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Bloating common but often ignored: Survey
, some of whom said they weren’t comfortable discussing it with their doctor, according to a large national survey.
The findings suggest doctors should “proactively” ask about bloating, especially in adults at increased risk, including women and those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), the researchers say.
“Bloating is common because it usually has multifactorial causes and can also be a secondary symptom to another gastrointestinal (GI) symptom or condition. Its mechanisms are complex and individualized, making it difficult for providers to identify and treat each patient,” Janice E. Oh, MD, department of medicine, Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Thus, many adults may be persistently suffering without proper diagnosis or management,” Dr. Oh added.
Results of the survey are published online in Clinical Gastroenterology and Hepatology.
Common problem, incompletely understood
To get a better handle on the nationwide prevalence and health-related impact of bloating in the United States, Dr. Oh and her colleagues conducted an online survey of a nationally representative group of 88,795 adults aged 18 years or older.
Altogether, 12,324 (14%) respondents reported bloating in the past week.
The likelihood of bloating was significantly higher in women (odds ratio, 2.56) and in those with certain comorbid conditions, especially IBS, chronic constipation, and ulcerative colitis, the authors write.
The odds of bloating were also higher in adults with other concomitant GI symptoms, especially abdominal pain and excess gas.
Factors associated with more severe bloating included the presence of IBS, IBD, celiac disease, bowel incontinence, abdominal pain, constipation (functional and opioid-induced), and excess gas.
Bloating severity increased with age up to 59 years and then decreased in people aged 60 years or older.
Suffering in silence?
Notably, more than half (59%) of people who reported recent bloating never sought care for the problem. About one-third of them reported that bloating resolved on its own, and 30% said the symptoms were not bothersome.
About 1 in 5 adults who did not seek care said that they were managing symptoms on their own with over-the-counter medications or lifestyle modifications. And 9% of those who did not seek care said that they were uncomfortable discussing the problem with their doctor.
“The hesitancy in seeking health care or discussing bloating in patients may be attributed to lack of routine screening for bloating, lack of focus on bloating complaints by providers, or patients’ dissatisfaction with management of bloating symptoms,” the researchers say.
Adults most apt to seek care for bloating were those older than 29 years; non-Hispanic Black persons; those with comorbid conditions, such as celiac disease, IBD, and IBS; and those with more severe bloating symptoms.
A limitation is that individuals with GI symptoms or conditions may be more likely to participate in a GI-focused survey, leading to a possible overestimation of the prevalence of bloating.
Also, the survey was conducted during the COVID-19 pandemic, which has the potential to overestimate the prevalence or severity of bloating because COVID-19 is known to affect the GI system.
Despite these limitations, the researchers encourage health care professionals to routinely ask their patients about bloating as a first step in appropriate management.
“Bloating can be associated with nutrition/diet, the gut microbiome, anatomical issues, or underlying conditions that range from neurologic to gynecologic disorders. And, the majority of the time, it is usually more than one distinct issue that is attributing to the bloating,” Dr. Oh said.
“Understanding the patterns of bloating occurrence, psychosocial factors, past medical history, and nutrition can help providers determine the causes. We hope to identify a more standardized method to identify causes of bloating,” Dr. Oh added.
Support for the survey was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai. The authors have no relevant disclosures.
A version of this article first appeared on Medscape.com.
, some of whom said they weren’t comfortable discussing it with their doctor, according to a large national survey.
The findings suggest doctors should “proactively” ask about bloating, especially in adults at increased risk, including women and those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), the researchers say.
“Bloating is common because it usually has multifactorial causes and can also be a secondary symptom to another gastrointestinal (GI) symptom or condition. Its mechanisms are complex and individualized, making it difficult for providers to identify and treat each patient,” Janice E. Oh, MD, department of medicine, Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Thus, many adults may be persistently suffering without proper diagnosis or management,” Dr. Oh added.
Results of the survey are published online in Clinical Gastroenterology and Hepatology.
Common problem, incompletely understood
To get a better handle on the nationwide prevalence and health-related impact of bloating in the United States, Dr. Oh and her colleagues conducted an online survey of a nationally representative group of 88,795 adults aged 18 years or older.
Altogether, 12,324 (14%) respondents reported bloating in the past week.
The likelihood of bloating was significantly higher in women (odds ratio, 2.56) and in those with certain comorbid conditions, especially IBS, chronic constipation, and ulcerative colitis, the authors write.
The odds of bloating were also higher in adults with other concomitant GI symptoms, especially abdominal pain and excess gas.
Factors associated with more severe bloating included the presence of IBS, IBD, celiac disease, bowel incontinence, abdominal pain, constipation (functional and opioid-induced), and excess gas.
Bloating severity increased with age up to 59 years and then decreased in people aged 60 years or older.
Suffering in silence?
Notably, more than half (59%) of people who reported recent bloating never sought care for the problem. About one-third of them reported that bloating resolved on its own, and 30% said the symptoms were not bothersome.
About 1 in 5 adults who did not seek care said that they were managing symptoms on their own with over-the-counter medications or lifestyle modifications. And 9% of those who did not seek care said that they were uncomfortable discussing the problem with their doctor.
“The hesitancy in seeking health care or discussing bloating in patients may be attributed to lack of routine screening for bloating, lack of focus on bloating complaints by providers, or patients’ dissatisfaction with management of bloating symptoms,” the researchers say.
Adults most apt to seek care for bloating were those older than 29 years; non-Hispanic Black persons; those with comorbid conditions, such as celiac disease, IBD, and IBS; and those with more severe bloating symptoms.
A limitation is that individuals with GI symptoms or conditions may be more likely to participate in a GI-focused survey, leading to a possible overestimation of the prevalence of bloating.
Also, the survey was conducted during the COVID-19 pandemic, which has the potential to overestimate the prevalence or severity of bloating because COVID-19 is known to affect the GI system.
Despite these limitations, the researchers encourage health care professionals to routinely ask their patients about bloating as a first step in appropriate management.
“Bloating can be associated with nutrition/diet, the gut microbiome, anatomical issues, or underlying conditions that range from neurologic to gynecologic disorders. And, the majority of the time, it is usually more than one distinct issue that is attributing to the bloating,” Dr. Oh said.
“Understanding the patterns of bloating occurrence, psychosocial factors, past medical history, and nutrition can help providers determine the causes. We hope to identify a more standardized method to identify causes of bloating,” Dr. Oh added.
Support for the survey was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai. The authors have no relevant disclosures.
A version of this article first appeared on Medscape.com.
, some of whom said they weren’t comfortable discussing it with their doctor, according to a large national survey.
The findings suggest doctors should “proactively” ask about bloating, especially in adults at increased risk, including women and those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), the researchers say.
“Bloating is common because it usually has multifactorial causes and can also be a secondary symptom to another gastrointestinal (GI) symptom or condition. Its mechanisms are complex and individualized, making it difficult for providers to identify and treat each patient,” Janice E. Oh, MD, department of medicine, Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Thus, many adults may be persistently suffering without proper diagnosis or management,” Dr. Oh added.
Results of the survey are published online in Clinical Gastroenterology and Hepatology.
Common problem, incompletely understood
To get a better handle on the nationwide prevalence and health-related impact of bloating in the United States, Dr. Oh and her colleagues conducted an online survey of a nationally representative group of 88,795 adults aged 18 years or older.
Altogether, 12,324 (14%) respondents reported bloating in the past week.
The likelihood of bloating was significantly higher in women (odds ratio, 2.56) and in those with certain comorbid conditions, especially IBS, chronic constipation, and ulcerative colitis, the authors write.
The odds of bloating were also higher in adults with other concomitant GI symptoms, especially abdominal pain and excess gas.
Factors associated with more severe bloating included the presence of IBS, IBD, celiac disease, bowel incontinence, abdominal pain, constipation (functional and opioid-induced), and excess gas.
Bloating severity increased with age up to 59 years and then decreased in people aged 60 years or older.
Suffering in silence?
Notably, more than half (59%) of people who reported recent bloating never sought care for the problem. About one-third of them reported that bloating resolved on its own, and 30% said the symptoms were not bothersome.
About 1 in 5 adults who did not seek care said that they were managing symptoms on their own with over-the-counter medications or lifestyle modifications. And 9% of those who did not seek care said that they were uncomfortable discussing the problem with their doctor.
“The hesitancy in seeking health care or discussing bloating in patients may be attributed to lack of routine screening for bloating, lack of focus on bloating complaints by providers, or patients’ dissatisfaction with management of bloating symptoms,” the researchers say.
Adults most apt to seek care for bloating were those older than 29 years; non-Hispanic Black persons; those with comorbid conditions, such as celiac disease, IBD, and IBS; and those with more severe bloating symptoms.
A limitation is that individuals with GI symptoms or conditions may be more likely to participate in a GI-focused survey, leading to a possible overestimation of the prevalence of bloating.
Also, the survey was conducted during the COVID-19 pandemic, which has the potential to overestimate the prevalence or severity of bloating because COVID-19 is known to affect the GI system.
Despite these limitations, the researchers encourage health care professionals to routinely ask their patients about bloating as a first step in appropriate management.
“Bloating can be associated with nutrition/diet, the gut microbiome, anatomical issues, or underlying conditions that range from neurologic to gynecologic disorders. And, the majority of the time, it is usually more than one distinct issue that is attributing to the bloating,” Dr. Oh said.
“Understanding the patterns of bloating occurrence, psychosocial factors, past medical history, and nutrition can help providers determine the causes. We hope to identify a more standardized method to identify causes of bloating,” Dr. Oh added.
Support for the survey was provided by Ironwood Pharmaceuticals in the form of an institutional research grant to Cedars-Sinai. The authors have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Exosomes may drive HBV spread
Hepatitis B virus (HBV), which can lead to acute and chronic hepatitis, infects more than 2 billion people worldwide, according to serological evidence. Although vaccines and treatments are available, there are approximately 1.5 million new HBV infections each year globally.
A new study has revealed a key step in the HBV life cycle: Researchers found that HBV virions can be released within exosomes, which are capable of infecting neighboring cells. The authors, led by Qingyan Wu of the department of virology, Paul-Ehrlich-Institute, Langen, Germany, suggest this strategy may help the virus escape immune surveillance and target a new hepatocyte.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology.
The researchers isolated exosomes from the supernatants of HBV-producing cells using exosomal and HBV markers. Electron microscopy using ultrathin sectioning along with immunogold labeling confirmed the presence of intact HBV virions in exosomes. The ultracentrifugation enabled the separation of the free virion fraction from the virions enclosed in exosomes. These findings fit in with previous discoveries of quasi-enveloped hepatitis A virus and hepatitis E virus.
The exosomes released free HBV virion and naked capsid after exposure to detergent. Cellular exposure to exosome morphogenesis inhibitors interfered with the release of exosome-packaged HBV. The researchers also observed large HBV surface antigens (LHB) on the external surface of the exosomes and found that the antigens allowed the exosome to infect susceptible cells through interaction with the sodium-taurocholate co-transporting polypeptide. LHB may also play an additional role in infectivity by countering the ability of antibodies to neutralize HBV.
However, the researchers also found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells with exosome-containing HBV. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
To investigate the release pathway, the researchers used three different exosome release inhibitors and found that all three interfered with HBV exosomal release. They also found that cells deficient in the exosome proteins Alix and syntenin did not release exosomal HBV.
Alix appears to be involved in HBV exosomal release, as evidenced by the fact that release of exosomal HBV is boosted in Alix-deficient cells following rescue through overexpression of mCherry-Alix fusion construct. Overexpression of mCherry-Alix had no effect on release of free HBV virions.
The researchers also found evidence that two other exosomal proteins, CD63 and TSG101, play a role in incorporation of LHBs in the HBV envelope, as well as release of HBV through interactions with the protein alpha-taxilin. CD63 and TSG101 are also critical to the formation of exosomes, and the authors suggest further research into their functioning could be fruitful.
Whether exosome-released HBV results from crosstalk between the virus and host cells still needs to be determined. If host factors play a role in connecting HBV to exosomes, it will be interesting to work out which conditions trigger this process, as well as determine which events trigger the release of free virus through multivesicular bodies.
The researchers posit that LHBs could perform a similar function as classical hepatitis B surface antigens and filaments in foiling the immune response. Such a function would require that the virus escape from antibodies before opsonin proteins tag the antigens. It’s also possible that LHBs enable infection of nonhepatic tissues, though this would likely be inefficient.
Many other host proteins have been observed in exosomes released by HBV-infected hepatocytes, suggesting that host proteins may play other roles. A proteomics analysis found proteasome subunit proteins in HepAD38-derived exosomes. The authors suggest that those proteins may allow the exosomes to mediate transcellular immune regulation.
Subviral particles may enhance viral infection, and exosomes from HBV-positive cells may contribute, possibly through exosome surface LHBs, according to the authors. They found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
“This previously undiscovered strategy of sequestering HBV particles in exosomes could be a strategy to escape from the immune response and to target them, protected by the exosomal membrane, to the hepatocyte. Exosomes that carry HBV particles seem also to have the potential to deliver HBV to nonpermissive cells with low efficiency. This suggests that exosomes could be an additional factor that contributes to the spread of HBV,” the authors wrote.
The authors had no financial conflicts. This research was funded by the LOEWE Center ACLF, DRUID, the Germany Research Foundation, and the China Scholarship Council.
Viral cell entry and viral neutralization by antibodies are largely defined by the virion structure. Not surprisingly, viruses have evolved strategies to hijack cellular pathways for their morphogenesis to promote their dissemination and escape host immune responses. Hepatitis B viruses (HBV) are released as infectious enveloped virions from infected cells through the multivesicular body pathway. Moreover, excess HBV envelope proteins are exported as noninfectious subviral particles that can act as decoys to trap neutralizing antibodies.
Using cell culture models, investigators from the Hildt lab show in this study that a minority of enveloped virions are released within exosomes, the biogenesis of which is closely linked to HBV morphogenesis. The authors report that exosome-associated HBV can infect HBV-susceptible hepatoma cells and thus contribute to viral dissemination. The molecular mechanisms underlying infection of target cells by exosome-associated HBV and virions are largely comparable.
There is no major alternative entry pathway for HBV transported by exosomes, thus they can be inhibited by antibodies directed against the large HBV surface antigen (LHB) and the entry inhibitor Myrcludex. In addition to its role in exosome-cell interaction, the LHB on the exosome surface represents a target for neutralizing antibodies and, by providing an alternative target for humoral responses, could contribute to the evasion of infectious virions. The relative contribution of exosomes to HBV dissemination vs. escape remains to be determined.
Studies using HBV derived from the blood of HBV-infected patients are required to assess the relevance of these processes in vivo and if/how these are affected by antiviral therapies.
Mirjam B. Zeisel, PharmD, PhD, is with the Cancer Research Center of Lyon, Université de Lyon, France, and reports no conflicts of interest.
Viral cell entry and viral neutralization by antibodies are largely defined by the virion structure. Not surprisingly, viruses have evolved strategies to hijack cellular pathways for their morphogenesis to promote their dissemination and escape host immune responses. Hepatitis B viruses (HBV) are released as infectious enveloped virions from infected cells through the multivesicular body pathway. Moreover, excess HBV envelope proteins are exported as noninfectious subviral particles that can act as decoys to trap neutralizing antibodies.
