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AGA Clinical Practice Update: P-CABs Can Help When PPI Therapy Fails
, according to a recent clinical practice update from the American Gastroenterological Association (AGA).
However, P-CABs are recommended in place of proton pump inhibitors (PPIs) for most patients with Helicobacter pylori and other conditions where patients haven’t responded to PPIs.
“P-CABs are a newer medication class now available in the US, associated with more rapid, potent, and prolonged gastric acid inhibition than PPI formulations,” said lead author Amit Patel, MD, a gastroenterologist at the Duke University School of Medicine and Durham Veterans Affairs Medical Center, Durham, North Carolina.
“P-CABs have potentially significant clinical benefits in the management of Helicobacter pylori infection and GERD, particularly more severe erosive esophagitis,” he said. “Emerging data are affording additional insights into the clinical benefits of P-CABs in settings such as on-demand therapy for reflux-associated symptoms, bleeding gastroduodenal ulcers, and endoscopic eradication therapy for Barrett’s esophagus.”
The update was published in Gastroenterology .
P-CAB Developments
For most patients, PPIs and histamine-2 receptor antagonists remain the primary way to inhibit gastric acid secretion for common upper gastrointestinal conditions, the authors wrote. However, P-CABs such as vonoprazan and tegoprazan may provide relief when PPIs have limitations.
Unlike PPIs, P-CABs are considered acid-stable, don’t require premeal dosing, aren’t prodrugs, and don’t require conversion to an active form to provide pharmacologic effects. They tend to have longer half-lives and more rapid onset. Serum gastrin levels typically remain higher with P-CABs.
In terms of safety, randomized trial data indicate that P-CABs are generally well tolerated and have short-term and medium-term safety similar to PPIs. Due to potent acid suppression, enteric infection risks remain higher, though long-term safety data is needed, the authors wrote.
Overall, P-CABs appear to be equally as potent or more potent than PPIs, though more potent acid inhibition isn’t necessarily associated with better outcomes, the authors wrote. For most foregut acid-related disorders — such as heartburn and prevention of nonsteroidal anti-inflammatory drug–associated ulcers — P-CABs can help when patients fail PPI therapy.
In general, though, nonclinical factors related to cost, barriers to obtaining medication, and limited long-term safety data may outweigh the advantages of P-CABs, especially if clinical superiority isn’t yet known, the authors wrote.
For GERD, clinicians generally shouldn’t use P-CABs as first-line therapy for patients with uninvestigated heartburn symptoms or nonerosive reflux disease. However, P-CABs should be used for those with documented acid-related reflux who fail therapy with twice-daily PPIs. They may also be appropriate for on-demand heartburn therapy, although more evidence is needed.
For erosive esophagitis, P-CABs generally shouldn’t be used for milder cases but can be considered for patients with more severe cases that haven’t responded to PPIs, including refractory esophagitis.
For H pylori, P-CABs should be used in place of PPIs for eradication regimens, including among patients with clarithromycin-resistant strains. In contrast with most of the other indications in the update, the short-term duration of H pylori treatment reduced the authors’ concerns about P-CAB costs and safety.
For peptic ulcer disease, P-CABs generally shouldn’t be used as first-line treatment or prophylaxis. However, the rapid onset and potent acid inhibition could be useful for patients with bleeding gastroduodenal ulcers and high-risk stigmata.
“Emerging data will allow refinements in the populations and clinical settings for which P-CABs at various doses may be considered and advised — and may reveal more clinical scenarios in which they can provide meaningful benefit,” Patel said. “Further investigations, including additional populations and novel indicators, as well as evaluating long-term safety data and cost-effectiveness, are warranted, as P-CABs are incorporated more broadly into clinical practice worldwide.”
The authors received no specific funding for this update. Patel reported no relevant disclosures.
A version of this article appeared on Medscape.com.
, according to a recent clinical practice update from the American Gastroenterological Association (AGA).
However, P-CABs are recommended in place of proton pump inhibitors (PPIs) for most patients with Helicobacter pylori and other conditions where patients haven’t responded to PPIs.
“P-CABs are a newer medication class now available in the US, associated with more rapid, potent, and prolonged gastric acid inhibition than PPI formulations,” said lead author Amit Patel, MD, a gastroenterologist at the Duke University School of Medicine and Durham Veterans Affairs Medical Center, Durham, North Carolina.
“P-CABs have potentially significant clinical benefits in the management of Helicobacter pylori infection and GERD, particularly more severe erosive esophagitis,” he said. “Emerging data are affording additional insights into the clinical benefits of P-CABs in settings such as on-demand therapy for reflux-associated symptoms, bleeding gastroduodenal ulcers, and endoscopic eradication therapy for Barrett’s esophagus.”
The update was published in Gastroenterology .
P-CAB Developments
For most patients, PPIs and histamine-2 receptor antagonists remain the primary way to inhibit gastric acid secretion for common upper gastrointestinal conditions, the authors wrote. However, P-CABs such as vonoprazan and tegoprazan may provide relief when PPIs have limitations.
Unlike PPIs, P-CABs are considered acid-stable, don’t require premeal dosing, aren’t prodrugs, and don’t require conversion to an active form to provide pharmacologic effects. They tend to have longer half-lives and more rapid onset. Serum gastrin levels typically remain higher with P-CABs.
In terms of safety, randomized trial data indicate that P-CABs are generally well tolerated and have short-term and medium-term safety similar to PPIs. Due to potent acid suppression, enteric infection risks remain higher, though long-term safety data is needed, the authors wrote.
Overall, P-CABs appear to be equally as potent or more potent than PPIs, though more potent acid inhibition isn’t necessarily associated with better outcomes, the authors wrote. For most foregut acid-related disorders — such as heartburn and prevention of nonsteroidal anti-inflammatory drug–associated ulcers — P-CABs can help when patients fail PPI therapy.
In general, though, nonclinical factors related to cost, barriers to obtaining medication, and limited long-term safety data may outweigh the advantages of P-CABs, especially if clinical superiority isn’t yet known, the authors wrote.
For GERD, clinicians generally shouldn’t use P-CABs as first-line therapy for patients with uninvestigated heartburn symptoms or nonerosive reflux disease. However, P-CABs should be used for those with documented acid-related reflux who fail therapy with twice-daily PPIs. They may also be appropriate for on-demand heartburn therapy, although more evidence is needed.
For erosive esophagitis, P-CABs generally shouldn’t be used for milder cases but can be considered for patients with more severe cases that haven’t responded to PPIs, including refractory esophagitis.
For H pylori, P-CABs should be used in place of PPIs for eradication regimens, including among patients with clarithromycin-resistant strains. In contrast with most of the other indications in the update, the short-term duration of H pylori treatment reduced the authors’ concerns about P-CAB costs and safety.
For peptic ulcer disease, P-CABs generally shouldn’t be used as first-line treatment or prophylaxis. However, the rapid onset and potent acid inhibition could be useful for patients with bleeding gastroduodenal ulcers and high-risk stigmata.
“Emerging data will allow refinements in the populations and clinical settings for which P-CABs at various doses may be considered and advised — and may reveal more clinical scenarios in which they can provide meaningful benefit,” Patel said. “Further investigations, including additional populations and novel indicators, as well as evaluating long-term safety data and cost-effectiveness, are warranted, as P-CABs are incorporated more broadly into clinical practice worldwide.”
The authors received no specific funding for this update. Patel reported no relevant disclosures.
A version of this article appeared on Medscape.com.
, according to a recent clinical practice update from the American Gastroenterological Association (AGA).
However, P-CABs are recommended in place of proton pump inhibitors (PPIs) for most patients with Helicobacter pylori and other conditions where patients haven’t responded to PPIs.
“P-CABs are a newer medication class now available in the US, associated with more rapid, potent, and prolonged gastric acid inhibition than PPI formulations,” said lead author Amit Patel, MD, a gastroenterologist at the Duke University School of Medicine and Durham Veterans Affairs Medical Center, Durham, North Carolina.
“P-CABs have potentially significant clinical benefits in the management of Helicobacter pylori infection and GERD, particularly more severe erosive esophagitis,” he said. “Emerging data are affording additional insights into the clinical benefits of P-CABs in settings such as on-demand therapy for reflux-associated symptoms, bleeding gastroduodenal ulcers, and endoscopic eradication therapy for Barrett’s esophagus.”
The update was published in Gastroenterology .
P-CAB Developments
For most patients, PPIs and histamine-2 receptor antagonists remain the primary way to inhibit gastric acid secretion for common upper gastrointestinal conditions, the authors wrote. However, P-CABs such as vonoprazan and tegoprazan may provide relief when PPIs have limitations.
Unlike PPIs, P-CABs are considered acid-stable, don’t require premeal dosing, aren’t prodrugs, and don’t require conversion to an active form to provide pharmacologic effects. They tend to have longer half-lives and more rapid onset. Serum gastrin levels typically remain higher with P-CABs.
In terms of safety, randomized trial data indicate that P-CABs are generally well tolerated and have short-term and medium-term safety similar to PPIs. Due to potent acid suppression, enteric infection risks remain higher, though long-term safety data is needed, the authors wrote.
Overall, P-CABs appear to be equally as potent or more potent than PPIs, though more potent acid inhibition isn’t necessarily associated with better outcomes, the authors wrote. For most foregut acid-related disorders — such as heartburn and prevention of nonsteroidal anti-inflammatory drug–associated ulcers — P-CABs can help when patients fail PPI therapy.
In general, though, nonclinical factors related to cost, barriers to obtaining medication, and limited long-term safety data may outweigh the advantages of P-CABs, especially if clinical superiority isn’t yet known, the authors wrote.
