Her two coauthors, Douglas Drossman, MD, of the Rome Foundation and the University of North Carolina, Chapel Hill, and Aasma Shaukat, MD, of New York University, also disclosed industry support.
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AGA Pick</storyname> <articleType>2</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20230911T140508</QCDate> <firstPublished>20230919T161620</firstPublished> <LastPublished>20230919T161620</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20230919T161620</CMSDate> <articleSource>FROM GASTROENTEROLOGY</articleSource> <facebookInfo/> <meetingNumber/> <byline>Jennie Smith</byline> <bylineText>JENNIE SMITH</bylineText> <bylineFull>JENNIE SMITH</bylineFull> <bylineTitleText>MDedge News</bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType>News</newsDocType> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>A new Clinical Practice Update from the AGA on belching, abdominal bloating, and distention offers practical management strategies for a class of disorders that</metaDescription> <articlePDF/> <teaserImage/> <teaser>The Clinical Practice Update helps untangle which tests are indicated and when for these common conditions.</teaser> <title>AGA CPU stresses brain-gut aspects of bloating, distention and belching</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gih</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">17</term> </publications> <sections> <term>39313</term> <term canonical="true">69</term> </sections> <topics> <term canonical="true">347</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>AGA CPU stresses brain-gut aspects of bloating, distention and belching</title> <deck/> </itemMeta> <itemContent> <p>A new Clinical Practice Update from the AGA on belching, abdominal bloating, and distention offers practical management strategies for a class of disorders that, while highly prevalent, can be confusing to clinicians because of their nonspecific and overlapping symptomatology and wide range of possible causes.</p> <p>The <span class="Hyperlink"><a href="https://www.gastrojournal.org/article/S0016-5085(23)00823-5/fulltext">expert review</a></span>, published online in Gastroenterology, is the first guidance dedicated to these specific disorders, which, when not caused by bacteria, food intolerance, or autoimmune disease, are increasingly viewed as stemming from dysregulation of the brain-gut axis, and therefore responsive to interventions such as biofeedback therapy and central nervous system modulators, including antidepressants referred to as neuromodulators due to their pain modulating effects in the gut.<br/><br/><a href="https://atriumhealth.org/provider-profile/baharak-moshiree-1609979715">Baharak Moshiree</a>, MD, of Atrium Health, Wake Forest Medical University, Charlotte, N.C., the lead author, said the guidance is aimed at GI specialists as much as primary care physicians and other providers who treat patients with these disorders. <br/><br/>Clinicians may not always know which diagnostic studies to order for a patient with bloating, distention, or belching, Dr. Moshiree said, and since large randomized controlled trials in these patient groups are not available, making evidence-based treatment recommendations is challenging. Because the disorders are ubiquitous, “there’s a lot of social media attention around them, and these include fad diets and drugs labeled as medical foods, like probiotics, that patients will often try.” <br/><br/>The guidance includes 15 best practice advice statements along with two diagnostic and treatment algorithms, one for belching and the other for bloating and distention. <br/><br/>For belching, the authors stress discerning between gastric and supragastric belching using clinical history and examination, and if needed, impedance Ph monitoring. For supragastric belching, or esophageal belching, treatment considerations may include cognitive behavioral therapy, biofeedback training, and neuromodulator (antidepressant) drugs either alone or combined with psychological therapies.<br/><br/>Abdominal bloating and distention should be diagnosed using the Rome IV criteria, and in patients with suspected carbohydrate enzyme deficiencies, dietary restriction of potentially problematic carbohydrates or breath testing may be used to rule out intolerance. In a subset of at-risk patients, “small bowel aspiration and glucose- or lactulose-based hydrogen breath testing may be used to evaluate for small intestinal bacterial overgrowth,” the guidance says. Blood testing may be used to rule out celiac disease, and, if positive, a definitive diagnosis should be confirmed with small bowel tissue biopsy obtained during an upper endoscopy, Dr. Moshiree and her colleagues wrote. <br/><br/>Endoscopy and imaging should be restricted to patients with alarm features such as vomiting or weight loss, rapid worsening of symptoms, or an abnormal physical exam. Tests such as gastric emptying transit studies should not be routinely ordered unless nausea and vomiting are present. Similarly, whole-gut motility studies should be ordered only if there are symptoms suggestive of motility disorders, with testing carried out at specialized centers.<br/><br/>When constipation occurs with bloating, clinicians should use anorectal physiology testing to rule out a pelvic-floor disorder, which, if present, can be treated with pelvic floor biofeedback training. Constipation in the context of bloating may also be treated with laxatives. Probiotics are not advised as treatment for bloating and distention in this guidance, given a lack of robust studies. However, neuromodulators may help reduce visceral or gut hypersensitivity and improve psychological comorbidities if these are present, the authors wrote. <br/><br/>Conditions treated with dietary modifications should be overseen by dietitians, and diaphragmatic breathing and neuromodulators can be used to treat a condition called abdominophrenic dyssynergia, the guidance says. <br/><br/>“We tried to make it clinically useful,” Dr. Moshiree said of the practice update, which was not the result of systematic reviews or meta-analyses of multicenter randomized controlled trials. The update contains no ratings on its recommendations and does not grade the evidence used. Rather, the three coauthors looked to results from published randomized trials and observational studies, along with their own expert opinion. <br/><br/>For example, the guidance’s best practice advice on abdominophrenic dyssynergia came from single center studies in Italy where bloating improved with use of biofeedback therapy for this condition. Although this was a single center study, experts have found that biofeedback therapy is helpful for relaxing the pelvic floor muscles which can help bloating and distension symptoms.<br/><br/>Dr. Moshiree also pointed to a 2021 <a href="https://theromefoundation.org/wp-content/uploads/Lacy-article.pdf">narrative review</a> by Brian E. Lacy, MD. and David Cangemi, MD, of the Mayo Clinic in Jacksonville, Fla., that helped inform the framework for this clinical practice update. <br/><br/>Dr. Moshiree disclosed financial relationships with several pharmaceutical companies including Salix, AbbVie, Medtronic, and Takeda. Her two coauthors, Douglas Drossman, MD, of the Rome Foundation and the University of North Carolina, Chapel Hill, and Aasma Shaukat, MD, of New York University, also disclosed industry support.</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM GASTROENTEROLOGY
Hemostatic powder superior in controlling tumor bleeding
The findings, published online in Gastroenterology (2023 Jun 3. doi: 10.1053/j.gastro.2023.05.042), come from the largest randomized trial to date of TC-325 (Hemospray, Cook Medical), compared with standard endoscopic hemostatic interventions for tumor bleeding.
For their research, Rapat Pittayanon, MD, of Chulalongkorn University in Bangkok and her colleagues, randomized patients (60% male, mean age 63) with active malignant upper or lower GI bleeding and low disability levels related to their cancers (ECOG score 0-2). The study was conducted at nine hospitals in Thailand.
The 106 patients who passed screening underwent either TC-325 or standard endoscopic hemostasis, which could involve use of thermal or mechanical methods or adrenaline injection, alone or combined with another modality, at the endoscopist’s discretion. Crossover between treatment allocations was permitted if hemostasis was not achieved. Investigators assessed rates of immediate hemostasis and rebleeding at 30 days.
Dr. Pittayanon and colleagues found rebleeding to be significantly lower among TC-325 treated patients, at 2.1%, compared with 21.3% for standard care (odds ratio, 0.09; 95% confidence interval, 0.01-0.80; P = .03). Rates of immediate hemostasis were 100% for TC-325–treated subjects, compared with 68.6% in the conventional-treatment group (OR, 1.45; 95% CI, 0.93-2.29; P < .001).
None of the 55 patients in the TC-325 group underwent crossover treatment, but 15 patients in the standard care group were crossed over to TC-325 after their endoscopic treatment was deemed to have failed. One-fifth of patients who got TC-325 as a crossover treatment developed rebleeding at 30 days, which the investigators surmised was related to mucosal damage incurred during the endoscopic procedure.
The study was not powered to adequately assess survival outcomes. Seven patients in the TC-325 group and four in the conventional care group died before 30 days’ follow-up, and no death was directly related to recurrent tumor bleeding.
“To our knowledge, our trial is the first to show such significant findings in an RCT setting, which now provide a long-awaited efficacious hemostatic approach where one had been lacking when managing patients with malignant GI bleeding,” the investigators wrote in their analysis.
“Perhaps most importantly, this carefully controlled study also highlights the unreliable hemostatic effect of standard endoscopic modalities available for GI tumor hemostasis, with high 30-day rebleeding rates in our patient population.”
Dr. Pittayanon and colleagues noted several limitations of their study. These included the inability to blind patients to an endoscopist, which “may have influenced subsequent management decisions … including the decision to cross over.”
Only in 5 of 15 cases of crossover did the treating endoscopist provide photo evidence of treatment failure as required by the trial’s protocol. Also, the use of adrenaline injection alone was permitted in the study, in contrast to best practice guidelines for endoscopic hemostasis to treat peptic ulcer bleeding. Finally, the study was conducted in Thailand, potentially reducing the generalizability of the results.
The study was funded by King Chulalongkorn Memorial Hospital; the Thai Red Cross; and Chulalongkorn University. Cook Medical donated some of the TC-325 kits used in the study.
One study coauthor, Alan N. Barkun, disclosed consulting work for Medtronic and past paid work for Cook Medical. The remaining authors disclosed no conflicts of interest.
Gastrointestinal tumor bleeding is a challenging problem that can lead to prolonged hospitalization and interruption of curative or palliative oncologic interventions. Standard endoscopic hemostasis interventions, such as subepithelial epinephrine injection and mechanical and thermal treatments, can be limited because of the underlying tumor biology that alters angiogenesis, distorts the surrounding mucosa, and undermines the normal coagulation process. This randomized trial by Pittayanon et al. demonstrated that the hemostatic powder TC-325 (Hemospray, Cook Medical) was superior to standard endoscopic intervention in achieving immediate hemostasis (100% vs. 69%) and reducing 30-day rebleeding rate (2% vs. 21%).
[[{"fid":"297525","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"}},"attributes":{"alt":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","class":"media-element file-medstat-image-flush-right","data-delta":"1"}}]]Hemostatic powder has been shown to be a useful tool in managing nonmalignant GI bleeds, and recent studies have supported its role in GI tumor bleeding. The nonabsorbable granules adhere to the actively bleeding site and then pull water from the vessels to stimulate the normal coagulation pathway. Its noncontact, easy to use application and ability to treat a wide defect area make it an appealing first-line treatment option in this setting. Several other hemostatic powders are available including Nexpowder Endoscopic Hemostasis System (UI-EW, Nextbiomedical) and Endoclot Polysaccharide Hemostatic System (Endoclot Plus, Santa Clara, Calif.). As the use of hemostatic powder becomes more popular, we need to be mindful of its contraindications, namely fistulas, active perforation, or lesions that are high risk for perforation because the pressure generated during application can exacerbate a transmural defect, although this adverse event is rare.
