User login
Medtronic to discontinue SmartPill capsule
a spokesperson for its manufacturer, Medtronic, confirmed.
In a June 22 email, company representative Oded Cojocaru stated that the decision followed “several months of ongoing challenges with reliable supply of critical components to our SmartPill motility testing system.”
The SmartPill motility testing system’s maturity “means we cannot source an alternative supplier for the specialized components required to manufacture the SmartPill capsules and recorders. As a result, we have made the difficult decision to discontinue global sales,” Mr. Cojocaru said.
Customers have been notified and all sales of the device will be discontinued across all clinical applications when available inventory is exhausted, which is expected to occur in September. Medtronic has no plans to develop an alternative to the device.
Braden Kuo, MD, of Massachusetts General Hospital, Boston, a motility specialist who took part in the SmartPill’s development and testing at various stages, said that Medtronic’s decision to discontinue the device was already known among his GI colleagues, and was the subject of concern as there is no analogous Food and Drug Administration–approved device on the market.
While the device’s clinical adoption “is not extremely widespread,” Dr. Kuo said, thousands of SmartPills are still used in GI clinics every year, and insurance tends to cover their use, especially in major metropolitan areas.
Originally developed by the SmartPill Corporation of Buffalo, N.Y., the device was first cleared by the FDA in 2006 for the evaluation of colonic transit time in patients with chronic constipation and suspected gastroparesis. Six years later that company was sold to Given Imaging, an Israeli firm making ingestible capsule endoscopy devices with cameras. In 2015, Given Imaging was purchased by Medtronic.
The SmartPill is ingested under clinical supervision, after which a patient can return home and allow the capsule to pass naturally through the body over a period of days. It is used in tandem with proprietary monitoring hardware, software, and a special food product. Known limitations of the device include that it can be difficult for some patients to swallow, and that it can get stuck in the lower digestive tract. Its use is contraindicated in patients with dysphagia, stricture, or bowel obstruction.
“Many motility doctors and some general GI docs find this test helpful,” said Dr. Kuo, who formerly served as a scientific adviser to SmartPill and later ran trials of the technology for Medtronic. It is useful as an alternative to costlier scintigraphy, he said, or to follow up after a negative endoscopy result.
The SmartPill has also been fruitful for GI research, Dr. Kuo added, because the capsule is easy to administer, compared with nonambulatory ways of studying motility, which limited enrollment. “Now we can do studies with several hundred people, because this is much more easily tolerated, and we’ve made a lot of interesting insights about GI physiology and pathophysiology as a result of this technology.”
During its 17 years on the market, Dr. Kuo said, the SmartPill has helped galvanize interest in other capsule applications, including for drug delivery, imaging and sampling. 
Jack Semler, PhD, the former chief technology officer of SmartPill and who alongside Dr. Kuo has coauthored some 40 papers on the SmartPill, said he, too, lamented the decision by Medtronic. “The company has only so many resources to devote to upgrading technology and those resources just aren’t available for this particular product,” he speculated. Nonetheless, Dr. Semler said, “I still feel there is a real untapped potential.”
Dr. Kuo and Dr. Semler both disclosed previous paid work for SmartPill and Medtronic. Both are currently consulting for Atmo Biosciences, a company that is developing a different motility capsule technology.
a spokesperson for its manufacturer, Medtronic, confirmed.
In a June 22 email, company representative Oded Cojocaru stated that the decision followed “several months of ongoing challenges with reliable supply of critical components to our SmartPill motility testing system.”
The SmartPill motility testing system’s maturity “means we cannot source an alternative supplier for the specialized components required to manufacture the SmartPill capsules and recorders. As a result, we have made the difficult decision to discontinue global sales,” Mr. Cojocaru said.
Customers have been notified and all sales of the device will be discontinued across all clinical applications when available inventory is exhausted, which is expected to occur in September. Medtronic has no plans to develop an alternative to the device.
Braden Kuo, MD, of Massachusetts General Hospital, Boston, a motility specialist who took part in the SmartPill’s development and testing at various stages, said that Medtronic’s decision to discontinue the device was already known among his GI colleagues, and was the subject of concern as there is no analogous Food and Drug Administration–approved device on the market.
While the device’s clinical adoption “is not extremely widespread,” Dr. Kuo said, thousands of SmartPills are still used in GI clinics every year, and insurance tends to cover their use, especially in major metropolitan areas.
Originally developed by the SmartPill Corporation of Buffalo, N.Y., the device was first cleared by the FDA in 2006 for the evaluation of colonic transit time in patients with chronic constipation and suspected gastroparesis. Six years later that company was sold to Given Imaging, an Israeli firm making ingestible capsule endoscopy devices with cameras. In 2015, Given Imaging was purchased by Medtronic.
The SmartPill is ingested under clinical supervision, after which a patient can return home and allow the capsule to pass naturally through the body over a period of days. It is used in tandem with proprietary monitoring hardware, software, and a special food product. Known limitations of the device include that it can be difficult for some patients to swallow, and that it can get stuck in the lower digestive tract. Its use is contraindicated in patients with dysphagia, stricture, or bowel obstruction.
“Many motility doctors and some general GI docs find this test helpful,” said Dr. Kuo, who formerly served as a scientific adviser to SmartPill and later ran trials of the technology for Medtronic. It is useful as an alternative to costlier scintigraphy, he said, or to follow up after a negative endoscopy result.
The SmartPill has also been fruitful for GI research, Dr. Kuo added, because the capsule is easy to administer, compared with nonambulatory ways of studying motility, which limited enrollment. “Now we can do studies with several hundred people, because this is much more easily tolerated, and we’ve made a lot of interesting insights about GI physiology and pathophysiology as a result of this technology.”
During its 17 years on the market, Dr. Kuo said, the SmartPill has helped galvanize interest in other capsule applications, including for drug delivery, imaging and sampling.
Jack Semler, PhD, the former chief technology officer of SmartPill and who alongside Dr. Kuo has coauthored some 40 papers on the SmartPill, said he, too, lamented the decision by Medtronic. “The company has only so many resources to devote to upgrading technology and those resources just aren’t available for this particular product,” he speculated. Nonetheless, Dr. Semler said, “I still feel there is a real untapped potential.”
Dr. Kuo and Dr. Semler both disclosed previous paid work for SmartPill and Medtronic. Both are currently consulting for Atmo Biosciences, a company that is developing a different motility capsule technology.
a spokesperson for its manufacturer, Medtronic, confirmed.
In a June 22 email, company representative Oded Cojocaru stated that the decision followed “several months of ongoing challenges with reliable supply of critical components to our SmartPill motility testing system.”
The SmartPill motility testing system’s maturity “means we cannot source an alternative supplier for the specialized components required to manufacture the SmartPill capsules and recorders. As a result, we have made the difficult decision to discontinue global sales,” Mr. Cojocaru said.
Customers have been notified and all sales of the device will be discontinued across all clinical applications when available inventory is exhausted, which is expected to occur in September. Medtronic has no plans to develop an alternative to the device.
Braden Kuo, MD, of Massachusetts General Hospital, Boston, a motility specialist who took part in the SmartPill’s development and testing at various stages, said that Medtronic’s decision to discontinue the device was already known among his GI colleagues, and was the subject of concern as there is no analogous Food and Drug Administration–approved device on the market.
While the device’s clinical adoption “is not extremely widespread,” Dr. Kuo said, thousands of SmartPills are still used in GI clinics every year, and insurance tends to cover their use, especially in major metropolitan areas.
Originally developed by the SmartPill Corporation of Buffalo, N.Y., the device was first cleared by the FDA in 2006 for the evaluation of colonic transit time in patients with chronic constipation and suspected gastroparesis. Six years later that company was sold to Given Imaging, an Israeli firm making ingestible capsule endoscopy devices with cameras. In 2015, Given Imaging was purchased by Medtronic.
The SmartPill is ingested under clinical supervision, after which a patient can return home and allow the capsule to pass naturally through the body over a period of days. It is used in tandem with proprietary monitoring hardware, software, and a special food product. Known limitations of the device include that it can be difficult for some patients to swallow, and that it can get stuck in the lower digestive tract. Its use is contraindicated in patients with dysphagia, stricture, or bowel obstruction.
“Many motility doctors and some general GI docs find this test helpful,” said Dr. Kuo, who formerly served as a scientific adviser to SmartPill and later ran trials of the technology for Medtronic. It is useful as an alternative to costlier scintigraphy, he said, or to follow up after a negative endoscopy result.
The SmartPill has also been fruitful for GI research, Dr. Kuo added, because the capsule is easy to administer, compared with nonambulatory ways of studying motility, which limited enrollment. “Now we can do studies with several hundred people, because this is much more easily tolerated, and we’ve made a lot of interesting insights about GI physiology and pathophysiology as a result of this technology.”
During its 17 years on the market, Dr. Kuo said, the SmartPill has helped galvanize interest in other capsule applications, including for drug delivery, imaging and sampling.
Jack Semler, PhD, the former chief technology officer of SmartPill and who alongside Dr. Kuo has coauthored some 40 papers on the SmartPill, said he, too, lamented the decision by Medtronic. “The company has only so many resources to devote to upgrading technology and those resources just aren’t available for this particular product,” he speculated. Nonetheless, Dr. Semler said, “I still feel there is a real untapped potential.”
Dr. Kuo and Dr. Semler both disclosed previous paid work for SmartPill and Medtronic. Both are currently consulting for Atmo Biosciences, a company that is developing a different motility capsule technology.
New AGA CPU focuses on gastric peroral endoscopic myotomy for gastroparesis
Authored by Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Medicine, Baltimore; Andrew Y. Wang, MD, AGAF, chief of interventional endoscopy, University of Virginia, Charlottesville; and, Qiang Cai, MD, PhD, chief of gastroenterology, Ochsner LSU Health Shreveport (La.), the update covers patient selection, procedural considerations, adverse events (AEs), and other topics.
“G-POEM is being performed worldwide to treat patients with refractory gastroparesis,” the investigators wrote in Gastroenterology). “G-POEM is an overall safe procedure with high technical success rates, particularly when performed by an endoscopist experienced in third-space endoscopy. Even if the durable clinical success of G-POEM is in the 50% to 60% range, this represents a huge clinical benefit to patients with refractory gastroparesis, which is a disease associated with substantial morbidity, poor quality of life, and a paucity of safe and effective treatments.”
The authors listed treatment alternatives, noting how associated clinical data have fallen short.
“Although endoscopic pyloric balloon dilation, intrapyloric botulinum toxin injection, gastric electrical stimulation, and transpyloric stenting have been used in patients [with gastroparesis] who have not responded to medical therapy, published studies concerning these therapies have been inconsistent, shown no benefit, or lacked methodologic rigor,” they wrote.
Patient selection
G-POEM should be considered in patients with medically refractory gastroparesis due to diabetes, prior surgery, or idiopathic causes. Candidates should undergo endoscopy to confirm no mechanical obstruction, as well as a solid-phase gastric emptying scan to confirm delayed emptying, with ideal candidates showing at least 20% retention at 4 hours, as this threshold has been linked with better clinical outcomes.
G-POEM is most beneficial when moderate to severe symptoms are present, the investigators wrote, particularly vomiting and nausea. The Gastroparesis Cardinal Symptom Index (GCSI) can be used to determine severity, with a score greater than 2 indicating moderate to severe presentation.
Procedural considerations
The CPU offers detailed procedural considerations, including preparation and equipment, technical guidance, and postprocedural strategy.
“G-POEM should only be performed by interventional endoscopists with expertise or training in third-space endoscopy,” Dr. Khashab and colleagues wrote. “Although experience in endoscopic submucosal dissection (ESD) is not mandatory before performing G-POEM, it likely shortens the learning curve.”
Equipment minimums are also described, including “a high-definition gastroscope, with a waterjet, affixed with a clear distal cap” and “a modern electrosurgical generator capable of modulating power based on tissue resistance and circuit impedance.”