For GERD, clinicians generally shouldn’t use P-CABs as first-line therapy for patients with uninvestigated heartburn symptoms or nonerosive reflux disease. However, P-CABs should be used for those with documented acid-related reflux who fail therapy with twice-daily PPIs. They may also be appropriate for on-demand heartburn therapy, although more evidence is needed.
For erosive esophagitis, P-CABs generally shouldn’t be used for milder cases but can be considered for patients with more severe cases that haven’t responded to PPIs, including refractory esophagitis.
For H pylori, P-CABs should be used in place of PPIs for eradication regimens, including among patients with clarithromycin-resistant strains. In contrast with most of the other indications in the update, the short-term duration of H pylori treatment reduced the authors’ concerns about P-CAB costs and safety.
For peptic ulcer disease, P-CABs generally shouldn’t be used as first-line treatment or prophylaxis. However, the rapid onset and potent acid inhibition could be useful for patients with bleeding gastroduodenal ulcers and high-risk stigmata.
“Emerging data will allow refinements in the populations and clinical settings for which P-CABs at various doses may be considered and advised — and may reveal more clinical scenarios in which they can provide meaningful benefit,” Patel said. “Further investigations, including additional populations and novel indicators, as well as evaluating long-term safety data and cost-effectiveness, are warranted, as P-CABs are incorporated more broadly into clinical practice worldwide.”
The authors received no specific funding for this update. Patel reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM GASTROENTEROLOGY
Liver Stiffness Measurement Predicts Long-Term Outcomes In Pediatric Biliary Atresia
according to investigators.
These findings suggest that LSM may serve as a noninvasive tool for risk stratification and treatment planning in this population, reported lead author Jean P. Molleston, MD, of Indiana University School of Medicine, Indianapolis, and colleagues.
“Biliary atresia is frequently complicated by hepatic fibrosis with progression to cirrhosis and portal hypertension manifested by ascites, hepatopulmonary syndrome, and variceal bleeding,” the investigators wrote in Gastroenterology. “The ability to predict these outcomes can inform clinical decision-making.”
To this end, VCTE has been gaining increasing support in the pediatric setting.
“Advantages of VCTE over liver biopsy include convenience, cost, sampling bias, and risk,” the investigators wrote. “VCTE potentially allows (1) fibrosis estimation, (2) prediction of portal hypertension complications/survival, and (3) ability to noninvasively monitor liver stiffness as a fibrosis surrogate.”
The present multicenter study aimed to gauge the prognostic utility of VCTE among 254 patients, aged 21 years or younger, with biliary atresia. All patients had a valid baseline LSM, plus longitudinal clinical and laboratory data drawn from studies by the Childhood Liver Disease Research Network (ChiLDReN). Liver stiffness was assessed noninvasively with FibroScan devices, adhering to protocols that required at least 10 valid measurements and a variability of less than 30%.
The primary outcomes were survival with native liver (SNL), defined as the time to liver transplantation or death, and a composite measure of liver-related events, including the first occurrence of transplantation, death, ascites, variceal bleeding, or hepatopulmonary syndrome. Secondary outcomes focused on the trajectory of platelet decline, a marker of disease progression. The study also explored the relationship between baseline LSM and conventional biomarkers, including platelet count, albumin, and bilirubin.
LSM was a strong predictor of long-term outcomes. Specifically, Kaplan-Meier analysis showed significant differences in 5-year SNL across LSM strata (P < .001). Children with LSM values less than 10 kPa had excellent 5-year SNL rates (LSM 10 to < 15 kPa, 88.9%; 95% CI, 75.1-95.3%), while those with LSM of at least 15 kPa exhibited substantially lower 5-year SNL (58.9%; 95% CI, 46.0-69.7%).
Similarly, event-free survival (EFS) rates declined as LSM values increased (P < .001). Participants with LSM less than 10 kPa had a 5-year EFS rate of 92.2% versus with 61.2% for those with LSM of at least 15 kPa.
LSM also predicted platelet decline. For every twofold increase in baseline LSM, platelet counts declined by an additional 4,000/mm3 per year (P < .001). This association was illustrated through predicted trajectories for participants with LSM values of 4, 7, 12, 18, and 42 kPa, corresponding to different percentiles of disease severity.
Cox proportional hazards analysis indicated that a two-fold increase in LSM was associated with a hazard ratio of 3.3 (P < .001) for liver transplant or death. While LSM had good discrimination on its own (C statistic = 0.83), it did not significantly improve predictive accuracy when added to models based on platelet count, albumin, and bilirubin.
“This noninvasive measurement could potentially be used to predict natural history, stratify patients for clinical trials, plan interventions, and provide anticipatory guidance,” Molleston and colleagues concluded. This study was supported by grants from the National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; Childhood Liver Disease Research Network; and others. The investigators disclosed no conflicts of interest.
Grading liver stiffness using elastography is a widely utilized tool in adult populations, and its application is expanding in pediatric hepatology clinics. Clinicians incorporate liver stiffness measurements (LSM) alongside clinical findings and biochemical markers to noninvasively assess the degree of hepatic fibrosis and cirrhosis. Molleston and colleagues leveraged the robust data from the National Institute of Diabetes and Digestive and Kidney Diseases–supported network ChiLDReN and found that LSM in children with biliary atresia (BA) correlate with the progression to complications associated with portal hypertension and liver transplantation. While these findings are not unexpected, this compelling investigation accomplishes the important function of validating the utility of elastography in this cohort.
Prognosticating the timeline of complications stemming from biliary atresia is a central tenet of pediatric hepatology. Helping families understand what the future may hold for their child is critical in fostering long-term relationships between clinicians and caregivers. Furthermore, establishing clear expectations regarding follow-up care and monitoring is beneficial for both providers and patients. Of particular importance is minimizing the need for invasive procedures, such as liver biopsy, which, while relatively safe, remains burdensome and is rarely used to assess fibrosis in BA.
Pediatric hepatologists already consider multiple factors — including age at hepatoportoenterostomy, subsequent clearance of cholestasis, exam findings such as splenomegaly, and platelet count — to predict the clinical course of infants with BA. The addition of a data-driven approach to interpreting liver stiffness measurements represents a valuable new tool in this expanding repertoire, offering an encouraging prospect for both providers and families navigating the complexities of pediatric liver disease.
Aaron Bennett, MD, is a fellow in the Division of Gastroenterology, Hepatology and Nutrition at Children’s Hospital of Philadelphia in Pennsylvania. Elizabeth B. Rand, MD, is the medical director of the Liver Transplant Program, director of the Gastroenterology Fellowship Program, and director of the Advanced Transplant Hepatology Program at Children’s Hospital of Philadelphia.
Grading liver stiffness using elastography is a widely utilized tool in adult populations, and its application is expanding in pediatric hepatology clinics. Clinicians incorporate liver stiffness measurements (LSM) alongside clinical findings and biochemical markers to noninvasively assess the degree of hepatic fibrosis and cirrhosis. Molleston and colleagues leveraged the robust data from the National Institute of Diabetes and Digestive and Kidney Diseases–supported network ChiLDReN and found that LSM in children with biliary atresia (BA) correlate with the progression to complications associated with portal hypertension and liver transplantation. While these findings are not unexpected, this compelling investigation accomplishes the important function of validating the utility of elastography in this cohort.
Prognosticating the timeline of complications stemming from biliary atresia is a central tenet of pediatric hepatology. Helping families understand what the future may hold for their child is critical in fostering long-term relationships between clinicians and caregivers. Furthermore, establishing clear expectations regarding follow-up care and monitoring is beneficial for both providers and patients. Of particular importance is minimizing the need for invasive procedures, such as liver biopsy, which, while relatively safe, remains burdensome and is rarely used to assess fibrosis in BA.
Pediatric hepatologists already consider multiple factors — including age at hepatoportoenterostomy, subsequent clearance of cholestasis, exam findings such as splenomegaly, and platelet count — to predict the clinical course of infants with BA. The addition of a data-driven approach to interpreting liver stiffness measurements represents a valuable new tool in this expanding repertoire, offering an encouraging prospect for both providers and families navigating the complexities of pediatric liver disease.
Aaron Bennett, MD, is a fellow in the Division of Gastroenterology, Hepatology and Nutrition at Children’s Hospital of Philadelphia in Pennsylvania. Elizabeth B. Rand, MD, is the medical director of the Liver Transplant Program, director of the Gastroenterology Fellowship Program, and director of the Advanced Transplant Hepatology Program at Children’s Hospital of Philadelphia.
Grading liver stiffness using elastography is a widely utilized tool in adult populations, and its application is expanding in pediatric hepatology clinics. Clinicians incorporate liver stiffness measurements (LSM) alongside clinical findings and biochemical markers to noninvasively assess the degree of hepatic fibrosis and cirrhosis. Molleston and colleagues leveraged the robust data from the National Institute of Diabetes and Digestive and Kidney Diseases–supported network ChiLDReN and found that LSM in children with biliary atresia (BA) correlate with the progression to complications associated with portal hypertension and liver transplantation. While these findings are not unexpected, this compelling investigation accomplishes the important function of validating the utility of elastography in this cohort.
Prognosticating the timeline of complications stemming from biliary atresia is a central tenet of pediatric hepatology. Helping families understand what the future may hold for their child is critical in fostering long-term relationships between clinicians and caregivers. Furthermore, establishing clear expectations regarding follow-up care and monitoring is beneficial for both providers and patients. Of particular importance is minimizing the need for invasive procedures, such as liver biopsy, which, while relatively safe, remains burdensome and is rarely used to assess fibrosis in BA.