As clinicians and endoscopists, our ultimate goals in treating GI tumor bleeding are to provide safe and efficient hemostasis, to decrease hospital stay and to minimize delay and interruption of oncologic or palliative treatments. This study advocates that TC-325 may be a better primary option than standard endoscopic treatments for GI tumor bleeding in the appropriate setting. Safety, efficacy, and feasibility studies comparing TC-325 to the other hemostatic powder products are needed.
Malorie K. Simons, MD, is an interventional endoscopist with Fox Chase Cancer Center, Temple University Health System, Philadelphia. She specializes in colorectal cancer, esophageal cancer, and gastric cancer. She has no conflicts of interest.
Gastrointestinal tumor bleeding is a challenging problem that can lead to prolonged hospitalization and interruption of curative or palliative oncologic interventions. Standard endoscopic hemostasis interventions, such as subepithelial epinephrine injection and mechanical and thermal treatments, can be limited because of the underlying tumor biology that alters angiogenesis, distorts the surrounding mucosa, and undermines the normal coagulation process. This randomized trial by Pittayanon et al. demonstrated that the hemostatic powder TC-325 (Hemospray, Cook Medical) was superior to standard endoscopic intervention in achieving immediate hemostasis (100% vs. 69%) and reducing 30-day rebleeding rate (2% vs. 21%).
[[{"fid":"297525","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"}},"attributes":{"alt":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","class":"media-element file-medstat-image-flush-right","data-delta":"1"}}]]Hemostatic powder has been shown to be a useful tool in managing nonmalignant GI bleeds, and recent studies have supported its role in GI tumor bleeding. The nonabsorbable granules adhere to the actively bleeding site and then pull water from the vessels to stimulate the normal coagulation pathway. Its noncontact, easy to use application and ability to treat a wide defect area make it an appealing first-line treatment option in this setting. Several other hemostatic powders are available including Nexpowder Endoscopic Hemostasis System (UI-EW, Nextbiomedical) and Endoclot Polysaccharide Hemostatic System (Endoclot Plus, Santa Clara, Calif.). As the use of hemostatic powder becomes more popular, we need to be mindful of its contraindications, namely fistulas, active perforation, or lesions that are high risk for perforation because the pressure generated during application can exacerbate a transmural defect, although this adverse event is rare.
As clinicians and endoscopists, our ultimate goals in treating GI tumor bleeding are to provide safe and efficient hemostasis, to decrease hospital stay and to minimize delay and interruption of oncologic or palliative treatments. This study advocates that TC-325 may be a better primary option than standard endoscopic treatments for GI tumor bleeding in the appropriate setting. Safety, efficacy, and feasibility studies comparing TC-325 to the other hemostatic powder products are needed.
Malorie K. Simons, MD, is an interventional endoscopist with Fox Chase Cancer Center, Temple University Health System, Philadelphia. She specializes in colorectal cancer, esophageal cancer, and gastric cancer. She has no conflicts of interest.
Gastrointestinal tumor bleeding is a challenging problem that can lead to prolonged hospitalization and interruption of curative or palliative oncologic interventions. Standard endoscopic hemostasis interventions, such as subepithelial epinephrine injection and mechanical and thermal treatments, can be limited because of the underlying tumor biology that alters angiogenesis, distorts the surrounding mucosa, and undermines the normal coagulation process. This randomized trial by Pittayanon et al. demonstrated that the hemostatic powder TC-325 (Hemospray, Cook Medical) was superior to standard endoscopic intervention in achieving immediate hemostasis (100% vs. 69%) and reducing 30-day rebleeding rate (2% vs. 21%).
[[{"fid":"297525","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"}},"attributes":{"alt":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","class":"media-element file-medstat-image-flush-right","data-delta":"1"}}]]Hemostatic powder has been shown to be a useful tool in managing nonmalignant GI bleeds, and recent studies have supported its role in GI tumor bleeding. The nonabsorbable granules adhere to the actively bleeding site and then pull water from the vessels to stimulate the normal coagulation pathway. Its noncontact, easy to use application and ability to treat a wide defect area make it an appealing first-line treatment option in this setting. Several other hemostatic powders are available including Nexpowder Endoscopic Hemostasis System (UI-EW, Nextbiomedical) and Endoclot Polysaccharide Hemostatic System (Endoclot Plus, Santa Clara, Calif.). As the use of hemostatic powder becomes more popular, we need to be mindful of its contraindications, namely fistulas, active perforation, or lesions that are high risk for perforation because the pressure generated during application can exacerbate a transmural defect, although this adverse event is rare.
As clinicians and endoscopists, our ultimate goals in treating GI tumor bleeding are to provide safe and efficient hemostasis, to decrease hospital stay and to minimize delay and interruption of oncologic or palliative treatments. This study advocates that TC-325 may be a better primary option than standard endoscopic treatments for GI tumor bleeding in the appropriate setting. Safety, efficacy, and feasibility studies comparing TC-325 to the other hemostatic powder products are needed.
Malorie K. Simons, MD, is an interventional endoscopist with Fox Chase Cancer Center, Temple University Health System, Philadelphia. She specializes in colorectal cancer, esophageal cancer, and gastric cancer. She has no conflicts of interest.
The findings, published online in Gastroenterology (2023 Jun 3. doi: 10.1053/j.gastro.2023.05.042), come from the largest randomized trial to date of TC-325 (Hemospray, Cook Medical), compared with standard endoscopic hemostatic interventions for tumor bleeding.
For their research, Rapat Pittayanon, MD, of Chulalongkorn University in Bangkok and her colleagues, randomized patients (60% male, mean age 63) with active malignant upper or lower GI bleeding and low disability levels related to their cancers (ECOG score 0-2). The study was conducted at nine hospitals in Thailand.
The 106 patients who passed screening underwent either TC-325 or standard endoscopic hemostasis, which could involve use of thermal or mechanical methods or adrenaline injection, alone or combined with another modality, at the endoscopist’s discretion. Crossover between treatment allocations was permitted if hemostasis was not achieved. Investigators assessed rates of immediate hemostasis and rebleeding at 30 days.
Dr. Pittayanon and colleagues found rebleeding to be significantly lower among TC-325 treated patients, at 2.1%, compared with 21.3% for standard care (odds ratio, 0.09; 95% confidence interval, 0.01-0.80; P = .03). Rates of immediate hemostasis were 100% for TC-325–treated subjects, compared with 68.6% in the conventional-treatment group (OR, 1.45; 95% CI, 0.93-2.29; P < .001).
None of the 55 patients in the TC-325 group underwent crossover treatment, but 15 patients in the standard care group were crossed over to TC-325 after their endoscopic treatment was deemed to have failed. One-fifth of patients who got TC-325 as a crossover treatment developed rebleeding at 30 days, which the investigators surmised was related to mucosal damage incurred during the endoscopic procedure.
The study was not powered to adequately assess survival outcomes. Seven patients in the TC-325 group and four in the conventional care group died before 30 days’ follow-up, and no death was directly related to recurrent tumor bleeding.
“To our knowledge, our trial is the first to show such significant findings in an RCT setting, which now provide a long-awaited efficacious hemostatic approach where one had been lacking when managing patients with malignant GI bleeding,” the investigators wrote in their analysis.
“Perhaps most importantly, this carefully controlled study also highlights the unreliable hemostatic effect of standard endoscopic modalities available for GI tumor hemostasis, with high 30-day rebleeding rates in our patient population.”
Dr. Pittayanon and colleagues noted several limitations of their study. These included the inability to blind patients to an endoscopist, which “may have influenced subsequent management decisions … including the decision to cross over.”
Only in 5 of 15 cases of crossover did the treating endoscopist provide photo evidence of treatment failure as required by the trial’s protocol. Also, the use of adrenaline injection alone was permitted in the study, in contrast to best practice guidelines for endoscopic hemostasis to treat peptic ulcer bleeding. Finally, the study was conducted in Thailand, potentially reducing the generalizability of the results.
The study was funded by King Chulalongkorn Memorial Hospital; the Thai Red Cross; and Chulalongkorn University. Cook Medical donated some of the TC-325 kits used in the study.
One study coauthor, Alan N. Barkun, disclosed consulting work for Medtronic and past paid work for Cook Medical. The remaining authors disclosed no conflicts of interest.
The findings, published online in Gastroenterology (2023 Jun 3. doi: 10.1053/j.gastro.2023.05.042), come from the largest randomized trial to date of TC-325 (Hemospray, Cook Medical), compared with standard endoscopic hemostatic interventions for tumor bleeding.
For their research, Rapat Pittayanon, MD, of Chulalongkorn University in Bangkok and her colleagues, randomized patients (60% male, mean age 63) with active malignant upper or lower GI bleeding and low disability levels related to their cancers (ECOG score 0-2). The study was conducted at nine hospitals in Thailand.
The 106 patients who passed screening underwent either TC-325 or standard endoscopic hemostasis, which could involve use of thermal or mechanical methods or adrenaline injection, alone or combined with another modality, at the endoscopist’s discretion. Crossover between treatment allocations was permitted if hemostasis was not achieved. Investigators assessed rates of immediate hemostasis and rebleeding at 30 days.
Dr. Pittayanon and colleagues found rebleeding to be significantly lower among TC-325 treated patients, at 2.1%, compared with 21.3% for standard care (odds ratio, 0.09; 95% confidence interval, 0.01-0.80; P = .03). Rates of immediate hemostasis were 100% for TC-325–treated subjects, compared with 68.6% in the conventional-treatment group (OR, 1.45; 95% CI, 0.93-2.29; P < .001).
None of the 55 patients in the TC-325 group underwent crossover treatment, but 15 patients in the standard care group were crossed over to TC-325 after their endoscopic treatment was deemed to have failed. One-fifth of patients who got TC-325 as a crossover treatment developed rebleeding at 30 days, which the investigators surmised was related to mucosal damage incurred during the endoscopic procedure.
The study was not powered to adequately assess survival outcomes. Seven patients in the TC-325 group and four in the conventional care group died before 30 days’ follow-up, and no death was directly related to recurrent tumor bleeding.