Using cell culture models, investigators from the Hildt lab show in this study that a minority of enveloped virions are released within exosomes, the biogenesis of which is closely linked to HBV morphogenesis. The authors report that exosome-associated HBV can infect HBV-susceptible hepatoma cells and thus contribute to viral dissemination. The molecular mechanisms underlying infection of target cells by exosome-associated HBV and virions are largely comparable.
There is no major alternative entry pathway for HBV transported by exosomes, thus they can be inhibited by antibodies directed against the large HBV surface antigen (LHB) and the entry inhibitor Myrcludex. In addition to its role in exosome-cell interaction, the LHB on the exosome surface represents a target for neutralizing antibodies and, by providing an alternative target for humoral responses, could contribute to the evasion of infectious virions. The relative contribution of exosomes to HBV dissemination vs. escape remains to be determined.
Studies using HBV derived from the blood of HBV-infected patients are required to assess the relevance of these processes in vivo and if/how these are affected by antiviral therapies.
Mirjam B. Zeisel, PharmD, PhD, is with the Cancer Research Center of Lyon, Université de Lyon, France, and reports no conflicts of interest.
Viral cell entry and viral neutralization by antibodies are largely defined by the virion structure. Not surprisingly, viruses have evolved strategies to hijack cellular pathways for their morphogenesis to promote their dissemination and escape host immune responses. Hepatitis B viruses (HBV) are released as infectious enveloped virions from infected cells through the multivesicular body pathway. Moreover, excess HBV envelope proteins are exported as noninfectious subviral particles that can act as decoys to trap neutralizing antibodies.
Using cell culture models, investigators from the Hildt lab show in this study that a minority of enveloped virions are released within exosomes, the biogenesis of which is closely linked to HBV morphogenesis. The authors report that exosome-associated HBV can infect HBV-susceptible hepatoma cells and thus contribute to viral dissemination. The molecular mechanisms underlying infection of target cells by exosome-associated HBV and virions are largely comparable.
There is no major alternative entry pathway for HBV transported by exosomes, thus they can be inhibited by antibodies directed against the large HBV surface antigen (LHB) and the entry inhibitor Myrcludex. In addition to its role in exosome-cell interaction, the LHB on the exosome surface represents a target for neutralizing antibodies and, by providing an alternative target for humoral responses, could contribute to the evasion of infectious virions. The relative contribution of exosomes to HBV dissemination vs. escape remains to be determined.
Studies using HBV derived from the blood of HBV-infected patients are required to assess the relevance of these processes in vivo and if/how these are affected by antiviral therapies.
Mirjam B. Zeisel, PharmD, PhD, is with the Cancer Research Center of Lyon, Université de Lyon, France, and reports no conflicts of interest.
Hepatitis B virus (HBV), which can lead to acute and chronic hepatitis, infects more than 2 billion people worldwide, according to serological evidence. Although vaccines and treatments are available, there are approximately 1.5 million new HBV infections each year globally.
A new study has revealed a key step in the HBV life cycle: Researchers found that HBV virions can be released within exosomes, which are capable of infecting neighboring cells. The authors, led by Qingyan Wu of the department of virology, Paul-Ehrlich-Institute, Langen, Germany, suggest this strategy may help the virus escape immune surveillance and target a new hepatocyte.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology.
The researchers isolated exosomes from the supernatants of HBV-producing cells using exosomal and HBV markers. Electron microscopy using ultrathin sectioning along with immunogold labeling confirmed the presence of intact HBV virions in exosomes. The ultracentrifugation enabled the separation of the free virion fraction from the virions enclosed in exosomes. These findings fit in with previous discoveries of quasi-enveloped hepatitis A virus and hepatitis E virus.
The exosomes released free HBV virion and naked capsid after exposure to detergent. Cellular exposure to exosome morphogenesis inhibitors interfered with the release of exosome-packaged HBV. The researchers also observed large HBV surface antigens (LHB) on the external surface of the exosomes and found that the antigens allowed the exosome to infect susceptible cells through interaction with the sodium-taurocholate co-transporting polypeptide. LHB may also play an additional role in infectivity by countering the ability of antibodies to neutralize HBV.
However, the researchers also found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells with exosome-containing HBV. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
To investigate the release pathway, the researchers used three different exosome release inhibitors and found that all three interfered with HBV exosomal release. They also found that cells deficient in the exosome proteins Alix and syntenin did not release exosomal HBV.
Alix appears to be involved in HBV exosomal release, as evidenced by the fact that release of exosomal HBV is boosted in Alix-deficient cells following rescue through overexpression of mCherry-Alix fusion construct. Overexpression of mCherry-Alix had no effect on release of free HBV virions.
The researchers also found evidence that two other exosomal proteins, CD63 and TSG101, play a role in incorporation of LHBs in the HBV envelope, as well as release of HBV through interactions with the protein alpha-taxilin. CD63 and TSG101 are also critical to the formation of exosomes, and the authors suggest further research into their functioning could be fruitful.
Whether exosome-released HBV results from crosstalk between the virus and host cells still needs to be determined. If host factors play a role in connecting HBV to exosomes, it will be interesting to work out which conditions trigger this process, as well as determine which events trigger the release of free virus through multivesicular bodies.
The researchers posit that LHBs could perform a similar function as classical hepatitis B surface antigens and filaments in foiling the immune response. Such a function would require that the virus escape from antibodies before opsonin proteins tag the antigens. It’s also possible that LHBs enable infection of nonhepatic tissues, though this would likely be inefficient.
Many other host proteins have been observed in exosomes released by HBV-infected hepatocytes, suggesting that host proteins may play other roles. A proteomics analysis found proteasome subunit proteins in HepAD38-derived exosomes. The authors suggest that those proteins may allow the exosomes to mediate transcellular immune regulation.
Subviral particles may enhance viral infection, and exosomes from HBV-positive cells may contribute, possibly through exosome surface LHBs, according to the authors. They found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
“This previously undiscovered strategy of sequestering HBV particles in exosomes could be a strategy to escape from the immune response and to target them, protected by the exosomal membrane, to the hepatocyte. Exosomes that carry HBV particles seem also to have the potential to deliver HBV to nonpermissive cells with low efficiency. This suggests that exosomes could be an additional factor that contributes to the spread of HBV,” the authors wrote.
The authors had no financial conflicts. This research was funded by the LOEWE Center ACLF, DRUID, the Germany Research Foundation, and the China Scholarship Council.
Hepatitis B virus (HBV), which can lead to acute and chronic hepatitis, infects more than 2 billion people worldwide, according to serological evidence. Although vaccines and treatments are available, there are approximately 1.5 million new HBV infections each year globally.
A new study has revealed a key step in the HBV life cycle: Researchers found that HBV virions can be released within exosomes, which are capable of infecting neighboring cells. The authors, led by Qingyan Wu of the department of virology, Paul-Ehrlich-Institute, Langen, Germany, suggest this strategy may help the virus escape immune surveillance and target a new hepatocyte.
The study was published online in Cellular and Molecular Gastroenterology and Hepatology.
The researchers isolated exosomes from the supernatants of HBV-producing cells using exosomal and HBV markers. Electron microscopy using ultrathin sectioning along with immunogold labeling confirmed the presence of intact HBV virions in exosomes. The ultracentrifugation enabled the separation of the free virion fraction from the virions enclosed in exosomes. These findings fit in with previous discoveries of quasi-enveloped hepatitis A virus and hepatitis E virus.
The exosomes released free HBV virion and naked capsid after exposure to detergent. Cellular exposure to exosome morphogenesis inhibitors interfered with the release of exosome-packaged HBV. The researchers also observed large HBV surface antigens (LHB) on the external surface of the exosomes and found that the antigens allowed the exosome to infect susceptible cells through interaction with the sodium-taurocholate co-transporting polypeptide. LHB may also play an additional role in infectivity by countering the ability of antibodies to neutralize HBV.
However, the researchers also found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells with exosome-containing HBV. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
To investigate the release pathway, the researchers used three different exosome release inhibitors and found that all three interfered with HBV exosomal release. They also found that cells deficient in the exosome proteins Alix and syntenin did not release exosomal HBV.
Alix appears to be involved in HBV exosomal release, as evidenced by the fact that release of exosomal HBV is boosted in Alix-deficient cells following rescue through overexpression of mCherry-Alix fusion construct. Overexpression of mCherry-Alix had no effect on release of free HBV virions.
The researchers also found evidence that two other exosomal proteins, CD63 and TSG101, play a role in incorporation of LHBs in the HBV envelope, as well as release of HBV through interactions with the protein alpha-taxilin. CD63 and TSG101 are also critical to the formation of exosomes, and the authors suggest further research into their functioning could be fruitful.
Whether exosome-released HBV results from crosstalk between the virus and host cells still needs to be determined. If host factors play a role in connecting HBV to exosomes, it will be interesting to work out which conditions trigger this process, as well as determine which events trigger the release of free virus through multivesicular bodies.
The researchers posit that LHBs could perform a similar function as classical hepatitis B surface antigens and filaments in foiling the immune response. Such a function would require that the virus escape from antibodies before opsonin proteins tag the antigens. It’s also possible that LHBs enable infection of nonhepatic tissues, though this would likely be inefficient.
Many other host proteins have been observed in exosomes released by HBV-infected hepatocytes, suggesting that host proteins may play other roles. A proteomics analysis found proteasome subunit proteins in HepAD38-derived exosomes. The authors suggest that those proteins may allow the exosomes to mediate transcellular immune regulation.
Subviral particles may enhance viral infection, and exosomes from HBV-positive cells may contribute, possibly through exosome surface LHBs, according to the authors. They found that an LHB-specific neutralizing antibody inhibited infection of differentiated HepaRG cells. One explanation is that the antibody blocks the interaction between LHB and the target cell. Another is that the exosome disassembles near the target cell membrane and releases the virus, which is then blocked by the antibody since it can block entry of released virus.
“This previously undiscovered strategy of sequestering HBV particles in exosomes could be a strategy to escape from the immune response and to target them, protected by the exosomal membrane, to the hepatocyte. Exosomes that carry HBV particles seem also to have the potential to deliver HBV to nonpermissive cells with low efficiency. This suggests that exosomes could be an additional factor that contributes to the spread of HBV,” the authors wrote.
The authors had no financial conflicts. This research was funded by the LOEWE Center ACLF, DRUID, the Germany Research Foundation, and the China Scholarship Council.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
New algorithm for large nonpedunculated rectal polyps
Large nonpedunculated rectal polyps (LNPRPs), defined as 20 mm or larger, are associated with a high risk of submucosal invasive cancer (SMIC). Although LNPRPs can be removed by distal colorectal surgery, this approach has an increased risk of morbidity, mortality, and permanent ostomy formation.
The first-line resection technique for LNPRPs is endoscopic mucosal resection (EMR); however, for larger lesions, piecemeal removal is required. When SMIC is revealed after piecemeal resection, surgery is generally recommended, since this is the only way to determine if R0 margins and curative oncologic resection have been achieved.
In such cases, an alternative is endoscopic submucosal dissection (ESD), but there is no current algorithm to choose between the two procedures based on lesion identity.
Optical methods can determine a lesion’s pit and microvascular pattern in real time to determine if SMIC is present, but the performance is modest. Researchers sought to bolster optical detection by combining it with SMIC risk stratification to streamline the choice between EMR and ESD for LNPRPs.
In a study published online in Clinical Gastroenterology and Hepatology, researchers led by Neal Shahidi, MD, of the division of gastroenterology, St. Paul’s Hospital, Vancouver, described a selective resection algorithm (SRA) that could assist gastroenterologists in determining the best procedure to use when confronted with an LNPRP.
“Cost-effectiveness analyses have shown that an SRA using EMR and ESD is the optimal approach. However, a mechanism to facilitate modality selection has not been delineated. To our knowledge, this study is the first to show that a rectum-specific SRA, based on real-time optical evaluation and covert SMIC risk stratification, increases the frequency of curative oncologic resection and minimizes the risk of piecemeal resection of malignant LNPRPs. ... Piecemeal resection of endoscopically curable malignant LNPRPs negates the very benefit that they are intended to provide. the authors wrote.
The researchers conducted a prospective observational study of 480 LNPRPs that were detected between July 2008 and April 2021. They compared the performance of the SRA to that of a universal EMR algorithm (UEA) for procedure determination. The SRA flagged LNPRPs with features consistent with SMIC (< 1,000 mm or Kudo pit pattern Vi) for endoscopic dissection. The latter included Paris 0-Is or 0-IIa+Is nongranular, or 0-IIa+Is granular with a dominant nodule 10 mm or larger. Other LNPRPs were designated to undergo EMR.
The median patient age was 67 years, and 54.2% were men; 90.1% of participants were ASA I-II; 290 LNPRPs were evaluated with the UEA and 190 with the SRA. The median lesion size was 40 mm. Overall, 11.7% of LPNRPs were identified as containing SMIC.
In the SRA, only 1.0% of LNPRPs removed by EMR contained SMIC, while the UEA identified cancer in 12.1%, a significant difference (P = .001). The SRA led to 33.3% as curative oncologic resections, while the UEA achieved only 5.7% (P = .010).
There were no significant differences in technical success or adverse events between the two algorithms.
Procedures determined by SRA took longer than those decided by UEA (median resection duration, 45 vs. 29 minutes; P < .001). Among LNPRPs that were removed through EMR and margin thermal ablation, there was no significant difference in recurrence whether SRA or UEA was used to determine the procedure.
Compared with UEA, SRA was associated with higher rates of en bloc resection (90.5% vs. 11.4%; P < .001), R0 resection (85.7% vs. 5.7%; P < .001), and curative oncologic resection (33.3% vs. 5.7%; P = .010).
“In this study, using analogous optical evaluation and covert SMIC risk stratification criteria, only one (1.0%) [of] malignant LNPRP underwent piecemeal resection within the SRA. This is a pivotal advance in the application of minimally invasive endoscopic resection techniques. It demonstrates an effective approach to optical evaluation; thereby, delineating which LNPRPs can be effectively, efficiently, and safely managed by EMR, compared with those which may derive benefit from ESD,” the authors wrote.
The authors recommended ESD only be used for lesions with suspected superficial SMIC or when there is a heightened risk of SMIC.
A key finding of the study is the frequency of curative resection following ESD. “At 33.3%, this represents a critical improvement in patient outcomes and the application of minimally invasive endoscopic resection techniques; especially when taking into consideration the potential negative ramifications of distal colorectal surgery and evidence showing that endoscopic resection does not impair subsequent surgical intervention,” the authors wrote.
There was no significant difference in recurrence at surveillance colonoscopy between SRA and UEA when undergoing margin thermal ablation. The finding suggests that margin thermal ablation should be considered a vital component of EMR, according to the authors.
Dr. Shahidi received speaker honorarium from Boston Scientific and Pharmascience, and one coauthor received research support from Olympus, Cook Medical, and Boston Scientific.
In clinical practice there is widespread variation in the utilization of endoscopic submucosal dissection (ESD) versus endoscopic mucosal resection (EMR) for resection of large nonpedunculated rectal polyps (LNPRPs).
EMR is easier to learn and faster to perform than ESD and results in fewer perforations. EMR for LNPRPs is usually performed piecemeal, as opposed to ESD in which the goal is en bloc resection. When apparently successful piecemeal EMR is followed by cancer in the pathology report, surgical resection is frequently recommended. This is because assessment of residual cancer risk in the bowel wall or lymph nodes is often considered unachievable after piecemeal resection. Conversely, patients with superficial submucosal invasion after ESD may avoid surgical resection.