Pediatric hepatologists already consider multiple factors — including age at hepatoportoenterostomy, subsequent clearance of cholestasis, exam findings such as splenomegaly, and platelet count — to predict the clinical course of infants with BA. The addition of a data-driven approach to interpreting liver stiffness measurements represents a valuable new tool in this expanding repertoire, offering an encouraging prospect for both providers and families navigating the complexities of pediatric liver disease.
Aaron Bennett, MD, is a fellow in the Division of Gastroenterology, Hepatology and Nutrition at Children’s Hospital of Philadelphia in Pennsylvania. Elizabeth B. Rand, MD, is the medical director of the Liver Transplant Program, director of the Gastroenterology Fellowship Program, and director of the Advanced Transplant Hepatology Program at Children’s Hospital of Philadelphia.
according to investigators.
These findings suggest that LSM may serve as a noninvasive tool for risk stratification and treatment planning in this population, reported lead author Jean P. Molleston, MD, of Indiana University School of Medicine, Indianapolis, and colleagues.
“Biliary atresia is frequently complicated by hepatic fibrosis with progression to cirrhosis and portal hypertension manifested by ascites, hepatopulmonary syndrome, and variceal bleeding,” the investigators wrote in Gastroenterology. “The ability to predict these outcomes can inform clinical decision-making.”
To this end, VCTE has been gaining increasing support in the pediatric setting.
“Advantages of VCTE over liver biopsy include convenience, cost, sampling bias, and risk,” the investigators wrote. “VCTE potentially allows (1) fibrosis estimation, (2) prediction of portal hypertension complications/survival, and (3) ability to noninvasively monitor liver stiffness as a fibrosis surrogate.”
The present multicenter study aimed to gauge the prognostic utility of VCTE among 254 patients, aged 21 years or younger, with biliary atresia. All patients had a valid baseline LSM, plus longitudinal clinical and laboratory data drawn from studies by the Childhood Liver Disease Research Network (ChiLDReN). Liver stiffness was assessed noninvasively with FibroScan devices, adhering to protocols that required at least 10 valid measurements and a variability of less than 30%.
The primary outcomes were survival with native liver (SNL), defined as the time to liver transplantation or death, and a composite measure of liver-related events, including the first occurrence of transplantation, death, ascites, variceal bleeding, or hepatopulmonary syndrome. Secondary outcomes focused on the trajectory of platelet decline, a marker of disease progression. The study also explored the relationship between baseline LSM and conventional biomarkers, including platelet count, albumin, and bilirubin.
LSM was a strong predictor of long-term outcomes. Specifically, Kaplan-Meier analysis showed significant differences in 5-year SNL across LSM strata (P < .001). Children with LSM values less than 10 kPa had excellent 5-year SNL rates (LSM 10 to < 15 kPa, 88.9%; 95% CI, 75.1-95.3%), while those with LSM of at least 15 kPa exhibited substantially lower 5-year SNL (58.9%; 95% CI, 46.0-69.7%).
Similarly, event-free survival (EFS) rates declined as LSM values increased (P < .001). Participants with LSM less than 10 kPa had a 5-year EFS rate of 92.2% versus with 61.2% for those with LSM of at least 15 kPa.
LSM also predicted platelet decline. For every twofold increase in baseline LSM, platelet counts declined by an additional 4,000/mm3 per year (P < .001). This association was illustrated through predicted trajectories for participants with LSM values of 4, 7, 12, 18, and 42 kPa, corresponding to different percentiles of disease severity.
Cox proportional hazards analysis indicated that a two-fold increase in LSM was associated with a hazard ratio of 3.3 (P < .001) for liver transplant or death. While LSM had good discrimination on its own (C statistic = 0.83), it did not significantly improve predictive accuracy when added to models based on platelet count, albumin, and bilirubin.
“This noninvasive measurement could potentially be used to predict natural history, stratify patients for clinical trials, plan interventions, and provide anticipatory guidance,” Molleston and colleagues concluded. This study was supported by grants from the National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; Childhood Liver Disease Research Network; and others. The investigators disclosed no conflicts of interest.
according to investigators.
These findings suggest that LSM may serve as a noninvasive tool for risk stratification and treatment planning in this population, reported lead author Jean P. Molleston, MD, of Indiana University School of Medicine, Indianapolis, and colleagues.
“Biliary atresia is frequently complicated by hepatic fibrosis with progression to cirrhosis and portal hypertension manifested by ascites, hepatopulmonary syndrome, and variceal bleeding,” the investigators wrote in Gastroenterology. “The ability to predict these outcomes can inform clinical decision-making.”
To this end, VCTE has been gaining increasing support in the pediatric setting.
“Advantages of VCTE over liver biopsy include convenience, cost, sampling bias, and risk,” the investigators wrote. “VCTE potentially allows (1) fibrosis estimation, (2) prediction of portal hypertension complications/survival, and (3) ability to noninvasively monitor liver stiffness as a fibrosis surrogate.”
The present multicenter study aimed to gauge the prognostic utility of VCTE among 254 patients, aged 21 years or younger, with biliary atresia. All patients had a valid baseline LSM, plus longitudinal clinical and laboratory data drawn from studies by the Childhood Liver Disease Research Network (ChiLDReN). Liver stiffness was assessed noninvasively with FibroScan devices, adhering to protocols that required at least 10 valid measurements and a variability of less than 30%.
The primary outcomes were survival with native liver (SNL), defined as the time to liver transplantation or death, and a composite measure of liver-related events, including the first occurrence of transplantation, death, ascites, variceal bleeding, or hepatopulmonary syndrome. Secondary outcomes focused on the trajectory of platelet decline, a marker of disease progression. The study also explored the relationship between baseline LSM and conventional biomarkers, including platelet count, albumin, and bilirubin.
LSM was a strong predictor of long-term outcomes. Specifically, Kaplan-Meier analysis showed significant differences in 5-year SNL across LSM strata (P < .001). Children with LSM values less than 10 kPa had excellent 5-year SNL rates (LSM 10 to < 15 kPa, 88.9%; 95% CI, 75.1-95.3%), while those with LSM of at least 15 kPa exhibited substantially lower 5-year SNL (58.9%; 95% CI, 46.0-69.7%).
Similarly, event-free survival (EFS) rates declined as LSM values increased (P < .001). Participants with LSM less than 10 kPa had a 5-year EFS rate of 92.2% versus with 61.2% for those with LSM of at least 15 kPa.
LSM also predicted platelet decline. For every twofold increase in baseline LSM, platelet counts declined by an additional 4,000/mm3 per year (P < .001). This association was illustrated through predicted trajectories for participants with LSM values of 4, 7, 12, 18, and 42 kPa, corresponding to different percentiles of disease severity.
Cox proportional hazards analysis indicated that a two-fold increase in LSM was associated with a hazard ratio of 3.3 (P < .001) for liver transplant or death. While LSM had good discrimination on its own (C statistic = 0.83), it did not significantly improve predictive accuracy when added to models based on platelet count, albumin, and bilirubin.
“This noninvasive measurement could potentially be used to predict natural history, stratify patients for clinical trials, plan interventions, and provide anticipatory guidance,” Molleston and colleagues concluded. This study was supported by grants from the National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; Childhood Liver Disease Research Network; and others. The investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
Lipophilic Statins May Protect Against HCC In Select Liver Disease Patients
according to investigators.
These findings also pave the way for new research into targeted therapies, personalized prevention strategies, and broader applications in high-risk populations, Erik Almazan, MD, and Raymond T. Chung, MD, of Harvard Medical School, Boston, Massachusetts, reported.
“Statins, metformin, and aspirin are low-cost medications often prescribed for the management of diseases associated with metabolic syndrome that have been associated with reduced HCC risk, the investigators wrote in Gastro Hep Advances. “Despite these findings, few studies have focused on populations in the US or without hepatitis B virus (HBV) or hepatitis C virus (HCV).”
To address this knowledge gap, Almazan and Chung retrospectively analyzed data from 3,677 patients with hepatic fibrosis and cirrhosis, drawn from the All of Us Controlled Tier Dataset v7, which spans May 2018 to July 2022.
Within this population, 94 patients had HCC, while 3,583 served as controls. Lipophilic statin use was compared with hydrophilic statins, metformin, and aspirin. Multivariable logistic regression controlled for confounders including age, sex, race, and the presence of HBV or HCV.
Participants in the HCC cohort were older (mean age, 64 vs 58 years), more likely to be male (64.1% vs 50.0%), and had higher rates of chronic HBV (9.6% vs 2.5%) and chronic HCV (36.2% vs. 20.5%) compared to controls (P ≤ .01).
As a class, lipophilic statins were associated with a 36% reduced risk of HCC (odds ratio [OR], 0.64; 95% CI, 0.41-1.00; P < .05). Specifically, atorvastatin was associated with a 41% reduced risk (OR, 0.59; 95% CI, 0.37-0.93; P = .02), while simvastatin was associated with a 54% reduced risk (OR, 0.46; 95% CI, 0.22-0.97; P = .04).
In contrast, hydrophilic statins, such as pravastatin and rosuvastatin, showed no significant association with HCC risk. Similarly, no protective association was observed for metformin or aspirin.
These findings suggest that lipophilic statins could provide a practical and cost-effective strategy for HCC prevention, particularly in patients with metabolic syndrome or alcohol-related liver disease, according to Almazan and Chung. These high-risk groups often lack accessible and noninvasive prevention options, further highlighting the clinical relevance of these results.
The investigators proposed that the chemopreventive effects of lipophilic statins may be linked to their ability to passively diffuse into cells and modulate pathways involved in cancer development, such as the mevalonate pathway. These potential mechanisms remain poorly understood.