While G-POEM is typically performed via a greater-curvature approach, similar outcomes have been documented for a lesser-curvature approach, Dr. Khashab and colleagues wrote. This alternative technique may increase difficulty of pyloromyotomy, they added.
Postprocedural care may involve an overnight stay, according to the update, with an upper GI study on the subsequent day to ensure no contrast leakage, though this is not mandatory.
Adverse events
“G-POEM is generally safe when performed by trained and/or experienced endoscopists, and AEs are uncommon,” the investigators wrote. “However, serious AEs can occur and have been reported.”
Reported AEs include capnoperitoneum, inadvertent mucosotomy, thermal-mucosal injury, abdominal pain, bleeding, gastric ulceration, and dumping syndrome.
Insurance companies called to action
After reviewing emerging data, the authors suggested the time has come to consider G-POEM as a routine, evidence-based procedure that deserves appropriate reimbursement by financial stakeholders.
“Many insurers still consider G-POEM investigational and refuse to cover this procedure for patients with medically refractory gastroparesis,” they wrote. “As the safety and clinical effectiveness of G-POEM is now well supported, insurance companies and payors should cover G-POEM for patients with significant gastroparesis.”
The clinical practice update was commissioned and approved by the American Gastroenterological Association. The investigators disclosed relationships with Boston Scientific, Medtronic, and Olympus, among others.
Authored by Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Medicine, Baltimore; Andrew Y. Wang, MD, AGAF, chief of interventional endoscopy, University of Virginia, Charlottesville; and, Qiang Cai, MD, PhD, chief of gastroenterology, Ochsner LSU Health Shreveport (La.), the update covers patient selection, procedural considerations, adverse events (AEs), and other topics.
“G-POEM is being performed worldwide to treat patients with refractory gastroparesis,” the investigators wrote in Gastroenterology). “G-POEM is an overall safe procedure with high technical success rates, particularly when performed by an endoscopist experienced in third-space endoscopy. Even if the durable clinical success of G-POEM is in the 50% to 60% range, this represents a huge clinical benefit to patients with refractory gastroparesis, which is a disease associated with substantial morbidity, poor quality of life, and a paucity of safe and effective treatments.”
The authors listed treatment alternatives, noting how associated clinical data have fallen short.
“Although endoscopic pyloric balloon dilation, intrapyloric botulinum toxin injection, gastric electrical stimulation, and transpyloric stenting have been used in patients [with gastroparesis] who have not responded to medical therapy, published studies concerning these therapies have been inconsistent, shown no benefit, or lacked methodologic rigor,” they wrote.
Patient selection
G-POEM should be considered in patients with medically refractory gastroparesis due to diabetes, prior surgery, or idiopathic causes. Candidates should undergo endoscopy to confirm no mechanical obstruction, as well as a solid-phase gastric emptying scan to confirm delayed emptying, with ideal candidates showing at least 20% retention at 4 hours, as this threshold has been linked with better clinical outcomes.
G-POEM is most beneficial when moderate to severe symptoms are present, the investigators wrote, particularly vomiting and nausea. The Gastroparesis Cardinal Symptom Index (GCSI) can be used to determine severity, with a score greater than 2 indicating moderate to severe presentation.
Procedural considerations
The CPU offers detailed procedural considerations, including preparation and equipment, technical guidance, and postprocedural strategy.
“G-POEM should only be performed by interventional endoscopists with expertise or training in third-space endoscopy,” Dr. Khashab and colleagues wrote. “Although experience in endoscopic submucosal dissection (ESD) is not mandatory before performing G-POEM, it likely shortens the learning curve.”
Equipment minimums are also described, including “a high-definition gastroscope, with a waterjet, affixed with a clear distal cap” and “a modern electrosurgical generator capable of modulating power based on tissue resistance and circuit impedance.”
While G-POEM is typically performed via a greater-curvature approach, similar outcomes have been documented for a lesser-curvature approach, Dr. Khashab and colleagues wrote. This alternative technique may increase difficulty of pyloromyotomy, they added.
Postprocedural care may involve an overnight stay, according to the update, with an upper GI study on the subsequent day to ensure no contrast leakage, though this is not mandatory.
Adverse events
“G-POEM is generally safe when performed by trained and/or experienced endoscopists, and AEs are uncommon,” the investigators wrote. “However, serious AEs can occur and have been reported.”
Reported AEs include capnoperitoneum, inadvertent mucosotomy, thermal-mucosal injury, abdominal pain, bleeding, gastric ulceration, and dumping syndrome.
Insurance companies called to action
After reviewing emerging data, the authors suggested the time has come to consider G-POEM as a routine, evidence-based procedure that deserves appropriate reimbursement by financial stakeholders.
“Many insurers still consider G-POEM investigational and refuse to cover this procedure for patients with medically refractory gastroparesis,” they wrote. “As the safety and clinical effectiveness of G-POEM is now well supported, insurance companies and payors should cover G-POEM for patients with significant gastroparesis.”
The clinical practice update was commissioned and approved by the American Gastroenterological Association. The investigators disclosed relationships with Boston Scientific, Medtronic, and Olympus, among others.
Authored by Mouen A. Khashab, MD, director of therapeutic endoscopy at Johns Hopkins Medicine, Baltimore; Andrew Y. Wang, MD, AGAF, chief of interventional endoscopy, University of Virginia, Charlottesville; and, Qiang Cai, MD, PhD, chief of gastroenterology, Ochsner LSU Health Shreveport (La.), the update covers patient selection, procedural considerations, adverse events (AEs), and other topics.
“G-POEM is being performed worldwide to treat patients with refractory gastroparesis,” the investigators wrote in Gastroenterology). “G-POEM is an overall safe procedure with high technical success rates, particularly when performed by an endoscopist experienced in third-space endoscopy. Even if the durable clinical success of G-POEM is in the 50% to 60% range, this represents a huge clinical benefit to patients with refractory gastroparesis, which is a disease associated with substantial morbidity, poor quality of life, and a paucity of safe and effective treatments.”
The authors listed treatment alternatives, noting how associated clinical data have fallen short.
“Although endoscopic pyloric balloon dilation, intrapyloric botulinum toxin injection, gastric electrical stimulation, and transpyloric stenting have been used in patients [with gastroparesis] who have not responded to medical therapy, published studies concerning these therapies have been inconsistent, shown no benefit, or lacked methodologic rigor,” they wrote.
Patient selection
G-POEM should be considered in patients with medically refractory gastroparesis due to diabetes, prior surgery, or idiopathic causes. Candidates should undergo endoscopy to confirm no mechanical obstruction, as well as a solid-phase gastric emptying scan to confirm delayed emptying, with ideal candidates showing at least 20% retention at 4 hours, as this threshold has been linked with better clinical outcomes.
G-POEM is most beneficial when moderate to severe symptoms are present, the investigators wrote, particularly vomiting and nausea. The Gastroparesis Cardinal Symptom Index (GCSI) can be used to determine severity, with a score greater than 2 indicating moderate to severe presentation.
Procedural considerations
The CPU offers detailed procedural considerations, including preparation and equipment, technical guidance, and postprocedural strategy.
“G-POEM should only be performed by interventional endoscopists with expertise or training in third-space endoscopy,” Dr. Khashab and colleagues wrote. “Although experience in endoscopic submucosal dissection (ESD) is not mandatory before performing G-POEM, it likely shortens the learning curve.”
Equipment minimums are also described, including “a high-definition gastroscope, with a waterjet, affixed with a clear distal cap” and “a modern electrosurgical generator capable of modulating power based on tissue resistance and circuit impedance.”
While G-POEM is typically performed via a greater-curvature approach, similar outcomes have been documented for a lesser-curvature approach, Dr. Khashab and colleagues wrote. This alternative technique may increase difficulty of pyloromyotomy, they added.
Postprocedural care may involve an overnight stay, according to the update, with an upper GI study on the subsequent day to ensure no contrast leakage, though this is not mandatory.
Adverse events
“G-POEM is generally safe when performed by trained and/or experienced endoscopists, and AEs are uncommon,” the investigators wrote. “However, serious AEs can occur and have been reported.”
Reported AEs include capnoperitoneum, inadvertent mucosotomy, thermal-mucosal injury, abdominal pain, bleeding, gastric ulceration, and dumping syndrome.
Insurance companies called to action
After reviewing emerging data, the authors suggested the time has come to consider G-POEM as a routine, evidence-based procedure that deserves appropriate reimbursement by financial stakeholders.
“Many insurers still consider G-POEM investigational and refuse to cover this procedure for patients with medically refractory gastroparesis,” they wrote. “As the safety and clinical effectiveness of G-POEM is now well supported, insurance companies and payors should cover G-POEM for patients with significant gastroparesis.”
The clinical practice update was commissioned and approved by the American Gastroenterological Association. The investigators disclosed relationships with Boston Scientific, Medtronic, and Olympus, among others.
FROM GASTROENTEROLOGY
Race and ethnicity loom large in CRC screening
Disparities in colorectal screening represent a serious public health challenge, say the authors of a new literature review that describes specific areas of concern and recommendations for improvement.
For their research, published in Techniques and Innovations in Gastrointestinal Endoscopy, gastroenterologists Abraham Segura, MD, and Shazia Mehmood Siddique, MD, of the University of Pennsylvania, Philadelphia, sought to identify studies that shed light on ethnicity or race-based differences in screening uptake, as well as known barriers and facilitators to screening.
Significant racial and ethnic disparities can be seen in rates of colonoscopy selection as a screening method, and of screening completion, Dr. Segura and Dr. Siddique noted, with White individuals who chose the method three times more likely to complete screening as Asian, Hispanic, or Black individuals. Disparities were also seen reflected in people’s choice of screening method, with non–English-speaking Hispanic individuals less likely to choose colonoscopy compared with other groups.
Use of stool-based screening methods, such as the fecal occult blood test (FOBT) and fecal immunochemical test (FIT), has risen over time across ethnic and racial groups. However, Hispanic and Asian individuals were more likely to complete and adhere to the FOBT, compared with non-Hispanic White individuals. Follow-up colonoscopy rates after FOBT or FIT also differ along ethnic and racial lines, Dr. Segura and Dr. Siddique noted, with Asian and American Indian groups less likely to complete follow-up after an abnormal result.
The study authors pointed to structural racism at the root of some observed disparities, citing barriers to healthcare access and quality that include higher rates of noninsurance among Black and Hispanic populations and a lower likelihood of the same populations to receive physician counseling regarding screening.
Barriers to economic stability, including living in impoverished neighborhoods, were also cited as contributors to lower colorectal screening. Patients covered by Medicaid were more than twice as likely as non-Medicaid patients to have suboptimal bowel preparation at screening, the authors noted. Access to transportation remained another frequently observed barrier to completing recommended testing and follow-up.
Mistrust of doctors has been linked to lower screening uptake among Black men. “Longstanding conscious and implicit racism, differences in communication, and socioeconomic context ... engender medical mistrust among racial and ethnic groups,” the authors wrote. Reversing it “ultimately requires vast societal change, and we as physicians can facilitate this by encouraging patient-centered discussions that humanize and empower traditionally marginalized populations.”
Dr. Segura and Dr. Siddique described strategies that have been shown to result in better uptake in specific populations, including removing out-of-pocket costs for screening and follow-up, and designing faith-based or culturally specific outreach delivered through churches and local businesses.
They recommended that researchers change how they study the disparities that bear on colorectal screening and outcomes. “Collection and use of data on race and ethnicity must be optimized and standardized to ensure that all groups are adequately captured,” they wrote. Standardizing self-reporting of race and ethnicity would help address issues of misclassification.
The authors also advised designing studies with longer follow-up, noting that “we must better understand the mechanisms of long-term adherence.” Additional research is needed, they said, to evaluate the efficacy of older outreach strategies after societal changes resulting from the COVID-19 pandemic. Efforts to increase the number of Black, Hispanic, Asian, and Alaskan Native/American Indian groups in CRC screening interventions and studies “must be prioritized.”