“To our knowledge, our trial is the first to show such significant findings in an RCT setting, which now provide a long-awaited efficacious hemostatic approach where one had been lacking when managing patients with malignant GI bleeding,” the investigators wrote in their analysis.
“Perhaps most importantly, this carefully controlled study also highlights the unreliable hemostatic effect of standard endoscopic modalities available for GI tumor hemostasis, with high 30-day rebleeding rates in our patient population.”
Dr. Pittayanon and colleagues noted several limitations of their study. These included the inability to blind patients to an endoscopist, which “may have influenced subsequent management decisions … including the decision to cross over.”
Only in 5 of 15 cases of crossover did the treating endoscopist provide photo evidence of treatment failure as required by the trial’s protocol. Also, the use of adrenaline injection alone was permitted in the study, in contrast to best practice guidelines for endoscopic hemostasis to treat peptic ulcer bleeding. Finally, the study was conducted in Thailand, potentially reducing the generalizability of the results.
The study was funded by King Chulalongkorn Memorial Hospital; the Thai Red Cross; and Chulalongkorn University. Cook Medical donated some of the TC-325 kits used in the study.
One study coauthor, Alan N. Barkun, disclosed consulting work for Medtronic and past paid work for Cook Medical. The remaining authors disclosed no conflicts of interest.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>164568</fileName> <TBEID>0C04B840.SIG</TBEID> <TBUniqueIdentifier>MD_0C04B840</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname>Needed 9/11 GI Sept AGA Pick</storyname> <articleType>2</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20230911T133849</QCDate> <firstPublished>20230911T133946</firstPublished> <LastPublished>20230911T133946</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20230911T133946</CMSDate> <articleSource>FROM GASTROENTEROLOGY</articleSource> <facebookInfo/> <meetingNumber/> <byline>Jennie Smith</byline> <bylineText>JENNIE SMITH</bylineText> <bylineFull>JENNIE SMITH</bylineFull> <bylineTitleText>MDedge News</bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType>News</newsDocType> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>A hemostatic powder was shown superior to standard endoscopic treatment in stopping and preventing recurrence of gastrointestinal bleeding caused by malignant t</metaDescription> <articlePDF/> <teaserImage>297525</teaserImage> <teaser>Standard endoscopic interventions resulted in lower rates of immediate hemostasis and more rebleeds.</teaser> <title>Hemostatic powder superior in controlling tumor bleeding</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gih</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">17</term> </publications> <sections> <term canonical="true">69</term> <term>39313</term> </sections> <topics> <term canonical="true">344</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/240121cb.jpg</altRep> <description role="drol:caption">Dr. Malorie K. Simons</description> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Hemostatic powder superior in controlling tumor bleeding</title> <deck/> </itemMeta> <itemContent> <p> <span class="tag metaDescription">A hemostatic powder was shown superior to standard endoscopic treatment in stopping and preventing recurrence of gastrointestinal bleeding caused by malignant tumors. </span> </p> <p><a href="https://www.gastrojournal.org/article/S0016-5085(23)00815-6/fulltext">The findings</a>, published online in Gastroenterology (2023 Jun 3. doi: 10.1053/j.gastro.2023.05.042), come from the largest <span class="Hyperlink"><a href="https://classic.clinicaltrials.gov/ct2/show/NCT02534571">randomized trial to date of TC-325</a></span> (Hemospray, Cook Medical), compared with standard endoscopic hemostatic interventions for tumor bleeding. <br/><br/>For their research, <a href="https://www.research.chula.ac.th/researcher-/rapat-pittayanon/">Rapat Pittayanon</a>, MD, of Chulalongkorn University in Bangkok and her colleagues, randomized patients (60% male, mean age 63) with active malignant upper or lower GI bleeding and low disability levels related to their cancers (ECOG score 0-2). The study was conducted at nine hospitals in Thailand.<br/><br/>The 106 patients who passed screening underwent either TC-325 or standard endoscopic hemostasis, which could involve use of thermal or mechanical methods or adrenaline injection, alone or combined with another modality, at the endoscopist’s discretion. Crossover between treatment allocations was permitted if hemostasis was not achieved. Investigators assessed rates of immediate hemostasis and rebleeding at 30 days. <br/><br/>Dr. Pittayanon and colleagues found rebleeding to be significantly lower among TC-325 treated patients, at 2.1%, compared with 21.3% for standard care (odds ratio, 0.09; 95% confidence interval, 0.01-0.80; <em>P</em> = .03). Rates of immediate hemostasis were 100% for TC-325–treated subjects, compared with 68.6% in the conventional-treatment group (OR, 1.45; 95% CI, 0.93-2.29; <em>P</em> < .001). <br/><br/>None of the 55 patients in the TC-325 group underwent crossover treatment, but 15 patients in the standard care group were crossed over to TC-325 after their endoscopic treatment was deemed to have failed. One-fifth of patients who got TC-325 as a crossover treatment developed rebleeding at 30 days, which the investigators surmised was related to mucosal damage incurred during the endoscopic procedure. <br/><br/>The study was not powered to adequately assess survival outcomes. Seven patients in the TC-325 group and four in the conventional care group died before 30 days’ follow-up, and no death was directly related to recurrent tumor bleeding. <br/><br/>“To our knowledge, our trial is the first to show such significant findings in an RCT setting, which now provide a long-awaited efficacious hemostatic approach where one had been lacking when managing patients with malignant GI bleeding,” the investigators wrote in their analysis. <br/><br/>“Perhaps most importantly, this carefully controlled study also highlights the unreliable hemostatic effect of standard endoscopic modalities available for GI tumor hemostasis, with high 30-day rebleeding rates in our patient population.” <br/><br/>Dr. Pittayanon and colleagues noted several limitations of their study. These included the inability to blind patients to an endoscopist, which “may have influenced subsequent management decisions … including the decision to cross over.” <br/><br/>Only in 5 of 15 cases of crossover did the treating endoscopist provide photo evidence of treatment failure as required by the trial’s protocol. Also, the use of adrenaline injection alone was permitted in the study, in contrast to best practice guidelines for endoscopic hemostasis to treat peptic ulcer bleeding. Finally, the study was conducted in Thailand, potentially reducing the generalizability of the results. <br/><br/>The study was funded by King Chulalongkorn Memorial Hospital; the Thai Red Cross; and Chulalongkorn University. Cook Medical donated some of the TC-325 kits used in the study. <br/><br/>One study coauthor, Alan N. Barkun, disclosed consulting work for Medtronic and past paid work for Cook Medical. The remaining authors disclosed no conflicts of interest.<span class="end"/> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>views</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>Gastrointestinal tumor bleeding is a challenging problem that can lead to prolonged hospitalization and interruption of curative or palliative oncologic interventions. Standard endoscopic hemostasis interventions, such as subepithelial epinephrine injection and mechanical and thermal treatments, can be limited because of the underlying tumor biology that alters angiogenesis, distorts the surrounding mucosa, and undermines the normal coagulation process. This randomized trial by Pittayanon et al. demonstrated that the hemostatic powder TC-325 (Hemospray, Cook Medical) was superior to standard endoscopic intervention in achieving immediate hemostasis (100% vs. 69%) and reducing 30-day rebleeding rate (2% vs. 21%). </p> <p>[[{"fid":"297525","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Malorie K. Simons, MD, Interventional Endoscopist at Fox Chase Cancer Center, Philadelphia","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Malorie K. Simons"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]Hemostatic powder has been shown to be a useful tool in managing nonmalignant GI bleeds, and recent studies have supported its role in GI tumor bleeding. The nonabsorbable granules adhere to the actively bleeding site and then pull water from the vessels to stimulate the normal coagulation pathway. Its noncontact, easy to use application and ability to treat a wide defect area make it an appealing first-line treatment option in this setting. Several other hemostatic powders are available including Nexpowder Endoscopic Hemostasis System (UI-EW, Nextbiomedical) and Endoclot Polysaccharide Hemostatic System (Endoclot Plus, Santa Clara, Calif.). As the use of hemostatic powder becomes more popular, we need to be mindful of its contraindications, namely fistulas, active perforation, or lesions that are high risk for perforation because the pressure generated during application can exacerbate a transmural defect, although this adverse event is rare. <br/><br/>As clinicians and endoscopists, our ultimate goals in treating GI tumor bleeding are to provide safe and efficient hemostasis, to decrease hospital stay and to minimize delay and interruption of oncologic or palliative treatments. This study advocates that TC-325 may be a better primary option than standard endoscopic treatments for GI tumor bleeding in the appropriate setting. Safety, efficacy, and feasibility studies comparing TC-325 to the other hemostatic powder products are needed.</p> <p> <em>Malorie K. Simons, MD, is an interventional endoscopist with Fox Chase Cancer Center, Temple University Health System, Philadelphia. She specializes in colorectal cancer, esophageal cancer, and gastric cancer. She has no conflicts of interest.</em> </p> </itemContent> </newsItem> </itemSet></root>
FROM GASTROENTEROLOGY
Crohn’s link seen for ultraprocessed foods
Ultraprocessed foods contain large amounts of artificial flavors, stabilizers, emulsifiers, sweeteners, or preservatives. Studies have linked higher consumption of them to cardiovascular disease, diabetes, obesity, and cancers.
For their research, published in Clinical Gastroenterology and Hepatology, Neeraj Nerula, MD of McMaster University, Hamilton, Ont., and colleagues pooled data from five recent cohort studies to assess whether their consumption was also linked to inflammatory bowel disease.
The included cohort studies together enrolled more than 1 million participants (mean age, 43-56; 55%-85% female). Of these, 916 developed Crohn’s disease, and 1,934 developed ulcerative colitis, during follow-up. None of the participants had IBD at baseline, and all were followed up at least 1 year. All the studies used the same food classification system, called NOVA, to assess foods eaten, and all were conducted between 2020 and 2022.
People who consumed more ultraprocessed foods saw higher Crohn’s risk, compared with those classed as consuming lower amounts of these foods (hazard ratio, 1.71; 95% confidence interval, 1.37-2.14). Also, lower risk of Crohn’s was observed among participants who consumed more unprocessed or minimally processed foods, such as vegetables, chicken, milk, and eggs (HR, 0.71; 95% CI, 0.53-0.94). The same associations were not seen for ulcerative colitis.
“Our findings support the hypothesis that consumption of [ultraprocessed foods] and low consumption of unprocessed/minimally processed foods may increase the risk for CD,” Dr. Nerula and colleagues wrote. The lack of association seen with ulcerative colitis might be explained by differences in the pathogenesis of each disease.