Almazan and Chung also pointed out several study limitations, including lack of granular data on statin doses and treatment duration, absence of serologic and imaging confirmation of hepatic fibrosis and cirrhosis, and a study cohort drawn from populations historically underrepresented in medical research, potentially limiting generalizability to the broader US population.
“Nevertheless, we believe that our study adds valuable information to the literature on statin use and its association with HCC with data from a US-based sample inclusive of individuals with risk factors other than HBV and HCV,” the investigators wrote. “These results provide further support for trials (such as NCT05028829) evaluating the utility of lipophilic statins for chemoprevention in HCC for persons at risk.”This study was supported by various National Institutes of Health grants. The investigators disclosed no conflicts of interest.
Hepatocellular carcinoma (HCC) incidence continues to increase in the United States. Because of its poor prognosis and limited treatment options, prevention strategies are critically needed, yet there are no Food and Drug Administration–approved treatments for HCC prevention. In the United States, metabolic syndrome has a high prevalence and is a significant contributor to HCC burden. Many individuals with metabolic syndrome are eligible for statin therapy, which has been associated with HCC chemoprevention. Evidence suggests that lipophilic statins may be more effective chemopreventive agents than hydrophilic statins. However, previous studies have largely focused on populations with hepatitis C virus, making it unclear whether these findings are generalizable to individuals with other liver disease etiologies.
Our findings support the chemopreventive potential of lipophilic statins in patients with hepatic fibrosis and cirrhosis, regardless of the underlying cause. If lipophilic statins are confirmed as effective chemopreventive agents, HCC prevention could begin in the primary care setting. For example, primary care providers treating patients with metabolic syndrome and an indication for statin therapy could select treatment with lipophilic statins over hydrophilic statins. This approach would be cost-effective, relatively simple to implement, and benefit many patients, including those from lower socioeconomic backgrounds who are at higher risk.
Large-scale clinical trials and basic science studies are necessary to confirm the role of lipophilic statins in HCC prevention. Supporting precision medicine initiatives like the All of Us Research Program could help identify individuals most likely to benefit and address gaps in current HCC prevention strategies.
Erik Almazan, MD, is a resident physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Raymond T. Chung, MD, is director of the Hepatology and Liver Center at Massachusetts General Hospital and Harvard Medical School, Boston. They have no conflicts to disclose.
Hepatocellular carcinoma (HCC) incidence continues to increase in the United States. Because of its poor prognosis and limited treatment options, prevention strategies are critically needed, yet there are no Food and Drug Administration–approved treatments for HCC prevention. In the United States, metabolic syndrome has a high prevalence and is a significant contributor to HCC burden. Many individuals with metabolic syndrome are eligible for statin therapy, which has been associated with HCC chemoprevention. Evidence suggests that lipophilic statins may be more effective chemopreventive agents than hydrophilic statins. However, previous studies have largely focused on populations with hepatitis C virus, making it unclear whether these findings are generalizable to individuals with other liver disease etiologies.
Our findings support the chemopreventive potential of lipophilic statins in patients with hepatic fibrosis and cirrhosis, regardless of the underlying cause. If lipophilic statins are confirmed as effective chemopreventive agents, HCC prevention could begin in the primary care setting. For example, primary care providers treating patients with metabolic syndrome and an indication for statin therapy could select treatment with lipophilic statins over hydrophilic statins. This approach would be cost-effective, relatively simple to implement, and benefit many patients, including those from lower socioeconomic backgrounds who are at higher risk.
Large-scale clinical trials and basic science studies are necessary to confirm the role of lipophilic statins in HCC prevention. Supporting precision medicine initiatives like the All of Us Research Program could help identify individuals most likely to benefit and address gaps in current HCC prevention strategies.
Erik Almazan, MD, is a resident physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Raymond T. Chung, MD, is director of the Hepatology and Liver Center at Massachusetts General Hospital and Harvard Medical School, Boston. They have no conflicts to disclose.
Hepatocellular carcinoma (HCC) incidence continues to increase in the United States. Because of its poor prognosis and limited treatment options, prevention strategies are critically needed, yet there are no Food and Drug Administration–approved treatments for HCC prevention. In the United States, metabolic syndrome has a high prevalence and is a significant contributor to HCC burden. Many individuals with metabolic syndrome are eligible for statin therapy, which has been associated with HCC chemoprevention. Evidence suggests that lipophilic statins may be more effective chemopreventive agents than hydrophilic statins. However, previous studies have largely focused on populations with hepatitis C virus, making it unclear whether these findings are generalizable to individuals with other liver disease etiologies.
Our findings support the chemopreventive potential of lipophilic statins in patients with hepatic fibrosis and cirrhosis, regardless of the underlying cause. If lipophilic statins are confirmed as effective chemopreventive agents, HCC prevention could begin in the primary care setting. For example, primary care providers treating patients with metabolic syndrome and an indication for statin therapy could select treatment with lipophilic statins over hydrophilic statins. This approach would be cost-effective, relatively simple to implement, and benefit many patients, including those from lower socioeconomic backgrounds who are at higher risk.
Large-scale clinical trials and basic science studies are necessary to confirm the role of lipophilic statins in HCC prevention. Supporting precision medicine initiatives like the All of Us Research Program could help identify individuals most likely to benefit and address gaps in current HCC prevention strategies.
Erik Almazan, MD, is a resident physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Raymond T. Chung, MD, is director of the Hepatology and Liver Center at Massachusetts General Hospital and Harvard Medical School, Boston. They have no conflicts to disclose.
according to investigators.
These findings also pave the way for new research into targeted therapies, personalized prevention strategies, and broader applications in high-risk populations, Erik Almazan, MD, and Raymond T. Chung, MD, of Harvard Medical School, Boston, Massachusetts, reported.
“Statins, metformin, and aspirin are low-cost medications often prescribed for the management of diseases associated with metabolic syndrome that have been associated with reduced HCC risk, the investigators wrote in Gastro Hep Advances. “Despite these findings, few studies have focused on populations in the US or without hepatitis B virus (HBV) or hepatitis C virus (HCV).”
To address this knowledge gap, Almazan and Chung retrospectively analyzed data from 3,677 patients with hepatic fibrosis and cirrhosis, drawn from the All of Us Controlled Tier Dataset v7, which spans May 2018 to July 2022.
Within this population, 94 patients had HCC, while 3,583 served as controls. Lipophilic statin use was compared with hydrophilic statins, metformin, and aspirin. Multivariable logistic regression controlled for confounders including age, sex, race, and the presence of HBV or HCV.
Participants in the HCC cohort were older (mean age, 64 vs 58 years), more likely to be male (64.1% vs 50.0%), and had higher rates of chronic HBV (9.6% vs 2.5%) and chronic HCV (36.2% vs. 20.5%) compared to controls (P ≤ .01).
As a class, lipophilic statins were associated with a 36% reduced risk of HCC (odds ratio [OR], 0.64; 95% CI, 0.41-1.00; P < .05). Specifically, atorvastatin was associated with a 41% reduced risk (OR, 0.59; 95% CI, 0.37-0.93; P = .02), while simvastatin was associated with a 54% reduced risk (OR, 0.46; 95% CI, 0.22-0.97; P = .04).
In contrast, hydrophilic statins, such as pravastatin and rosuvastatin, showed no significant association with HCC risk. Similarly, no protective association was observed for metformin or aspirin.
These findings suggest that lipophilic statins could provide a practical and cost-effective strategy for HCC prevention, particularly in patients with metabolic syndrome or alcohol-related liver disease, according to Almazan and Chung. These high-risk groups often lack accessible and noninvasive prevention options, further highlighting the clinical relevance of these results.
The investigators proposed that the chemopreventive effects of lipophilic statins may be linked to their ability to passively diffuse into cells and modulate pathways involved in cancer development, such as the mevalonate pathway. These potential mechanisms remain poorly understood.
Almazan and Chung also pointed out several study limitations, including lack of granular data on statin doses and treatment duration, absence of serologic and imaging confirmation of hepatic fibrosis and cirrhosis, and a study cohort drawn from populations historically underrepresented in medical research, potentially limiting generalizability to the broader US population.
“Nevertheless, we believe that our study adds valuable information to the literature on statin use and its association with HCC with data from a US-based sample inclusive of individuals with risk factors other than HBV and HCV,” the investigators wrote. “These results provide further support for trials (such as NCT05028829) evaluating the utility of lipophilic statins for chemoprevention in HCC for persons at risk.”This study was supported by various National Institutes of Health grants. The investigators disclosed no conflicts of interest.
according to investigators.
These findings also pave the way for new research into targeted therapies, personalized prevention strategies, and broader applications in high-risk populations, Erik Almazan, MD, and Raymond T. Chung, MD, of Harvard Medical School, Boston, Massachusetts, reported.
“Statins, metformin, and aspirin are low-cost medications often prescribed for the management of diseases associated with metabolic syndrome that have been associated with reduced HCC risk, the investigators wrote in Gastro Hep Advances. “Despite these findings, few studies have focused on populations in the US or without hepatitis B virus (HBV) or hepatitis C virus (HCV).”
To address this knowledge gap, Almazan and Chung retrospectively analyzed data from 3,677 patients with hepatic fibrosis and cirrhosis, drawn from the All of Us Controlled Tier Dataset v7, which spans May 2018 to July 2022.
Within this population, 94 patients had HCC, while 3,583 served as controls. Lipophilic statin use was compared with hydrophilic statins, metformin, and aspirin. Multivariable logistic regression controlled for confounders including age, sex, race, and the presence of HBV or HCV.