Dr. Segura’s and Dr. Siddique’s study was funded with grants from the National Institutes of Health. They disclosed no conflicts of interest.
Understanding disparities in medicine is the requisite first step toward achieving health equity. The review by Segura and Siddique highlight reasons for health disparities in colorectal cancer (CRC) screening, and propose some solutions.
Issues such as structural racism, socioeconomic status and lack of health insurance need to be addressed at the societal level. Recent elimination of cost-sharing for colonoscopy after a positive noninvasive screening test, and elimination of cost-sharing for screening exams with polypectomy, reduce financial barriers for those patients who have health care insurance and Medicare.
How can practitioners apply this information? Recognition of implicit bias among health care workers is an essential first step toward achieving equity. Providing equitable access to CRC screening works. In a study from Kaiser Permanente, disparities in CRC outcomes between non-Hispanic White versus Black patients, were eliminated within 10 years after implementing an annual mailed fecal immunochemical test kit. This is an exciting proof of principle – physicians and health care organizations can reduce health disparities.
David Lieberman, MD, professor of medicine and formerly chief of the division of gastroenterology and hepatology (1997-2021), Oregon Health and Science University, Portland. Dr. Lieberman does not have any relevant disclosures.
Understanding disparities in medicine is the requisite first step toward achieving health equity. The review by Segura and Siddique highlight reasons for health disparities in colorectal cancer (CRC) screening, and propose some solutions.
Issues such as structural racism, socioeconomic status and lack of health insurance need to be addressed at the societal level. Recent elimination of cost-sharing for colonoscopy after a positive noninvasive screening test, and elimination of cost-sharing for screening exams with polypectomy, reduce financial barriers for those patients who have health care insurance and Medicare.
How can practitioners apply this information? Recognition of implicit bias among health care workers is an essential first step toward achieving equity. Providing equitable access to CRC screening works. In a study from Kaiser Permanente, disparities in CRC outcomes between non-Hispanic White versus Black patients, were eliminated within 10 years after implementing an annual mailed fecal immunochemical test kit. This is an exciting proof of principle – physicians and health care organizations can reduce health disparities.
David Lieberman, MD, professor of medicine and formerly chief of the division of gastroenterology and hepatology (1997-2021), Oregon Health and Science University, Portland. Dr. Lieberman does not have any relevant disclosures.
Understanding disparities in medicine is the requisite first step toward achieving health equity. The review by Segura and Siddique highlight reasons for health disparities in colorectal cancer (CRC) screening, and propose some solutions.
Issues such as structural racism, socioeconomic status and lack of health insurance need to be addressed at the societal level. Recent elimination of cost-sharing for colonoscopy after a positive noninvasive screening test, and elimination of cost-sharing for screening exams with polypectomy, reduce financial barriers for those patients who have health care insurance and Medicare.
How can practitioners apply this information? Recognition of implicit bias among health care workers is an essential first step toward achieving equity. Providing equitable access to CRC screening works. In a study from Kaiser Permanente, disparities in CRC outcomes between non-Hispanic White versus Black patients, were eliminated within 10 years after implementing an annual mailed fecal immunochemical test kit. This is an exciting proof of principle – physicians and health care organizations can reduce health disparities.
David Lieberman, MD, professor of medicine and formerly chief of the division of gastroenterology and hepatology (1997-2021), Oregon Health and Science University, Portland. Dr. Lieberman does not have any relevant disclosures.
Disparities in colorectal screening represent a serious public health challenge, say the authors of a new literature review that describes specific areas of concern and recommendations for improvement.
For their research, published in Techniques and Innovations in Gastrointestinal Endoscopy, gastroenterologists Abraham Segura, MD, and Shazia Mehmood Siddique, MD, of the University of Pennsylvania, Philadelphia, sought to identify studies that shed light on ethnicity or race-based differences in screening uptake, as well as known barriers and facilitators to screening.
Significant racial and ethnic disparities can be seen in rates of colonoscopy selection as a screening method, and of screening completion, Dr. Segura and Dr. Siddique noted, with White individuals who chose the method three times more likely to complete screening as Asian, Hispanic, or Black individuals. Disparities were also seen reflected in people’s choice of screening method, with non–English-speaking Hispanic individuals less likely to choose colonoscopy compared with other groups.
Use of stool-based screening methods, such as the fecal occult blood test (FOBT) and fecal immunochemical test (FIT), has risen over time across ethnic and racial groups. However, Hispanic and Asian individuals were more likely to complete and adhere to the FOBT, compared with non-Hispanic White individuals. Follow-up colonoscopy rates after FOBT or FIT also differ along ethnic and racial lines, Dr. Segura and Dr. Siddique noted, with Asian and American Indian groups less likely to complete follow-up after an abnormal result.
The study authors pointed to structural racism at the root of some observed disparities, citing barriers to healthcare access and quality that include higher rates of noninsurance among Black and Hispanic populations and a lower likelihood of the same populations to receive physician counseling regarding screening.
Barriers to economic stability, including living in impoverished neighborhoods, were also cited as contributors to lower colorectal screening. Patients covered by Medicaid were more than twice as likely as non-Medicaid patients to have suboptimal bowel preparation at screening, the authors noted. Access to transportation remained another frequently observed barrier to completing recommended testing and follow-up.
Mistrust of doctors has been linked to lower screening uptake among Black men. “Longstanding conscious and implicit racism, differences in communication, and socioeconomic context ... engender medical mistrust among racial and ethnic groups,” the authors wrote. Reversing it “ultimately requires vast societal change, and we as physicians can facilitate this by encouraging patient-centered discussions that humanize and empower traditionally marginalized populations.”
Dr. Segura and Dr. Siddique described strategies that have been shown to result in better uptake in specific populations, including removing out-of-pocket costs for screening and follow-up, and designing faith-based or culturally specific outreach delivered through churches and local businesses.
They recommended that researchers change how they study the disparities that bear on colorectal screening and outcomes. “Collection and use of data on race and ethnicity must be optimized and standardized to ensure that all groups are adequately captured,” they wrote. Standardizing self-reporting of race and ethnicity would help address issues of misclassification.
The authors also advised designing studies with longer follow-up, noting that “we must better understand the mechanisms of long-term adherence.” Additional research is needed, they said, to evaluate the efficacy of older outreach strategies after societal changes resulting from the COVID-19 pandemic. Efforts to increase the number of Black, Hispanic, Asian, and Alaskan Native/American Indian groups in CRC screening interventions and studies “must be prioritized.”
Dr. Segura’s and Dr. Siddique’s study was funded with grants from the National Institutes of Health. They disclosed no conflicts of interest.
Disparities in colorectal screening represent a serious public health challenge, say the authors of a new literature review that describes specific areas of concern and recommendations for improvement.
For their research, published in Techniques and Innovations in Gastrointestinal Endoscopy, gastroenterologists Abraham Segura, MD, and Shazia Mehmood Siddique, MD, of the University of Pennsylvania, Philadelphia, sought to identify studies that shed light on ethnicity or race-based differences in screening uptake, as well as known barriers and facilitators to screening.
Significant racial and ethnic disparities can be seen in rates of colonoscopy selection as a screening method, and of screening completion, Dr. Segura and Dr. Siddique noted, with White individuals who chose the method three times more likely to complete screening as Asian, Hispanic, or Black individuals. Disparities were also seen reflected in people’s choice of screening method, with non–English-speaking Hispanic individuals less likely to choose colonoscopy compared with other groups.
Use of stool-based screening methods, such as the fecal occult blood test (FOBT) and fecal immunochemical test (FIT), has risen over time across ethnic and racial groups. However, Hispanic and Asian individuals were more likely to complete and adhere to the FOBT, compared with non-Hispanic White individuals. Follow-up colonoscopy rates after FOBT or FIT also differ along ethnic and racial lines, Dr. Segura and Dr. Siddique noted, with Asian and American Indian groups less likely to complete follow-up after an abnormal result.
The study authors pointed to structural racism at the root of some observed disparities, citing barriers to healthcare access and quality that include higher rates of noninsurance among Black and Hispanic populations and a lower likelihood of the same populations to receive physician counseling regarding screening.
Barriers to economic stability, including living in impoverished neighborhoods, were also cited as contributors to lower colorectal screening. Patients covered by Medicaid were more than twice as likely as non-Medicaid patients to have suboptimal bowel preparation at screening, the authors noted. Access to transportation remained another frequently observed barrier to completing recommended testing and follow-up.
Mistrust of doctors has been linked to lower screening uptake among Black men. “Longstanding conscious and implicit racism, differences in communication, and socioeconomic context ... engender medical mistrust among racial and ethnic groups,” the authors wrote. Reversing it “ultimately requires vast societal change, and we as physicians can facilitate this by encouraging patient-centered discussions that humanize and empower traditionally marginalized populations.”
Dr. Segura and Dr. Siddique described strategies that have been shown to result in better uptake in specific populations, including removing out-of-pocket costs for screening and follow-up, and designing faith-based or culturally specific outreach delivered through churches and local businesses.
They recommended that researchers change how they study the disparities that bear on colorectal screening and outcomes. “Collection and use of data on race and ethnicity must be optimized and standardized to ensure that all groups are adequately captured,” they wrote. Standardizing self-reporting of race and ethnicity would help address issues of misclassification.
The authors also advised designing studies with longer follow-up, noting that “we must better understand the mechanisms of long-term adherence.” Additional research is needed, they said, to evaluate the efficacy of older outreach strategies after societal changes resulting from the COVID-19 pandemic. Efforts to increase the number of Black, Hispanic, Asian, and Alaskan Native/American Indian groups in CRC screening interventions and studies “must be prioritized.”
Dr. Segura’s and Dr. Siddique’s study was funded with grants from the National Institutes of Health. They disclosed no conflicts of interest.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
Etrasimod looks safe for ulcerative colitis out to 2.5 years
CHICAGO – new evidence reveals.
Etrasimod (Arena Pharma/Pfizer) is an oral sphingosine-1-phosphate (S1P) receptor that binds with high affinity to receptors 1, 4, and 5. If approved by the FDA, etrasimod could become the second agent in the S1P class approved for ulcerative colitis in the United States. The other agent, ozanimod (Zeposia), received FDA approval for treating moderately to severely active UC in May 2021.
The updated safety profile of etrasimod, presented at the annual Digestive Disease Week® (DDW), is based on data from multiple clinical trials, including OASIS phase 2 and the ELEVATE phase 3, placebo-controlled trials, as well as an ongoing, open-label extension study.
“Etrasimod was well tolerated in patients with moderately to severely active UC and had an acceptable safety profile that did not appear to change with longer-term treatment up to 2.5 years,” said OASIS lead author Séverine Vermeire, MD, PhD, an expert on translational research in gastrointestinal disorders and professor of medicine at KU Leuven (Belgium), while presenting the findings at DDW.
Dr. Vermeire noted that data show an elevated risk for atrioventricular (AV) block or bradycardia in a minority of people treated with the agent during this time period. However, most of the heart-related risk was during induction, and the risks could be minimized by ordering an electrocardiogram before prescribing, she said.
Cumulative safety data
Researchers separated the trial participants into two cohorts. The all-UC cohort consisted of 956 patients who took at least one dose of etrasimod. The placebo-controlled cohort consisted of 629 patients taking etrasimod and 314 patients who took a placebo. Some patients participated in more than one study, the researchers noted.
In both cohorts, mean duration of disease was about 7 years, about 42% of all participants were female, and mean age was about 41 years.
The investigators looked at the frequency of adverse events and exposure-adjusted incidence rates from the OASIS phase 2 and the ELEVATE phase 3 placebo-controlled trials, as well as an ongoing, open-label extension study. They also assessed safety in placebo and 1 mg or 2 mg etrasimod in the phase 2 NCT02447302 or two phase 3 trials, NCT03945188 and NCT03996369, reported up until Jan. 31, 2022.