Ultraprocessed foods might contribute to Crohn’s by disrupting gut microbiota, the authors wrote. “For instance, emulsifiers have been shown to increase epithelial permeability, disruption of the intestinal barrier, and gut dysbiosis in mice. Carboxymethyl cellulose has been shown to facilitate bacterial adherence to gut epithelium, possibly leading to bacterial overgrowth and invasion of bacteria in between the intestinal villi. Furthermore, additives such as carrageenan, titanium dioxide, and maltodextrin have been shown to promote intestinal inflammation.”
Dr. Nerula and colleagues described as strengths of their study its large size, the low heterogenicity of the included studies, and the use of validated, standardized questionnaires to measure dietary intake in each study. Nonetheless, they cautioned, the results might not apply to younger age groups, and the majority of participants were White North Americans and Europeans, making it difficult to generalize results.
“Advancements in food processing and associated changes in dietary patterns could explain the rise of IBD incidence during the 20th and 21st centuries,” Dr. Narula and colleagues concluded. “Further investigations are needed to identify the specific potential culprits among processed foods that could account for the increased risk of CD observed.”
The study authors did not report outside funding. Dr. Narula disclosed receiving fees from pharmaceutical manufacturers including Janssen, AbbVie, Takeda, Pfizer, Merck, and others. Two of coauthors also disclosed receiving funds from industry, and five additional coauthors had no conflicts.
The causes of inflammatory bowel disease (IBD) are thought to be multifactorial and include genetic predisposition, dysregulated immune responses, imbalances in the intestinal microbiota, and environmental exposures.
Incidence and prevalence of IBD has increased over time, including in developing countries, and appear to parallel industrialization and “Westernization” of societies. One of the potential contributors to IBD risk is diet. Dietary changes associated with more modern or “Westernized” diets, including increases in processed foods, are some of the factors hypothesized to contribute to rising rates of IBD.
[[{"fid":"297033","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"}},"attributes":{"alt":"Ryan C Ungaro, MD","class":"media-element file-medstat-image-flush-right","data-delta":"1"}}]]There is accumulating data that certain diets, such as the Mediterranean diet, may have beneficial effects in established Crohn’s disease (CD) and ulcerative colitis (UC).
In the meta-analysis by Narula and colleagues, the authors observed a significant increase in the risk of CD, but not UC, in individuals who consumed significantly higher amounts of ultraprocessed foods (that is, frozen or long-shelf-life foods, products with thickeners/emulsifiers, etc.). Although there are limitations to the studies included in the meta-analysis, the association is intriguing and could point to potential lifestyle modifications that could form the basis of preventative interventions for individuals at higher risk for IBD, such as first-degree relatives.
More immediately, prospective research is needed to understand if restricting ultraprocessed foods (or increasing less-processed foods) can decrease disease activity or prevent flares in patients with IBD.
Understanding factors that predispose to or trigger IBD, such as specific dietary components, will lead to improved management strategies and ultimately preventative interventions.
Ryan Ungaro, MD, MS, is an associate professor of medicine in the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York. He is director of the Comprehensive Care for the Recently Diagnosed IBD Patient (COMPASS-IBD). He has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Celltrion, Lilly, Janssen, Pfizer, Roivant, and Takeda, and has received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lily, and Pfizer.
The causes of inflammatory bowel disease (IBD) are thought to be multifactorial and include genetic predisposition, dysregulated immune responses, imbalances in the intestinal microbiota, and environmental exposures.
Incidence and prevalence of IBD has increased over time, including in developing countries, and appear to parallel industrialization and “Westernization” of societies. One of the potential contributors to IBD risk is diet. Dietary changes associated with more modern or “Westernized” diets, including increases in processed foods, are some of the factors hypothesized to contribute to rising rates of IBD.
[[{"fid":"297033","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"}},"attributes":{"alt":"Ryan C Ungaro, MD","class":"media-element file-medstat-image-flush-right","data-delta":"1"}}]]There is accumulating data that certain diets, such as the Mediterranean diet, may have beneficial effects in established Crohn’s disease (CD) and ulcerative colitis (UC).
In the meta-analysis by Narula and colleagues, the authors observed a significant increase in the risk of CD, but not UC, in individuals who consumed significantly higher amounts of ultraprocessed foods (that is, frozen or long-shelf-life foods, products with thickeners/emulsifiers, etc.). Although there are limitations to the studies included in the meta-analysis, the association is intriguing and could point to potential lifestyle modifications that could form the basis of preventative interventions for individuals at higher risk for IBD, such as first-degree relatives.
More immediately, prospective research is needed to understand if restricting ultraprocessed foods (or increasing less-processed foods) can decrease disease activity or prevent flares in patients with IBD.
Understanding factors that predispose to or trigger IBD, such as specific dietary components, will lead to improved management strategies and ultimately preventative interventions.
Ryan Ungaro, MD, MS, is an associate professor of medicine in the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York. He is director of the Comprehensive Care for the Recently Diagnosed IBD Patient (COMPASS-IBD). He has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Celltrion, Lilly, Janssen, Pfizer, Roivant, and Takeda, and has received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lily, and Pfizer.
The causes of inflammatory bowel disease (IBD) are thought to be multifactorial and include genetic predisposition, dysregulated immune responses, imbalances in the intestinal microbiota, and environmental exposures.
Incidence and prevalence of IBD has increased over time, including in developing countries, and appear to parallel industrialization and “Westernization” of societies. One of the potential contributors to IBD risk is diet. Dietary changes associated with more modern or “Westernized” diets, including increases in processed foods, are some of the factors hypothesized to contribute to rising rates of IBD.
[[{"fid":"297033","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"},"type":"media","field_deltas":{"1":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"}},"attributes":{"alt":"Ryan C Ungaro, MD","class":"media-element file-medstat-image-flush-right","data-delta":"1"}}]]There is accumulating data that certain diets, such as the Mediterranean diet, may have beneficial effects in established Crohn’s disease (CD) and ulcerative colitis (UC).
In the meta-analysis by Narula and colleagues, the authors observed a significant increase in the risk of CD, but not UC, in individuals who consumed significantly higher amounts of ultraprocessed foods (that is, frozen or long-shelf-life foods, products with thickeners/emulsifiers, etc.). Although there are limitations to the studies included in the meta-analysis, the association is intriguing and could point to potential lifestyle modifications that could form the basis of preventative interventions for individuals at higher risk for IBD, such as first-degree relatives.
More immediately, prospective research is needed to understand if restricting ultraprocessed foods (or increasing less-processed foods) can decrease disease activity or prevent flares in patients with IBD.
Understanding factors that predispose to or trigger IBD, such as specific dietary components, will lead to improved management strategies and ultimately preventative interventions.
Ryan Ungaro, MD, MS, is an associate professor of medicine in the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York. He is director of the Comprehensive Care for the Recently Diagnosed IBD Patient (COMPASS-IBD). He has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Celltrion, Lilly, Janssen, Pfizer, Roivant, and Takeda, and has received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lily, and Pfizer.
Ultraprocessed foods contain large amounts of artificial flavors, stabilizers, emulsifiers, sweeteners, or preservatives. Studies have linked higher consumption of them to cardiovascular disease, diabetes, obesity, and cancers.
For their research, published in Clinical Gastroenterology and Hepatology, Neeraj Nerula, MD of McMaster University, Hamilton, Ont., and colleagues pooled data from five recent cohort studies to assess whether their consumption was also linked to inflammatory bowel disease.
The included cohort studies together enrolled more than 1 million participants (mean age, 43-56; 55%-85% female). Of these, 916 developed Crohn’s disease, and 1,934 developed ulcerative colitis, during follow-up. None of the participants had IBD at baseline, and all were followed up at least 1 year. All the studies used the same food classification system, called NOVA, to assess foods eaten, and all were conducted between 2020 and 2022.
People who consumed more ultraprocessed foods saw higher Crohn’s risk, compared with those classed as consuming lower amounts of these foods (hazard ratio, 1.71; 95% confidence interval, 1.37-2.14). Also, lower risk of Crohn’s was observed among participants who consumed more unprocessed or minimally processed foods, such as vegetables, chicken, milk, and eggs (HR, 0.71; 95% CI, 0.53-0.94). The same associations were not seen for ulcerative colitis.
“Our findings support the hypothesis that consumption of [ultraprocessed foods] and low consumption of unprocessed/minimally processed foods may increase the risk for CD,” Dr. Nerula and colleagues wrote. The lack of association seen with ulcerative colitis might be explained by differences in the pathogenesis of each disease.
Ultraprocessed foods might contribute to Crohn’s by disrupting gut microbiota, the authors wrote. “For instance, emulsifiers have been shown to increase epithelial permeability, disruption of the intestinal barrier, and gut dysbiosis in mice. Carboxymethyl cellulose has been shown to facilitate bacterial adherence to gut epithelium, possibly leading to bacterial overgrowth and invasion of bacteria in between the intestinal villi. Furthermore, additives such as carrageenan, titanium dioxide, and maltodextrin have been shown to promote intestinal inflammation.”
Dr. Nerula and colleagues described as strengths of their study its large size, the low heterogenicity of the included studies, and the use of validated, standardized questionnaires to measure dietary intake in each study. Nonetheless, they cautioned, the results might not apply to younger age groups, and the majority of participants were White North Americans and Europeans, making it difficult to generalize results.
“Advancements in food processing and associated changes in dietary patterns could explain the rise of IBD incidence during the 20th and 21st centuries,” Dr. Narula and colleagues concluded. “Further investigations are needed to identify the specific potential culprits among processed foods that could account for the increased risk of CD observed.”
The study authors did not report outside funding. Dr. Narula disclosed receiving fees from pharmaceutical manufacturers including Janssen, AbbVie, Takeda, Pfizer, Merck, and others. Two of coauthors also disclosed receiving funds from industry, and five additional coauthors had no conflicts.
Ultraprocessed foods contain large amounts of artificial flavors, stabilizers, emulsifiers, sweeteners, or preservatives. Studies have linked higher consumption of them to cardiovascular disease, diabetes, obesity, and cancers.
For their research, published in Clinical Gastroenterology and Hepatology, Neeraj Nerula, MD of McMaster University, Hamilton, Ont., and colleagues pooled data from five recent cohort studies to assess whether their consumption was also linked to inflammatory bowel disease.
The included cohort studies together enrolled more than 1 million participants (mean age, 43-56; 55%-85% female). Of these, 916 developed Crohn’s disease, and 1,934 developed ulcerative colitis, during follow-up. None of the participants had IBD at baseline, and all were followed up at least 1 year. All the studies used the same food classification system, called NOVA, to assess foods eaten, and all were conducted between 2020 and 2022.