Participants in the HCC cohort were older (mean age, 64 vs 58 years), more likely to be male (64.1% vs 50.0%), and had higher rates of chronic HBV (9.6% vs 2.5%) and chronic HCV (36.2% vs. 20.5%) compared to controls (P ≤ .01).
As a class, lipophilic statins were associated with a 36% reduced risk of HCC (odds ratio [OR], 0.64; 95% CI, 0.41-1.00; P < .05). Specifically, atorvastatin was associated with a 41% reduced risk (OR, 0.59; 95% CI, 0.37-0.93; P = .02), while simvastatin was associated with a 54% reduced risk (OR, 0.46; 95% CI, 0.22-0.97; P = .04).
In contrast, hydrophilic statins, such as pravastatin and rosuvastatin, showed no significant association with HCC risk. Similarly, no protective association was observed for metformin or aspirin.
These findings suggest that lipophilic statins could provide a practical and cost-effective strategy for HCC prevention, particularly in patients with metabolic syndrome or alcohol-related liver disease, according to Almazan and Chung. These high-risk groups often lack accessible and noninvasive prevention options, further highlighting the clinical relevance of these results.
The investigators proposed that the chemopreventive effects of lipophilic statins may be linked to their ability to passively diffuse into cells and modulate pathways involved in cancer development, such as the mevalonate pathway. These potential mechanisms remain poorly understood.
Almazan and Chung also pointed out several study limitations, including lack of granular data on statin doses and treatment duration, absence of serologic and imaging confirmation of hepatic fibrosis and cirrhosis, and a study cohort drawn from populations historically underrepresented in medical research, potentially limiting generalizability to the broader US population.
“Nevertheless, we believe that our study adds valuable information to the literature on statin use and its association with HCC with data from a US-based sample inclusive of individuals with risk factors other than HBV and HCV,” the investigators wrote. “These results provide further support for trials (such as NCT05028829) evaluating the utility of lipophilic statins for chemoprevention in HCC for persons at risk.”This study was supported by various National Institutes of Health grants. The investigators disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES
PPI-Responsive Disease a Subtype of EoE Rather Than GERD
, according to comparative proteomic analyses.
Notably, after PPI therapy, the protein profiles of responsive patients reverted and appeared similar to non-EoE patients, whereas the profiles of nonresponsive patients remained largely unchanged.
“Identifying protein biomarkers associated with PPI response may help distinguish EoE phenotypes and guide therapy selections,” said senior author Walter Chan, MD, AGAF, associate professor of medicine in the Division of Gastroenterology, Hepatology, and Endoscopy at Harvard Medical School and director of the center for gastrointestinal motility at Brigham and Women’s Hospital, Boston.
“These findings may provide the framework for developing protein biomarkers to assess response to therapy and monitor disease activity,” he added.
The study was published online in Gastroenterology.
Comparative Proteomic Analyses
Chan and colleagues conducted a prospective exploratory pilot study to identify the differences in esophageal protein profiles among PPI-responsive-EoE (PPI-R-EoE), PPI-nonresponsive-EoE (PPI-NR-EoE), and non-EoE controls using SOMAscan, a proteomics platform that allows simultaneous detection of 1305 human proteins.
The research team prospectively enrolled patients undergoing endoscopy for esophageal symptoms or for EoE follow-up, obtaining clinically indicated biopsies as well as extra samples from the midesophagus.
Patients who were diagnosed with EoE (at 15 or greater eosinophils per high-power field, or eos/hpf) were treated with 20 mg of omeprazole twice daily for 8 weeks, followed by repeat biopsies to assess treatment response.
Patients with histologic remission (fewer than 15 eos/hpf) were classified as PPI-R-EoE, whereas those with persistently active disease were classified as PPI-NR-EoE. Patients without EoE served as controls and were categorized as having erosive esophagitis (EE) or no esophagitis.
Overall, the study enrolled 32 patients, including 15 with PPI-R-EoE, eight with PPI-NR-EoE, three with EE, and six with no esophagitis. The demographics, symptoms, and endoscopic findings were similar between the PPI-R-EoE and PPI-NR-EoE patients.
At the index endoscopy, the PPI-R-EoE and PPI-NR-EoE patients had similar esophageal protein profiles, with only 20 proteins differentially expressed at a relaxed cutoff of P < .1. An analysis of the 20 proteins predicted lower expression of six proteins that may be associated with gastrointestinal inflammation in nonresponsive patients, including STAT1, STAT3, CFB, interleukin (IL)-17RA, TNFRSF1A, and SERPINA3.
In addition, 136 proteins — including 15 with corrected P < .05 — clearly discriminated PPI-R-EoE patients from non-EoE controls, and 255 proteins — including 249 with P < .05 — discriminated PPI-NR-EoE patients from controls. Both types of EoE patients had proteins associated with enhanced inflammation and vasculogenesis, as well as down-regulation of CRISP3 and DSG1 and upregulation of TNFAIP6.
The comparative analyses also showed that the follow-up biopsies of PPI-R-EoE patients had protein profiles that resembled non-EoE controls after PPI therapy.
“This further supports the hypothesis that despite the PPI response, PPI-R-EoE represents a subtype of EoE rather than gastroesophageal reflux disease (GERD),” Chan said.
Future EoE Considerations
Although most expressed proteins appeared similar between PPI-responsive and nonresponsive patients before treatment, a few proteins differed related to gastrointestinal inflammation, the study authors wrote, including some previously implicated in IL4 and IL13 inflammatory pathways.
“Further study of these proteins may provide insights into the EoE pathogenic pathway, explore their potential to predict PPI response at diagnosis, and identify possible therapeutic targets,” they wrote.
The authors pointed to the small study size as the primary limitation, noting that the pilot study was intended to explore the feasibility of using SomaScan to assess esophageal protein profiles in different EoE phenotypes. In the future, larger studies with more expansive candidate proteins could help characterize the differences and better identify specific proteins and pathways in EoE, they wrote.
“The takeaway is that PPI responsiveness does not distinguish EoE from GERD but rather PPI is a primary therapy for EoE independent of GERD,” said Marc Rothenberg, MD, director of allergy and immunology and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.
Rothenberg, who wasn’t involved with this study, has conducted transcriptome analyses of PPI-R-EoE, which showed PPI-reversible allergic inflammation.
“PPI-R-EoE and PPI-NR-EoE look the same at the molecular level,” he said. “After therapy, PPI-R-EoE normalizes, as per its definition.”
This study was supported by the Campaign Urging Research for Eosinophilic Disease Foundation Grant, the Kenneth and Louise Goldberg Junior Faculty Award, and a National Institutes of Health award. Chan declared advisory board positions with several pharmaceutical companies and Rothenberg reported no relevant disclosures.
A version of this article appeared on Medscape.com.
, according to comparative proteomic analyses.
Notably, after PPI therapy, the protein profiles of responsive patients reverted and appeared similar to non-EoE patients, whereas the profiles of nonresponsive patients remained largely unchanged.
“Identifying protein biomarkers associated with PPI response may help distinguish EoE phenotypes and guide therapy selections,” said senior author Walter Chan, MD, AGAF, associate professor of medicine in the Division of Gastroenterology, Hepatology, and Endoscopy at Harvard Medical School and director of the center for gastrointestinal motility at Brigham and Women’s Hospital, Boston.
“These findings may provide the framework for developing protein biomarkers to assess response to therapy and monitor disease activity,” he added.
The study was published online in Gastroenterology.
Comparative Proteomic Analyses
Chan and colleagues conducted a prospective exploratory pilot study to identify the differences in esophageal protein profiles among PPI-responsive-EoE (PPI-R-EoE), PPI-nonresponsive-EoE (PPI-NR-EoE), and non-EoE controls using SOMAscan, a proteomics platform that allows simultaneous detection of 1305 human proteins.
The research team prospectively enrolled patients undergoing endoscopy for esophageal symptoms or for EoE follow-up, obtaining clinically indicated biopsies as well as extra samples from the midesophagus.
Patients who were diagnosed with EoE (at 15 or greater eosinophils per high-power field, or eos/hpf) were treated with 20 mg of omeprazole twice daily for 8 weeks, followed by repeat biopsies to assess treatment response.
Patients with histologic remission (fewer than 15 eos/hpf) were classified as PPI-R-EoE, whereas those with persistently active disease were classified as PPI-NR-EoE. Patients without EoE served as controls and were categorized as having erosive esophagitis (EE) or no esophagitis.
Overall, the study enrolled 32 patients, including 15 with PPI-R-EoE, eight with PPI-NR-EoE, three with EE, and six with no esophagitis. The demographics, symptoms, and endoscopic findings were similar between the PPI-R-EoE and PPI-NR-EoE patients.
At the index endoscopy, the PPI-R-EoE and PPI-NR-EoE patients had similar esophageal protein profiles, with only 20 proteins differentially expressed at a relaxed cutoff of P < .1. An analysis of the 20 proteins predicted lower expression of six proteins that may be associated with gastrointestinal inflammation in nonresponsive patients, including STAT1, STAT3, CFB, interleukin (IL)-17RA, TNFRSF1A, and SERPINA3.
In addition, 136 proteins — including 15 with corrected P < .05 — clearly discriminated PPI-R-EoE patients from non-EoE controls, and 255 proteins — including 249 with P < .05 — discriminated PPI-NR-EoE patients from controls. Both types of EoE patients had proteins associated with enhanced inflammation and vasculogenesis, as well as down-regulation of CRISP3 and DSG1 and upregulation of TNFAIP6.
The comparative analyses also showed that the follow-up biopsies of PPI-R-EoE patients had protein profiles that resembled non-EoE controls after PPI therapy.
“This further supports the hypothesis that despite the PPI response, PPI-R-EoE represents a subtype of EoE rather than gastroesophageal reflux disease (GERD),” Chan said.