This study describes a selective approach to colorectal ESD based on two factors. First, consider ESD primarily in the rectum where the morbidity of surgical resection is highest. Second, consider ESD for those rectal lesions where the cancer risk is highest, including lesions with surface pit and vascular patterns indicating high cancer risk and those with a sessile or nodular component. When this policy was used, only 1% of rectal EMRs were followed by a diagnosis of submucosally invasive cancer. This selective approach to colorectal ESD seems a reasonable combination of procedural efficiency and optimal patient outcomes.
Douglas K. Rex, M.D., MACP, MACG, MASGE, AGAF, is distinguished professor emeritus of medicine, Indiana University, Indianapolis. He serves as a consultant to Olympus Corporation, Boston Scientific, Aries Pharmaceutical, Braintree Laboratories, Lumendi, Norgine, Endokey, GI Supply, Medtronic, and Acacia Pharmaceuticals. He has received research support from EndoAid, Olympus Corporation, Medivators, Erbe USA, Braintree Laboratories and is a shareholder in Satisfai Health.
In clinical practice there is widespread variation in the utilization of endoscopic submucosal dissection (ESD) versus endoscopic mucosal resection (EMR) for resection of large nonpedunculated rectal polyps (LNPRPs).
EMR is easier to learn and faster to perform than ESD and results in fewer perforations. EMR for LNPRPs is usually performed piecemeal, as opposed to ESD in which the goal is en bloc resection. When apparently successful piecemeal EMR is followed by cancer in the pathology report, surgical resection is frequently recommended. This is because assessment of residual cancer risk in the bowel wall or lymph nodes is often considered unachievable after piecemeal resection. Conversely, patients with superficial submucosal invasion after ESD may avoid surgical resection.
This study describes a selective approach to colorectal ESD based on two factors. First, consider ESD primarily in the rectum where the morbidity of surgical resection is highest. Second, consider ESD for those rectal lesions where the cancer risk is highest, including lesions with surface pit and vascular patterns indicating high cancer risk and those with a sessile or nodular component. When this policy was used, only 1% of rectal EMRs were followed by a diagnosis of submucosally invasive cancer. This selective approach to colorectal ESD seems a reasonable combination of procedural efficiency and optimal patient outcomes.
Douglas K. Rex, M.D., MACP, MACG, MASGE, AGAF, is distinguished professor emeritus of medicine, Indiana University, Indianapolis. He serves as a consultant to Olympus Corporation, Boston Scientific, Aries Pharmaceutical, Braintree Laboratories, Lumendi, Norgine, Endokey, GI Supply, Medtronic, and Acacia Pharmaceuticals. He has received research support from EndoAid, Olympus Corporation, Medivators, Erbe USA, Braintree Laboratories and is a shareholder in Satisfai Health.
In clinical practice there is widespread variation in the utilization of endoscopic submucosal dissection (ESD) versus endoscopic mucosal resection (EMR) for resection of large nonpedunculated rectal polyps (LNPRPs).
EMR is easier to learn and faster to perform than ESD and results in fewer perforations. EMR for LNPRPs is usually performed piecemeal, as opposed to ESD in which the goal is en bloc resection. When apparently successful piecemeal EMR is followed by cancer in the pathology report, surgical resection is frequently recommended. This is because assessment of residual cancer risk in the bowel wall or lymph nodes is often considered unachievable after piecemeal resection. Conversely, patients with superficial submucosal invasion after ESD may avoid surgical resection.
This study describes a selective approach to colorectal ESD based on two factors. First, consider ESD primarily in the rectum where the morbidity of surgical resection is highest. Second, consider ESD for those rectal lesions where the cancer risk is highest, including lesions with surface pit and vascular patterns indicating high cancer risk and those with a sessile or nodular component. When this policy was used, only 1% of rectal EMRs were followed by a diagnosis of submucosally invasive cancer. This selective approach to colorectal ESD seems a reasonable combination of procedural efficiency and optimal patient outcomes.
Douglas K. Rex, M.D., MACP, MACG, MASGE, AGAF, is distinguished professor emeritus of medicine, Indiana University, Indianapolis. He serves as a consultant to Olympus Corporation, Boston Scientific, Aries Pharmaceutical, Braintree Laboratories, Lumendi, Norgine, Endokey, GI Supply, Medtronic, and Acacia Pharmaceuticals. He has received research support from EndoAid, Olympus Corporation, Medivators, Erbe USA, Braintree Laboratories and is a shareholder in Satisfai Health.
Large nonpedunculated rectal polyps (LNPRPs), defined as 20 mm or larger, are associated with a high risk of submucosal invasive cancer (SMIC). Although LNPRPs can be removed by distal colorectal surgery, this approach has an increased risk of morbidity, mortality, and permanent ostomy formation.
The first-line resection technique for LNPRPs is endoscopic mucosal resection (EMR); however, for larger lesions, piecemeal removal is required. When SMIC is revealed after piecemeal resection, surgery is generally recommended, since this is the only way to determine if R0 margins and curative oncologic resection have been achieved.
In such cases, an alternative is endoscopic submucosal dissection (ESD), but there is no current algorithm to choose between the two procedures based on lesion identity.
Optical methods can determine a lesion’s pit and microvascular pattern in real time to determine if SMIC is present, but the performance is modest. Researchers sought to bolster optical detection by combining it with SMIC risk stratification to streamline the choice between EMR and ESD for LNPRPs.
In a study published online in Clinical Gastroenterology and Hepatology, researchers led by Neal Shahidi, MD, of the division of gastroenterology, St. Paul’s Hospital, Vancouver, described a selective resection algorithm (SRA) that could assist gastroenterologists in determining the best procedure to use when confronted with an LNPRP.
“Cost-effectiveness analyses have shown that an SRA using EMR and ESD is the optimal approach. However, a mechanism to facilitate modality selection has not been delineated. To our knowledge, this study is the first to show that a rectum-specific SRA, based on real-time optical evaluation and covert SMIC risk stratification, increases the frequency of curative oncologic resection and minimizes the risk of piecemeal resection of malignant LNPRPs. ... Piecemeal resection of endoscopically curable malignant LNPRPs negates the very benefit that they are intended to provide. the authors wrote.
The researchers conducted a prospective observational study of 480 LNPRPs that were detected between July 2008 and April 2021. They compared the performance of the SRA to that of a universal EMR algorithm (UEA) for procedure determination. The SRA flagged LNPRPs with features consistent with SMIC (< 1,000 mm or Kudo pit pattern Vi) for endoscopic dissection. The latter included Paris 0-Is or 0-IIa+Is nongranular, or 0-IIa+Is granular with a dominant nodule 10 mm or larger. Other LNPRPs were designated to undergo EMR.
The median patient age was 67 years, and 54.2% were men; 90.1% of participants were ASA I-II; 290 LNPRPs were evaluated with the UEA and 190 with the SRA. The median lesion size was 40 mm. Overall, 11.7% of LPNRPs were identified as containing SMIC.
In the SRA, only 1.0% of LNPRPs removed by EMR contained SMIC, while the UEA identified cancer in 12.1%, a significant difference (P = .001). The SRA led to 33.3% as curative oncologic resections, while the UEA achieved only 5.7% (P = .010).
There were no significant differences in technical success or adverse events between the two algorithms.
Procedures determined by SRA took longer than those decided by UEA (median resection duration, 45 vs. 29 minutes; P < .001). Among LNPRPs that were removed through EMR and margin thermal ablation, there was no significant difference in recurrence whether SRA or UEA was used to determine the procedure.
Compared with UEA, SRA was associated with higher rates of en bloc resection (90.5% vs. 11.4%; P < .001), R0 resection (85.7% vs. 5.7%; P < .001), and curative oncologic resection (33.3% vs. 5.7%; P = .010).
“In this study, using analogous optical evaluation and covert SMIC risk stratification criteria, only one (1.0%) [of] malignant LNPRP underwent piecemeal resection within the SRA. This is a pivotal advance in the application of minimally invasive endoscopic resection techniques. It demonstrates an effective approach to optical evaluation; thereby, delineating which LNPRPs can be effectively, efficiently, and safely managed by EMR, compared with those which may derive benefit from ESD,” the authors wrote.
The authors recommended ESD only be used for lesions with suspected superficial SMIC or when there is a heightened risk of SMIC.
A key finding of the study is the frequency of curative resection following ESD. “At 33.3%, this represents a critical improvement in patient outcomes and the application of minimally invasive endoscopic resection techniques; especially when taking into consideration the potential negative ramifications of distal colorectal surgery and evidence showing that endoscopic resection does not impair subsequent surgical intervention,” the authors wrote.
There was no significant difference in recurrence at surveillance colonoscopy between SRA and UEA when undergoing margin thermal ablation. The finding suggests that margin thermal ablation should be considered a vital component of EMR, according to the authors.
Dr. Shahidi received speaker honorarium from Boston Scientific and Pharmascience, and one coauthor received research support from Olympus, Cook Medical, and Boston Scientific.
Large nonpedunculated rectal polyps (LNPRPs), defined as 20 mm or larger, are associated with a high risk of submucosal invasive cancer (SMIC). Although LNPRPs can be removed by distal colorectal surgery, this approach has an increased risk of morbidity, mortality, and permanent ostomy formation.
The first-line resection technique for LNPRPs is endoscopic mucosal resection (EMR); however, for larger lesions, piecemeal removal is required. When SMIC is revealed after piecemeal resection, surgery is generally recommended, since this is the only way to determine if R0 margins and curative oncologic resection have been achieved.
In such cases, an alternative is endoscopic submucosal dissection (ESD), but there is no current algorithm to choose between the two procedures based on lesion identity.
Optical methods can determine a lesion’s pit and microvascular pattern in real time to determine if SMIC is present, but the performance is modest. Researchers sought to bolster optical detection by combining it with SMIC risk stratification to streamline the choice between EMR and ESD for LNPRPs.
In a study published online in Clinical Gastroenterology and Hepatology, researchers led by Neal Shahidi, MD, of the division of gastroenterology, St. Paul’s Hospital, Vancouver, described a selective resection algorithm (SRA) that could assist gastroenterologists in determining the best procedure to use when confronted with an LNPRP.
“Cost-effectiveness analyses have shown that an SRA using EMR and ESD is the optimal approach. However, a mechanism to facilitate modality selection has not been delineated. To our knowledge, this study is the first to show that a rectum-specific SRA, based on real-time optical evaluation and covert SMIC risk stratification, increases the frequency of curative oncologic resection and minimizes the risk of piecemeal resection of malignant LNPRPs. ... Piecemeal resection of endoscopically curable malignant LNPRPs negates the very benefit that they are intended to provide. the authors wrote.
The researchers conducted a prospective observational study of 480 LNPRPs that were detected between July 2008 and April 2021. They compared the performance of the SRA to that of a universal EMR algorithm (UEA) for procedure determination. The SRA flagged LNPRPs with features consistent with SMIC (< 1,000 mm or Kudo pit pattern Vi) for endoscopic dissection. The latter included Paris 0-Is or 0-IIa+Is nongranular, or 0-IIa+Is granular with a dominant nodule 10 mm or larger. Other LNPRPs were designated to undergo EMR.
The median patient age was 67 years, and 54.2% were men; 90.1% of participants were ASA I-II; 290 LNPRPs were evaluated with the UEA and 190 with the SRA. The median lesion size was 40 mm. Overall, 11.7% of LPNRPs were identified as containing SMIC.
In the SRA, only 1.0% of LNPRPs removed by EMR contained SMIC, while the UEA identified cancer in 12.1%, a significant difference (P = .001). The SRA led to 33.3% as curative oncologic resections, while the UEA achieved only 5.7% (P = .010).
There were no significant differences in technical success or adverse events between the two algorithms.
Procedures determined by SRA took longer than those decided by UEA (median resection duration, 45 vs. 29 minutes; P < .001). Among LNPRPs that were removed through EMR and margin thermal ablation, there was no significant difference in recurrence whether SRA or UEA was used to determine the procedure.
Compared with UEA, SRA was associated with higher rates of en bloc resection (90.5% vs. 11.4%; P < .001), R0 resection (85.7% vs. 5.7%; P < .001), and curative oncologic resection (33.3% vs. 5.7%; P = .010).
“In this study, using analogous optical evaluation and covert SMIC risk stratification criteria, only one (1.0%) [of] malignant LNPRP underwent piecemeal resection within the SRA. This is a pivotal advance in the application of minimally invasive endoscopic resection techniques. It demonstrates an effective approach to optical evaluation; thereby, delineating which LNPRPs can be effectively, efficiently, and safely managed by EMR, compared with those which may derive benefit from ESD,” the authors wrote.
The authors recommended ESD only be used for lesions with suspected superficial SMIC or when there is a heightened risk of SMIC.
A key finding of the study is the frequency of curative resection following ESD. “At 33.3%, this represents a critical improvement in patient outcomes and the application of minimally invasive endoscopic resection techniques; especially when taking into consideration the potential negative ramifications of distal colorectal surgery and evidence showing that endoscopic resection does not impair subsequent surgical intervention,” the authors wrote.
There was no significant difference in recurrence at surveillance colonoscopy between SRA and UEA when undergoing margin thermal ablation. The finding suggests that margin thermal ablation should be considered a vital component of EMR, according to the authors.
Dr. Shahidi received speaker honorarium from Boston Scientific and Pharmascience, and one coauthor received research support from Olympus, Cook Medical, and Boston Scientific.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Vonoprazan promising for erosive esophagitis
, according to results of the phase 3 PHALCON-EE trial.
Vonoprazan achieved higher rates of healing and maintenance of healing than lansoprazole, with the benefit seen primarily in patients with more severe esophagitis.
The differences in healing rates were evident after 2 weeks of therapy and were maintained throughout the 24-week study, report Loren Laine, MD, Yale University, New Haven, Conn., and colleagues.
The study was published online in Gastroenterology.
More potent acid suppression
Gastroesophageal reflux disease is one of the most common disorders of the gastrointestinal tract, and erosive esophagitis is its most common complication.
Although standard PPI therapy is effective for healing erosive esophagitis, some patients do not achieve success with this conventional treatment.
Studies suggest that lack of healing of erosive esophagitis with 8 weeks of PPI therapy can be expected in roughly 5%-20% of patients, with rates up to 30% reported in patients with more severe esophagitis.
The PCAB vonoprazan provides more potent inhibition of gastric acid than PPIs and is seen as a potential alternative. However, data on its efficacy for erosive esophagitis are limited, the authors note.
The PHALCON-EE trial enrolled 1,024 adults from the United States and Europe with erosive esophagitis without Helicobacter pylori infection or Barrett esophagus.
Participants were randomized to receive once-daily vonoprazan 20 mg or lansoprazole 30 mg for up to 8 weeks in the healing phase.
The 878 patients with healing were then rerandomized to receive once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks in the maintenance phase.
For healing by week 8, vonoprazan was noninferior to lansoprazole in the primary analysis and superior to lansoprazole in a predefined exploratory analysis (92.9% vs. 84.6%; P < .0001).
Secondary analyses showed that vonoprazan was noninferior to lansoprazole in mean 24-hour heartburn-free days and superior in healing at week 2 for grade C/D esophagitis (70.2% vs. 52.6%; P = .0008).