People who consumed more ultraprocessed foods saw higher Crohn’s risk, compared with those classed as consuming lower amounts of these foods (hazard ratio, 1.71; 95% confidence interval, 1.37-2.14). Also, lower risk of Crohn’s was observed among participants who consumed more unprocessed or minimally processed foods, such as vegetables, chicken, milk, and eggs (HR, 0.71; 95% CI, 0.53-0.94). The same associations were not seen for ulcerative colitis.
“Our findings support the hypothesis that consumption of [ultraprocessed foods] and low consumption of unprocessed/minimally processed foods may increase the risk for CD,” Dr. Nerula and colleagues wrote. The lack of association seen with ulcerative colitis might be explained by differences in the pathogenesis of each disease.
Ultraprocessed foods might contribute to Crohn’s by disrupting gut microbiota, the authors wrote. “For instance, emulsifiers have been shown to increase epithelial permeability, disruption of the intestinal barrier, and gut dysbiosis in mice. Carboxymethyl cellulose has been shown to facilitate bacterial adherence to gut epithelium, possibly leading to bacterial overgrowth and invasion of bacteria in between the intestinal villi. Furthermore, additives such as carrageenan, titanium dioxide, and maltodextrin have been shown to promote intestinal inflammation.”
Dr. Nerula and colleagues described as strengths of their study its large size, the low heterogenicity of the included studies, and the use of validated, standardized questionnaires to measure dietary intake in each study. Nonetheless, they cautioned, the results might not apply to younger age groups, and the majority of participants were White North Americans and Europeans, making it difficult to generalize results.
“Advancements in food processing and associated changes in dietary patterns could explain the rise of IBD incidence during the 20th and 21st centuries,” Dr. Narula and colleagues concluded. “Further investigations are needed to identify the specific potential culprits among processed foods that could account for the increased risk of CD observed.”
The study authors did not report outside funding. Dr. Narula disclosed receiving fees from pharmaceutical manufacturers including Janssen, AbbVie, Takeda, Pfizer, Merck, and others. Two of coauthors also disclosed receiving funds from industry, and five additional coauthors had no conflicts.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>High consumption of ultraprocessed foods increases the risk of developing Crohn’s disease, according to results from a large meta-analysis, but not ulcerative c</metaDescription> <articlePDF/> <teaserImage>297033</teaserImage> <teaser>A meta-analysis of longitudinal cohort studies showed that people who consumed more ultraprocessed foods saw higher incidence of Crohn’s.</teaser> <title>Crohn’s link seen for ultraprocessed foods</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>gih</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">17</term> </publications> <sections> <term canonical="true">69</term> <term>39313</term> </sections> <topics> <term canonical="true">345</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/240120dd.jpg</altRep> <description role="drol:caption">Dr. Ryan Ungaro</description> <description role="drol:credit">courtesy Mount Sinai Health System</description> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Crohn’s link seen for ultraprocessed foods</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">High consumption of ultraprocessed foods increases the risk of developing Crohn’s disease, according to results from a large meta-analysis, but not ulcerative colitis.</span> </p> <p>Ultraprocessed foods contain large amounts of artificial flavors, stabilizers, emulsifiers, sweeteners, or preservatives. Studies have linked higher consumption of them to cardiovascular disease, diabetes, obesity, and cancers.<br/><br/>For their <a href="https://www.cghjournal.org/article/S1542-3565(23)00071-X/fulltext">research</a>, published in Clinical Gastroenterology and Hepatology, <a href="https://experts.mcmaster.ca/display/narulan">Neeraj Nerula, MD</a> of McMaster University, Hamilton, Ont., and colleagues pooled data from five recent cohort studies to assess whether their consumption was also linked to inflammatory bowel disease.<br/><br/>The included cohort studies together enrolled more than 1 million participants (mean age, 43-56; 55%-85% female). Of these, 916 developed Crohn’s disease, and 1,934 developed ulcerative colitis, during follow-up. None of the participants had IBD at baseline, and all were followed up at least 1 year. All the studies used the same food classification system, called NOVA, to assess foods eaten, and all were conducted between 2020 and 2022.<br/><br/>People who consumed more ultraprocessed foods saw higher Crohn’s risk, compared with those classed as consuming lower amounts of these foods (hazard ratio, 1.71; 95% confidence interval, 1.37-2.14). Also, lower risk of Crohn’s was observed among participants who consumed more unprocessed or minimally processed foods, such as vegetables, chicken, milk, and eggs (HR, 0.71; 95% CI, 0.53-0.94). The same associations were not seen for ulcerative colitis. <br/><br/>“Our findings support the hypothesis that consumption of [ultraprocessed foods] and low consumption of unprocessed/minimally processed foods may increase the risk for CD,” Dr. Nerula and colleagues wrote. The lack of association seen with ulcerative colitis might be explained by differences in the pathogenesis of each disease.<br/><br/>Ultraprocessed foods might contribute to Crohn’s by disrupting gut microbiota, the authors wrote. “For instance, emulsifiers have been shown to increase epithelial permeability, disruption of the intestinal barrier, and gut dysbiosis in mice. Carboxymethyl cellulose has been shown to facilitate bacterial adherence to gut epithelium, possibly leading to bacterial overgrowth and invasion of bacteria in between the intestinal villi. Furthermore, additives such as carrageenan, titanium dioxide, and maltodextrin have been shown to promote intestinal inflammation.”<br/><br/>Dr. Nerula and colleagues described as strengths of their study its large size, the low heterogenicity of the included studies, and the use of validated, standardized questionnaires to measure dietary intake in each study. Nonetheless, they cautioned, the results might not apply to younger age groups, and the majority of participants were White North Americans and Europeans, making it difficult to generalize results. <br/><br/>“Advancements in food processing and associated changes in dietary patterns could explain the rise of IBD incidence during the 20th and 21st centuries,” Dr. Narula and colleagues concluded. “Further investigations are needed to identify the specific potential culprits among processed foods that could account for the increased risk of CD observed.” <br/><br/>The study authors did not report outside funding. Dr. Narula disclosed receiving fees from pharmaceutical manufacturers including Janssen, AbbVie, Takeda, Pfizer, Merck, and others. Two of coauthors also disclosed receiving funds from industry, and five additional coauthors had no conflicts.</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>views</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>The causes of inflammatory bowel disease (IBD) are thought to be multifactorial and include genetic predisposition, dysregulated immune responses, imbalances in the intestinal microbiota, and environmental exposures. </p> <p>Incidence and prevalence of IBD has increased over time, including in developing countries, and appear to parallel industrialization and “Westernization” of societies. One of the potential contributors to IBD risk is diet. Dietary changes associated with more modern or “Westernized” diets, including increases in processed foods, are some of the factors hypothesized to contribute to rising rates of IBD. <br/><br/>[[{"fid":"297033","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Ryan C Ungaro, MD","field_file_image_credit[und][0][value]":"courtesy Mount Sinai Health System","field_file_image_caption[und][0][value]":"Dr. Ryan Ungaro"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]There is accumulating data that certain diets, such as the Mediterranean diet, may have beneficial effects in established Crohn’s disease (CD) and ulcerative colitis (UC). <br/><br/>In the meta-analysis by Narula and colleagues, the authors observed a significant increase in the risk of CD, but not UC, in individuals who consumed significantly higher amounts of ultraprocessed foods (that is, frozen or long-shelf-life foods, products with thickeners/emulsifiers, etc.). Although there are limitations to the studies included in the meta-analysis, the association is intriguing and could point to potential lifestyle modifications that could form the basis of preventative interventions for individuals at higher risk for IBD, such as first-degree relatives. <br/><br/>More immediately, prospective research is needed to understand if restricting ultraprocessed foods (or increasing less-processed foods) can decrease disease activity or prevent flares in patients with IBD. <br/><br/>Understanding factors that predispose to or trigger IBD, such as specific dietary components, will lead to improved management strategies and ultimately preventative interventions.</p> <p><em>Ryan Ungaro, MD, MS, is an associate professor of medicine in the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York. He is director of the Comprehensive Care for the Recently Diagnosed IBD Patient (COMPASS-IBD). He has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Celltrion, Lilly, Janssen, Pfizer, Roivant, and Takeda, and has received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lily, and Pfizer.</em></p> </itemContent> </newsItem> </itemSet></root>
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Daily aspirin for stroke prevention in healthy elderly should be avoided
according to results from a large randomized trial.
The findings, published in JAMA Network Open, bolster recommendations published in 2022 by the U.S. Preventive Services Task Force against daily aspirin for primary prevention of stroke in older adults and add to a mounting consensus that it should be avoided in the healthy elderly, for whom bleeding risks outweigh potential benefits.
Stroke was a preplanned secondary outcome of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which randomized 19,114 community-living people in Australia and the United States (56% women, 91% White) to 100 mg. daily aspirin or placebo. Participants were aged 70 and older, with the exception of U.S. Black and Hispanic individuals, who could be as young as 65. Participants did not have disability or known cardiovascular disease at baseline, and blood pressure was adequately controlled.
ASPEE findings
In 2018 the ASPREE authors, led by John McNeil, PhD, of Monash University, Melbourne, published their findings that aspirin did not reduce mortality or cardiovascular events (including stroke) in the same large cohort.
The new analysis, led by Geoffrey Cloud, MB, BS, of Monash University, focuses on stroke and intracranial bleeding outcomes. At 5 years’ follow up, the ASPREE investigators saw no significant reduction in ischemic stroke incidence associated with aspirin (hazard ratio, 0.89; 95% confidence interval, 0.71-1.11), while incidence of all types of intracranial bleeding, including hemorrhagic stroke, was significantly increased (HR, 1.38; 95% CI, 1.03-1.84).
Altogether 108 of participants taking aspirin (1.1%) experienced some form of intracranial bleeding (subdural, extradural, and/or subarachnoid), compared with 79 (0.8%) in the placebo group. Aspirin-treated patients also saw more hemorrhagic stroke (0.5% vs. 0.4%). As the ASPREE investigators had reported in an earlier paper, upper gastrointestinal bleeding occurred in significantly more aspirin-treated patients than those on placebo (HR, 1.87; 95% CI, 1.32-2.66).
“These outcomes may alter the balance of risks and benefits of an antiplatelet drug, especially if given to individuals at low risk in a primary prevention setting. This concern is relevant given the high stroke risk in older individuals, worldwide increases in populations of older individuals, and the importance of evaluating preventive strategies in this age group,” the investigators wrote.