Future EoE Considerations
Although most expressed proteins appeared similar between PPI-responsive and nonresponsive patients before treatment, a few proteins differed related to gastrointestinal inflammation, the study authors wrote, including some previously implicated in IL4 and IL13 inflammatory pathways.
“Further study of these proteins may provide insights into the EoE pathogenic pathway, explore their potential to predict PPI response at diagnosis, and identify possible therapeutic targets,” they wrote.
The authors pointed to the small study size as the primary limitation, noting that the pilot study was intended to explore the feasibility of using SomaScan to assess esophageal protein profiles in different EoE phenotypes. In the future, larger studies with more expansive candidate proteins could help characterize the differences and better identify specific proteins and pathways in EoE, they wrote.
“The takeaway is that PPI responsiveness does not distinguish EoE from GERD but rather PPI is a primary therapy for EoE independent of GERD,” said Marc Rothenberg, MD, director of allergy and immunology and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.
Rothenberg, who wasn’t involved with this study, has conducted transcriptome analyses of PPI-R-EoE, which showed PPI-reversible allergic inflammation.
“PPI-R-EoE and PPI-NR-EoE look the same at the molecular level,” he said. “After therapy, PPI-R-EoE normalizes, as per its definition.”
This study was supported by the Campaign Urging Research for Eosinophilic Disease Foundation Grant, the Kenneth and Louise Goldberg Junior Faculty Award, and a National Institutes of Health award. Chan declared advisory board positions with several pharmaceutical companies and Rothenberg reported no relevant disclosures.
A version of this article appeared on Medscape.com.
, according to comparative proteomic analyses.
Notably, after PPI therapy, the protein profiles of responsive patients reverted and appeared similar to non-EoE patients, whereas the profiles of nonresponsive patients remained largely unchanged.
“Identifying protein biomarkers associated with PPI response may help distinguish EoE phenotypes and guide therapy selections,” said senior author Walter Chan, MD, AGAF, associate professor of medicine in the Division of Gastroenterology, Hepatology, and Endoscopy at Harvard Medical School and director of the center for gastrointestinal motility at Brigham and Women’s Hospital, Boston.
“These findings may provide the framework for developing protein biomarkers to assess response to therapy and monitor disease activity,” he added.
The study was published online in Gastroenterology.
Comparative Proteomic Analyses
Chan and colleagues conducted a prospective exploratory pilot study to identify the differences in esophageal protein profiles among PPI-responsive-EoE (PPI-R-EoE), PPI-nonresponsive-EoE (PPI-NR-EoE), and non-EoE controls using SOMAscan, a proteomics platform that allows simultaneous detection of 1305 human proteins.
The research team prospectively enrolled patients undergoing endoscopy for esophageal symptoms or for EoE follow-up, obtaining clinically indicated biopsies as well as extra samples from the midesophagus.
Patients who were diagnosed with EoE (at 15 or greater eosinophils per high-power field, or eos/hpf) were treated with 20 mg of omeprazole twice daily for 8 weeks, followed by repeat biopsies to assess treatment response.
Patients with histologic remission (fewer than 15 eos/hpf) were classified as PPI-R-EoE, whereas those with persistently active disease were classified as PPI-NR-EoE. Patients without EoE served as controls and were categorized as having erosive esophagitis (EE) or no esophagitis.
Overall, the study enrolled 32 patients, including 15 with PPI-R-EoE, eight with PPI-NR-EoE, three with EE, and six with no esophagitis. The demographics, symptoms, and endoscopic findings were similar between the PPI-R-EoE and PPI-NR-EoE patients.
At the index endoscopy, the PPI-R-EoE and PPI-NR-EoE patients had similar esophageal protein profiles, with only 20 proteins differentially expressed at a relaxed cutoff of P < .1. An analysis of the 20 proteins predicted lower expression of six proteins that may be associated with gastrointestinal inflammation in nonresponsive patients, including STAT1, STAT3, CFB, interleukin (IL)-17RA, TNFRSF1A, and SERPINA3.
In addition, 136 proteins — including 15 with corrected P < .05 — clearly discriminated PPI-R-EoE patients from non-EoE controls, and 255 proteins — including 249 with P < .05 — discriminated PPI-NR-EoE patients from controls. Both types of EoE patients had proteins associated with enhanced inflammation and vasculogenesis, as well as down-regulation of CRISP3 and DSG1 and upregulation of TNFAIP6.
The comparative analyses also showed that the follow-up biopsies of PPI-R-EoE patients had protein profiles that resembled non-EoE controls after PPI therapy.
“This further supports the hypothesis that despite the PPI response, PPI-R-EoE represents a subtype of EoE rather than gastroesophageal reflux disease (GERD),” Chan said.
Future EoE Considerations
Although most expressed proteins appeared similar between PPI-responsive and nonresponsive patients before treatment, a few proteins differed related to gastrointestinal inflammation, the study authors wrote, including some previously implicated in IL4 and IL13 inflammatory pathways.
“Further study of these proteins may provide insights into the EoE pathogenic pathway, explore their potential to predict PPI response at diagnosis, and identify possible therapeutic targets,” they wrote.
The authors pointed to the small study size as the primary limitation, noting that the pilot study was intended to explore the feasibility of using SomaScan to assess esophageal protein profiles in different EoE phenotypes. In the future, larger studies with more expansive candidate proteins could help characterize the differences and better identify specific proteins and pathways in EoE, they wrote.
“The takeaway is that PPI responsiveness does not distinguish EoE from GERD but rather PPI is a primary therapy for EoE independent of GERD,” said Marc Rothenberg, MD, director of allergy and immunology and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.
Rothenberg, who wasn’t involved with this study, has conducted transcriptome analyses of PPI-R-EoE, which showed PPI-reversible allergic inflammation.
“PPI-R-EoE and PPI-NR-EoE look the same at the molecular level,” he said. “After therapy, PPI-R-EoE normalizes, as per its definition.”
This study was supported by the Campaign Urging Research for Eosinophilic Disease Foundation Grant, the Kenneth and Louise Goldberg Junior Faculty Award, and a National Institutes of Health award. Chan declared advisory board positions with several pharmaceutical companies and Rothenberg reported no relevant disclosures.
A version of this article appeared on Medscape.com.
Digestive Disease Mortality Higher for US Indigenous Communities
which experience the highest death rates and ongoing increases, according to a recent study.
Policymakers, healthcare providers, and communities need to respond with targeted interventions and collaborative efforts that address these inequities and advance digestive health equity, lead author Wafa A. Aldhaleei, MD, of Mayo Clinic, Rochester, Minnesota, and colleagues reported.
“Several studies have reported the epidemiological characteristics of certain digestive diseases such as pancreatitis, liver and biliary diseases, and inflammatory bowel disease,” the investigators wrote in Clinical Gastroenterology and Hepatology. “These studies provide insights into the US burden by sex and racial and ethnic disparities of various digestive diseases individually. However, little is known about racial disparities in the United States digestive diseases mortality burden.”
As part of the Global Burden of Disease Study, the investigators analyzed data from the Institute of Health Metrics and Evaluation Global Health Data Exchange, including age-standardized digestive disease mortality rates for five racial and ethnic groups (Black, White, American Indian and Alaska Native, Asian and Pacific Islander, and Latino) between 2000 and 2019, with further subgroups based on sex, state, and county. Joinpoint regression analysis was employed to determine overall temporal trends by demography.
Results showed striking mortality rate differences across racial and ethnic groups. In 2019, digestive disease mortality rates were highest among American Indian and Alaska Native individuals, reaching 86.2 per 100,000 — over twice the rate seen in White (35.5 per 100,000), Black (33.6 per 100,000), and Latino (33.6 per 100,000) populations, and more than five times higher than in Asian and Pacific Islander individuals (15.6 per 100,000). Over the study period, American Indian and Alaska Native individuals experienced a significant 0.87% average annual increase in mortality rates, while White individuals saw a smaller increase of 0.12% annually. In contrast, Latino, Black, and Asian and Pacific Islander individuals had declining average annual rates.
Geographic disparities in digestive disease mortality were significant, with West Virginia recording the highest state-level rate in 2019 at 44.8 deaths per 100,000, well above the national rate of 34.5 per 100,000. Certain regions with high concentrations of American Indian and Alaska Native populations, such as the Southwest Tribes service area (including Arizona and New Mexico) and the Plain Indians service area (spanning Montana, North Dakota, and South Dakota), reported mortality rates exceeding 70 per 100,000, more than double the national average. In Alaska, the American Indian and Alaska Native population’s mortality rate surged with annual increases of up to 3.53% during some periods.
Analyses also revealed some notable sex-based trends. Among American Indian and Alaska Native individuals, males experienced a mortality rate increase of 0.87% annually, reaching 93.5 per 100,000 by 2019, while females saw an even sharper rise at 1.11% per year, with a mortality rate of 79.6 per 100,000 in 2019. For White individuals, the average annual percentage increase was 0.12% for males, bringing their rate to 40.2 per 100,000, and 0.30% for females, with a rate of 31.0 per 100,000 in 2019.
“Our study reveals persistent racial, ethnic, and geographic disparities in digestive diseases mortality in the United States,” the investigators concluded. “Targeted interventions and further research are needed to address these disparities and promote digestive health equity. Collaboration among researchers, policymakers, healthcare providers, and communities is essential to achieve this goal.”This research was conducted as part of Global Burden of Disease, Injuries and Risk Factors Study, coordinated by the Institute of Health Metrics and Evaluation. The investigators disclosed no conflicts of interest.
which experience the highest death rates and ongoing increases, according to a recent study.