There were 770 patient-years of etrasimod exposure in the all-UC cohort, while exposure in the placebo-controlled cohort was 288 patient-years in the etrasimod group and 115 patient-years in the placebo group. Mean exposure to etrasimod was 42 weeks in the all-UC cohort. Mean exposure in the placebo-controlled cohort was 24 weeks in the etrasimod group and 19 weeks in the placebo group.
Because of the mechanism of action of etrasimod, Dr. Vermeire and colleagues focused on cardiovascular events, macular edema, severe or opportunistic infections, herpes zoster infections, and malignancies.
Eleven patients (1.8%) treated with etrasimod reported bradycardia or sinus bradycardia in the placebo-controlled research, and 9 of 11 were asymptomatic. No bradycardia was associated with taking a placebo. In the all-UC cohort, bradycardia or sinus bradycardia was reported in 14 patients (1.5%).
“Bradycardia is something you need to tell patients may occur,” Dr. Vermeire said. “Most of the bradycardia occurred on day one or day two, mostly on day one.”
Four people taking etrasimod in the placebo-controlled cohort and 7 people in the all-UC cohort had AV block of the first or second degree. No reports of AV block occurred in the placebo group.
“Other adverse events of special interest, including hypertension and macular edema, were all rare and similar between the treatment arms,” Dr. Vermeire said.
Herpes zoster infections were reported in two patients taking etrasimod and two taking placebo in the placebo-controlled cohort. Seven cases were reported in the all-UC cohort. Dr. Vermeire said she advocates vaccinating patients against herpes zoster soon after UC diagnosis, if possible.
In the placebo-controlled cohort, 11 patients taking etrasimod and two patients taking placebo experienced elevated ALT. This was fewer than 2% of patients. One patient taking etrasimod and one receiving placebo discontinued the study for this reason. In the all-UC cohort, 27 people experienced elevated ALT.
In the placebo-controlled cohort, 13 people treated with etrasimod and two taking placebo developed elevated gamma-glutamyltransferase. This adverse event was reported in 32 patients in the all-UC cohort.
There were no deaths reported in the placebo-controlled cohort of patients. One patient in the all-UC cohort developed a neuroendocrine tumor and died. The person received etrasimod 2 mg daily for about 6 months before the event’s onset. “This was assessed as unlikely related to the study treatment as judged by investigators,” Dr. Vermeire said.
Limitations of the study include a relatively short average duration of exposure to etrasimod.
“As the study continues, we will continue collecting and reporting the safety data,” Dr. Vermeire said.
A well-tolerated therapy
“The important take-home message is that patients tolerated therapy very well,” said session comoderator Jordan E. Axelrad, MD, MPH, when asked to comment.
There were very few adverse events, and of these, they were mostly minor, with patients being able to continue on therapy in large part, added Dr. Axelrad, a gastroenterologist at the Inflammatory Bowel Disease Center at NYU Langone Health, New York.
Physicians will “need to get comfortable” with ordering an ECG to screen patients before prescribing etrasimod, he noted.
“Once we can get past that hurdle [of ordering an ECG], we should be integrating it into our practice,” Dr. Axelrad said.
The study was funded by Arena Pharmaceuticals, which was acquired by Pfizer; Pfizer completed the acquisition in March 2022. Dr. Vermeire reported receiving consulting and speaking fees from Arena Pharmaceuticals and grant and research support from Pfizer. Dr. Axelrad reported no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.
A version of this article originally appeared on Medscape.com.
CHICAGO – new evidence reveals.
Etrasimod (Arena Pharma/Pfizer) is an oral sphingosine-1-phosphate (S1P) receptor that binds with high affinity to receptors 1, 4, and 5. If approved by the FDA, etrasimod could become the second agent in the S1P class approved for ulcerative colitis in the United States. The other agent, ozanimod (Zeposia), received FDA approval for treating moderately to severely active UC in May 2021.
The updated safety profile of etrasimod, presented at the annual Digestive Disease Week® (DDW), is based on data from multiple clinical trials, including OASIS phase 2 and the ELEVATE phase 3, placebo-controlled trials, as well as an ongoing, open-label extension study.
“Etrasimod was well tolerated in patients with moderately to severely active UC and had an acceptable safety profile that did not appear to change with longer-term treatment up to 2.5 years,” said OASIS lead author Séverine Vermeire, MD, PhD, an expert on translational research in gastrointestinal disorders and professor of medicine at KU Leuven (Belgium), while presenting the findings at DDW.
Dr. Vermeire noted that data show an elevated risk for atrioventricular (AV) block or bradycardia in a minority of people treated with the agent during this time period. However, most of the heart-related risk was during induction, and the risks could be minimized by ordering an electrocardiogram before prescribing, she said.
Cumulative safety data
Researchers separated the trial participants into two cohorts. The all-UC cohort consisted of 956 patients who took at least one dose of etrasimod. The placebo-controlled cohort consisted of 629 patients taking etrasimod and 314 patients who took a placebo. Some patients participated in more than one study, the researchers noted.
In both cohorts, mean duration of disease was about 7 years, about 42% of all participants were female, and mean age was about 41 years.
The investigators looked at the frequency of adverse events and exposure-adjusted incidence rates from the OASIS phase 2 and the ELEVATE phase 3 placebo-controlled trials, as well as an ongoing, open-label extension study. They also assessed safety in placebo and 1 mg or 2 mg etrasimod in the phase 2 NCT02447302 or two phase 3 trials, NCT03945188 and NCT03996369, reported up until Jan. 31, 2022.
There were 770 patient-years of etrasimod exposure in the all-UC cohort, while exposure in the placebo-controlled cohort was 288 patient-years in the etrasimod group and 115 patient-years in the placebo group. Mean exposure to etrasimod was 42 weeks in the all-UC cohort. Mean exposure in the placebo-controlled cohort was 24 weeks in the etrasimod group and 19 weeks in the placebo group.
Because of the mechanism of action of etrasimod, Dr. Vermeire and colleagues focused on cardiovascular events, macular edema, severe or opportunistic infections, herpes zoster infections, and malignancies.
Eleven patients (1.8%) treated with etrasimod reported bradycardia or sinus bradycardia in the placebo-controlled research, and 9 of 11 were asymptomatic. No bradycardia was associated with taking a placebo. In the all-UC cohort, bradycardia or sinus bradycardia was reported in 14 patients (1.5%).
“Bradycardia is something you need to tell patients may occur,” Dr. Vermeire said. “Most of the bradycardia occurred on day one or day two, mostly on day one.”
Four people taking etrasimod in the placebo-controlled cohort and 7 people in the all-UC cohort had AV block of the first or second degree. No reports of AV block occurred in the placebo group.
“Other adverse events of special interest, including hypertension and macular edema, were all rare and similar between the treatment arms,” Dr. Vermeire said.
Herpes zoster infections were reported in two patients taking etrasimod and two taking placebo in the placebo-controlled cohort. Seven cases were reported in the all-UC cohort. Dr. Vermeire said she advocates vaccinating patients against herpes zoster soon after UC diagnosis, if possible.
In the placebo-controlled cohort, 11 patients taking etrasimod and two patients taking placebo experienced elevated ALT. This was fewer than 2% of patients. One patient taking etrasimod and one receiving placebo discontinued the study for this reason. In the all-UC cohort, 27 people experienced elevated ALT.
In the placebo-controlled cohort, 13 people treated with etrasimod and two taking placebo developed elevated gamma-glutamyltransferase. This adverse event was reported in 32 patients in the all-UC cohort.
There were no deaths reported in the placebo-controlled cohort of patients. One patient in the all-UC cohort developed a neuroendocrine tumor and died. The person received etrasimod 2 mg daily for about 6 months before the event’s onset. “This was assessed as unlikely related to the study treatment as judged by investigators,” Dr. Vermeire said.
Limitations of the study include a relatively short average duration of exposure to etrasimod.
“As the study continues, we will continue collecting and reporting the safety data,” Dr. Vermeire said.
A well-tolerated therapy
“The important take-home message is that patients tolerated therapy very well,” said session comoderator Jordan E. Axelrad, MD, MPH, when asked to comment.
There were very few adverse events, and of these, they were mostly minor, with patients being able to continue on therapy in large part, added Dr. Axelrad, a gastroenterologist at the Inflammatory Bowel Disease Center at NYU Langone Health, New York.
Physicians will “need to get comfortable” with ordering an ECG to screen patients before prescribing etrasimod, he noted.
“Once we can get past that hurdle [of ordering an ECG], we should be integrating it into our practice,” Dr. Axelrad said.
The study was funded by Arena Pharmaceuticals, which was acquired by Pfizer; Pfizer completed the acquisition in March 2022. Dr. Vermeire reported receiving consulting and speaking fees from Arena Pharmaceuticals and grant and research support from Pfizer. Dr. Axelrad reported no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.
A version of this article originally appeared on Medscape.com.
CHICAGO – new evidence reveals.
Etrasimod (Arena Pharma/Pfizer) is an oral sphingosine-1-phosphate (S1P) receptor that binds with high affinity to receptors 1, 4, and 5. If approved by the FDA, etrasimod could become the second agent in the S1P class approved for ulcerative colitis in the United States. The other agent, ozanimod (Zeposia), received FDA approval for treating moderately to severely active UC in May 2021.
The updated safety profile of etrasimod, presented at the annual Digestive Disease Week® (DDW), is based on data from multiple clinical trials, including OASIS phase 2 and the ELEVATE phase 3, placebo-controlled trials, as well as an ongoing, open-label extension study.
“Etrasimod was well tolerated in patients with moderately to severely active UC and had an acceptable safety profile that did not appear to change with longer-term treatment up to 2.5 years,” said OASIS lead author Séverine Vermeire, MD, PhD, an expert on translational research in gastrointestinal disorders and professor of medicine at KU Leuven (Belgium), while presenting the findings at DDW.
Dr. Vermeire noted that data show an elevated risk for atrioventricular (AV) block or bradycardia in a minority of people treated with the agent during this time period. However, most of the heart-related risk was during induction, and the risks could be minimized by ordering an electrocardiogram before prescribing, she said.
Cumulative safety data
Researchers separated the trial participants into two cohorts. The all-UC cohort consisted of 956 patients who took at least one dose of etrasimod. The placebo-controlled cohort consisted of 629 patients taking etrasimod and 314 patients who took a placebo. Some patients participated in more than one study, the researchers noted.
In both cohorts, mean duration of disease was about 7 years, about 42% of all participants were female, and mean age was about 41 years.
The investigators looked at the frequency of adverse events and exposure-adjusted incidence rates from the OASIS phase 2 and the ELEVATE phase 3 placebo-controlled trials, as well as an ongoing, open-label extension study. They also assessed safety in placebo and 1 mg or 2 mg etrasimod in the phase 2 NCT02447302 or two phase 3 trials, NCT03945188 and NCT03996369, reported up until Jan. 31, 2022.
There were 770 patient-years of etrasimod exposure in the all-UC cohort, while exposure in the placebo-controlled cohort was 288 patient-years in the etrasimod group and 115 patient-years in the placebo group. Mean exposure to etrasimod was 42 weeks in the all-UC cohort. Mean exposure in the placebo-controlled cohort was 24 weeks in the etrasimod group and 19 weeks in the placebo group.
Because of the mechanism of action of etrasimod, Dr. Vermeire and colleagues focused on cardiovascular events, macular edema, severe or opportunistic infections, herpes zoster infections, and malignancies.
Eleven patients (1.8%) treated with etrasimod reported bradycardia or sinus bradycardia in the placebo-controlled research, and 9 of 11 were asymptomatic. No bradycardia was associated with taking a placebo. In the all-UC cohort, bradycardia or sinus bradycardia was reported in 14 patients (1.5%).
“Bradycardia is something you need to tell patients may occur,” Dr. Vermeire said. “Most of the bradycardia occurred on day one or day two, mostly on day one.”
Four people taking etrasimod in the placebo-controlled cohort and 7 people in the all-UC cohort had AV block of the first or second degree. No reports of AV block occurred in the placebo group.