The investigators cited the study’s large size as a strength while noting among its weaknesses that fewer stroke and bleeding events occurred during follow-up than expected, and that not all ischemic stroke events among older participants were thoroughly investigated.
Patients need to know their risk
In an interview, Shlee Song, MD, director of the stroke center at Cedars-Sinai, Los Angeles, said that the new ASPREE findings underscore the importance of careful communication with patients and their families, who may be confused about which risk group they belong to and either cease taking aspirin when it is in fact indicated, or take it when it could harm them.
“We need to be clear for our patients whether these results are relevant to them or not,” Dr. Song said. “People with a history of ischemic stroke need to know aspirin therapy is helpful in reducing risk of another stroke.”
Some patients may come to believe that because their stroke occurred a long time ago, they are in a lower-risk group. “But people need to understand that with a history of a heart attack or stroke, you’re always a separate group,” Dr. Song said. “Our job is also surveillance screening – have you had a fall this past year? Have you had a change in bowel movements? The bleeding events seen in ASPREE include bleeding in the head and bleeding in the gut.”
A key issue to stress with patients, Dr. Song said, is blood pressure management. “Patients might take aspirin because a family member had a stroke, without controlling blood pressure first. That could be the perfect storm for a head bleed: uncontrolled hypertension and an antiplatelet agent.”
The ASPREE study was funded by the National Institutes of Health in the United States and Monash University and the Victorian Cancer Agency in Australia. Three coauthors reported receiving funding or fees from drug manufacturers. Dr. Song disclosed no financial conflicts related to her comments.
according to results from a large randomized trial.
The findings, published in JAMA Network Open, bolster recommendations published in 2022 by the U.S. Preventive Services Task Force against daily aspirin for primary prevention of stroke in older adults and add to a mounting consensus that it should be avoided in the healthy elderly, for whom bleeding risks outweigh potential benefits.
Stroke was a preplanned secondary outcome of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which randomized 19,114 community-living people in Australia and the United States (56% women, 91% White) to 100 mg. daily aspirin or placebo. Participants were aged 70 and older, with the exception of U.S. Black and Hispanic individuals, who could be as young as 65. Participants did not have disability or known cardiovascular disease at baseline, and blood pressure was adequately controlled.
ASPEE findings
In 2018 the ASPREE authors, led by John McNeil, PhD, of Monash University, Melbourne, published their findings that aspirin did not reduce mortality or cardiovascular events (including stroke) in the same large cohort.
The new analysis, led by Geoffrey Cloud, MB, BS, of Monash University, focuses on stroke and intracranial bleeding outcomes. At 5 years’ follow up, the ASPREE investigators saw no significant reduction in ischemic stroke incidence associated with aspirin (hazard ratio, 0.89; 95% confidence interval, 0.71-1.11), while incidence of all types of intracranial bleeding, including hemorrhagic stroke, was significantly increased (HR, 1.38; 95% CI, 1.03-1.84).
Altogether 108 of participants taking aspirin (1.1%) experienced some form of intracranial bleeding (subdural, extradural, and/or subarachnoid), compared with 79 (0.8%) in the placebo group. Aspirin-treated patients also saw more hemorrhagic stroke (0.5% vs. 0.4%). As the ASPREE investigators had reported in an earlier paper, upper gastrointestinal bleeding occurred in significantly more aspirin-treated patients than those on placebo (HR, 1.87; 95% CI, 1.32-2.66).
“These outcomes may alter the balance of risks and benefits of an antiplatelet drug, especially if given to individuals at low risk in a primary prevention setting. This concern is relevant given the high stroke risk in older individuals, worldwide increases in populations of older individuals, and the importance of evaluating preventive strategies in this age group,” the investigators wrote.
The investigators cited the study’s large size as a strength while noting among its weaknesses that fewer stroke and bleeding events occurred during follow-up than expected, and that not all ischemic stroke events among older participants were thoroughly investigated.
Patients need to know their risk
In an interview, Shlee Song, MD, director of the stroke center at Cedars-Sinai, Los Angeles, said that the new ASPREE findings underscore the importance of careful communication with patients and their families, who may be confused about which risk group they belong to and either cease taking aspirin when it is in fact indicated, or take it when it could harm them.
“We need to be clear for our patients whether these results are relevant to them or not,” Dr. Song said. “People with a history of ischemic stroke need to know aspirin therapy is helpful in reducing risk of another stroke.”
Some patients may come to believe that because their stroke occurred a long time ago, they are in a lower-risk group. “But people need to understand that with a history of a heart attack or stroke, you’re always a separate group,” Dr. Song said. “Our job is also surveillance screening – have you had a fall this past year? Have you had a change in bowel movements? The bleeding events seen in ASPREE include bleeding in the head and bleeding in the gut.”
A key issue to stress with patients, Dr. Song said, is blood pressure management. “Patients might take aspirin because a family member had a stroke, without controlling blood pressure first. That could be the perfect storm for a head bleed: uncontrolled hypertension and an antiplatelet agent.”
The ASPREE study was funded by the National Institutes of Health in the United States and Monash University and the Victorian Cancer Agency in Australia. Three coauthors reported receiving funding or fees from drug manufacturers. Dr. Song disclosed no financial conflicts related to her comments.
according to results from a large randomized trial.
The findings, published in JAMA Network Open, bolster recommendations published in 2022 by the U.S. Preventive Services Task Force against daily aspirin for primary prevention of stroke in older adults and add to a mounting consensus that it should be avoided in the healthy elderly, for whom bleeding risks outweigh potential benefits.
Stroke was a preplanned secondary outcome of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which randomized 19,114 community-living people in Australia and the United States (56% women, 91% White) to 100 mg. daily aspirin or placebo. Participants were aged 70 and older, with the exception of U.S. Black and Hispanic individuals, who could be as young as 65. Participants did not have disability or known cardiovascular disease at baseline, and blood pressure was adequately controlled.
ASPEE findings
In 2018 the ASPREE authors, led by John McNeil, PhD, of Monash University, Melbourne, published their findings that aspirin did not reduce mortality or cardiovascular events (including stroke) in the same large cohort.
The new analysis, led by Geoffrey Cloud, MB, BS, of Monash University, focuses on stroke and intracranial bleeding outcomes. At 5 years’ follow up, the ASPREE investigators saw no significant reduction in ischemic stroke incidence associated with aspirin (hazard ratio, 0.89; 95% confidence interval, 0.71-1.11), while incidence of all types of intracranial bleeding, including hemorrhagic stroke, was significantly increased (HR, 1.38; 95% CI, 1.03-1.84).
Altogether 108 of participants taking aspirin (1.1%) experienced some form of intracranial bleeding (subdural, extradural, and/or subarachnoid), compared with 79 (0.8%) in the placebo group. Aspirin-treated patients also saw more hemorrhagic stroke (0.5% vs. 0.4%). As the ASPREE investigators had reported in an earlier paper, upper gastrointestinal bleeding occurred in significantly more aspirin-treated patients than those on placebo (HR, 1.87; 95% CI, 1.32-2.66).
“These outcomes may alter the balance of risks and benefits of an antiplatelet drug, especially if given to individuals at low risk in a primary prevention setting. This concern is relevant given the high stroke risk in older individuals, worldwide increases in populations of older individuals, and the importance of evaluating preventive strategies in this age group,” the investigators wrote.
The investigators cited the study’s large size as a strength while noting among its weaknesses that fewer stroke and bleeding events occurred during follow-up than expected, and that not all ischemic stroke events among older participants were thoroughly investigated.
Patients need to know their risk
In an interview, Shlee Song, MD, director of the stroke center at Cedars-Sinai, Los Angeles, said that the new ASPREE findings underscore the importance of careful communication with patients and their families, who may be confused about which risk group they belong to and either cease taking aspirin when it is in fact indicated, or take it when it could harm them.
“We need to be clear for our patients whether these results are relevant to them or not,” Dr. Song said. “People with a history of ischemic stroke need to know aspirin therapy is helpful in reducing risk of another stroke.”
Some patients may come to believe that because their stroke occurred a long time ago, they are in a lower-risk group. “But people need to understand that with a history of a heart attack or stroke, you’re always a separate group,” Dr. Song said. “Our job is also surveillance screening – have you had a fall this past year? Have you had a change in bowel movements? The bleeding events seen in ASPREE include bleeding in the head and bleeding in the gut.”
A key issue to stress with patients, Dr. Song said, is blood pressure management. “Patients might take aspirin because a family member had a stroke, without controlling blood pressure first. That could be the perfect storm for a head bleed: uncontrolled hypertension and an antiplatelet agent.”