Policymakers, healthcare providers, and communities need to respond with targeted interventions and collaborative efforts that address these inequities and advance digestive health equity, lead author Wafa A. Aldhaleei, MD, of Mayo Clinic, Rochester, Minnesota, and colleagues reported.
“Several studies have reported the epidemiological characteristics of certain digestive diseases such as pancreatitis, liver and biliary diseases, and inflammatory bowel disease,” the investigators wrote in Clinical Gastroenterology and Hepatology. “These studies provide insights into the US burden by sex and racial and ethnic disparities of various digestive diseases individually. However, little is known about racial disparities in the United States digestive diseases mortality burden.”
As part of the Global Burden of Disease Study, the investigators analyzed data from the Institute of Health Metrics and Evaluation Global Health Data Exchange, including age-standardized digestive disease mortality rates for five racial and ethnic groups (Black, White, American Indian and Alaska Native, Asian and Pacific Islander, and Latino) between 2000 and 2019, with further subgroups based on sex, state, and county. Joinpoint regression analysis was employed to determine overall temporal trends by demography.
Results showed striking mortality rate differences across racial and ethnic groups. In 2019, digestive disease mortality rates were highest among American Indian and Alaska Native individuals, reaching 86.2 per 100,000 — over twice the rate seen in White (35.5 per 100,000), Black (33.6 per 100,000), and Latino (33.6 per 100,000) populations, and more than five times higher than in Asian and Pacific Islander individuals (15.6 per 100,000). Over the study period, American Indian and Alaska Native individuals experienced a significant 0.87% average annual increase in mortality rates, while White individuals saw a smaller increase of 0.12% annually. In contrast, Latino, Black, and Asian and Pacific Islander individuals had declining average annual rates.
Geographic disparities in digestive disease mortality were significant, with West Virginia recording the highest state-level rate in 2019 at 44.8 deaths per 100,000, well above the national rate of 34.5 per 100,000. Certain regions with high concentrations of American Indian and Alaska Native populations, such as the Southwest Tribes service area (including Arizona and New Mexico) and the Plain Indians service area (spanning Montana, North Dakota, and South Dakota), reported mortality rates exceeding 70 per 100,000, more than double the national average. In Alaska, the American Indian and Alaska Native population’s mortality rate surged with annual increases of up to 3.53% during some periods.
Analyses also revealed some notable sex-based trends. Among American Indian and Alaska Native individuals, males experienced a mortality rate increase of 0.87% annually, reaching 93.5 per 100,000 by 2019, while females saw an even sharper rise at 1.11% per year, with a mortality rate of 79.6 per 100,000 in 2019. For White individuals, the average annual percentage increase was 0.12% for males, bringing their rate to 40.2 per 100,000, and 0.30% for females, with a rate of 31.0 per 100,000 in 2019.
“Our study reveals persistent racial, ethnic, and geographic disparities in digestive diseases mortality in the United States,” the investigators concluded. “Targeted interventions and further research are needed to address these disparities and promote digestive health equity. Collaboration among researchers, policymakers, healthcare providers, and communities is essential to achieve this goal.”This research was conducted as part of Global Burden of Disease, Injuries and Risk Factors Study, coordinated by the Institute of Health Metrics and Evaluation. The investigators disclosed no conflicts of interest.
which experience the highest death rates and ongoing increases, according to a recent study.
Policymakers, healthcare providers, and communities need to respond with targeted interventions and collaborative efforts that address these inequities and advance digestive health equity, lead author Wafa A. Aldhaleei, MD, of Mayo Clinic, Rochester, Minnesota, and colleagues reported.
“Several studies have reported the epidemiological characteristics of certain digestive diseases such as pancreatitis, liver and biliary diseases, and inflammatory bowel disease,” the investigators wrote in Clinical Gastroenterology and Hepatology. “These studies provide insights into the US burden by sex and racial and ethnic disparities of various digestive diseases individually. However, little is known about racial disparities in the United States digestive diseases mortality burden.”
As part of the Global Burden of Disease Study, the investigators analyzed data from the Institute of Health Metrics and Evaluation Global Health Data Exchange, including age-standardized digestive disease mortality rates for five racial and ethnic groups (Black, White, American Indian and Alaska Native, Asian and Pacific Islander, and Latino) between 2000 and 2019, with further subgroups based on sex, state, and county. Joinpoint regression analysis was employed to determine overall temporal trends by demography.
Results showed striking mortality rate differences across racial and ethnic groups. In 2019, digestive disease mortality rates were highest among American Indian and Alaska Native individuals, reaching 86.2 per 100,000 — over twice the rate seen in White (35.5 per 100,000), Black (33.6 per 100,000), and Latino (33.6 per 100,000) populations, and more than five times higher than in Asian and Pacific Islander individuals (15.6 per 100,000). Over the study period, American Indian and Alaska Native individuals experienced a significant 0.87% average annual increase in mortality rates, while White individuals saw a smaller increase of 0.12% annually. In contrast, Latino, Black, and Asian and Pacific Islander individuals had declining average annual rates.
Geographic disparities in digestive disease mortality were significant, with West Virginia recording the highest state-level rate in 2019 at 44.8 deaths per 100,000, well above the national rate of 34.5 per 100,000. Certain regions with high concentrations of American Indian and Alaska Native populations, such as the Southwest Tribes service area (including Arizona and New Mexico) and the Plain Indians service area (spanning Montana, North Dakota, and South Dakota), reported mortality rates exceeding 70 per 100,000, more than double the national average. In Alaska, the American Indian and Alaska Native population’s mortality rate surged with annual increases of up to 3.53% during some periods.
Analyses also revealed some notable sex-based trends. Among American Indian and Alaska Native individuals, males experienced a mortality rate increase of 0.87% annually, reaching 93.5 per 100,000 by 2019, while females saw an even sharper rise at 1.11% per year, with a mortality rate of 79.6 per 100,000 in 2019. For White individuals, the average annual percentage increase was 0.12% for males, bringing their rate to 40.2 per 100,000, and 0.30% for females, with a rate of 31.0 per 100,000 in 2019.
“Our study reveals persistent racial, ethnic, and geographic disparities in digestive diseases mortality in the United States,” the investigators concluded. “Targeted interventions and further research are needed to address these disparities and promote digestive health equity. Collaboration among researchers, policymakers, healthcare providers, and communities is essential to achieve this goal.”This research was conducted as part of Global Burden of Disease, Injuries and Risk Factors Study, coordinated by the Institute of Health Metrics and Evaluation. The investigators disclosed no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Human Milk Boosts Intestinal Growth, Immune Health of Fetal Organoids
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES
Biomarkers Predict Villous Atrophy in Potential Celiac Disease Patients
according to investigators.
Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.
“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”
The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.
After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.
Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.
Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.
“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”
The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.
“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”
The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.
Patients with positive celiac serologies but normal villous architecture on biopsy are considered to have potential celiac disease (PCD). While the prevalence of PCD is not well-established, it is estimated to be around 1%. This study by Auricchio and colleagues investigates seven serum proteomic biomarkers that could help predict whether asymptomatic patients with PCD are at risk of developing villous atrophy (VA).
The study also identifies specific inflammatory proteins present in PCD patients who are likely to develop VA. These biomarkers provide valuable insights into the pathogenesis of celiac disease and the development of VA in genetically predisposed individuals.
As celiac disease is increasingly diagnosed without biopsies, serum proteomic biomarkers could be crucial in identifying patients who may benefit from starting a gluten-free diet (GFD) earlier, potentially preventing complications. According to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines, children can be diagnosed with celiac disease if their tissue transglutaminase IgA level is 10 times the upper limit of normal, confirmed by a positive endomysial antibody test. However, this approach may lead to many patients committing to a lifelong GFD despite having only PCD, as biopsies may not have been performed. In this study, 60% of patients with PCD did not progress to VA, suggesting that biomarkers could help prevent unnecessary long-term GFD commitments.
Stephanie M. Moleski, MD, is the director of the Jefferson Celiac Center and associate professor in the division of gastroenterology at Thomas Jefferson University Hospital in Philadelphia. She reported no conflicts of interest.
Patients with positive celiac serologies but normal villous architecture on biopsy are considered to have potential celiac disease (PCD). While the prevalence of PCD is not well-established, it is estimated to be around 1%. This study by Auricchio and colleagues investigates seven serum proteomic biomarkers that could help predict whether asymptomatic patients with PCD are at risk of developing villous atrophy (VA).
The study also identifies specific inflammatory proteins present in PCD patients who are likely to develop VA. These biomarkers provide valuable insights into the pathogenesis of celiac disease and the development of VA in genetically predisposed individuals.
As celiac disease is increasingly diagnosed without biopsies, serum proteomic biomarkers could be crucial in identifying patients who may benefit from starting a gluten-free diet (GFD) earlier, potentially preventing complications. According to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines, children can be diagnosed with celiac disease if their tissue transglutaminase IgA level is 10 times the upper limit of normal, confirmed by a positive endomysial antibody test. However, this approach may lead to many patients committing to a lifelong GFD despite having only PCD, as biopsies may not have been performed. In this study, 60% of patients with PCD did not progress to VA, suggesting that biomarkers could help prevent unnecessary long-term GFD commitments.
Stephanie M. Moleski, MD, is the director of the Jefferson Celiac Center and associate professor in the division of gastroenterology at Thomas Jefferson University Hospital in Philadelphia. She reported no conflicts of interest.
Patients with positive celiac serologies but normal villous architecture on biopsy are considered to have potential celiac disease (PCD). While the prevalence of PCD is not well-established, it is estimated to be around 1%. This study by Auricchio and colleagues investigates seven serum proteomic biomarkers that could help predict whether asymptomatic patients with PCD are at risk of developing villous atrophy (VA).