For maintenance of healing at week 24, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on secondary analysis of healing (80.7% for vonoprazan 20 mg and 79.2% for vonoprazan 10 mg vs. 72.0% for lansoprazole; P < .0001 for both comparisons).
The most common adverse event reported in the healing phase was diarrhea and in the maintenance phase was COVID-19. Two deaths occurred, both from COVID-19, during the maintenance phase in the vonoprazan 20-mg group.
As expected, serum gastrin increased to a greater extent with vonoprazan than lansoprazole, with levels > 500 pg/mL in 16% of those taking 20 mg at the end of maintenance therapy, the authors report. After stopping vonoprazan, gastrin levels dropped by roughly 60%-65% within 4 weeks.
Promising new option
“PCABs are a promising new option,” Avin Aggarwal, MD, who was not involved in the study, told this news organization.
They have a “more potent acid inhibitory effect” and have shown “superior healing of erosive esophagitis,” said Dr. Aggarwal, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona in Tucson.
The results of the PHALCON-EE trial “validate noninferiority of PCABs compared to standard PPI therapy in the Western population after being proven in multiple Asian studies,” he said.
Dr. Aggarwal noted that PCABs work the same way as PPIs, by blocking the proton pumps, but “the longer half-life of PCABs and action on both active and inactive proton channels result in greater acid inhibition.”
Long-term effects of PCAB therapy from stronger acid inhibition and resulting hypergastrinemia still remain to be determined, he said.
Earlier this year, the U.S. Food and Drug Administration accepted Phathom Pharmaceuticals’ new drug application for vonoprazan for the treatment of erosive esophagitis.
Last May, the FDA approved two vonoprazan-based therapies for the treatment of H. pylori infection.
The study was funded by Phathom Pharmaceuticals. Dr. Laine and several coauthors have disclosed financial relationships with the company. Dr. Aggarwal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to results of the phase 3 PHALCON-EE trial.
Vonoprazan achieved higher rates of healing and maintenance of healing than lansoprazole, with the benefit seen primarily in patients with more severe esophagitis.
The differences in healing rates were evident after 2 weeks of therapy and were maintained throughout the 24-week study, report Loren Laine, MD, Yale University, New Haven, Conn., and colleagues.
The study was published online in Gastroenterology.
More potent acid suppression
Gastroesophageal reflux disease is one of the most common disorders of the gastrointestinal tract, and erosive esophagitis is its most common complication.
Although standard PPI therapy is effective for healing erosive esophagitis, some patients do not achieve success with this conventional treatment.
Studies suggest that lack of healing of erosive esophagitis with 8 weeks of PPI therapy can be expected in roughly 5%-20% of patients, with rates up to 30% reported in patients with more severe esophagitis.
The PCAB vonoprazan provides more potent inhibition of gastric acid than PPIs and is seen as a potential alternative. However, data on its efficacy for erosive esophagitis are limited, the authors note.
The PHALCON-EE trial enrolled 1,024 adults from the United States and Europe with erosive esophagitis without Helicobacter pylori infection or Barrett esophagus.
Participants were randomized to receive once-daily vonoprazan 20 mg or lansoprazole 30 mg for up to 8 weeks in the healing phase.
The 878 patients with healing were then rerandomized to receive once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks in the maintenance phase.
For healing by week 8, vonoprazan was noninferior to lansoprazole in the primary analysis and superior to lansoprazole in a predefined exploratory analysis (92.9% vs. 84.6%; P < .0001).
Secondary analyses showed that vonoprazan was noninferior to lansoprazole in mean 24-hour heartburn-free days and superior in healing at week 2 for grade C/D esophagitis (70.2% vs. 52.6%; P = .0008).
For maintenance of healing at week 24, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on secondary analysis of healing (80.7% for vonoprazan 20 mg and 79.2% for vonoprazan 10 mg vs. 72.0% for lansoprazole; P < .0001 for both comparisons).
The most common adverse event reported in the healing phase was diarrhea and in the maintenance phase was COVID-19. Two deaths occurred, both from COVID-19, during the maintenance phase in the vonoprazan 20-mg group.
As expected, serum gastrin increased to a greater extent with vonoprazan than lansoprazole, with levels > 500 pg/mL in 16% of those taking 20 mg at the end of maintenance therapy, the authors report. After stopping vonoprazan, gastrin levels dropped by roughly 60%-65% within 4 weeks.
Promising new option
“PCABs are a promising new option,” Avin Aggarwal, MD, who was not involved in the study, told this news organization.
They have a “more potent acid inhibitory effect” and have shown “superior healing of erosive esophagitis,” said Dr. Aggarwal, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona in Tucson.
The results of the PHALCON-EE trial “validate noninferiority of PCABs compared to standard PPI therapy in the Western population after being proven in multiple Asian studies,” he said.
Dr. Aggarwal noted that PCABs work the same way as PPIs, by blocking the proton pumps, but “the longer half-life of PCABs and action on both active and inactive proton channels result in greater acid inhibition.”
Long-term effects of PCAB therapy from stronger acid inhibition and resulting hypergastrinemia still remain to be determined, he said.
Earlier this year, the U.S. Food and Drug Administration accepted Phathom Pharmaceuticals’ new drug application for vonoprazan for the treatment of erosive esophagitis.
Last May, the FDA approved two vonoprazan-based therapies for the treatment of H. pylori infection.
The study was funded by Phathom Pharmaceuticals. Dr. Laine and several coauthors have disclosed financial relationships with the company. Dr. Aggarwal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to results of the phase 3 PHALCON-EE trial.
Vonoprazan achieved higher rates of healing and maintenance of healing than lansoprazole, with the benefit seen primarily in patients with more severe esophagitis.
The differences in healing rates were evident after 2 weeks of therapy and were maintained throughout the 24-week study, report Loren Laine, MD, Yale University, New Haven, Conn., and colleagues.
The study was published online in Gastroenterology.
More potent acid suppression
Gastroesophageal reflux disease is one of the most common disorders of the gastrointestinal tract, and erosive esophagitis is its most common complication.
Although standard PPI therapy is effective for healing erosive esophagitis, some patients do not achieve success with this conventional treatment.
Studies suggest that lack of healing of erosive esophagitis with 8 weeks of PPI therapy can be expected in roughly 5%-20% of patients, with rates up to 30% reported in patients with more severe esophagitis.
The PCAB vonoprazan provides more potent inhibition of gastric acid than PPIs and is seen as a potential alternative. However, data on its efficacy for erosive esophagitis are limited, the authors note.
The PHALCON-EE trial enrolled 1,024 adults from the United States and Europe with erosive esophagitis without Helicobacter pylori infection or Barrett esophagus.
Participants were randomized to receive once-daily vonoprazan 20 mg or lansoprazole 30 mg for up to 8 weeks in the healing phase.
The 878 patients with healing were then rerandomized to receive once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks in the maintenance phase.
For healing by week 8, vonoprazan was noninferior to lansoprazole in the primary analysis and superior to lansoprazole in a predefined exploratory analysis (92.9% vs. 84.6%; P < .0001).
Secondary analyses showed that vonoprazan was noninferior to lansoprazole in mean 24-hour heartburn-free days and superior in healing at week 2 for grade C/D esophagitis (70.2% vs. 52.6%; P = .0008).
For maintenance of healing at week 24, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on secondary analysis of healing (80.7% for vonoprazan 20 mg and 79.2% for vonoprazan 10 mg vs. 72.0% for lansoprazole; P < .0001 for both comparisons).
The most common adverse event reported in the healing phase was diarrhea and in the maintenance phase was COVID-19. Two deaths occurred, both from COVID-19, during the maintenance phase in the vonoprazan 20-mg group.
As expected, serum gastrin increased to a greater extent with vonoprazan than lansoprazole, with levels > 500 pg/mL in 16% of those taking 20 mg at the end of maintenance therapy, the authors report. After stopping vonoprazan, gastrin levels dropped by roughly 60%-65% within 4 weeks.
Promising new option
“PCABs are a promising new option,” Avin Aggarwal, MD, who was not involved in the study, told this news organization.
They have a “more potent acid inhibitory effect” and have shown “superior healing of erosive esophagitis,” said Dr. Aggarwal, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona in Tucson.
The results of the PHALCON-EE trial “validate noninferiority of PCABs compared to standard PPI therapy in the Western population after being proven in multiple Asian studies,” he said.
Dr. Aggarwal noted that PCABs work the same way as PPIs, by blocking the proton pumps, but “the longer half-life of PCABs and action on both active and inactive proton channels result in greater acid inhibition.”
Long-term effects of PCAB therapy from stronger acid inhibition and resulting hypergastrinemia still remain to be determined, he said.
Earlier this year, the U.S. Food and Drug Administration accepted Phathom Pharmaceuticals’ new drug application for vonoprazan for the treatment of erosive esophagitis.
Last May, the FDA approved two vonoprazan-based therapies for the treatment of H. pylori infection.
The study was funded by Phathom Pharmaceuticals. Dr. Laine and several coauthors have disclosed financial relationships with the company. Dr. Aggarwal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
HCC surveillance screening increased slightly with invitations, reminders
Mailing invitations for hepatocellular carcinoma (HCC) surveillance screening to patients with cirrhosis increased ultrasound uptake by 13 percentage points, but the majority of patients still did not receive the recommended semiannual screenings, according to findings published in Clinical Gastroenterology and Hepatology.
“These data highlight the need for more intensive interventions to further increase surveillance,” wrote Amit Singal, MD, of University of Texas Southwestern Medical Center and Parkland Health Hospital System in Dallas, and colleagues. “The underuse of HCC surveillance has been attributed to a combination of patient- and provider-level barriers, which can serve as future additional intervention targets.” These include transportation and financial barriers and possibly new blood-based screening modalities when they become available, thereby removing the need for a separate ultrasound appointment.
According to one study, more than 90% of hepatocellular carcinoma cases occur in people with chronic liver disease, and the cancer is a leading cause of death in those with compensated cirrhosis. Multiple medical associations therefore recommend an abdominal ultrasound every 6 months with or without alpha-fetoprotein (AFP) for surveillance in at-risk patients, including anyone with cirrhosis of any kind, but too few patients receive these surveillance ultrasounds, the authors write.
The researchers therefore conducted a pragmatic randomized clinical trial from March 2018 to September 2019 to compare surveillance ultrasound uptake for two groups of people with cirrhosis: 1,436 people who were mailed invitations to get a surveillance ultrasound and 1,436 people who received usual care, with surveillance recommended only at usual visits. The patients all received care at one of three health systems: a tertiary care referral center, a safety net health system, and a Veterans Affairs medical center. The primary outcome was semiannual surveillance in the patients over 1 year.
The researchers identified patients using ICD-9 and ICD-10 codes for cirrhosis and cirrhosis complications, as well as those with suspected but undocumented cirrhosis based on electronic medical record notes such as an elevated Fibrosis-4 index. They confirmed the diagnoses with chart review, confirmed that the patients had at least one outpatient visit in the previous year, and excluded those in whom surveillance is not recommended, who lacked contact information, or who spoke a language besides English or Spanish.
The mailing was a one-page letter in English and Spanish, written at a low literacy level, that explained hepatocellular carcinoma risk and recommended surveillance. Those who didn’t respond to the mailed invitation within 2 weeks received a reminder call to undergo surveillance, and those who scheduled an ultrasound received a reminder call about a week before the visit. Primary and subspecialty providers were blinded to the patients’ study arm assignments.
“We conducted the study as a pragmatic trial whereby patients in either arm could also be offered HCC surveillance by primary or specialty care providers during clinic visits,” the researchers wrote. “The frequency of the clinic visits and provider discussions regarding HCC surveillance were conducted per usual care and not dictated by the study protocol.”
Two-thirds of the patients (67.7%) were men, with a median age of 61.2 years. Just over a third (37.0%) were white, 31.9% were Hispanic, and 27.6% were Black. More than half the patients had hepatitis C (56.4%), 18.1% had alcohol-related liver disease, 14.5% had nonalcoholic fatty liver disease, and 2.4% had hepatitis B. Most of the patients had compensated cirrhosis, including 36.7% with ascites and 17.1% with hepatic encephalopathy.
Nearly a quarter of the patients in the outreach arm (23%) could not be contacted or lacked working phone numbers, but they remained in the intent-to-screen analysis. Just over a third of the patients who received mailed outreach (35.1%; 95% confidence interval, 32.6%-37.6%) received semiannual surveillance, compared to 21.9% (95% CI, 19.8%-24.2%) of the usual-care patients. The increased surveillance in the outreach group applied to most subgroups, including race/ethnicity and cirrhosis severity based on the Child-Turcotte-Pugh class.
“However, we observed site-level differences in the intervention effect, with significant increases in semiannual surveillance at the VA and safety net health systems (both P < .001) but not at the tertiary care referral center (P = .52),” the authors wrote. “In a post hoc subgroup analysis among patients with at least 1 primary care or gastroenterology outpatient visit during the study period, mailed outreach continued to increase semiannual surveillance, compared with usual care (46.8% vs. 32.7%; P < .001).”
Despite the improved rates from the intervention, the majority of patients still did not receive semiannual surveillance across all three sites, and almost 30% underwent no surveillance the entire year.
The research was funded by the National Cancer Institute, the Cancer Prevention Research Institute of Texas, and the Center for Innovations in Quality, Effectiveness and Safety. Dr. Singal has consulted for or served on the advisory boards of Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, and GRAIL. The other authors had no industry disclosures.
Hepatocellular carcinoma is a deadly cancer that is usually incurable unless detected at an early stage through regular surveillance. Current American guidelines support 6-monthly abdominal ultrasonography, with or without serum alpha-fetoprotein, for HCC surveillance in at-risk patients, such as those with cirrhosis. However, even in such a high-risk group, the uptake of and adherence to surveillance are far from satisfactory. This study by Dr. Singal and colleagues is therefore important and practical. Randomized controlled trials in HCC surveillance are rare. The authors clearly demonstrate that an outreach program comprising mail invitations followed by phone contacts if there was no response could increase the surveillance uptake by more than 10%.
None of these can work if chronic liver disease and cirrhosis are not diagnosed in the first place. Disease awareness, access to care (and racial discrepancies), and clinical care pathways are hurdles we need to overcome in order to make an impact on HCC mortality at the population level.
Vincent Wong, MD, is an academic hepatologist at the Chinese University of Hong Kong. He does not have relevant conflicts of interest in this article.
Hepatocellular carcinoma is a deadly cancer that is usually incurable unless detected at an early stage through regular surveillance. Current American guidelines support 6-monthly abdominal ultrasonography, with or without serum alpha-fetoprotein, for HCC surveillance in at-risk patients, such as those with cirrhosis. However, even in such a high-risk group, the uptake of and adherence to surveillance are far from satisfactory. This study by Dr. Singal and colleagues is therefore important and practical. Randomized controlled trials in HCC surveillance are rare. The authors clearly demonstrate that an outreach program comprising mail invitations followed by phone contacts if there was no response could increase the surveillance uptake by more than 10%.
None of these can work if chronic liver disease and cirrhosis are not diagnosed in the first place. Disease awareness, access to care (and racial discrepancies), and clinical care pathways are hurdles we need to overcome in order to make an impact on HCC mortality at the population level.
Vincent Wong, MD, is an academic hepatologist at the Chinese University of Hong Kong. He does not have relevant conflicts of interest in this article.