“Other adverse events of special interest, including hypertension and macular edema, were all rare and similar between the treatment arms,” Dr. Vermeire said.
Herpes zoster infections were reported in two patients taking etrasimod and two taking placebo in the placebo-controlled cohort. Seven cases were reported in the all-UC cohort. Dr. Vermeire said she advocates vaccinating patients against herpes zoster soon after UC diagnosis, if possible.
In the placebo-controlled cohort, 11 patients taking etrasimod and two patients taking placebo experienced elevated ALT. This was fewer than 2% of patients. One patient taking etrasimod and one receiving placebo discontinued the study for this reason. In the all-UC cohort, 27 people experienced elevated ALT.
In the placebo-controlled cohort, 13 people treated with etrasimod and two taking placebo developed elevated gamma-glutamyltransferase. This adverse event was reported in 32 patients in the all-UC cohort.
There were no deaths reported in the placebo-controlled cohort of patients. One patient in the all-UC cohort developed a neuroendocrine tumor and died. The person received etrasimod 2 mg daily for about 6 months before the event’s onset. “This was assessed as unlikely related to the study treatment as judged by investigators,” Dr. Vermeire said.
Limitations of the study include a relatively short average duration of exposure to etrasimod.
“As the study continues, we will continue collecting and reporting the safety data,” Dr. Vermeire said.
A well-tolerated therapy
“The important take-home message is that patients tolerated therapy very well,” said session comoderator Jordan E. Axelrad, MD, MPH, when asked to comment.
There were very few adverse events, and of these, they were mostly minor, with patients being able to continue on therapy in large part, added Dr. Axelrad, a gastroenterologist at the Inflammatory Bowel Disease Center at NYU Langone Health, New York.
Physicians will “need to get comfortable” with ordering an ECG to screen patients before prescribing etrasimod, he noted.
“Once we can get past that hurdle [of ordering an ECG], we should be integrating it into our practice,” Dr. Axelrad said.
The study was funded by Arena Pharmaceuticals, which was acquired by Pfizer; Pfizer completed the acquisition in March 2022. Dr. Vermeire reported receiving consulting and speaking fees from Arena Pharmaceuticals and grant and research support from Pfizer. Dr. Axelrad reported no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and The Society for Surgery of the Alimentary Tract.
A version of this article originally appeared on Medscape.com.
AT DDW 2023
Upadacitinib shows promise in treatment-resistant UC and Crohn’s
according to results from a real-world study at a Chicago treatment center.
The results suggest that upadacitinib may be an appropriate salvage treatment for patients who have failed other advanced therapies, including tofacitinib.
For their research, published in Clinical Gastroenterology and Hepatology, Scott Friedberg, MD, and colleagues at the University of Chicago’s Inflammatory Bowel Disease Center, looked at results from 44 patients diagnosed with ulcerative colitis and 40 with Crohn’s disease, all with active luminal or perianal disease. All patients in the study had previous exposure to tumor necrosis factor inhibitors, and nearly 90% had exposure to two or more advanced therapies, including tofacitinib (n = 17), before being switched to upadacitinib.
Upadacitinib (Rinvoq, AbbVie) is the second small-molecule Janus kinase (JAK) inhibitor approved for ulcerative colitis by the Food and Drug Administration in March 2022 after tofacitinib (Xeljanz, Pfizer) in 2018. Upadacitinib received an additional indication in May 2023 as a treatment for Crohn’s disease. It selectively inhibits JAK1, while tofacitinib inhibits JAK1 and JAK3.
Among the ulcerative colitis patients in Dr. Friedberg and colleagues’ study (mean age, 39 years; 48% female), 85% had a clinical response and 82% achieved clinical remission by week 8. Of nine patients previously treated with tofacitinib, seven (78%) achieved remission at 8 weeks.
Some 76% of the Crohn’s disease patients in the study (mean age, 37 years; 53% female) saw clinical response by 8 weeks, and 71% achieved remission by that time. More than 60% of all participants who had increased fecal calprotectin and C-reactive protein levels at baseline saw normalization of these biomarkers by week 8.
Some patients saw an especially fast response, with 36% of the ulcerative colitis patients and 56% of the Crohn’s patients experiencing clinical remission by week 2.
Acne was the most common reported adverse event, occurring in 23% of patients. Only one serious adverse event, an anemia requiring hospitalization, occurred during the study.
No wash-out period occurred before starting patients on upadacitinib. There were no adverse events seen associated with this strategy, Dr. Friedberg and colleagues noted, a finding with important implications for real-world practice.
“When patients with active IBD are sick, starting a new therapy as soon as it is available is not only reasonable, it is required,” the investigators wrote. Additionally, the findings support the use of upadacitinib in ulcerative colitis patients with previous exposure to tofacitinib, as “selectivity of JAK targets may have different effectiveness profiles.”
Upadacitinib’s rapid onset “has multiple advantages,” the investigators wrote, “not only by being an option for severely active disease but also by allowing for a rapid taper or complete avoidance of corticosteroids.”
The authors noted their study’s small sample size as a key limitation. Several of Dr. Friedberg’s coauthors disclosed financial relationships with drug manufacturers, including AbbVie.
Understanding the efficacy, onset of action and safety of newly approved inflammatory bowel disease (IBD) therapies is difficult in the absence of real-world data as clinical trial populations are much more restrictive and typically do not reflect the patient populations seen in most IBD clinics. This single-center study by Friedberg and colleagues reports on their experience with upadacitinib use in patients with ulcerative colitis (UC) and Crohn’s disease (CD). One key finding of this study is the rapid onset of action with high rates of clinical response and remission within 2 weeks of initiation (60% and 36%) for UC and (50% and 56%) for CD. Further, these high rates of clinical response and remission were noted despite exposure to multiple prior therapies (including prior tofacitinib use), which has been a limitation with other IBD therapies.
With the concerns for safety of tofacitinib use, another Janus kinase inhibitor, raised by the ORAL surveillance study, many patients and practitioners are concerned about the safety of upadacitinib use. This study highlighted the low rate of adverse events including no incidences of herpes zoster infection, venous thromboembolism or major adverse cardiovascular events. Acne was noted to be the most common adverse event, occurring in 22% of the study population.
Further research is needed to assess the long term clinical and endoscopic response rates as well as long-term safety assessments, however these results will facilitate conversations with patients who could potentially benefit from treatment with this new therapy.
Jill K. J. Gaidos, MD, FACG, AGAF, is associate professor of medicine, vice chief of clinical research, section of digestive diseases, Yale University, and director of clinical research, Yale Inflammatory Bowel Disease Program, New Haven, Conn.
Understanding the efficacy, onset of action and safety of newly approved inflammatory bowel disease (IBD) therapies is difficult in the absence of real-world data as clinical trial populations are much more restrictive and typically do not reflect the patient populations seen in most IBD clinics. This single-center study by Friedberg and colleagues reports on their experience with upadacitinib use in patients with ulcerative colitis (UC) and Crohn’s disease (CD). One key finding of this study is the rapid onset of action with high rates of clinical response and remission within 2 weeks of initiation (60% and 36%) for UC and (50% and 56%) for CD. Further, these high rates of clinical response and remission were noted despite exposure to multiple prior therapies (including prior tofacitinib use), which has been a limitation with other IBD therapies.
With the concerns for safety of tofacitinib use, another Janus kinase inhibitor, raised by the ORAL surveillance study, many patients and practitioners are concerned about the safety of upadacitinib use. This study highlighted the low rate of adverse events including no incidences of herpes zoster infection, venous thromboembolism or major adverse cardiovascular events. Acne was noted to be the most common adverse event, occurring in 22% of the study population.
Further research is needed to assess the long term clinical and endoscopic response rates as well as long-term safety assessments, however these results will facilitate conversations with patients who could potentially benefit from treatment with this new therapy.
Jill K. J. Gaidos, MD, FACG, AGAF, is associate professor of medicine, vice chief of clinical research, section of digestive diseases, Yale University, and director of clinical research, Yale Inflammatory Bowel Disease Program, New Haven, Conn.
Understanding the efficacy, onset of action and safety of newly approved inflammatory bowel disease (IBD) therapies is difficult in the absence of real-world data as clinical trial populations are much more restrictive and typically do not reflect the patient populations seen in most IBD clinics. This single-center study by Friedberg and colleagues reports on their experience with upadacitinib use in patients with ulcerative colitis (UC) and Crohn’s disease (CD). One key finding of this study is the rapid onset of action with high rates of clinical response and remission within 2 weeks of initiation (60% and 36%) for UC and (50% and 56%) for CD. Further, these high rates of clinical response and remission were noted despite exposure to multiple prior therapies (including prior tofacitinib use), which has been a limitation with other IBD therapies.
With the concerns for safety of tofacitinib use, another Janus kinase inhibitor, raised by the ORAL surveillance study, many patients and practitioners are concerned about the safety of upadacitinib use. This study highlighted the low rate of adverse events including no incidences of herpes zoster infection, venous thromboembolism or major adverse cardiovascular events. Acne was noted to be the most common adverse event, occurring in 22% of the study population.
Further research is needed to assess the long term clinical and endoscopic response rates as well as long-term safety assessments, however these results will facilitate conversations with patients who could potentially benefit from treatment with this new therapy.
Jill K. J. Gaidos, MD, FACG, AGAF, is associate professor of medicine, vice chief of clinical research, section of digestive diseases, Yale University, and director of clinical research, Yale Inflammatory Bowel Disease Program, New Haven, Conn.
according to results from a real-world study at a Chicago treatment center.
The results suggest that upadacitinib may be an appropriate salvage treatment for patients who have failed other advanced therapies, including tofacitinib.
For their research, published in Clinical Gastroenterology and Hepatology, Scott Friedberg, MD, and colleagues at the University of Chicago’s Inflammatory Bowel Disease Center, looked at results from 44 patients diagnosed with ulcerative colitis and 40 with Crohn’s disease, all with active luminal or perianal disease. All patients in the study had previous exposure to tumor necrosis factor inhibitors, and nearly 90% had exposure to two or more advanced therapies, including tofacitinib (n = 17), before being switched to upadacitinib.
Upadacitinib (Rinvoq, AbbVie) is the second small-molecule Janus kinase (JAK) inhibitor approved for ulcerative colitis by the Food and Drug Administration in March 2022 after tofacitinib (Xeljanz, Pfizer) in 2018. Upadacitinib received an additional indication in May 2023 as a treatment for Crohn’s disease. It selectively inhibits JAK1, while tofacitinib inhibits JAK1 and JAK3.
Among the ulcerative colitis patients in Dr. Friedberg and colleagues’ study (mean age, 39 years; 48% female), 85% had a clinical response and 82% achieved clinical remission by week 8. Of nine patients previously treated with tofacitinib, seven (78%) achieved remission at 8 weeks.
Some 76% of the Crohn’s disease patients in the study (mean age, 37 years; 53% female) saw clinical response by 8 weeks, and 71% achieved remission by that time. More than 60% of all participants who had increased fecal calprotectin and C-reactive protein levels at baseline saw normalization of these biomarkers by week 8.
Some patients saw an especially fast response, with 36% of the ulcerative colitis patients and 56% of the Crohn’s patients experiencing clinical remission by week 2.
Acne was the most common reported adverse event, occurring in 23% of patients. Only one serious adverse event, an anemia requiring hospitalization, occurred during the study.
No wash-out period occurred before starting patients on upadacitinib. There were no adverse events seen associated with this strategy, Dr. Friedberg and colleagues noted, a finding with important implications for real-world practice.
“When patients with active IBD are sick, starting a new therapy as soon as it is available is not only reasonable, it is required,” the investigators wrote. Additionally, the findings support the use of upadacitinib in ulcerative colitis patients with previous exposure to tofacitinib, as “selectivity of JAK targets may have different effectiveness profiles.”