The study also identifies specific inflammatory proteins present in PCD patients who are likely to develop VA. These biomarkers provide valuable insights into the pathogenesis of celiac disease and the development of VA in genetically predisposed individuals.
As celiac disease is increasingly diagnosed without biopsies, serum proteomic biomarkers could be crucial in identifying patients who may benefit from starting a gluten-free diet (GFD) earlier, potentially preventing complications. According to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines, children can be diagnosed with celiac disease if their tissue transglutaminase IgA level is 10 times the upper limit of normal, confirmed by a positive endomysial antibody test. However, this approach may lead to many patients committing to a lifelong GFD despite having only PCD, as biopsies may not have been performed. In this study, 60% of patients with PCD did not progress to VA, suggesting that biomarkers could help prevent unnecessary long-term GFD commitments.
Stephanie M. Moleski, MD, is the director of the Jefferson Celiac Center and associate professor in the division of gastroenterology at Thomas Jefferson University Hospital in Philadelphia. She reported no conflicts of interest.
according to investigators.
Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.
“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”
The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.
After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.
Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.
Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.
“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”
The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.
“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”
The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.
according to investigators.
Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.
“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”
The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.
After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.
Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.
Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.
“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”
The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.
“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”
The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
AGA Guidelines Endorse Earlier Use of High-Efficacy Drugs for Ulcerative Colitis
In a rapidly expanding therapeutic landscape,
“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.
Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.
“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.
The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”
One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated.
“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.
The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.
Specifics
Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.
The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.
The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.
Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:
- Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
- Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
- Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
- For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
- In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
- The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
- The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
- Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
- The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
- For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
- For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.
According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.
However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”
Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”
The Future
The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.
The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.
They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.
The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.
These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.
A version of this article appeared on Medscape.com.
In a rapidly expanding therapeutic landscape,
“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.
Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.
“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.
The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”
One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated.
“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.
The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.
Specifics
Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.
The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.
The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.
Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:
- Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
- Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
- Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
- For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
- In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
- The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
- The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
- Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
- The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
- For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
- For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.
According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.
However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”
Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”
The Future
The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.
The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.
They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.
The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.
These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.
A version of this article appeared on Medscape.com.
In a rapidly expanding therapeutic landscape,
“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.
Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.
“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.
The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”
One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated.
“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.
The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.
Specifics
Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.
The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.
The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.
Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:
- Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
- Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
- Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
- For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
- In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
- The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
- The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
- Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
- The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
- For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
- For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.
According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.
However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”
Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”
The Future
The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.
The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.
They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.
The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.
These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.
A version of this article appeared on Medscape.com.
FROM GASTROENTEROLOGY
Journal Highlights: Sept.-Oct. 2024
Upper GI
Levinthal DJ et al. AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.05.031.
Geeratragool T et al. Comparison of Vonoprazan Versus Intravenous Proton Pump Inhibitor for Prevention of High-Risk Peptic Ulcers Rebleeding After Successful Endoscopic Hemostasis: A Multicenter Randomized Noninferiority Trial. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.03.036.
Goodoory VC et al. Effect of Brain-Gut Behavioral Treatments on Abdominal Pain in Irritable Bowel Syndrome: Systematic Review and Network Meta-Analysis. Gastroenterology. 2024 Oct. doi: 10.1053/j.gastro.2024.05.010.
Kurlander JE et al; Gastrointestinal Bleeding Working Group. Prescribing of Proton Pump Inhibitors for Prevention of Upper Gastrointestinal Bleeding in US Outpatient Visits. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.01.047.
Oliva S et al. Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.020.
Lower GI
Redd WD et al. Follow-Up Colonoscopy for Detection of Missed Colorectal Cancer After Diverticulitis. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.03.036.
Peyrin-Biroulet L et al. Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn’s Disease Regardless of Prior Biologic Exposure. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.02.026.
Chang PW et al. ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.022.
Liver
Wang L et al. Association of GLP-1 Receptor Agonists and Hepatocellular Carcinoma Incidence and Hepatic Decompensation in Patients With Type 2 Diabetes. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.04.029.
Bajaj JS et al. Serum Ammonia Levels Do Not Correlate With Overt Hepatic Encephalopathy Severity in Hospitalized Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.02.015.
Endoscopy
Steinbrück I, et al. Cold Versus Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.05.013.
Misc.
Kothari S et al. AGA Clinical Practice Update on Pregnancy-Related Gastrointestinal and Liver Disease: Expert Review. Gastroenterology. 2024 Oct. doi: 10.1053/j.gastro.2024.06.014.
Chavannes M et al. AGA Clinical Practice Update on the Role of Intestinal Ultrasound in Inflammatory Bowel Disease: Commentary. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.039.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Upper GI
Levinthal DJ et al. AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.05.031.
Geeratragool T et al. Comparison of Vonoprazan Versus Intravenous Proton Pump Inhibitor for Prevention of High-Risk Peptic Ulcers Rebleeding After Successful Endoscopic Hemostasis: A Multicenter Randomized Noninferiority Trial. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.03.036.
Goodoory VC et al. Effect of Brain-Gut Behavioral Treatments on Abdominal Pain in Irritable Bowel Syndrome: Systematic Review and Network Meta-Analysis. Gastroenterology. 2024 Oct. doi: 10.1053/j.gastro.2024.05.010.
Kurlander JE et al; Gastrointestinal Bleeding Working Group. Prescribing of Proton Pump Inhibitors for Prevention of Upper Gastrointestinal Bleeding in US Outpatient Visits. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.01.047.
Oliva S et al. Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.020.
Lower GI
Redd WD et al. Follow-Up Colonoscopy for Detection of Missed Colorectal Cancer After Diverticulitis. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.03.036.
Peyrin-Biroulet L et al. Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn’s Disease Regardless of Prior Biologic Exposure. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.02.026.
Chang PW et al. ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.022.
Liver
Wang L et al. Association of GLP-1 Receptor Agonists and Hepatocellular Carcinoma Incidence and Hepatic Decompensation in Patients With Type 2 Diabetes. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.04.029.
Bajaj JS et al. Serum Ammonia Levels Do Not Correlate With Overt Hepatic Encephalopathy Severity in Hospitalized Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.02.015.
Endoscopy
Steinbrück I, et al. Cold Versus Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.05.013.
Misc.
Kothari S et al. AGA Clinical Practice Update on Pregnancy-Related Gastrointestinal and Liver Disease: Expert Review. Gastroenterology. 2024 Oct. doi: 10.1053/j.gastro.2024.06.014.
Chavannes M et al. AGA Clinical Practice Update on the Role of Intestinal Ultrasound in Inflammatory Bowel Disease: Commentary. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.039.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Upper GI
Levinthal DJ et al. AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.05.031.
Geeratragool T et al. Comparison of Vonoprazan Versus Intravenous Proton Pump Inhibitor for Prevention of High-Risk Peptic Ulcers Rebleeding After Successful Endoscopic Hemostasis: A Multicenter Randomized Noninferiority Trial. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.03.036.
Goodoory VC et al. Effect of Brain-Gut Behavioral Treatments on Abdominal Pain in Irritable Bowel Syndrome: Systematic Review and Network Meta-Analysis. Gastroenterology. 2024 Oct. doi: 10.1053/j.gastro.2024.05.010.
Kurlander JE et al; Gastrointestinal Bleeding Working Group. Prescribing of Proton Pump Inhibitors for Prevention of Upper Gastrointestinal Bleeding in US Outpatient Visits. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.01.047.
Oliva S et al. Crafting a Therapeutic Pyramid for Eosinophilic Esophagitis in the Age of Biologics. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.020.
Lower GI
Redd WD et al. Follow-Up Colonoscopy for Detection of Missed Colorectal Cancer After Diverticulitis. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.03.036.
Peyrin-Biroulet L et al. Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn’s Disease Regardless of Prior Biologic Exposure. Clin Gastroenterol Hepatol. 2024 Oct. doi: 10.1016/j.cgh.2024.02.026.
Chang PW et al. ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.022.
Liver
Wang L et al. Association of GLP-1 Receptor Agonists and Hepatocellular Carcinoma Incidence and Hepatic Decompensation in Patients With Type 2 Diabetes. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.04.029.
Bajaj JS et al. Serum Ammonia Levels Do Not Correlate With Overt Hepatic Encephalopathy Severity in Hospitalized Patients With Cirrhosis. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.02.015.
Endoscopy
Steinbrück I, et al. Cold Versus Hot Snare Endoscopic Resection of Large Nonpedunculated Colorectal Polyps: Randomized Controlled German CHRONICLE Trial. Gastroenterology. 2024 Sep. doi: 10.1053/j.gastro.2024.05.013.
Misc.
Kothari S et al. AGA Clinical Practice Update on Pregnancy-Related Gastrointestinal and Liver Disease: Expert Review. Gastroenterology. 2024 Oct. doi: 10.1053/j.gastro.2024.06.014.
Chavannes M et al. AGA Clinical Practice Update on the Role of Intestinal Ultrasound in Inflammatory Bowel Disease: Commentary. Clin Gastroenterol Hepatol. 2024 Sep. doi: 10.1016/j.cgh.2024.04.039.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Common Crohn’s Immune Response to Gut Bacteria Suggests Therapeutic Target
Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.
These findings suggest that lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.
Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.
“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.
To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.
Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.
This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.
Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.
“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”
Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.
Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.
These findings suggest that lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.
Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.
“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.
To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.
Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.
This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.
Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.
“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”
Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.
Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.
These findings suggest that lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.
Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.
“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.
To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.
Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.
This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.
Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.
“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”
Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.
FROM GASTROENTEROLOGY