Hepatocellular carcinoma is a deadly cancer that is usually incurable unless detected at an early stage through regular surveillance. Current American guidelines support 6-monthly abdominal ultrasonography, with or without serum alpha-fetoprotein, for HCC surveillance in at-risk patients, such as those with cirrhosis. However, even in such a high-risk group, the uptake of and adherence to surveillance are far from satisfactory. This study by Dr. Singal and colleagues is therefore important and practical. Randomized controlled trials in HCC surveillance are rare. The authors clearly demonstrate that an outreach program comprising mail invitations followed by phone contacts if there was no response could increase the surveillance uptake by more than 10%.
None of these can work if chronic liver disease and cirrhosis are not diagnosed in the first place. Disease awareness, access to care (and racial discrepancies), and clinical care pathways are hurdles we need to overcome in order to make an impact on HCC mortality at the population level.
Vincent Wong, MD, is an academic hepatologist at the Chinese University of Hong Kong. He does not have relevant conflicts of interest in this article.
Mailing invitations for hepatocellular carcinoma (HCC) surveillance screening to patients with cirrhosis increased ultrasound uptake by 13 percentage points, but the majority of patients still did not receive the recommended semiannual screenings, according to findings published in Clinical Gastroenterology and Hepatology.
“These data highlight the need for more intensive interventions to further increase surveillance,” wrote Amit Singal, MD, of University of Texas Southwestern Medical Center and Parkland Health Hospital System in Dallas, and colleagues. “The underuse of HCC surveillance has been attributed to a combination of patient- and provider-level barriers, which can serve as future additional intervention targets.” These include transportation and financial barriers and possibly new blood-based screening modalities when they become available, thereby removing the need for a separate ultrasound appointment.
According to one study, more than 90% of hepatocellular carcinoma cases occur in people with chronic liver disease, and the cancer is a leading cause of death in those with compensated cirrhosis. Multiple medical associations therefore recommend an abdominal ultrasound every 6 months with or without alpha-fetoprotein (AFP) for surveillance in at-risk patients, including anyone with cirrhosis of any kind, but too few patients receive these surveillance ultrasounds, the authors write.
The researchers therefore conducted a pragmatic randomized clinical trial from March 2018 to September 2019 to compare surveillance ultrasound uptake for two groups of people with cirrhosis: 1,436 people who were mailed invitations to get a surveillance ultrasound and 1,436 people who received usual care, with surveillance recommended only at usual visits. The patients all received care at one of three health systems: a tertiary care referral center, a safety net health system, and a Veterans Affairs medical center. The primary outcome was semiannual surveillance in the patients over 1 year.
The researchers identified patients using ICD-9 and ICD-10 codes for cirrhosis and cirrhosis complications, as well as those with suspected but undocumented cirrhosis based on electronic medical record notes such as an elevated Fibrosis-4 index. They confirmed the diagnoses with chart review, confirmed that the patients had at least one outpatient visit in the previous year, and excluded those in whom surveillance is not recommended, who lacked contact information, or who spoke a language besides English or Spanish.
The mailing was a one-page letter in English and Spanish, written at a low literacy level, that explained hepatocellular carcinoma risk and recommended surveillance. Those who didn’t respond to the mailed invitation within 2 weeks received a reminder call to undergo surveillance, and those who scheduled an ultrasound received a reminder call about a week before the visit. Primary and subspecialty providers were blinded to the patients’ study arm assignments.
“We conducted the study as a pragmatic trial whereby patients in either arm could also be offered HCC surveillance by primary or specialty care providers during clinic visits,” the researchers wrote. “The frequency of the clinic visits and provider discussions regarding HCC surveillance were conducted per usual care and not dictated by the study protocol.”
Two-thirds of the patients (67.7%) were men, with a median age of 61.2 years. Just over a third (37.0%) were white, 31.9% were Hispanic, and 27.6% were Black. More than half the patients had hepatitis C (56.4%), 18.1% had alcohol-related liver disease, 14.5% had nonalcoholic fatty liver disease, and 2.4% had hepatitis B. Most of the patients had compensated cirrhosis, including 36.7% with ascites and 17.1% with hepatic encephalopathy.
Nearly a quarter of the patients in the outreach arm (23%) could not be contacted or lacked working phone numbers, but they remained in the intent-to-screen analysis. Just over a third of the patients who received mailed outreach (35.1%; 95% confidence interval, 32.6%-37.6%) received semiannual surveillance, compared to 21.9% (95% CI, 19.8%-24.2%) of the usual-care patients. The increased surveillance in the outreach group applied to most subgroups, including race/ethnicity and cirrhosis severity based on the Child-Turcotte-Pugh class.
“However, we observed site-level differences in the intervention effect, with significant increases in semiannual surveillance at the VA and safety net health systems (both P < .001) but not at the tertiary care referral center (P = .52),” the authors wrote. “In a post hoc subgroup analysis among patients with at least 1 primary care or gastroenterology outpatient visit during the study period, mailed outreach continued to increase semiannual surveillance, compared with usual care (46.8% vs. 32.7%; P < .001).”
Despite the improved rates from the intervention, the majority of patients still did not receive semiannual surveillance across all three sites, and almost 30% underwent no surveillance the entire year.
The research was funded by the National Cancer Institute, the Cancer Prevention Research Institute of Texas, and the Center for Innovations in Quality, Effectiveness and Safety. Dr. Singal has consulted for or served on the advisory boards of Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, and GRAIL. The other authors had no industry disclosures.
Mailing invitations for hepatocellular carcinoma (HCC) surveillance screening to patients with cirrhosis increased ultrasound uptake by 13 percentage points, but the majority of patients still did not receive the recommended semiannual screenings, according to findings published in Clinical Gastroenterology and Hepatology.
“These data highlight the need for more intensive interventions to further increase surveillance,” wrote Amit Singal, MD, of University of Texas Southwestern Medical Center and Parkland Health Hospital System in Dallas, and colleagues. “The underuse of HCC surveillance has been attributed to a combination of patient- and provider-level barriers, which can serve as future additional intervention targets.” These include transportation and financial barriers and possibly new blood-based screening modalities when they become available, thereby removing the need for a separate ultrasound appointment.
According to one study, more than 90% of hepatocellular carcinoma cases occur in people with chronic liver disease, and the cancer is a leading cause of death in those with compensated cirrhosis. Multiple medical associations therefore recommend an abdominal ultrasound every 6 months with or without alpha-fetoprotein (AFP) for surveillance in at-risk patients, including anyone with cirrhosis of any kind, but too few patients receive these surveillance ultrasounds, the authors write.
The researchers therefore conducted a pragmatic randomized clinical trial from March 2018 to September 2019 to compare surveillance ultrasound uptake for two groups of people with cirrhosis: 1,436 people who were mailed invitations to get a surveillance ultrasound and 1,436 people who received usual care, with surveillance recommended only at usual visits. The patients all received care at one of three health systems: a tertiary care referral center, a safety net health system, and a Veterans Affairs medical center. The primary outcome was semiannual surveillance in the patients over 1 year.
The researchers identified patients using ICD-9 and ICD-10 codes for cirrhosis and cirrhosis complications, as well as those with suspected but undocumented cirrhosis based on electronic medical record notes such as an elevated Fibrosis-4 index. They confirmed the diagnoses with chart review, confirmed that the patients had at least one outpatient visit in the previous year, and excluded those in whom surveillance is not recommended, who lacked contact information, or who spoke a language besides English or Spanish.
The mailing was a one-page letter in English and Spanish, written at a low literacy level, that explained hepatocellular carcinoma risk and recommended surveillance. Those who didn’t respond to the mailed invitation within 2 weeks received a reminder call to undergo surveillance, and those who scheduled an ultrasound received a reminder call about a week before the visit. Primary and subspecialty providers were blinded to the patients’ study arm assignments.
“We conducted the study as a pragmatic trial whereby patients in either arm could also be offered HCC surveillance by primary or specialty care providers during clinic visits,” the researchers wrote. “The frequency of the clinic visits and provider discussions regarding HCC surveillance were conducted per usual care and not dictated by the study protocol.”
Two-thirds of the patients (67.7%) were men, with a median age of 61.2 years. Just over a third (37.0%) were white, 31.9% were Hispanic, and 27.6% were Black. More than half the patients had hepatitis C (56.4%), 18.1% had alcohol-related liver disease, 14.5% had nonalcoholic fatty liver disease, and 2.4% had hepatitis B. Most of the patients had compensated cirrhosis, including 36.7% with ascites and 17.1% with hepatic encephalopathy.
Nearly a quarter of the patients in the outreach arm (23%) could not be contacted or lacked working phone numbers, but they remained in the intent-to-screen analysis. Just over a third of the patients who received mailed outreach (35.1%; 95% confidence interval, 32.6%-37.6%) received semiannual surveillance, compared to 21.9% (95% CI, 19.8%-24.2%) of the usual-care patients. The increased surveillance in the outreach group applied to most subgroups, including race/ethnicity and cirrhosis severity based on the Child-Turcotte-Pugh class.
“However, we observed site-level differences in the intervention effect, with significant increases in semiannual surveillance at the VA and safety net health systems (both P < .001) but not at the tertiary care referral center (P = .52),” the authors wrote. “In a post hoc subgroup analysis among patients with at least 1 primary care or gastroenterology outpatient visit during the study period, mailed outreach continued to increase semiannual surveillance, compared with usual care (46.8% vs. 32.7%; P < .001).”
Despite the improved rates from the intervention, the majority of patients still did not receive semiannual surveillance across all three sites, and almost 30% underwent no surveillance the entire year.
The research was funded by the National Cancer Institute, the Cancer Prevention Research Institute of Texas, and the Center for Innovations in Quality, Effectiveness and Safety. Dr. Singal has consulted for or served on the advisory boards of Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, and GRAIL. The other authors had no industry disclosures.
REPORTING FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Sex-linked IL-22 activity may affect NAFLD outcomes
Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.
These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.
“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”
Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.
To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
Human data
To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.
“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
Mouse data
Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.
Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.
“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”
In the meantime, the present data may steer drug development.
“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.
The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.
The cytokine interleukin-22 has potential as a therapeutic for nonalcoholic fatty liver disease, as it has been shown to decrease fat accumulation in hepatocytes and has various other liver protective effects such as prevention of cell death, enhancement of proliferation, and, importantly, reduction of liver fibrosis progression. Indeed, a recombinant derivative of IL22 has been studied in a clinical trial of alcoholic liver disease and has been found to be safe. However, the beneficial effect of this cytokine is context dependent. High levels of IL22 increased inflammation or fibrosis in hepatitis B infection and in toxic injury models in mouse models.
This is in line with observations that progression to cirrhosis in NAFLD is greater after menopause. On the other hand, women are more likely to develop cirrhosis than men despite higher levels of IL22, indicating more factors are at play in the progression of NAFLD. Overall, this report should alert investigators to consider the sex-specific effects of emerging therapies for NAFLD. Future IL22-based trials must include sex-based subgroup analyses.
Kirk Wangensteen, MD, PhD, is with the department of medicine, division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. He declares no relevant conflicts of interest.
The cytokine interleukin-22 has potential as a therapeutic for nonalcoholic fatty liver disease, as it has been shown to decrease fat accumulation in hepatocytes and has various other liver protective effects such as prevention of cell death, enhancement of proliferation, and, importantly, reduction of liver fibrosis progression. Indeed, a recombinant derivative of IL22 has been studied in a clinical trial of alcoholic liver disease and has been found to be safe. However, the beneficial effect of this cytokine is context dependent. High levels of IL22 increased inflammation or fibrosis in hepatitis B infection and in toxic injury models in mouse models.
This is in line with observations that progression to cirrhosis in NAFLD is greater after menopause. On the other hand, women are more likely to develop cirrhosis than men despite higher levels of IL22, indicating more factors are at play in the progression of NAFLD. Overall, this report should alert investigators to consider the sex-specific effects of emerging therapies for NAFLD. Future IL22-based trials must include sex-based subgroup analyses.
Kirk Wangensteen, MD, PhD, is with the department of medicine, division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. He declares no relevant conflicts of interest.
The cytokine interleukin-22 has potential as a therapeutic for nonalcoholic fatty liver disease, as it has been shown to decrease fat accumulation in hepatocytes and has various other liver protective effects such as prevention of cell death, enhancement of proliferation, and, importantly, reduction of liver fibrosis progression. Indeed, a recombinant derivative of IL22 has been studied in a clinical trial of alcoholic liver disease and has been found to be safe. However, the beneficial effect of this cytokine is context dependent. High levels of IL22 increased inflammation or fibrosis in hepatitis B infection and in toxic injury models in mouse models.
This is in line with observations that progression to cirrhosis in NAFLD is greater after menopause. On the other hand, women are more likely to develop cirrhosis than men despite higher levels of IL22, indicating more factors are at play in the progression of NAFLD. Overall, this report should alert investigators to consider the sex-specific effects of emerging therapies for NAFLD. Future IL22-based trials must include sex-based subgroup analyses.
Kirk Wangensteen, MD, PhD, is with the department of medicine, division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. He declares no relevant conflicts of interest.
Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.
These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.
“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”
Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.
To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
Human data
To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.
“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
Mouse data
Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.
Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.
“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”
In the meantime, the present data may steer drug development.
“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.
The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.
Interleukin-22 may mitigate nonalcoholic fatty liver disease (NAFLD)–related fibrosis in females but not males, suggesting a sex-linked hepatoprotective pathway, according to investigators.
These differences between men and women should be considered when conducting clinical trials for IL-22–targeting therapies, reported lead author Mohamed N. Abdelnabi, MSc, of the Centre de Recherche du Centre Hospitalier de l’Université de Montréal and colleagues.
“IL-22 is a pleiotropic cytokine with both inflammatory and protective effects during injury and repair in various tissues including the liver,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, noting that IL-22 activity has been linked with both antifibrotic and profibrotic outcomes in previous preclinical studies. “These different observations highlight the dual nature of IL-22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs. exogenous IL-22 level, and the time of exposure.”
Prior research has left some questions unanswered, the investigators noted, because many studies have relied on exogenous administration of IL-22 in mouse models, some of which lack all the metabolic abnormalities observed in human disease. Furthermore, these mice were all male, which has prevented detection of possible sex-linked differences in IL-22–related pathophysiology, they added.
To address these gaps, the investigators conducted a series of experiments involving men and women with NAFLD, plus mice of both sexes with NAFLD induced by a high-fat diet, both wild-type and with knock-out of the IL-22 receptor.
Human data
To characterize IL-22 activity in men versus women with NAFLD, the investigators first analyzed two publicly available microarray datasets. These revealed notably increased expression of hepatic IL-22 mRNA in the livers of females compared with males. Supporting this finding, liver biopsies from 11 men and 9 women with NAFLD with similar levels of fibrosis showed significantly increased IL-22–producing cells in female patients compared with male patients.
“These results suggest a sexual dimorphic expression of IL-22 in the context of NAFLD,” the investigators wrote.
Mouse data
Echoing the human data, the livers of female wild-type mice with NAFLD had significantly greater IL-22 expression than male mice at both mRNA and protein levels.
Next, the investigators explored the effects of IL-22–receptor knockout. In addition to NAFLD, these knockout mice developed weight gain and metabolic alterations, especially insulin resistance, supporting previous work that highlighted the protective role of IL-22 against these outcomes. More relevant to the present study, female knockout mice had significantly worse hepatic liver injury, apoptosis, inflammation, and fibrosis than male knockout mice, suggesting that IL-22 signaling confers hepatoprotection in females but not males.