Upadacitinib’s rapid onset “has multiple advantages,” the investigators wrote, “not only by being an option for severely active disease but also by allowing for a rapid taper or complete avoidance of corticosteroids.”
The authors noted their study’s small sample size as a key limitation. Several of Dr. Friedberg’s coauthors disclosed financial relationships with drug manufacturers, including AbbVie.
according to results from a real-world study at a Chicago treatment center.
The results suggest that upadacitinib may be an appropriate salvage treatment for patients who have failed other advanced therapies, including tofacitinib.
For their research, published in Clinical Gastroenterology and Hepatology, Scott Friedberg, MD, and colleagues at the University of Chicago’s Inflammatory Bowel Disease Center, looked at results from 44 patients diagnosed with ulcerative colitis and 40 with Crohn’s disease, all with active luminal or perianal disease. All patients in the study had previous exposure to tumor necrosis factor inhibitors, and nearly 90% had exposure to two or more advanced therapies, including tofacitinib (n = 17), before being switched to upadacitinib.
Upadacitinib (Rinvoq, AbbVie) is the second small-molecule Janus kinase (JAK) inhibitor approved for ulcerative colitis by the Food and Drug Administration in March 2022 after tofacitinib (Xeljanz, Pfizer) in 2018. Upadacitinib received an additional indication in May 2023 as a treatment for Crohn’s disease. It selectively inhibits JAK1, while tofacitinib inhibits JAK1 and JAK3.
Among the ulcerative colitis patients in Dr. Friedberg and colleagues’ study (mean age, 39 years; 48% female), 85% had a clinical response and 82% achieved clinical remission by week 8. Of nine patients previously treated with tofacitinib, seven (78%) achieved remission at 8 weeks.
Some 76% of the Crohn’s disease patients in the study (mean age, 37 years; 53% female) saw clinical response by 8 weeks, and 71% achieved remission by that time. More than 60% of all participants who had increased fecal calprotectin and C-reactive protein levels at baseline saw normalization of these biomarkers by week 8.
Some patients saw an especially fast response, with 36% of the ulcerative colitis patients and 56% of the Crohn’s patients experiencing clinical remission by week 2.
Acne was the most common reported adverse event, occurring in 23% of patients. Only one serious adverse event, an anemia requiring hospitalization, occurred during the study.
No wash-out period occurred before starting patients on upadacitinib. There were no adverse events seen associated with this strategy, Dr. Friedberg and colleagues noted, a finding with important implications for real-world practice.
“When patients with active IBD are sick, starting a new therapy as soon as it is available is not only reasonable, it is required,” the investigators wrote. Additionally, the findings support the use of upadacitinib in ulcerative colitis patients with previous exposure to tofacitinib, as “selectivity of JAK targets may have different effectiveness profiles.”
Upadacitinib’s rapid onset “has multiple advantages,” the investigators wrote, “not only by being an option for severely active disease but also by allowing for a rapid taper or complete avoidance of corticosteroids.”
The authors noted their study’s small sample size as a key limitation. Several of Dr. Friedberg’s coauthors disclosed financial relationships with drug manufacturers, including AbbVie.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Pediatric Crohn’s disease: Adalimumab plus methotrexate offers strong benefit
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.
The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).
Impactful study
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
- Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
- Failure to complete a steroid taper by week 16.
- SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
- Hospitalization or surgery for Crohn’s disease beyond week 26.
- Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
- Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).
There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Shared decision-making
Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.
The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.
The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).
Impactful study
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
- Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
- Failure to complete a steroid taper by week 16.
- SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
- Hospitalization or surgery for Crohn’s disease beyond week 26.
- Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
- Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).
There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Shared decision-making
Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.
The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” said principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina.
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Dr. Kappelman added.
The study was published online in Gastroenterology and was presented in May in Chicago at the annual Digestive Disease Week® (DDW).
Impactful study
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, department of pediatric gastroenterology, hepatology and nutrition, Cleveland Clinic Children’s, who wasn’t involved in the study, said.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs. TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two-thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 kg to less than 40 kg, and 10 mg for children 20 kg to less than 30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
- Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26.
- Failure to complete a steroid taper by week 16.
- SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26.
- Hospitalization or surgery for Crohn’s disease beyond week 26.
- Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16.
- Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity.
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio, 0.69; 95% confidence interval, 0.45-1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55-1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19-0.81; P = .01).
There was a nonsignificant trend toward lower development of antidrug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Shared decision-making
Dr. Kappelman noted that the study was not designed to answer the question of which is better – adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he said.
The trial was not designed to evaluate the role of proactive therapeutic drug monitoring. However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Dr. Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Dr. Kurowski said.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Dr. Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Dr. Kurowski reports no relevant financial relationships.
DDW is sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.
FROM DDW 2023
FDA approves first treatment for constipation in children
The recommended dosage in pediatric patients is 72 mcg orally once daily.
Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.
There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.
The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.
The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
Study details
To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.
They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:
- History of stool withholding or excessive voluntary stool retention.
- History of painful or hard bowel movements.
- History of large diameter stools that may obstruct the toilet.
- Presence of a large fecal mass in the rectum.
- At least one episode of fecal incontinence per week.
The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.
SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.
The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.
The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.
Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.
Full prescribing information is available online.
The application for linaclotide in children received priority review.
A version of this article originally appeared on Medscape.com.
The recommended dosage in pediatric patients is 72 mcg orally once daily.
Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.
There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.
The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.
The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
Study details
To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.
They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:
- History of stool withholding or excessive voluntary stool retention.
- History of painful or hard bowel movements.
- History of large diameter stools that may obstruct the toilet.
- Presence of a large fecal mass in the rectum.
- At least one episode of fecal incontinence per week.
The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.
SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.
The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.
The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.
Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.
Full prescribing information is available online.
The application for linaclotide in children received priority review.
A version of this article originally appeared on Medscape.com.
The recommended dosage in pediatric patients is 72 mcg orally once daily.
Functional constipation is common in children and adolescents. Symptoms include infrequent bowel movements with hard stools that can be difficult or painful to pass.
There is no known underlying organic cause and there are typically multiple contributing factors, the FDA noted in a statement announcing the approval.
The efficacy of linaclotide in children with functional constipation was demonstrated in a 12-week double-blind, placebo-controlled, randomized, multicenter clinical trial (Trial 7; NCT04026113) and supported by efficacy data from trials in adults with chronic idiopathic constipation, the FDA said.
The FDA first approved linaclotide in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
Study details
To be eligible for the pediatric clinical trial, patients had to have experienced fewer than three spontaneous bowel movements (SBMs) per week.
They also had to experience one or more of the following at least once weekly, for at least 2 months prior to the trial screening visit:
- History of stool withholding or excessive voluntary stool retention.
- History of painful or hard bowel movements.
- History of large diameter stools that may obstruct the toilet.
- Presence of a large fecal mass in the rectum.
- At least one episode of fecal incontinence per week.
The primary efficacy endpoint was a 12-week change from baseline in SBM frequency rate. Children on linaclotide experienced greater improvement in the average number of SBMs per week than peers given placebo.
SBM frequency improved during the first week and was maintained throughout the remainder of the 12-week treatment period, the FDA said.
The most common adverse reaction is diarrhea. If severe diarrhea occurs, linaclotide should be discontinued and rehydration started.
The product’s boxed warning states that linaclotide is contraindicated in children younger than 2 years. In neonatal mice, linaclotide caused deaths due to dehydration.
Patients with known or suspected mechanical gastrointestinal obstruction should not take linaclotide.
Full prescribing information is available online.
The application for linaclotide in children received priority review.
A version of this article originally appeared on Medscape.com.
Distal fecal washes reveal inflammation across ileac-colonic axis
, not only in the distal colon itself, but the proximal colon and terminal ileum.
The noninvasive distal washes also reveal information on gene expression that can predict response to therapies in inflammatory bowel disease.
The findings, from the research group of Shalev Itzkovitz, MD, at the Weizmann Institute of Science in Rehovot, Israel, were published online in the journal Cellular and Molecular Gastroenterology and Hepatology.
Dr. Itzkovitz and his colleagues performed colonoscopies on 29 patients with ulcerative colitis (UC) and 30 with Crohn’s disease (CD) recruited from a single center, as well as 50 healthy controls. The researchers took biopsies and obtained fecal washes at different locations on the ileal-colonic axis. Results were analyzed using host transcriptomics, a method to determine which genes are being expressed in tissue samples.
While previous studies established the value of distal fecal washes in disease affecting the distal colon, Dr. Itzkovitz and colleagues found that the washes obtained from the distal colon contained accurate information “not only of distal colonic inflammation in UC patients, but also of CD inflammation, including when the inflammatory segments are ileal and no colonic involvement is observed.”
They also found that the distal fecal washes, including from CD patients with no distal involvement, showed gene expression of immune, stromal, and epithelial origin correlating with disease severity. The sequencing revealed “a strong transcriptomic signature of gene modules” seen in previous studies to be associated with response to biological therapies, the study authors wrote,
Remarkably, the transcriptomics from fecal washes were more sensitive and specific in revealing inflammation, compared with transcriptomics conducted on the tissue biopsies. “This higher statistical power may be a result of the fact that fecal washes capture cells that are shed throughout the gastrointestinal tract and therefore are not sensitive to the precise location from which a biopsy specimen is obtained,” the authors surmised.
Fecal wash host transcriptomics offer a noninvasive option, without the risks associated with colonoscopy, for selecting therapies in inflammatory bowel disease, the researchers wrote. “This is critical, given that current clinical remission rates with different biological agents are only approximately 30%-60%.”
Dr. Itzkovitz and colleagues’ study was supported by outside entities including the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Dr. Beth Rom-Rymer Stem Cell Research Fund, the Minerva Stiftung grant, the Weizmann-Sheba joint research program, the Israel Science Foundation, and the European Research Council, among others. Three coauthors disclosed financial relationships with drug manufacturers.
Distal fecal wash host transcriptomics identifies inflammation throughout the colon and terminal ileum. For assessing disease severity in inflammatory bowel disease, distribution and phenotype, endoscopy has been the standard. In line, calprotectin as fecal inflammation marker has been serving as a monitoring tool. But considering recent suggestions of molecular phenotypes, these diagnostic measures may need to advance in clinical practice.
Thus, this strategy of distal fecal wash transcriptomics requires prospective validation in larger cohorts, but clearly underlines the potential of a strong diagnostic tool combining the luminal nature of inflammatory bowel disease and modern molecular techniques.
Britta Siegmund, MD, is the medical director for the division of gastroenterology, infectiology and rheumatology at Charité Universitätsmedizin Berlin. She has served as a consultant for Abbvie, Arena, BMS, Boehringer, Celgene, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Lilly, Pfizer, PredictImmune, Prometheus, and Takeda, and received speaker’s fees from Abbvie, CED Service GmbH, Falk, Ferring, Galapagos, Janssen, Lilly, Novartis, Pfizer, and Takeda.
Distal fecal wash host transcriptomics identifies inflammation throughout the colon and terminal ileum. For assessing disease severity in inflammatory bowel disease, distribution and phenotype, endoscopy has been the standard. In line, calprotectin as fecal inflammation marker has been serving as a monitoring tool. But considering recent suggestions of molecular phenotypes, these diagnostic measures may need to advance in clinical practice.
Thus, this strategy of distal fecal wash transcriptomics requires prospective validation in larger cohorts, but clearly underlines the potential of a strong diagnostic tool combining the luminal nature of inflammatory bowel disease and modern molecular techniques.
Britta Siegmund, MD, is the medical director for the division of gastroenterology, infectiology and rheumatology at Charité Universitätsmedizin Berlin. She has served as a consultant for Abbvie, Arena, BMS, Boehringer, Celgene, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Lilly, Pfizer, PredictImmune, Prometheus, and Takeda, and received speaker’s fees from Abbvie, CED Service GmbH, Falk, Ferring, Galapagos, Janssen, Lilly, Novartis, Pfizer, and Takeda.
Distal fecal wash host transcriptomics identifies inflammation throughout the colon and terminal ileum. For assessing disease severity in inflammatory bowel disease, distribution and phenotype, endoscopy has been the standard. In line, calprotectin as fecal inflammation marker has been serving as a monitoring tool. But considering recent suggestions of molecular phenotypes, these diagnostic measures may need to advance in clinical practice.
Thus, this strategy of distal fecal wash transcriptomics requires prospective validation in larger cohorts, but clearly underlines the potential of a strong diagnostic tool combining the luminal nature of inflammatory bowel disease and modern molecular techniques.
Britta Siegmund, MD, is the medical director for the division of gastroenterology, infectiology and rheumatology at Charité Universitätsmedizin Berlin. She has served as a consultant for Abbvie, Arena, BMS, Boehringer, Celgene, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Lilly, Pfizer, PredictImmune, Prometheus, and Takeda, and received speaker’s fees from Abbvie, CED Service GmbH, Falk, Ferring, Galapagos, Janssen, Lilly, Novartis, Pfizer, and Takeda.
, not only in the distal colon itself, but the proximal colon and terminal ileum.
The noninvasive distal washes also reveal information on gene expression that can predict response to therapies in inflammatory bowel disease.
The findings, from the research group of Shalev Itzkovitz, MD, at the Weizmann Institute of Science in Rehovot, Israel, were published online in the journal Cellular and Molecular Gastroenterology and Hepatology.
Dr. Itzkovitz and his colleagues performed colonoscopies on 29 patients with ulcerative colitis (UC) and 30 with Crohn’s disease (CD) recruited from a single center, as well as 50 healthy controls. The researchers took biopsies and obtained fecal washes at different locations on the ileal-colonic axis. Results were analyzed using host transcriptomics, a method to determine which genes are being expressed in tissue samples.
While previous studies established the value of distal fecal washes in disease affecting the distal colon, Dr. Itzkovitz and colleagues found that the washes obtained from the distal colon contained accurate information “not only of distal colonic inflammation in UC patients, but also of CD inflammation, including when the inflammatory segments are ileal and no colonic involvement is observed.”
They also found that the distal fecal washes, including from CD patients with no distal involvement, showed gene expression of immune, stromal, and epithelial origin correlating with disease severity. The sequencing revealed “a strong transcriptomic signature of gene modules” seen in previous studies to be associated with response to biological therapies, the study authors wrote,
Remarkably, the transcriptomics from fecal washes were more sensitive and specific in revealing inflammation, compared with transcriptomics conducted on the tissue biopsies. “This higher statistical power may be a result of the fact that fecal washes capture cells that are shed throughout the gastrointestinal tract and therefore are not sensitive to the precise location from which a biopsy specimen is obtained,” the authors surmised.
Fecal wash host transcriptomics offer a noninvasive option, without the risks associated with colonoscopy, for selecting therapies in inflammatory bowel disease, the researchers wrote. “This is critical, given that current clinical remission rates with different biological agents are only approximately 30%-60%.”
Dr. Itzkovitz and colleagues’ study was supported by outside entities including the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Dr. Beth Rom-Rymer Stem Cell Research Fund, the Minerva Stiftung grant, the Weizmann-Sheba joint research program, the Israel Science Foundation, and the European Research Council, among others. Three coauthors disclosed financial relationships with drug manufacturers.
, not only in the distal colon itself, but the proximal colon and terminal ileum.
The noninvasive distal washes also reveal information on gene expression that can predict response to therapies in inflammatory bowel disease.
The findings, from the research group of Shalev Itzkovitz, MD, at the Weizmann Institute of Science in Rehovot, Israel, were published online in the journal Cellular and Molecular Gastroenterology and Hepatology.
Dr. Itzkovitz and his colleagues performed colonoscopies on 29 patients with ulcerative colitis (UC) and 30 with Crohn’s disease (CD) recruited from a single center, as well as 50 healthy controls. The researchers took biopsies and obtained fecal washes at different locations on the ileal-colonic axis. Results were analyzed using host transcriptomics, a method to determine which genes are being expressed in tissue samples.
While previous studies established the value of distal fecal washes in disease affecting the distal colon, Dr. Itzkovitz and colleagues found that the washes obtained from the distal colon contained accurate information “not only of distal colonic inflammation in UC patients, but also of CD inflammation, including when the inflammatory segments are ileal and no colonic involvement is observed.”
They also found that the distal fecal washes, including from CD patients with no distal involvement, showed gene expression of immune, stromal, and epithelial origin correlating with disease severity. The sequencing revealed “a strong transcriptomic signature of gene modules” seen in previous studies to be associated with response to biological therapies, the study authors wrote,
Remarkably, the transcriptomics from fecal washes were more sensitive and specific in revealing inflammation, compared with transcriptomics conducted on the tissue biopsies. “This higher statistical power may be a result of the fact that fecal washes capture cells that are shed throughout the gastrointestinal tract and therefore are not sensitive to the precise location from which a biopsy specimen is obtained,” the authors surmised.
Fecal wash host transcriptomics offer a noninvasive option, without the risks associated with colonoscopy, for selecting therapies in inflammatory bowel disease, the researchers wrote. “This is critical, given that current clinical remission rates with different biological agents are only approximately 30%-60%.”
Dr. Itzkovitz and colleagues’ study was supported by outside entities including the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Dr. Beth Rom-Rymer Stem Cell Research Fund, the Minerva Stiftung grant, the Weizmann-Sheba joint research program, the Israel Science Foundation, and the European Research Council, among others. Three coauthors disclosed financial relationships with drug manufacturers.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
New guideline weighs medication options for chronic constipation
The guideline, published simultaneously in the American Journal of Gastroenterology and in Gastroenterology, was developed jointly by the American Gastroenterological Association and the American College of Gastroenterology. It marks the AGA’s first update on chronic idiopathic constipation (CIC), also called functional constipation, in a decade.
In an interview, guideline lead author Lin Chang, MD, of the University of California, Los Angeles, noted that CIC – defined as constipation lasting at least 3 months in the absence of malignancy or obstruction, a medication side effect, or inflammatory bowel disease – is common, affecting between 8% and 12% of all U.S. adults. Most will be treated by primary care physicians, not specialists, Dr. Chang said. And most will see their physicians having already tried different over-the-counter treatments.
“The criteria for CIC or functional constipation hasn’t really changed” since the last AGA guideline on it was published in 2013, Dr. Chang said, adding that the diagnostic standard currently used is the Rome IV criteria for functional constipation. “There are just more medications right now than there were 10 years ago.”
The new guideline, into which evidence from 28 studies was integrated, offers recommendations regarding different types of fiber; the osmotic laxatives polyethylene glycol, magnesium oxide, and lactulose; and the stimulant laxatives bisacodyl, sodium picosulfate, and senna. It also assesses the secretagogues lubiprostone, linaclotide, plecanatide, and the serotonin type 4 agonist prucalopride.
One commonly used agent in clinical practice, the stool softener docusate sodium, does not appear in the guideline, as there was too little data available on it to make an assessment, Dr. Chang said. Fruit-based laxatives were excluded because they were the subject of a recent evidence review. Lifestyle modifications such as exercise, surgical interventions, and probiotics were not assessed.
The guideline’s strongest recommendations are for polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride, with conditional recommendations for fiber, lactulose, senna, magnesium oxide, and lubiprostone.
As costs of the recommended therapies vary from less than $10 a month to over $500, the authors also included price information, noting that “patient values, costs, and health equity considerations” must be factored into treatment choices. “For polyethylene glycol there’s a strong recommendation, although the certainty of evidence was moderate,” Dr. Chang said. “And with fiber, even though we made only a conditional recommendation based on the evidence, our remarks and our algorithm make clear that it should be considered as a first-line treatment.”
In general, “if someone has more mild symptoms, you should try fiber or increase their fiber intake in their diet,” Dr. Chang commented. “If that doesn’t work, try over-the-counter remedies like polyethylene glycol. Then if symptoms are more severe, or if they fail the first-line treatments, then you go to prescription agents.”
In clinical practice, “there always considerations besides scientific evidence of safety and efficacy,” Dr. Chang stressed. “You have to personalize treatment for the patient.” A patient may present having already failed with fiber, or who does not want to use magnesium or can’t afford a costlier agent.
The guidelines contain implementation advice that might guide choice of therapy or dosing. With the prescription osmotic laxative lactulose, for example, “you may not wish to use it as a first-line treatment because bloating and flatulence are very common,” Dr. Chang said. “Our implementation advice makes that clear.” For senna, a stimulant laxative derived from the leaves of the senna plant and for which quality evidence is limited, the guideline authors stressed that patients should be started on low doses to avoid cramping.
Dr. Chang said that, while the new guideline covers medication options for otherwise-healthy adults, clinicians should be mindful that patients presenting with CIC might still have a defecatory disorder. “A person could also have pelvic floor dysfunction as a primary cause or contributing factor. If someone fails fiber or polyethylene glycol, consider a digital rectal examination as part of the physical exam. If this is abnormal, consider referring them for anorectal manometry.”
Untreated constipation carries risks, Dr. Chang noted, but “sometimes people with bothersome symptoms don’t treat them because they’re worried they’ll become dependent on treatment. It’s a dependency in the sense that you have to treat any chronic condition, such as high blood pressure or diabetes, but the treatments aren’t addictive, except for some stimulant laxatives to which people can develop tolerance.”
Hemorrhoids and defecatory disorders can occur over time because of straining, Dr. Chang said. “The pelvic wall can also get very lax, and that is hard to fix. Or, one can develop a rectal prolapse. Another thing that happens when people have longstanding constipation for many years is they start losing the urge to have a bowel movement.”
For more information, see the related clinical decision support tool in Gastroenterology.
The guideline’s development was funded by the AGA and ACG, without industry support. Authors with conflicts of interest regarding a specific intervention or drug were not allowed to weigh in on those interventions.
The guideline, published simultaneously in the American Journal of Gastroenterology and in Gastroenterology, was developed jointly by the American Gastroenterological Association and the American College of Gastroenterology. It marks the AGA’s first update on chronic idiopathic constipation (CIC), also called functional constipation, in a decade.
In an interview, guideline lead author Lin Chang, MD, of the University of California, Los Angeles, noted that CIC – defined as constipation lasting at least 3 months in the absence of malignancy or obstruction, a medication side effect, or inflammatory bowel disease – is common, affecting between 8% and 12% of all U.S. adults. Most will be treated by primary care physicians, not specialists, Dr. Chang said. And most will see their physicians having already tried different over-the-counter treatments.
“The criteria for CIC or functional constipation hasn’t really changed” since the last AGA guideline on it was published in 2013, Dr. Chang said, adding that the diagnostic standard currently used is the Rome IV criteria for functional constipation. “There are just more medications right now than there were 10 years ago.”
The new guideline, into which evidence from 28 studies was integrated, offers recommendations regarding different types of fiber; the osmotic laxatives polyethylene glycol, magnesium oxide, and lactulose; and the stimulant laxatives bisacodyl, sodium picosulfate, and senna. It also assesses the secretagogues lubiprostone, linaclotide, plecanatide, and the serotonin type 4 agonist prucalopride.
One commonly used agent in clinical practice, the stool softener docusate sodium, does not appear in the guideline, as there was too little data available on it to make an assessment, Dr. Chang said. Fruit-based laxatives were excluded because they were the subject of a recent evidence review. Lifestyle modifications such as exercise, surgical interventions, and probiotics were not assessed.
The guideline’s strongest recommendations are for polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride, with conditional recommendations for fiber, lactulose, senna, magnesium oxide, and lubiprostone.
As costs of the recommended therapies vary from less than $10 a month to over $500, the authors also included price information, noting that “patient values, costs, and health equity considerations” must be factored into treatment choices. “For polyethylene glycol there’s a strong recommendation, although the certainty of evidence was moderate,” Dr. Chang said. “And with fiber, even though we made only a conditional recommendation based on the evidence, our remarks and our algorithm make clear that it should be considered as a first-line treatment.”