The ASPREE study was funded by the National Institutes of Health in the United States and Monash University and the Victorian Cancer Agency in Australia. Three coauthors reported receiving funding or fees from drug manufacturers. Dr. Song disclosed no financial conflicts related to her comments.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Daily low-dose aspirin increased the risk of intracranial bleeding, including hemorrhagic stroke, by 38% among healthy older people with no history of cardiovas</metaDescription> <articlePDF/> <teaserImage/> <teaser>Data from a large randomized trial suggest that aspirin increases bleeding risk and is ineffective for primary stroke prevention in the elderly </teaser> <title>Daily aspirin for stroke prevention in healthy elderly should be avoided</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2023</pubPubdateYear> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>CARD</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle>Cardiology news</journalFullTitle> <copyrightStatement/> </publicationData> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName>January 2021</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>FP</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement>Copyright 2017 Frontline Medical News</copyrightStatement> </publicationData> <publicationData> <publicationCode>IM</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> </publications_g> <publications> <term>5</term> <term canonical="true">22</term> <term>15</term> <term>21</term> </publications> <sections> <term>39313</term> <term>86</term> <term canonical="true">27970</term> </sections> <topics> <term canonical="true">301</term> <term>258</term> <term>194</term> <term>280</term> <term>215</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Daily aspirin for stroke prevention in healthy elderly should be avoided</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">Daily low-dose aspirin increased the risk of intracranial bleeding, including hemorrhagic stroke, by 38% among healthy older people with no history of cardiovascular events, and did not help prevent ischemic stroke,</span> according to results from a large randomized trial. </p> <p>The <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2807630">findings</a>, published in JAMA Network Open, bolster <a href="https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/aspirin-to-prevent-cardiovascular-disease-preventive-medication">recommendations</a> published in 2022 by the U.S. Preventive Services Task Force against daily aspirin for primary prevention of stroke in older adults and add to a mounting consensus that it should be avoided in the healthy elderly, for whom bleeding risks outweigh potential benefits.<br/><br/>Stroke was a preplanned secondary outcome of the Aspirin in Reducing Events in the Elderly (<a href="https://aspree.org/usa/">ASPREE</a>) trial, which randomized 19,114 community-living people in Australia and the United States (56% women, 91% White) to 100 mg. daily aspirin or placebo. Participants were aged 70 and older, with the exception of U.S. Black and Hispanic individuals, who could be as young as 65. Participants did not have disability or known cardiovascular disease at baseline, and blood pressure was adequately controlled. <br/><br/></p> <h2>ASPEE findings</h2> <p>In 2018 the ASPREE authors, led by John McNeil, PhD, of Monash University, Melbourne, published their findings that aspirin did not reduce <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1803955?query=recirc_curatedRelated_article">mortality</a> or <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1805819?query=recirc_curatedRelated_article">cardiovascular events</a> (including stroke) in the same large cohort.</p> <p>The new analysis, led by Geoffrey Cloud, MB, BS, of Monash University, focuses on stroke and intracranial bleeding outcomes. At 5 years’ follow up, the ASPREE investigators saw no significant reduction in ischemic stroke incidence associated with aspirin (hazard ratio, 0.89; 95% confidence interval, 0.71-1.11), while incidence of all types of intracranial bleeding, including hemorrhagic stroke, was significantly increased (HR, 1.38; 95% CI, 1.03-1.84). <br/><br/>Altogether 108 of participants taking aspirin (1.1%) experienced some form of intracranial bleeding (subdural, extradural, and/or subarachnoid), compared with 79 (0.8%) in the placebo group. Aspirin-treated patients also saw more hemorrhagic stroke (0.5% vs. 0.4%). As the ASPREE investigators had reported in an earlier paper, upper gastrointestinal bleeding occurred in significantly more aspirin-treated patients than those on placebo (HR, 1.87; 95% CI, 1.32-2.66).<br/><br/>“These outcomes may alter the balance of risks and benefits of an antiplatelet drug, especially if given to individuals at low risk in a primary prevention setting. This concern is relevant given the high stroke risk in older individuals, worldwide increases in populations of older individuals, and the importance of evaluating preventive strategies in this age group,” the investigators wrote.<br/><br/>The investigators cited the study’s large size as a strength while noting among its weaknesses that fewer stroke and bleeding events occurred during follow-up than expected, and that not all ischemic stroke events among older participants were thoroughly investigated. <br/><br/></p> <h2>Patients need to know their risk</h2> <p>In an interview, <a href="https://www.cedars-sinai.org/provider/shlee-song-1790954.html">Shlee Song</a>, MD, director of the stroke center at Cedars-Sinai, Los Angeles, said that the new ASPREE findings underscore the importance of careful communication with patients and their families, who may be confused about which risk group they belong to and either cease taking aspirin when it is in fact indicated, or take it when it could harm them. </p> <p>“We need to be clear for our patients whether these results are relevant to them or not,” Dr. Song said. “People with a history of ischemic stroke need to know aspirin therapy is helpful in reducing risk of another stroke.”<br/><br/>Some patients may come to believe that because their stroke occurred a long time ago, they are in a lower-risk group. “But people need to understand that with a history of a heart attack or stroke, you’re always a separate group,” Dr. Song said. “Our job is also surveillance screening – have you had a fall this past year? Have you had a change in bowel movements? The bleeding events seen in ASPREE include bleeding in the head and bleeding in the gut.”<br/><br/>A key issue to stress with patients, Dr. Song said, is blood pressure management. “Patients might take aspirin because a family member had a stroke, without controlling blood pressure first. That could be the perfect storm for a head bleed: uncontrolled hypertension and an antiplatelet agent.”<br/><br/>The ASPREE study was funded by the National Institutes of Health in the United States and Monash University and the Victorian Cancer Agency in Australia. Three coauthors reported receiving funding or fees from drug manufacturers. Dr. Song disclosed no financial conflicts related to her comments. </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM JAMA NETWORK OPEN
Liver disease gets new name and diagnostic criteria
Nonalcoholic fatty liver disease will now be called metabolic dysfunction–associated steatotic liver disease, or MASLD, according to new nomenclature adopted by a global consensus panel composed mostly of hepatology researchers and clinicians.
The new nomenclature, published in the journal Hepatology, includes the umbrella term steatotic liver disease, or SLD, which will cover MASLD and MetALD, a term describing people with MASLD who consume more than 140 grams of alcohol per week for women and 210 grams per week for men.
Metabolic dysfunction–associated steatohepatitis, or MASH, will replace the term nonalcoholic steatohepatitis, or NASH.
Mary E. Rinella, MD, of University of Chicago Medicine led the consensus group. The changes were needed, Dr. Rinella and her colleagues argued, because the terms “fatty liver disease” “and nonalcoholic” could be considered to confer stigma, and to better reflect the metabolic dysfunction occurring in the disease. Under the new nomenclature, people with MASLD must have a cardiometabolic risk factor, such as type 2 diabetes. People without metabolic parameters and no known cause will be classed as having cryptogenic SLD.
While the new nomenclature largely conserves existing disease definitions, it allows for alcohol consumption beyond current parameters for nonalcoholic forms of the disease. “There are individuals with risk factors for NAFLD, such as type 2 diabetes, who consume more alcohol than the relatively strict thresholds used to define the nonalcoholic nature of the disease [and] are excluded from trials and consideration for treatments,” the authors wrote.
Moreover, they wrote, “within MetALD there is a continuum where conceptually the condition can be seen to be MASLD or ALD predominant. This may vary over time within a given individual.”
Respondents overwhelmingly agreed, however, that even moderate alcohol use alters the natural history of the disease and that patients with more than minimal alcohol consumption should be analyzed separately in clinical trials.
The new nomenclature reflects a 3-year effort involving some 236 panelists from 56 countries who participated in several rounds of online surveys using a Delphi process. Pediatricians, gastroenterologists, and endocrinologists also participated as well as some patient advocates. Changes were based on a super-majority of opinion (67% or higher), though the consensus on whether the term “fatty” was stigmatizing never reached that threshold. In early rounds of surveys only 44% of respondents considered the word “fatty” to be stigmatizing, while more considered “nonalcoholic” to be problematic.
“Substantial proportions of the respondents deemed terms such as ‘fatty’ stigmatizing, hence its exclusion as part of any new name,” Dr. Rinella and her colleagues wrote. “Although health care professionals may contend that patients have not reported this previously, this likely reflects in part a failure to ask the question in the first place and the power imbalance in the doctor-patient relationship.” The authors noted that the new terminology may help raise awareness at a time when new therapeutics are in sight and it becomes more important to identify at-risk individuals.
Of concern was whether the new definitions would alter the utility of earlier data from registries and trials. However, the authors determined that some 98% of people registered in a European NAFLD cohort would meet the new criteria for MASLD. “Maintenance of the term, and clinical definition, of steatohepatitis ensures retention and validity of prior data from clinical trials and biomarker discovery studies of patients with NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature, without impeding the efficiency of research,” they stated.
The effort was spearheaded by three international liver societies: La Asociación Latinoamericana para el Estudio del Hígado, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver, as well as the cochairs of the NAFLD Nomenclature Initiative.
Each of the authors disclosed a number of potential conflicts of interest.
Nonalcoholic fatty liver disease will now be called metabolic dysfunction–associated steatotic liver disease, or MASLD, according to new nomenclature adopted by a global consensus panel composed mostly of hepatology researchers and clinicians.
The new nomenclature, published in the journal Hepatology, includes the umbrella term steatotic liver disease, or SLD, which will cover MASLD and MetALD, a term describing people with MASLD who consume more than 140 grams of alcohol per week for women and 210 grams per week for men.
Metabolic dysfunction–associated steatohepatitis, or MASH, will replace the term nonalcoholic steatohepatitis, or NASH.
Mary E. Rinella, MD, of University of Chicago Medicine led the consensus group. The changes were needed, Dr. Rinella and her colleagues argued, because the terms “fatty liver disease” “and nonalcoholic” could be considered to confer stigma, and to better reflect the metabolic dysfunction occurring in the disease. Under the new nomenclature, people with MASLD must have a cardiometabolic risk factor, such as type 2 diabetes. People without metabolic parameters and no known cause will be classed as having cryptogenic SLD.
While the new nomenclature largely conserves existing disease definitions, it allows for alcohol consumption beyond current parameters for nonalcoholic forms of the disease. “There are individuals with risk factors for NAFLD, such as type 2 diabetes, who consume more alcohol than the relatively strict thresholds used to define the nonalcoholic nature of the disease [and] are excluded from trials and consideration for treatments,” the authors wrote.
Moreover, they wrote, “within MetALD there is a continuum where conceptually the condition can be seen to be MASLD or ALD predominant. This may vary over time within a given individual.”
Respondents overwhelmingly agreed, however, that even moderate alcohol use alters the natural history of the disease and that patients with more than minimal alcohol consumption should be analyzed separately in clinical trials.
The new nomenclature reflects a 3-year effort involving some 236 panelists from 56 countries who participated in several rounds of online surveys using a Delphi process. Pediatricians, gastroenterologists, and endocrinologists also participated as well as some patient advocates. Changes were based on a super-majority of opinion (67% or higher), though the consensus on whether the term “fatty” was stigmatizing never reached that threshold. In early rounds of surveys only 44% of respondents considered the word “fatty” to be stigmatizing, while more considered “nonalcoholic” to be problematic.
“Substantial proportions of the respondents deemed terms such as ‘fatty’ stigmatizing, hence its exclusion as part of any new name,” Dr. Rinella and her colleagues wrote. “Although health care professionals may contend that patients have not reported this previously, this likely reflects in part a failure to ask the question in the first place and the power imbalance in the doctor-patient relationship.” The authors noted that the new terminology may help raise awareness at a time when new therapeutics are in sight and it becomes more important to identify at-risk individuals.
Of concern was whether the new definitions would alter the utility of earlier data from registries and trials. However, the authors determined that some 98% of people registered in a European NAFLD cohort would meet the new criteria for MASLD. “Maintenance of the term, and clinical definition, of steatohepatitis ensures retention and validity of prior data from clinical trials and biomarker discovery studies of patients with NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature, without impeding the efficiency of research,” they stated.
The effort was spearheaded by three international liver societies: La Asociación Latinoamericana para el Estudio del Hígado, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver, as well as the cochairs of the NAFLD Nomenclature Initiative.
Each of the authors disclosed a number of potential conflicts of interest.
Nonalcoholic fatty liver disease will now be called metabolic dysfunction–associated steatotic liver disease, or MASLD, according to new nomenclature adopted by a global consensus panel composed mostly of hepatology researchers and clinicians.