“These observations may suggest a regulation of IL-22 expression by the female sex hormone estrogen,” the investigators wrote. “Indeed, estrogen is known to modulate inflammatory responses in NAFLD, but the underlying mechanisms remain undefined. ... Further in vivo studies are warranted to investigate whether endogenous estrogen regulates hepatic IL-22 expression in the context of NAFLD.”
In the meantime, the present data may steer drug development.
“These findings should be considered in clinical trials testing IL-22–based therapeutic approaches in treatment of female vs. male subjects with NAFLD,” the investigators concluded.
The study was partially funded by the Canadian Liver Foundation and the Canadian Institutes of Health Research, the Bourse d’Exemption des Droits de Scolarité Supplémentaires from the Université de Montréal, the Canadian Network on Hepatitis, and others. The investigators disclosed no competing interests.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Oral FMT on par with colonic FMT for recurrent C. difficile
A real-world analysis confirms that fecal microbiota transplantation (FMT) is highly effective for recurrent Clostridioides difficile infection (rCDI) – and there is no difference between delivery by capsule (cap-FMT) and colonoscopy (colo-FMT).
“We present one of the largest cohorts involving people who received capsule FMT. Byron Vaughn, MD, with the division of gastroenterology, hepatology, and nutrition, University of Minnesota, Minneapolis, said in an interview.
The study was published online in Clinical Gastroenterology and Hepatology.
The Food and Drug Administration allows FMT to be used for patients who have failed standard treatment for rCDI under a policy of enforcement discretion.
The past decade has seen an increase in the use of FMT in clinical practice, owing to an increase in cases of rCDI after failure of standard antibiotic therapy.
Unlike antibiotics, which perpetuate and worsen intestinal dysbiosis, FMT restores the diversity and function of host microbiota, effectively breaking the cycle of rCDI, the authors of the study noted. But it’s been unclear whether the efficacy and safety of FMT vary by route of administration.
Effective without procedural risks
To investigate, Dr. Vaughn and colleagues evaluated clinical outcomes and adverse events in 170 patients with rCDI who underwent cap-FMT and 96 peers who underwent colo-FMT.
FMT was performed using one of two standardized formulations of microbiota manufactured by the University of Minnesota microbiota therapeutics program: freeze-dried/encapsulated or frozen-thawed/liquid.
Overall, the cure rates of CDI were 86% at 1 month and 81% at 2 months. There was no statistically significant difference at either time between cap-FMT and colo-FMT.
The 1-month cure rate was 84% with cap-FMT and 91% with colo-FMT; at 2 months, the cure rates were 81% and 83%, respectively.
Cap-FMT has a safety and effectiveness profile similar to that of colo-FMT, without the procedural risks of colonoscopy, the researchers concluded.
They cautioned that, although FMT is highly effective overall, patient selection is a key factor to optimizing FMT success.
Older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression.
“These risk factors can help determine if a patient should receive FMT or an alternative therapy for rCDI. This is not to say FMT should be avoided in older patients or those on dialysis, but clinicians should be aware of these associations in light of other options for rCDI,” Dr. Vaughn said.
Confirming prior studies, antibiotic use after FMT was a major factor in its failure. Patient selection for FMT should include an assessment of the potential need for antibiotics after transplant, the researchers noted.
One serious adverse event (aspiration pneumonia) was related to colonoscopy; otherwise, no new safety signals were identified.
As reported in other studies, changes in bowel function, including diarrhea, constipation, gas, and bloating were common, although it’s tough to disentangle gastrointestinal symptoms related to FMT from those after CDI, the researchers said. Importantly, no transmission of an infectious agent related to FMT was identified.
Two good options
The researchers said their findings are “highly generalizable” because the population reflects all FMT use by participating institutions and contains a mix of academic centers and private practices.
Many patients included in the study would not have been eligible for a clinical trial, owing to their having many comorbid conditions, including immune compromise and inflammatory bowel disease, the authors noted.
“FMT is recommended by major gastroenterology and infectious disease society guidelines,” Dr. Vaughn said. “Our group, and others, have consistently found strategies that incorporate FMT as cost-effective strategies for treating rCDI.”
However, lack of access to FMT products often is a barrier to treatment, he said.
“A stool banking model, similar to the nonprofit blood banking model, may be a useful solution to ensure equitable access to FMT to all who need it,” Dr. Vaughn added.
Reached for comment, Majdi Osman, MD, MPH, told this news organization that the study is valuable, “as it nicely shows in a real-world setting that capsules and colonoscopy are good options for patients who need this.”
Dr. Osman is chief medical officer of OpenBiome, a nonprofit organization that operates a public stool bank and is the major FMT source in the United States. The organization has provided over 63,000 FMT treatments to over 1,200 hospitals in the United States.
“FMT has become standard of care for patients who failed antibiotic therapy, and certainly is being used widely as a treatment option for these patients who have often run out of existing options,” Dr. Osman said.
Support for the study was provided by a donation from Achieving Cures Together, a nonprofit organization dedicated to advancing microbiome-based research. Dr. Vaughn receives grant support from Takeda, Roche, Celgene, and Diasorin and has received consulting fees from Prometheus and AbbVie. Dr. Osman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A real-world analysis confirms that fecal microbiota transplantation (FMT) is highly effective for recurrent Clostridioides difficile infection (rCDI) – and there is no difference between delivery by capsule (cap-FMT) and colonoscopy (colo-FMT).
“We present one of the largest cohorts involving people who received capsule FMT. Byron Vaughn, MD, with the division of gastroenterology, hepatology, and nutrition, University of Minnesota, Minneapolis, said in an interview.
The study was published online in Clinical Gastroenterology and Hepatology.
The Food and Drug Administration allows FMT to be used for patients who have failed standard treatment for rCDI under a policy of enforcement discretion.
The past decade has seen an increase in the use of FMT in clinical practice, owing to an increase in cases of rCDI after failure of standard antibiotic therapy.
Unlike antibiotics, which perpetuate and worsen intestinal dysbiosis, FMT restores the diversity and function of host microbiota, effectively breaking the cycle of rCDI, the authors of the study noted. But it’s been unclear whether the efficacy and safety of FMT vary by route of administration.
Effective without procedural risks
To investigate, Dr. Vaughn and colleagues evaluated clinical outcomes and adverse events in 170 patients with rCDI who underwent cap-FMT and 96 peers who underwent colo-FMT.
FMT was performed using one of two standardized formulations of microbiota manufactured by the University of Minnesota microbiota therapeutics program: freeze-dried/encapsulated or frozen-thawed/liquid.
Overall, the cure rates of CDI were 86% at 1 month and 81% at 2 months. There was no statistically significant difference at either time between cap-FMT and colo-FMT.
The 1-month cure rate was 84% with cap-FMT and 91% with colo-FMT; at 2 months, the cure rates were 81% and 83%, respectively.
Cap-FMT has a safety and effectiveness profile similar to that of colo-FMT, without the procedural risks of colonoscopy, the researchers concluded.
They cautioned that, although FMT is highly effective overall, patient selection is a key factor to optimizing FMT success.
Older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression.
“These risk factors can help determine if a patient should receive FMT or an alternative therapy for rCDI. This is not to say FMT should be avoided in older patients or those on dialysis, but clinicians should be aware of these associations in light of other options for rCDI,” Dr. Vaughn said.
Confirming prior studies, antibiotic use after FMT was a major factor in its failure. Patient selection for FMT should include an assessment of the potential need for antibiotics after transplant, the researchers noted.
One serious adverse event (aspiration pneumonia) was related to colonoscopy; otherwise, no new safety signals were identified.
As reported in other studies, changes in bowel function, including diarrhea, constipation, gas, and bloating were common, although it’s tough to disentangle gastrointestinal symptoms related to FMT from those after CDI, the researchers said. Importantly, no transmission of an infectious agent related to FMT was identified.
Two good options
The researchers said their findings are “highly generalizable” because the population reflects all FMT use by participating institutions and contains a mix of academic centers and private practices.
Many patients included in the study would not have been eligible for a clinical trial, owing to their having many comorbid conditions, including immune compromise and inflammatory bowel disease, the authors noted.
“FMT is recommended by major gastroenterology and infectious disease society guidelines,” Dr. Vaughn said. “Our group, and others, have consistently found strategies that incorporate FMT as cost-effective strategies for treating rCDI.”
However, lack of access to FMT products often is a barrier to treatment, he said.
“A stool banking model, similar to the nonprofit blood banking model, may be a useful solution to ensure equitable access to FMT to all who need it,” Dr. Vaughn added.
Reached for comment, Majdi Osman, MD, MPH, told this news organization that the study is valuable, “as it nicely shows in a real-world setting that capsules and colonoscopy are good options for patients who need this.”
Dr. Osman is chief medical officer of OpenBiome, a nonprofit organization that operates a public stool bank and is the major FMT source in the United States. The organization has provided over 63,000 FMT treatments to over 1,200 hospitals in the United States.
“FMT has become standard of care for patients who failed antibiotic therapy, and certainly is being used widely as a treatment option for these patients who have often run out of existing options,” Dr. Osman said.
Support for the study was provided by a donation from Achieving Cures Together, a nonprofit organization dedicated to advancing microbiome-based research. Dr. Vaughn receives grant support from Takeda, Roche, Celgene, and Diasorin and has received consulting fees from Prometheus and AbbVie. Dr. Osman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A real-world analysis confirms that fecal microbiota transplantation (FMT) is highly effective for recurrent Clostridioides difficile infection (rCDI) – and there is no difference between delivery by capsule (cap-FMT) and colonoscopy (colo-FMT).
“We present one of the largest cohorts involving people who received capsule FMT. Byron Vaughn, MD, with the division of gastroenterology, hepatology, and nutrition, University of Minnesota, Minneapolis, said in an interview.
The study was published online in Clinical Gastroenterology and Hepatology.
The Food and Drug Administration allows FMT to be used for patients who have failed standard treatment for rCDI under a policy of enforcement discretion.
The past decade has seen an increase in the use of FMT in clinical practice, owing to an increase in cases of rCDI after failure of standard antibiotic therapy.
Unlike antibiotics, which perpetuate and worsen intestinal dysbiosis, FMT restores the diversity and function of host microbiota, effectively breaking the cycle of rCDI, the authors of the study noted. But it’s been unclear whether the efficacy and safety of FMT vary by route of administration.
Effective without procedural risks
To investigate, Dr. Vaughn and colleagues evaluated clinical outcomes and adverse events in 170 patients with rCDI who underwent cap-FMT and 96 peers who underwent colo-FMT.
FMT was performed using one of two standardized formulations of microbiota manufactured by the University of Minnesota microbiota therapeutics program: freeze-dried/encapsulated or frozen-thawed/liquid.
Overall, the cure rates of CDI were 86% at 1 month and 81% at 2 months. There was no statistically significant difference at either time between cap-FMT and colo-FMT.
The 1-month cure rate was 84% with cap-FMT and 91% with colo-FMT; at 2 months, the cure rates were 81% and 83%, respectively.
Cap-FMT has a safety and effectiveness profile similar to that of colo-FMT, without the procedural risks of colonoscopy, the researchers concluded.
They cautioned that, although FMT is highly effective overall, patient selection is a key factor to optimizing FMT success.
Older age and hemodialysis were associated with FMT failure by 2 months on multivariate logistic regression.
“These risk factors can help determine if a patient should receive FMT or an alternative therapy for rCDI. This is not to say FMT should be avoided in older patients or those on dialysis, but clinicians should be aware of these associations in light of other options for rCDI,” Dr. Vaughn said.
Confirming prior studies, antibiotic use after FMT was a major factor in its failure. Patient selection for FMT should include an assessment of the potential need for antibiotics after transplant, the researchers noted.
One serious adverse event (aspiration pneumonia) was related to colonoscopy; otherwise, no new safety signals were identified.
As reported in other studies, changes in bowel function, including diarrhea, constipation, gas, and bloating were common, although it’s tough to disentangle gastrointestinal symptoms related to FMT from those after CDI, the researchers said. Importantly, no transmission of an infectious agent related to FMT was identified.
Two good options
The researchers said their findings are “highly generalizable” because the population reflects all FMT use by participating institutions and contains a mix of academic centers and private practices.
Many patients included in the study would not have been eligible for a clinical trial, owing to their having many comorbid conditions, including immune compromise and inflammatory bowel disease, the authors noted.
“FMT is recommended by major gastroenterology and infectious disease society guidelines,” Dr. Vaughn said. “Our group, and others, have consistently found strategies that incorporate FMT as cost-effective strategies for treating rCDI.”
However, lack of access to FMT products often is a barrier to treatment, he said.
“A stool banking model, similar to the nonprofit blood banking model, may be a useful solution to ensure equitable access to FMT to all who need it,” Dr. Vaughn added.
Reached for comment, Majdi Osman, MD, MPH, told this news organization that the study is valuable, “as it nicely shows in a real-world setting that capsules and colonoscopy are good options for patients who need this.”
Dr. Osman is chief medical officer of OpenBiome, a nonprofit organization that operates a public stool bank and is the major FMT source in the United States. The organization has provided over 63,000 FMT treatments to over 1,200 hospitals in the United States.
“FMT has become standard of care for patients who failed antibiotic therapy, and certainly is being used widely as a treatment option for these patients who have often run out of existing options,” Dr. Osman said.
Support for the study was provided by a donation from Achieving Cures Together, a nonprofit organization dedicated to advancing microbiome-based research. Dr. Vaughn receives grant support from Takeda, Roche, Celgene, and Diasorin and has received consulting fees from Prometheus and AbbVie. Dr. Osman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major U.S. GI societies issue strategic plan on environmental sustainability
according to a new joint strategic plan published simultaneously in Gastroenterology, Gastrointestinal Endoscopy, American Journal of Gastroenterology, and Hepatology.
The plan outlines numerous strategic goals and objectives across clinical care, education, research, and industry to support sustainable practices. With first author Heiko Pohl, MD, a gastroenterologist and hepatologist at the Veterans Affairs Medical Center in White River Junction, Vermont, and professor of medicine at the Geisel School of Medicine at Dartmouth, Hanover, N.H., the joint statement includes task force members from the American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy.
“It is clear that the evolving climate crisis, with its deleterious effects on planetary ecosystems, also poses harm to the health of humankind,” the authors wrote in Gastroenterology.
“Climate change affects many social and environmental determinants of health, including water and food security, shelter, physical activity, and accessible health care,” they added. These changes influence gastrointestinal practice (for example, increased risk of obesity and fatty liver disease, disruption of the microbiome, compromised gut immune function).
At the same time, health care delivery contributes to climate change and greenhouse gas emissions worldwide, they wrote. As a procedure-intensive specialty, digestive health care adds to the health care carbon footprint through single-use supplies and high levels of waste.
“As is the case for the impact of climate change by and on health care systems, there is a vicious cycle whereby climate change negatively impacts individual digestive health, which accelerates specialized health care activity, which further contributes to the climate crisis,” the authors wrote.
The multisociety task force noted the transition to a more sustainable model will be challenging and require major modification of current habits in practice. However, the long-term effects “will promote health, save cost, and ... correspond with a broader shared vision of planetary health,” they wrote.