In general, “if someone has more mild symptoms, you should try fiber or increase their fiber intake in their diet,” Dr. Chang commented. “If that doesn’t work, try over-the-counter remedies like polyethylene glycol. Then if symptoms are more severe, or if they fail the first-line treatments, then you go to prescription agents.”
In clinical practice, “there always considerations besides scientific evidence of safety and efficacy,” Dr. Chang stressed. “You have to personalize treatment for the patient.” A patient may present having already failed with fiber, or who does not want to use magnesium or can’t afford a costlier agent.
The guidelines contain implementation advice that might guide choice of therapy or dosing. With the prescription osmotic laxative lactulose, for example, “you may not wish to use it as a first-line treatment because bloating and flatulence are very common,” Dr. Chang said. “Our implementation advice makes that clear.” For senna, a stimulant laxative derived from the leaves of the senna plant and for which quality evidence is limited, the guideline authors stressed that patients should be started on low doses to avoid cramping.
Dr. Chang said that, while the new guideline covers medication options for otherwise-healthy adults, clinicians should be mindful that patients presenting with CIC might still have a defecatory disorder. “A person could also have pelvic floor dysfunction as a primary cause or contributing factor. If someone fails fiber or polyethylene glycol, consider a digital rectal examination as part of the physical exam. If this is abnormal, consider referring them for anorectal manometry.”
Untreated constipation carries risks, Dr. Chang noted, but “sometimes people with bothersome symptoms don’t treat them because they’re worried they’ll become dependent on treatment. It’s a dependency in the sense that you have to treat any chronic condition, such as high blood pressure or diabetes, but the treatments aren’t addictive, except for some stimulant laxatives to which people can develop tolerance.”
Hemorrhoids and defecatory disorders can occur over time because of straining, Dr. Chang said. “The pelvic wall can also get very lax, and that is hard to fix. Or, one can develop a rectal prolapse. Another thing that happens when people have longstanding constipation for many years is they start losing the urge to have a bowel movement.”
For more information, see the related clinical decision support tool in Gastroenterology.
The guideline’s development was funded by the AGA and ACG, without industry support. Authors with conflicts of interest regarding a specific intervention or drug were not allowed to weigh in on those interventions.
The guideline, published simultaneously in the American Journal of Gastroenterology and in Gastroenterology, was developed jointly by the American Gastroenterological Association and the American College of Gastroenterology. It marks the AGA’s first update on chronic idiopathic constipation (CIC), also called functional constipation, in a decade.
In an interview, guideline lead author Lin Chang, MD, of the University of California, Los Angeles, noted that CIC – defined as constipation lasting at least 3 months in the absence of malignancy or obstruction, a medication side effect, or inflammatory bowel disease – is common, affecting between 8% and 12% of all U.S. adults. Most will be treated by primary care physicians, not specialists, Dr. Chang said. And most will see their physicians having already tried different over-the-counter treatments.
“The criteria for CIC or functional constipation hasn’t really changed” since the last AGA guideline on it was published in 2013, Dr. Chang said, adding that the diagnostic standard currently used is the Rome IV criteria for functional constipation. “There are just more medications right now than there were 10 years ago.”
The new guideline, into which evidence from 28 studies was integrated, offers recommendations regarding different types of fiber; the osmotic laxatives polyethylene glycol, magnesium oxide, and lactulose; and the stimulant laxatives bisacodyl, sodium picosulfate, and senna. It also assesses the secretagogues lubiprostone, linaclotide, plecanatide, and the serotonin type 4 agonist prucalopride.
One commonly used agent in clinical practice, the stool softener docusate sodium, does not appear in the guideline, as there was too little data available on it to make an assessment, Dr. Chang said. Fruit-based laxatives were excluded because they were the subject of a recent evidence review. Lifestyle modifications such as exercise, surgical interventions, and probiotics were not assessed.
The guideline’s strongest recommendations are for polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride, with conditional recommendations for fiber, lactulose, senna, magnesium oxide, and lubiprostone.
As costs of the recommended therapies vary from less than $10 a month to over $500, the authors also included price information, noting that “patient values, costs, and health equity considerations” must be factored into treatment choices. “For polyethylene glycol there’s a strong recommendation, although the certainty of evidence was moderate,” Dr. Chang said. “And with fiber, even though we made only a conditional recommendation based on the evidence, our remarks and our algorithm make clear that it should be considered as a first-line treatment.”
In general, “if someone has more mild symptoms, you should try fiber or increase their fiber intake in their diet,” Dr. Chang commented. “If that doesn’t work, try over-the-counter remedies like polyethylene glycol. Then if symptoms are more severe, or if they fail the first-line treatments, then you go to prescription agents.”
In clinical practice, “there always considerations besides scientific evidence of safety and efficacy,” Dr. Chang stressed. “You have to personalize treatment for the patient.” A patient may present having already failed with fiber, or who does not want to use magnesium or can’t afford a costlier agent.
The guidelines contain implementation advice that might guide choice of therapy or dosing. With the prescription osmotic laxative lactulose, for example, “you may not wish to use it as a first-line treatment because bloating and flatulence are very common,” Dr. Chang said. “Our implementation advice makes that clear.” For senna, a stimulant laxative derived from the leaves of the senna plant and for which quality evidence is limited, the guideline authors stressed that patients should be started on low doses to avoid cramping.
Dr. Chang said that, while the new guideline covers medication options for otherwise-healthy adults, clinicians should be mindful that patients presenting with CIC might still have a defecatory disorder. “A person could also have pelvic floor dysfunction as a primary cause or contributing factor. If someone fails fiber or polyethylene glycol, consider a digital rectal examination as part of the physical exam. If this is abnormal, consider referring them for anorectal manometry.”
Untreated constipation carries risks, Dr. Chang noted, but “sometimes people with bothersome symptoms don’t treat them because they’re worried they’ll become dependent on treatment. It’s a dependency in the sense that you have to treat any chronic condition, such as high blood pressure or diabetes, but the treatments aren’t addictive, except for some stimulant laxatives to which people can develop tolerance.”
Hemorrhoids and defecatory disorders can occur over time because of straining, Dr. Chang said. “The pelvic wall can also get very lax, and that is hard to fix. Or, one can develop a rectal prolapse. Another thing that happens when people have longstanding constipation for many years is they start losing the urge to have a bowel movement.”
For more information, see the related clinical decision support tool in Gastroenterology.
The guideline’s development was funded by the AGA and ACG, without industry support. Authors with conflicts of interest regarding a specific intervention or drug were not allowed to weigh in on those interventions.
FROM GASTROENTEROLOGY
Sucralose damages DNA, linked to leaky gut: Study
Sucralose is sold under the brand name Splenda and is also used as an ingredient in packaged foods and beverages.
The findings were published in the Journal of Toxicology and Environmental Health, Part B. The researchers conducted a series of laboratory experiments exposing human blood cells and gut tissue to sucralose-6-acetate. The findings build on previous research that linked sucralose to gut health problems.
The researchers found that sucralose causes DNA to break apart, putting people at risk for disease. They also linked sucralose to leaky gut syndrome, which means the lining of the intestines are worn down and become permeable. Symptoms are a burning sensation, painful digestion, diarrhea, gas, and bloating.
When a substance damages DNA, it is called genotoxic. Researchers have found that eating sucralose results in the body producing a substance called sucralose-6-acetate, which the new study now shows is genotoxic. The researchers also found sucralose-6-acetate in trace amounts in off-the-shelf products that are so high, they would exceed the safety levels currently allowed in Europe.
“It’s time to revisit the safety and regulatory status of sucralose because the evidence is mounting that it carries significant risks. If nothing else, I encourage people to avoid products containing sucralose,” researcher Susan Schiffman, PhD, adjunct professor of biomedical engineering at North Carolina State University, Raleigh, said in a statement. “It’s something you should not be eating.”
The FDA says sucralose is safe, describing it as 600 times sweeter than table sugar and used in “baked goods, beverages, chewing gum, gelatins, and frozen dairy desserts.”
“To determine the safety of sucralose, the FDA reviewed more than 110 studies designed to identify possible toxic effects, including studies on the reproductive and nervous systems, carcinogenicity, and metabolism,” the agency explained on its website. “The FDA also reviewed human clinical trials to address metabolism and effects on patients with diabetes.”
The study authors reported that they had no conflicts of interest.A version of this article first appeared on WebMD.com.
Sucralose is sold under the brand name Splenda and is also used as an ingredient in packaged foods and beverages.
The findings were published in the Journal of Toxicology and Environmental Health, Part B. The researchers conducted a series of laboratory experiments exposing human blood cells and gut tissue to sucralose-6-acetate. The findings build on previous research that linked sucralose to gut health problems.
The researchers found that sucralose causes DNA to break apart, putting people at risk for disease. They also linked sucralose to leaky gut syndrome, which means the lining of the intestines are worn down and become permeable. Symptoms are a burning sensation, painful digestion, diarrhea, gas, and bloating.
When a substance damages DNA, it is called genotoxic. Researchers have found that eating sucralose results in the body producing a substance called sucralose-6-acetate, which the new study now shows is genotoxic. The researchers also found sucralose-6-acetate in trace amounts in off-the-shelf products that are so high, they would exceed the safety levels currently allowed in Europe.
“It’s time to revisit the safety and regulatory status of sucralose because the evidence is mounting that it carries significant risks. If nothing else, I encourage people to avoid products containing sucralose,” researcher Susan Schiffman, PhD, adjunct professor of biomedical engineering at North Carolina State University, Raleigh, said in a statement. “It’s something you should not be eating.”
The FDA says sucralose is safe, describing it as 600 times sweeter than table sugar and used in “baked goods, beverages, chewing gum, gelatins, and frozen dairy desserts.”
“To determine the safety of sucralose, the FDA reviewed more than 110 studies designed to identify possible toxic effects, including studies on the reproductive and nervous systems, carcinogenicity, and metabolism,” the agency explained on its website. “The FDA also reviewed human clinical trials to address metabolism and effects on patients with diabetes.”
The study authors reported that they had no conflicts of interest.A version of this article first appeared on WebMD.com.
Sucralose is sold under the brand name Splenda and is also used as an ingredient in packaged foods and beverages.
The findings were published in the Journal of Toxicology and Environmental Health, Part B. The researchers conducted a series of laboratory experiments exposing human blood cells and gut tissue to sucralose-6-acetate. The findings build on previous research that linked sucralose to gut health problems.
The researchers found that sucralose causes DNA to break apart, putting people at risk for disease. They also linked sucralose to leaky gut syndrome, which means the lining of the intestines are worn down and become permeable. Symptoms are a burning sensation, painful digestion, diarrhea, gas, and bloating.
When a substance damages DNA, it is called genotoxic. Researchers have found that eating sucralose results in the body producing a substance called sucralose-6-acetate, which the new study now shows is genotoxic. The researchers also found sucralose-6-acetate in trace amounts in off-the-shelf products that are so high, they would exceed the safety levels currently allowed in Europe.
“It’s time to revisit the safety and regulatory status of sucralose because the evidence is mounting that it carries significant risks. If nothing else, I encourage people to avoid products containing sucralose,” researcher Susan Schiffman, PhD, adjunct professor of biomedical engineering at North Carolina State University, Raleigh, said in a statement. “It’s something you should not be eating.”
The FDA says sucralose is safe, describing it as 600 times sweeter than table sugar and used in “baked goods, beverages, chewing gum, gelatins, and frozen dairy desserts.”
“To determine the safety of sucralose, the FDA reviewed more than 110 studies designed to identify possible toxic effects, including studies on the reproductive and nervous systems, carcinogenicity, and metabolism,” the agency explained on its website. “The FDA also reviewed human clinical trials to address metabolism and effects on patients with diabetes.”
The study authors reported that they had no conflicts of interest.A version of this article first appeared on WebMD.com.
FROM THE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH, PART B