The new nomenclature, published in the journal Hepatology, includes the umbrella term steatotic liver disease, or SLD, which will cover MASLD and MetALD, a term describing people with MASLD who consume more than 140 grams of alcohol per week for women and 210 grams per week for men.
Metabolic dysfunction–associated steatohepatitis, or MASH, will replace the term nonalcoholic steatohepatitis, or NASH.
Mary E. Rinella, MD, of University of Chicago Medicine led the consensus group. The changes were needed, Dr. Rinella and her colleagues argued, because the terms “fatty liver disease” “and nonalcoholic” could be considered to confer stigma, and to better reflect the metabolic dysfunction occurring in the disease. Under the new nomenclature, people with MASLD must have a cardiometabolic risk factor, such as type 2 diabetes. People without metabolic parameters and no known cause will be classed as having cryptogenic SLD.
While the new nomenclature largely conserves existing disease definitions, it allows for alcohol consumption beyond current parameters for nonalcoholic forms of the disease. “There are individuals with risk factors for NAFLD, such as type 2 diabetes, who consume more alcohol than the relatively strict thresholds used to define the nonalcoholic nature of the disease [and] are excluded from trials and consideration for treatments,” the authors wrote.
Moreover, they wrote, “within MetALD there is a continuum where conceptually the condition can be seen to be MASLD or ALD predominant. This may vary over time within a given individual.”
Respondents overwhelmingly agreed, however, that even moderate alcohol use alters the natural history of the disease and that patients with more than minimal alcohol consumption should be analyzed separately in clinical trials.
The new nomenclature reflects a 3-year effort involving some 236 panelists from 56 countries who participated in several rounds of online surveys using a Delphi process. Pediatricians, gastroenterologists, and endocrinologists also participated as well as some patient advocates. Changes were based on a super-majority of opinion (67% or higher), though the consensus on whether the term “fatty” was stigmatizing never reached that threshold. In early rounds of surveys only 44% of respondents considered the word “fatty” to be stigmatizing, while more considered “nonalcoholic” to be problematic.
“Substantial proportions of the respondents deemed terms such as ‘fatty’ stigmatizing, hence its exclusion as part of any new name,” Dr. Rinella and her colleagues wrote. “Although health care professionals may contend that patients have not reported this previously, this likely reflects in part a failure to ask the question in the first place and the power imbalance in the doctor-patient relationship.” The authors noted that the new terminology may help raise awareness at a time when new therapeutics are in sight and it becomes more important to identify at-risk individuals.
Of concern was whether the new definitions would alter the utility of earlier data from registries and trials. However, the authors determined that some 98% of people registered in a European NAFLD cohort would meet the new criteria for MASLD. “Maintenance of the term, and clinical definition, of steatohepatitis ensures retention and validity of prior data from clinical trials and biomarker discovery studies of patients with NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature, without impeding the efficiency of research,” they stated.
The effort was spearheaded by three international liver societies: La Asociación Latinoamericana para el Estudio del Hígado, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver, as well as the cochairs of the NAFLD Nomenclature Initiative.
Each of the authors disclosed a number of potential conflicts of interest.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Nonalcoholic fatty liver disease will now be called metabolic dysfunction–associated steatotic liver disease, or MASLD, according to new nomenclature adopted by</metaDescription> <articlePDF/> <teaserImage/> <teaser>Formerly known as nonalcoholic fatty liver disease, the condition will now be known as metabolic dysfunction–associated steatotic liver disease (MASLD). </teaser> <title>Liver disease gets new name and diagnostic criteria</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>GIHOLD</publicationCode> <pubIssueName>January 2014</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">21</term> </publications> <sections> <term>39313</term> <term canonical="true">27970</term> </sections> <topics> <term canonical="true">213</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Liver disease gets new name and diagnostic criteria</title> <deck/> </itemMeta> <itemContent> <p>Nonalcoholic fatty liver disease will now be called metabolic dysfunction–associated steatotic liver disease, or MASLD, according to new nomenclature adopted by a global consensus panel composed mostly of hepatology researchers and clinicians. </p> <p>The new nomenclature, published in the journal <span class="Hyperlink"><a href="https://journals.lww.com/hep/Fulltext/9900/A_multi_society_Delphi_consensus_statement_on_new.488.aspx">Hepatology</a></span>, includes the umbrella term steatotic liver disease, or SLD, which will cover MASLD and MetALD, a term describing people with MASLD who consume more than 140 grams of alcohol per week for women and 210 grams per week for men.<br/><br/>Metabolic dysfunction–associated steatohepatitis, or MASH, will replace the term nonalcoholic steatohepatitis, or NASH. <br/><br/><span class="Hyperlink"><a href="https://www.uchicagomedicine.org/find-a-physician/physician/mary-e-rinella">Mary E. Rinella, MD</a></span>, of University of Chicago Medicine led the consensus group. The changes were needed, Dr. Rinella and her colleagues argued, because the terms “fatty liver disease” “and nonalcoholic” could be considered to confer stigma, and to better reflect the metabolic dysfunction occurring in the disease. Under the new nomenclature, people with MASLD must have a cardiometabolic risk factor, such as type 2 diabetes. People without metabolic parameters and no known cause will be classed as having cryptogenic SLD.<br/><br/>While the new nomenclature largely conserves existing disease definitions, it allows for alcohol consumption beyond current parameters for nonalcoholic forms of the disease. “There are individuals with risk factors for NAFLD, such as type 2 diabetes, who consume more alcohol than the relatively strict thresholds used to define the nonalcoholic nature of the disease [and] are excluded from trials and consideration for treatments,” the authors wrote. <br/><br/>Moreover, they wrote, “within MetALD there is a continuum where conceptually the condition can be seen to be MASLD or ALD predominant. This may vary over time within a given individual.”<br/><br/>Respondents overwhelmingly agreed, however, that even moderate alcohol use alters the natural history of the disease and that patients with more than minimal alcohol consumption should be analyzed separately in clinical trials.<br/><br/>The new nomenclature reflects a 3-year effort involving some 236 panelists from 56 countries who participated in several rounds of online surveys using a Delphi process. Pediatricians, gastroenterologists, and endocrinologists also participated as well as some patient advocates. Changes were based on a super-majority of opinion (67% or higher), though the consensus on whether the term “fatty” was stigmatizing never reached that threshold. In early rounds of surveys only 44% of respondents considered the word “fatty” to be stigmatizing, while more considered “nonalcoholic” to be problematic. <br/><br/>“Substantial proportions of the respondents deemed terms such as ‘fatty’ stigmatizing, hence its exclusion as part of any new name,” Dr. Rinella and her colleagues wrote. “Although health care professionals may contend that patients have not reported this previously, this likely reflects in part a failure to ask the question in the first place and the power imbalance in the doctor-patient relationship.” The authors noted that the new terminology may help raise awareness at a time when new therapeutics are in sight and it becomes more important to identify at-risk individuals. <br/><br/>Of concern was whether the new definitions would alter the utility of earlier data from registries and trials. However, the authors determined that some 98% of people registered in a European NAFLD cohort would meet the new criteria for MASLD. “Maintenance of the term, and clinical definition, of steatohepatitis ensures retention and validity of prior data from clinical trials and biomarker discovery studies of patients with NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature, without impeding the efficiency of research,” they stated. <br/><br/>The effort was spearheaded by three international liver societies: La Asociación Latinoamericana para el Estudio del Hígado, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver, as well as the cochairs of the <a href="https://easl.eu/news/new_fatty_liver_disease_nomenclature-2/">NAFLD Nomenclature Initiative.</a><br/><br/>Each of the authors disclosed a number of potential conflicts of interest.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM HEPATOLOGY
In head and neck cancer, better outcomes seen in patients with overweight
The findings, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity.
While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss.
Methods and results
For their research, Sung Jun Ma, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded.
The researchers found that overweight BMI (25-29.9 kg/m2) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.
Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.
Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.
The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”
It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.
“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”
Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.”
The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose.
Importance of nutritional support during treatment highlighted
In an interview, Ari Rosenberg, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation.
“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”
Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment.
The findings, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity.
While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss.
Methods and results
For their research, Sung Jun Ma, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded.
The researchers found that overweight BMI (25-29.9 kg/m2) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.
Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.
Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.
The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”
It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.
“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”
Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.”
The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose.
Importance of nutritional support during treatment highlighted
In an interview, Ari Rosenberg, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation.
“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”
Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment.
The findings, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity.
While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss.
Methods and results
For their research, Sung Jun Ma, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded.
The researchers found that overweight BMI (25-29.9 kg/m2) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.
Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.
Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.
The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”
It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.
“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”
Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.”
The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose.
Importance of nutritional support during treatment highlighted
In an interview, Ari Rosenberg, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation.
“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”
Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Patients with head and neck cancer and overweight saw better treatment response and survival after chemoradiation, compared with patients with the same type of </metaDescription> <articlePDF/> <teaserImage/> <teaser>Among 445 patients treated with chemoradiation, those with overweight saw improvements in survival and tumor recurrence, compared with patients with normal weight. </teaser> <title>In head and neck cancer, better outcomes seen in patients with overweight</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>endo</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> <term>15</term> <term>21</term> <term>34</term> </publications> <sections> <term canonical="true">27970</term> <term>39313</term> <term>27980</term> </sections> <topics> <term>270</term> <term>280</term> <term canonical="true">221</term> <term>263</term> <term>261</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>In head and neck cancer, better outcomes seen in patients with overweight</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">Patients with head and neck cancer and overweight saw better treatment response and survival after chemoradiation, compared with patients with the same type of cancer but a normal weight, a new study finds.</span> </p> <p>The <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2806416?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamanetworkopen.2023.20513">findings</a>, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity. <br/><br/>While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss. <br/><br/></p> <h2>Methods and results</h2> <p>For their research, <a href="https://www.roswellpark.org/sung-jun-ma">Sung Jun Ma, MD</a>, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded. </p> <p>The researchers found that overweight BMI (25-29.9 kg/m<sup>2</sup>) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.<br/><br/>Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.<br/><br/>Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.<br/><br/>The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”<br/><br/>It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.<br/><br/>“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”<br/><br/>Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.” <br/><br/>The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose. <br/><br/></p> <h2>Importance of nutritional support during treatment highlighted</h2> <p>In an interview, <a href="https://www.uchicagomedicine.org/find-a-physician/physician/ari-rosenberg">Ari Rosenberg</a>, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation. </p> <p>“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”<br/><br/>Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment. <br/><br/><br/><br/><br/><br/><br/><br/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
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