The strategic plan covers seven domains: clinical settings, education, research, society efforts, intersociety efforts, industry, and advocacy. Each domain has specific initiatives for 2023 to 2027. Years 1 and 2 are conceived as a period of self-assessment and planning, followed by implementation and assessment during years 3-5.
In the plan, clinical settings would assess the carbon footprint and waste within all areas of practice and identify low-carbon and low-waste alternatives, such as immediate, short-term, and long-term solutions. This involves creating a framework for GI practices to develop sustainability metrics and offer affordable testing and treatment alternatives with a favorable environmental impact.
Through education, the societies would raise awareness and share sustainability practices with health care leadership, practitioners, and patients regarding the interactions among climate change, digestive health, and health care services. This would include discussions about the professional and ethical implications of old and new patterns of shared resource utilization.
The societies also support raising and allocating resources for research related to the intersections of climate change, digestive health, and health care, with an emphasis on vulnerable groups. This would encourage the inclusion of environmental considerations in research proposals.
At the GI society level, the groups suggest assessing and monitoring the current environmental impact of society-related activities. This entails identifying and implementing measures that would decrease the carbon footprint and reduce waste, as well as track financial costs and savings and environmental benefits from efforts included in a sustainability model.
At the intersociety level, the U.S. groups would collaborate with national and international GI and hepatology societies to support sustainability efforts and use validated metrics to evaluate their efforts. The multisociety plan has received endorsements from nearly two-dozen groups, including the Crohn’s & Colitis Foundation, World Endoscopy Organization, and World Gastroenterology Organisation.
The plan calls for engagement with GI- and hepatology-focused industry and pharmaceutical partners to develop environmentally friendly products, publish information on carbon footprint implications, and promote options for recycling.
Through advocacy efforts, the societies would also identify and incorporate principles of sustainable health care among the goals of relevant political action committees, as well as leverage collaborative advocacy efforts with national and international health care and research agencies, political leaders, and payors.
“We are grateful that several other GI organizations have endorsed our plan, which reflects the importance and timeliness of the opportunity to work together and share best practices to overcome the burden of climate change on digestive health and help mitigate the environmental impact of GI practice,” the authors concluded.
The authors did not declare a funding source for the report. Several of the authors declared financial relationships with pharmaceutical companies, serving as a consultant or receiving research funding.
according to a new joint strategic plan published simultaneously in Gastroenterology, Gastrointestinal Endoscopy, American Journal of Gastroenterology, and Hepatology.
The plan outlines numerous strategic goals and objectives across clinical care, education, research, and industry to support sustainable practices. With first author Heiko Pohl, MD, a gastroenterologist and hepatologist at the Veterans Affairs Medical Center in White River Junction, Vermont, and professor of medicine at the Geisel School of Medicine at Dartmouth, Hanover, N.H., the joint statement includes task force members from the American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy.
“It is clear that the evolving climate crisis, with its deleterious effects on planetary ecosystems, also poses harm to the health of humankind,” the authors wrote in Gastroenterology.
“Climate change affects many social and environmental determinants of health, including water and food security, shelter, physical activity, and accessible health care,” they added. These changes influence gastrointestinal practice (for example, increased risk of obesity and fatty liver disease, disruption of the microbiome, compromised gut immune function).
At the same time, health care delivery contributes to climate change and greenhouse gas emissions worldwide, they wrote. As a procedure-intensive specialty, digestive health care adds to the health care carbon footprint through single-use supplies and high levels of waste.
“As is the case for the impact of climate change by and on health care systems, there is a vicious cycle whereby climate change negatively impacts individual digestive health, which accelerates specialized health care activity, which further contributes to the climate crisis,” the authors wrote.
The multisociety task force noted the transition to a more sustainable model will be challenging and require major modification of current habits in practice. However, the long-term effects “will promote health, save cost, and ... correspond with a broader shared vision of planetary health,” they wrote.
The strategic plan covers seven domains: clinical settings, education, research, society efforts, intersociety efforts, industry, and advocacy. Each domain has specific initiatives for 2023 to 2027. Years 1 and 2 are conceived as a period of self-assessment and planning, followed by implementation and assessment during years 3-5.
In the plan, clinical settings would assess the carbon footprint and waste within all areas of practice and identify low-carbon and low-waste alternatives, such as immediate, short-term, and long-term solutions. This involves creating a framework for GI practices to develop sustainability metrics and offer affordable testing and treatment alternatives with a favorable environmental impact.
Through education, the societies would raise awareness and share sustainability practices with health care leadership, practitioners, and patients regarding the interactions among climate change, digestive health, and health care services. This would include discussions about the professional and ethical implications of old and new patterns of shared resource utilization.
The societies also support raising and allocating resources for research related to the intersections of climate change, digestive health, and health care, with an emphasis on vulnerable groups. This would encourage the inclusion of environmental considerations in research proposals.
At the GI society level, the groups suggest assessing and monitoring the current environmental impact of society-related activities. This entails identifying and implementing measures that would decrease the carbon footprint and reduce waste, as well as track financial costs and savings and environmental benefits from efforts included in a sustainability model.
At the intersociety level, the U.S. groups would collaborate with national and international GI and hepatology societies to support sustainability efforts and use validated metrics to evaluate their efforts. The multisociety plan has received endorsements from nearly two-dozen groups, including the Crohn’s & Colitis Foundation, World Endoscopy Organization, and World Gastroenterology Organisation.
The plan calls for engagement with GI- and hepatology-focused industry and pharmaceutical partners to develop environmentally friendly products, publish information on carbon footprint implications, and promote options for recycling.
Through advocacy efforts, the societies would also identify and incorporate principles of sustainable health care among the goals of relevant political action committees, as well as leverage collaborative advocacy efforts with national and international health care and research agencies, political leaders, and payors.
“We are grateful that several other GI organizations have endorsed our plan, which reflects the importance and timeliness of the opportunity to work together and share best practices to overcome the burden of climate change on digestive health and help mitigate the environmental impact of GI practice,” the authors concluded.
The authors did not declare a funding source for the report. Several of the authors declared financial relationships with pharmaceutical companies, serving as a consultant or receiving research funding.
according to a new joint strategic plan published simultaneously in Gastroenterology, Gastrointestinal Endoscopy, American Journal of Gastroenterology, and Hepatology.
The plan outlines numerous strategic goals and objectives across clinical care, education, research, and industry to support sustainable practices. With first author Heiko Pohl, MD, a gastroenterologist and hepatologist at the Veterans Affairs Medical Center in White River Junction, Vermont, and professor of medicine at the Geisel School of Medicine at Dartmouth, Hanover, N.H., the joint statement includes task force members from the American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy.
“It is clear that the evolving climate crisis, with its deleterious effects on planetary ecosystems, also poses harm to the health of humankind,” the authors wrote in Gastroenterology.
“Climate change affects many social and environmental determinants of health, including water and food security, shelter, physical activity, and accessible health care,” they added. These changes influence gastrointestinal practice (for example, increased risk of obesity and fatty liver disease, disruption of the microbiome, compromised gut immune function).
At the same time, health care delivery contributes to climate change and greenhouse gas emissions worldwide, they wrote. As a procedure-intensive specialty, digestive health care adds to the health care carbon footprint through single-use supplies and high levels of waste.
“As is the case for the impact of climate change by and on health care systems, there is a vicious cycle whereby climate change negatively impacts individual digestive health, which accelerates specialized health care activity, which further contributes to the climate crisis,” the authors wrote.
The multisociety task force noted the transition to a more sustainable model will be challenging and require major modification of current habits in practice. However, the long-term effects “will promote health, save cost, and ... correspond with a broader shared vision of planetary health,” they wrote.
The strategic plan covers seven domains: clinical settings, education, research, society efforts, intersociety efforts, industry, and advocacy. Each domain has specific initiatives for 2023 to 2027. Years 1 and 2 are conceived as a period of self-assessment and planning, followed by implementation and assessment during years 3-5.
In the plan, clinical settings would assess the carbon footprint and waste within all areas of practice and identify low-carbon and low-waste alternatives, such as immediate, short-term, and long-term solutions. This involves creating a framework for GI practices to develop sustainability metrics and offer affordable testing and treatment alternatives with a favorable environmental impact.
Through education, the societies would raise awareness and share sustainability practices with health care leadership, practitioners, and patients regarding the interactions among climate change, digestive health, and health care services. This would include discussions about the professional and ethical implications of old and new patterns of shared resource utilization.
The societies also support raising and allocating resources for research related to the intersections of climate change, digestive health, and health care, with an emphasis on vulnerable groups. This would encourage the inclusion of environmental considerations in research proposals.
At the GI society level, the groups suggest assessing and monitoring the current environmental impact of society-related activities. This entails identifying and implementing measures that would decrease the carbon footprint and reduce waste, as well as track financial costs and savings and environmental benefits from efforts included in a sustainability model.
At the intersociety level, the U.S. groups would collaborate with national and international GI and hepatology societies to support sustainability efforts and use validated metrics to evaluate their efforts. The multisociety plan has received endorsements from nearly two-dozen groups, including the Crohn’s & Colitis Foundation, World Endoscopy Organization, and World Gastroenterology Organisation.
The plan calls for engagement with GI- and hepatology-focused industry and pharmaceutical partners to develop environmentally friendly products, publish information on carbon footprint implications, and promote options for recycling.
Through advocacy efforts, the societies would also identify and incorporate principles of sustainable health care among the goals of relevant political action committees, as well as leverage collaborative advocacy efforts with national and international health care and research agencies, political leaders, and payors.
“We are grateful that several other GI organizations have endorsed our plan, which reflects the importance and timeliness of the opportunity to work together and share best practices to overcome the burden of climate change on digestive health and help mitigate the environmental impact of GI practice,” the authors concluded.
The authors did not declare a funding source for the report. Several of the authors declared financial relationships with pharmaceutical companies, serving as a consultant or receiving research funding.
FROM GASTROENTEROLOGY
Latiglutenase reduces symptoms in celiac patients exposed to gluten
according to a new study published in Gastroenterology.
Latiglutenase led to 95% gluten degradation in the stomach, as indicated by measurements of gluten-immunogenic peptides in urine, wrote Joseph A. Murray, MD, a gastroenterologist at the Mayo Clinic, Rochester, Minn., and Jack A. Syage, PhD, CEO and cofounder of ImmunogenX Inc., Newport Beach, Calif., and colleagues on behalf of the CeliacShield Study Group.
For patients with celiac disease, the only available treatment is a life-long gluten-free diet (GFD). Low levels of gluten exposure can lead to ongoing inflammation and the risk of complications, and about half of patients continue to experience moderate to severe symptoms.
“Although a GFD can reduce symptoms and intestinal damage, the diet is neither easy nor readily achievable by many patients and, furthermore, can be lacking in essential nutrients,” the authors wrote.
In a randomized, double-blind, placebo-controlled gluten challenge study, the research team assessed the efficacy and safety of a 1,200-mg dose of IMGX003, formerly known as ALV003. The dual-enzyme supplementation therapy was “designed to mitigate the impact of gluten exposure in patients who are attempting to adhere to a GFD.”
The phase 2 trial was conducted at the Mayo Clinic with adult patients (aged 18-80 years) who had physician-diagnosed and biopsy-confirmed celiac disease, followed a GFD for more than 1 year, and had histologically well-controlled disease. During the study, they were exposed to 2 g of gluten per day for 6 weeks.
The primary endpoint focused on the change in the ratio of villus height to crypt depth. The “secondary endpoints included density of intraepithelial lymphocytes and symptom severity. Additional endpoints included serology and gluten-immunogenic peptides in urine.”
Among the 50 patients randomized, 43 completed the study, with 21 assigned to the IMGX003 group. About 74% of the participants were women; the mean age of all participants was 43.8 years.
Overall, the mean change in the ratio of villus height to crypt depth was –0.04 for IMGX003, compared with –0.35 for placebo. In addition, the mean change in the density of intraepithelial lymphocytes for IMGX003 was 9.8, compared with 24.8 for placebo. Based on the ratio of the means for both groups, the researchers estimated an 88% reduction of change in villus height to crypt depth and a 60% reduction of change in intraepithelial lymphocytes.
The mean changes, or worsening from baseline, in symptom severity for IMGX003 vs. placebo were 0.22 vs. 1.63 for abdominal pain, 0.96 vs. 3.29 for bloating, 0.02 vs. 3.2 for tiredness, and 0.64 vs. 2.27 for nonstool composite. The calculated symptom reduction values were 93% for abdominal pain, 53% for bloating, 99% for tiredness, and 70% for nonstool composite.
The mean change from baseline for symptom severity was evaluated over three 2-week periods, and the percent changes showed consistent reduction of symptom worsening during that time. Based on the effect size and trend significance, the P values were .014 for abdominal pain, .030 for bloating, .002 for tiredness, and < . 001 for nonstool composite.
The mean change in gluten-immunogenic peptides in urine (GIP) relative to baseline was 0.59 for IMGX003, compared with 11.53 for placebo. The researchers estimated an efficacy of gluten degradation in vivo of 95%.
“Measurement of GIP in urine demonstrated the purported mechanism of action of IMGX003, namely, degradation of gluten in the stomach, thereby preventing the triggering of the immunogenic autoimmune response,” the authors wrote. “Targeting gluten by degrading the immunogenic peptides before absorption minimizes or abrogates the cascading innate and adaptive immune responses that characterize the inflammatory response to gluten in CeD [celiac disease].”
The study was sponsored by ImmunogenX Inc., and partially funded by a grant from the National Center for Complementary and Integrative Health. The project was further supported by grants from the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. Several authors reported receiving grants from numerous funders, including ImmunogenX, and some reported being a cofounder, stockholder, or board director of the company.
From the perspective of patients affected by other chronic GI diseases requiring constant treatment with drugs, the life of celiac patients must appear “a piece of cake” (pun intended). But this is not the case. In fact, the burden of following a gluten-free diet (GFD) can profoundly impact their quality of life. Furthermore, a substantial portion of patients trying their best on a GFD do not experience full clinical and histologic remission, mainly because of ongoing involuntary gluten ingestion. Therefore, it’s not surprising that several lines of research have been actively trying to address this unmet need.
In this phase 2 trial, the proprietary enzyme combination called IMGX003 (latiglutenase) was investigated for safety and efficacy. IMGX003 can digest gluten in the stomach, thus preventing its intact entry into the small intestine where it would trigger the immune reaction leading to the villi destruction. The study did indeed demonstrate that administering it to patients on GFD exposed to 2 grams of gluten daily (roughly the equivalent of half a slice of wheat bread) effectively reduced both the mucosal damage and symptom severity. Is this good news for patients with celiac? You bet it is! While not replacing the need for a GFD, having a safe drug that adds a substantial layer of protection to inadvertent gluten exposure or the so-called “cross-contamination” is surely to be welcome by them.
If and once approved for use, IMGX003 could be taken sporadically by patients on GFD: For instance, while eating out in “new” places, traveling, going to parties, or for younger patients, when having sleepovers, birthday celebrations, and so on. With the caveat, not to be forgotten, that this is not meant to be a wonder drug eliminating the need for vigilance; we still need to wait patiently for science to advance further for that.
Stefano Guandalini, MD, AGAF, is professor emeritus of pediatrics at the University of Chicago and director emeritus of the University of Chicago Celiac Disease Center. He declares no relevant conflicts of interest.
From the perspective of patients affected by other chronic GI diseases requiring constant treatment with drugs, the life of celiac patients must appear “a piece of cake” (pun intended). But this is not the case. In fact, the burden of following a gluten-free diet (GFD) can profoundly impact their quality of life. Furthermore, a substantial portion of patients trying their best on a GFD do not experience full clinical and histologic remission, mainly because of ongoing involuntary gluten ingestion. Therefore, it’s not surprising that several lines of research have been actively trying to address this unmet need.
In this phase 2 trial, the proprietary enzyme combination called IMGX003 (latiglutenase) was investigated for safety and efficacy. IMGX003 can digest gluten in the stomach, thus preventing its intact entry into the small intestine where it would trigger the immune reaction leading to the villi destruction. The study did indeed demonstrate that administering it to patients on GFD exposed to 2 grams of gluten daily (roughly the equivalent of half a slice of wheat bread) effectively reduced both the mucosal damage and symptom severity. Is this good news for patients with celiac? You bet it is! While not replacing the need for a GFD, having a safe drug that adds a substantial layer of protection to inadvertent gluten exposure or the so-called “cross-contamination” is surely to be welcome by them.
If and once approved for use, IMGX003 could be taken sporadically by patients on GFD: For instance, while eating out in “new” places, traveling, going to parties, or for younger patients, when having sleepovers, birthday celebrations, and so on. With the caveat, not to be forgotten, that this is not meant to be a wonder drug eliminating the need for vigilance; we still need to wait patiently for science to advance further for that.
Stefano Guandalini, MD, AGAF, is professor emeritus of pediatrics at the University of Chicago and director emeritus of the University of Chicago Celiac Disease Center. He declares no relevant conflicts of interest.
From the perspective of patients affected by other chronic GI diseases requiring constant treatment with drugs, the life of celiac patients must appear “a piece of cake” (pun intended). But this is not the case. In fact, the burden of following a gluten-free diet (GFD) can profoundly impact their quality of life. Furthermore, a substantial portion of patients trying their best on a GFD do not experience full clinical and histologic remission, mainly because of ongoing involuntary gluten ingestion. Therefore, it’s not surprising that several lines of research have been actively trying to address this unmet need.
In this phase 2 trial, the proprietary enzyme combination called IMGX003 (latiglutenase) was investigated for safety and efficacy. IMGX003 can digest gluten in the stomach, thus preventing its intact entry into the small intestine where it would trigger the immune reaction leading to the villi destruction. The study did indeed demonstrate that administering it to patients on GFD exposed to 2 grams of gluten daily (roughly the equivalent of half a slice of wheat bread) effectively reduced both the mucosal damage and symptom severity. Is this good news for patients with celiac? You bet it is! While not replacing the need for a GFD, having a safe drug that adds a substantial layer of protection to inadvertent gluten exposure or the so-called “cross-contamination” is surely to be welcome by them.
If and once approved for use, IMGX003 could be taken sporadically by patients on GFD: For instance, while eating out in “new” places, traveling, going to parties, or for younger patients, when having sleepovers, birthday celebrations, and so on. With the caveat, not to be forgotten, that this is not meant to be a wonder drug eliminating the need for vigilance; we still need to wait patiently for science to advance further for that.
Stefano Guandalini, MD, AGAF, is professor emeritus of pediatrics at the University of Chicago and director emeritus of the University of Chicago Celiac Disease Center. He declares no relevant conflicts of interest.
according to a new study published in Gastroenterology.
Latiglutenase led to 95% gluten degradation in the stomach, as indicated by measurements of gluten-immunogenic peptides in urine, wrote Joseph A. Murray, MD, a gastroenterologist at the Mayo Clinic, Rochester, Minn., and Jack A. Syage, PhD, CEO and cofounder of ImmunogenX Inc., Newport Beach, Calif., and colleagues on behalf of the CeliacShield Study Group.
For patients with celiac disease, the only available treatment is a life-long gluten-free diet (GFD). Low levels of gluten exposure can lead to ongoing inflammation and the risk of complications, and about half of patients continue to experience moderate to severe symptoms.
“Although a GFD can reduce symptoms and intestinal damage, the diet is neither easy nor readily achievable by many patients and, furthermore, can be lacking in essential nutrients,” the authors wrote.
In a randomized, double-blind, placebo-controlled gluten challenge study, the research team assessed the efficacy and safety of a 1,200-mg dose of IMGX003, formerly known as ALV003. The dual-enzyme supplementation therapy was “designed to mitigate the impact of gluten exposure in patients who are attempting to adhere to a GFD.”
The phase 2 trial was conducted at the Mayo Clinic with adult patients (aged 18-80 years) who had physician-diagnosed and biopsy-confirmed celiac disease, followed a GFD for more than 1 year, and had histologically well-controlled disease. During the study, they were exposed to 2 g of gluten per day for 6 weeks.
The primary endpoint focused on the change in the ratio of villus height to crypt depth. The “secondary endpoints included density of intraepithelial lymphocytes and symptom severity. Additional endpoints included serology and gluten-immunogenic peptides in urine.”
Among the 50 patients randomized, 43 completed the study, with 21 assigned to the IMGX003 group. About 74% of the participants were women; the mean age of all participants was 43.8 years.
Overall, the mean change in the ratio of villus height to crypt depth was –0.04 for IMGX003, compared with –0.35 for placebo. In addition, the mean change in the density of intraepithelial lymphocytes for IMGX003 was 9.8, compared with 24.8 for placebo. Based on the ratio of the means for both groups, the researchers estimated an 88% reduction of change in villus height to crypt depth and a 60% reduction of change in intraepithelial lymphocytes.
The mean changes, or worsening from baseline, in symptom severity for IMGX003 vs. placebo were 0.22 vs. 1.63 for abdominal pain, 0.96 vs. 3.29 for bloating, 0.02 vs. 3.2 for tiredness, and 0.64 vs. 2.27 for nonstool composite. The calculated symptom reduction values were 93% for abdominal pain, 53% for bloating, 99% for tiredness, and 70% for nonstool composite.
The mean change from baseline for symptom severity was evaluated over three 2-week periods, and the percent changes showed consistent reduction of symptom worsening during that time. Based on the effect size and trend significance, the P values were .014 for abdominal pain, .030 for bloating, .002 for tiredness, and < . 001 for nonstool composite.
The mean change in gluten-immunogenic peptides in urine (GIP) relative to baseline was 0.59 for IMGX003, compared with 11.53 for placebo. The researchers estimated an efficacy of gluten degradation in vivo of 95%.
“Measurement of GIP in urine demonstrated the purported mechanism of action of IMGX003, namely, degradation of gluten in the stomach, thereby preventing the triggering of the immunogenic autoimmune response,” the authors wrote. “Targeting gluten by degrading the immunogenic peptides before absorption minimizes or abrogates the cascading innate and adaptive immune responses that characterize the inflammatory response to gluten in CeD [celiac disease].”
The study was sponsored by ImmunogenX Inc., and partially funded by a grant from the National Center for Complementary and Integrative Health. The project was further supported by grants from the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. Several authors reported receiving grants from numerous funders, including ImmunogenX, and some reported being a cofounder, stockholder, or board director of the company.
according to a new study published in Gastroenterology.
Latiglutenase led to 95% gluten degradation in the stomach, as indicated by measurements of gluten-immunogenic peptides in urine, wrote Joseph A. Murray, MD, a gastroenterologist at the Mayo Clinic, Rochester, Minn., and Jack A. Syage, PhD, CEO and cofounder of ImmunogenX Inc., Newport Beach, Calif., and colleagues on behalf of the CeliacShield Study Group.
For patients with celiac disease, the only available treatment is a life-long gluten-free diet (GFD). Low levels of gluten exposure can lead to ongoing inflammation and the risk of complications, and about half of patients continue to experience moderate to severe symptoms.
“Although a GFD can reduce symptoms and intestinal damage, the diet is neither easy nor readily achievable by many patients and, furthermore, can be lacking in essential nutrients,” the authors wrote.
In a randomized, double-blind, placebo-controlled gluten challenge study, the research team assessed the efficacy and safety of a 1,200-mg dose of IMGX003, formerly known as ALV003. The dual-enzyme supplementation therapy was “designed to mitigate the impact of gluten exposure in patients who are attempting to adhere to a GFD.”
The phase 2 trial was conducted at the Mayo Clinic with adult patients (aged 18-80 years) who had physician-diagnosed and biopsy-confirmed celiac disease, followed a GFD for more than 1 year, and had histologically well-controlled disease. During the study, they were exposed to 2 g of gluten per day for 6 weeks.
The primary endpoint focused on the change in the ratio of villus height to crypt depth. The “secondary endpoints included density of intraepithelial lymphocytes and symptom severity. Additional endpoints included serology and gluten-immunogenic peptides in urine.”
Among the 50 patients randomized, 43 completed the study, with 21 assigned to the IMGX003 group. About 74% of the participants were women; the mean age of all participants was 43.8 years.
Overall, the mean change in the ratio of villus height to crypt depth was –0.04 for IMGX003, compared with –0.35 for placebo. In addition, the mean change in the density of intraepithelial lymphocytes for IMGX003 was 9.8, compared with 24.8 for placebo. Based on the ratio of the means for both groups, the researchers estimated an 88% reduction of change in villus height to crypt depth and a 60% reduction of change in intraepithelial lymphocytes.
The mean changes, or worsening from baseline, in symptom severity for IMGX003 vs. placebo were 0.22 vs. 1.63 for abdominal pain, 0.96 vs. 3.29 for bloating, 0.02 vs. 3.2 for tiredness, and 0.64 vs. 2.27 for nonstool composite. The calculated symptom reduction values were 93% for abdominal pain, 53% for bloating, 99% for tiredness, and 70% for nonstool composite.
The mean change from baseline for symptom severity was evaluated over three 2-week periods, and the percent changes showed consistent reduction of symptom worsening during that time. Based on the effect size and trend significance, the P values were .014 for abdominal pain, .030 for bloating, .002 for tiredness, and < . 001 for nonstool composite.
The mean change in gluten-immunogenic peptides in urine (GIP) relative to baseline was 0.59 for IMGX003, compared with 11.53 for placebo. The researchers estimated an efficacy of gluten degradation in vivo of 95%.
“Measurement of GIP in urine demonstrated the purported mechanism of action of IMGX003, namely, degradation of gluten in the stomach, thereby preventing the triggering of the immunogenic autoimmune response,” the authors wrote. “Targeting gluten by degrading the immunogenic peptides before absorption minimizes or abrogates the cascading innate and adaptive immune responses that characterize the inflammatory response to gluten in CeD [celiac disease].”
The study was sponsored by ImmunogenX Inc., and partially funded by a grant from the National Center for Complementary and Integrative Health. The project was further supported by grants from the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. Several authors reported receiving grants from numerous funders, including ImmunogenX, and some reported being a cofounder, stockholder, or board director of the company.
FROM GASTROENTEROLOGY
New update focuses on acute kidney injury management in cirrhosis
Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.
AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.
Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.
To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.
The update was published online in Clinical Gastroenterology and Hepatology.
Some key takeaways
Among its 14 best practice statements, it describes three situations indicative of AKI:
- A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
- A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
- Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.
The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.
Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.
Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.
She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.
In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
‘Timely’ update
Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”
This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.
Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.
He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.
Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.
Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.
“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.
“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”
Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 12/12/2022.
Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.
AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.
Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.
To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.
The update was published online in Clinical Gastroenterology and Hepatology.
Some key takeaways
Among its 14 best practice statements, it describes three situations indicative of AKI:
- A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
- A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
- Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.
The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.
Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.
Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.
She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.
In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
‘Timely’ update
Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”
This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.
Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.
He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.
Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.
Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.
“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.
“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”
Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 12/12/2022.
Acute kidney injury (AKI) in patients with cirrhosis is potentially preventable, and there are clear steps that can be taken to manage and reverse the condition, concludes a clinical practice update from the American Gastroenterological Association.
AKI occurs in 47% of patients hospitalized with complications of cirrhosis and in approximately 30% of outpatients with cirrhosis, resulting in a total cost in the United States of $4 billion, explained Patrick S. Kamath, MD, division of gastroenterology and hepatology, Mayo Medical School, Rochester, Minn., one of the authors of this update.
Moreover, Dr. Kamath told this news organization, among patients with cirrhosis and AKI, morbidity and mortality is sevenfold higher in comparison to those without cirrhosis, and repeated episodes of AKI increase the risk of progression to chronic kidney disease.
To provide practical advice for the clinical management of patients with cirrhosis and AKI, the authors conducted an expert review of the best available published evidence and gathered expert opinion.
The update was published online in Clinical Gastroenterology and Hepatology.
Some key takeaways
Among its 14 best practice statements, it describes three situations indicative of AKI:
- A serum creatinine increase of 0.3 mg/dL or more within 48 hours, or
- A serum creatinine increase of 50% or more from baseline, which is a stable serum creatinine in the past 3 months.
- Reduction in urine output of up to 0.5 mL/kg per hour for more than 6 hours.
The update also emphasizes the importance of an accurate diagnosis, inasmuch as not all cases of AKI are due to hepatorenal syndrome (HRS), for example. It goes on to advise that the specific type of AKI be identified through medical history and physical examination, as well as with blood biochemistry, urine microscopic examination, urine chemistry, selected urinary biomarkers, and renal ultrasound.
Additionally, it underscores the need to identify and treat infections and to closely monitor fluid status.
Nancy S. Reau, MD, Rush Medical College, Chicago, who was not involved in the update, commented to this news organization that fluid status is important when giving albumin replacement therapy because of the increased risk for pulmonary edema.
She also highlighted that this update advises against transjugular intrahepatic portosystemic shunts (TIPSs) as a specific treatment for HRS-AKI, noting that, although the 2022 North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension do not advocate for TIPS for this indication, they also indicated that there was enough evidence to advise against it.
In other key best practice advice statements, the update advises clinicians to hold diuretics and nonselective beta blockers and to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs).
‘Timely’ update
Overall, Dr. Reau believes that the update is “timely, especially in light of the recent [U.S.] approval of terlipressin, which will change our treatment options.”
This update also supports the American Association for the Study of Liver Diseases (AASLD) 2021 Practice Guidance guidelines on HRS, she added.
Zobair Younossi, MD, MPH, professor of medicine, Virginia Commonwealth University, Inova Campus, Falls Church, Va., who was not involved in writing the update, told this news organization that the document is important because of the huge increase in mortality among patients with cirrhosis and AKI.
He commented that there has been much advancement in understanding the condition, with updated nomenclature and novel medical treatments, and that this makes the update timely.
Moreover, the update will help clinicians who are involved in the care of patients with cirrhosis, he added.
Dr. Younossi said the update offers a very clearly stated algorithm for how to identify patients whose condition is easily reversible with volume repletion, in comparison with those patients who require medical treatment or even liver transplantation.
“Those things are important because that pathway gives clinicians an idea of how to do this properly,” he said.
“The key for clinicians is to make sure they understand, in the context of cirrhosis, some of the easy things that they can do to prevent AKI,” he continued. He added that the use of NSAIDs in these patients is “going to be problematic.”
Dr. Kamath has a relationship with Sequana Medical. Other authors’ relevant financial relationships are listed in the original article. Dr. Reau has relationships with Salix and Intercept. Dr. Younossi has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
This article was updated 12/12/2022.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY