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Health care costs nearly doubled for patients with NAFLD
The health care costs of patients with nonalcoholic fatty liver disease (NAFLD) were nearly twice that of matched population controls, according to the results of a longitudinal cohort study.
Patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were hospitalized an average of 0.27 times per year versus 0.16 times for controls (P < .001), for an annual incremental cost of $635, reported Hannes Hagström, MD, PhD, of Karolinska University Hospital in Stockholm. Patients with NAFLD also made significantly more outpatient care visits than controls (P < .001), he said. “Patients with advanced fibrosis [had] the highest costs, suggesting that reducing fibrosis progression is important to reduce future health care costs” among patients with NASH, Dr. Hagström and his associates wrote in Clinical Gastroenterology and Hepatology.
The retrospective longitudinal cohort study included all 646 patients diagnosed with biopsy-confirmed NAFLD at two hospitals in Sweden between 1971 and 2019. Patients with other liver diseases were excluded, as were heavy drinkers: men who drank more than 30 g of alcohol (just under four units) daily and women who drank more than 20 g daily. Each patient with NAFLD was matched with 10 population controls matched by age, sex, and county of residence.
Over a mean of 19.9 years of follow-up (range, 0-40 years), patients with NASH were hospitalized a total of 3,478 times, an average of 5.4 hospitalizations per patient. Controls were hospitalized an average of 3.2 times during the same time period (P < .001 vs. NASH patients). “This corresponded to a higher incremental cost in NAFLD patients of $635 per year (95% confidence interval, $407-$864; P < .001),” the researchers reported.
Between 2001 and 2009, patients with NAFLD averaged 5.4 more outpatient visits than controls (P < .001), with annual averages of 1.46 versus 0.86 visits (P < .001). Consequently, patient with NASH incurred $255 more per year in annual outpatient care costs. Liver disease accounted for 6% of outpatient care costs among NASH patients versus 0.2% of costs among controls.
“Cumulative costs in the [fibrosis stage 3 and 4] subgroup were relatively matched with the control population until around year 4 after biopsy, when costs diverged,” the researchers said. “This could possibly be an effect of the larger F3 population developing cirrhosis and increasing costs due to decompensation events.”
They noted that the rising prevalence of NAFLD will further burden health care budgets. “Costs [among patients with NASH] were higher in conjunction with liver biopsy, which is why using noninvasive diagnostic methods (e.g., transient elastography) is likely to reduce total costs,” they added. Of note, although patients with NAFLD also incurred somewhat more per year in prescription costs, the difference was not statistically significant.
The study was supported by Stockholm City Council, the Bengt Ihre Foundation, the County Council of Östergötland, and Gilead. The researchers reported having no conflicts of interest.
SOURCE: Kim H et al. Clin Gastroenterol Hepatol. 2019 Sep 12. doi: 10.1016/j.cgh.2019.10.023.
The possibility of FDA approval of NASH-modifying drugs later this year brings the hope of improving outcomes for patients with NAFLD. Inevitably, the cost effectiveness of those drugs also will be scrutinized as we evaluate their impact in the coming years. To that end, Hagstrom et al. provide useful insight regarding the real-world costs of medical care among patients with histologically staged NAFLD in Sweden.
Their main finding is that medical costs for a patient with NAFLD over 20 years is double that for a random control patient from the general population.
It is worth taking a deeper dive into the factors that drove the cost differential. First, higher inpatient and outpatient specialty care costs accounted for the incremental cost of NAFLD care; drug costs were materially similar in the two groups, albeit examined over a very short time period in the study due to limited national registry data. Second, the cost differential was largest in the first year of diagnosis and attributed to the cost of liver biopsy and related expenses. Last, as one would expect, the cost differential was largest between patients who had stage 3-4 fibrosis, possibly explained by the costs of NASH-related complications.
While we hope that NASH-modifying drugs will reduce the risk of liver-specific complications, the cumulative financial impact of such therapies remains to be seen. On the one hand, short-term costs may increase because of the direct expense of the NASH-modifying drugs plus additional expenses related to management of side effects. In addition, it is likely patients treated with NASH-modifying drugs will need more frequent assessments of liver disease severity to evaluate whether the medication is working, which even if done noninvasively, is likely the add to medical costs. In the long term however, NASH-modifying treatments may reduce the risk of NAFLD complications over time, mitigating the cumulative cost of NAFLD care. The true net effect remains to be seen. In the meantime, we need further studies that quantify costs of NAFLD care - ideally by disease severity and that provide greater insight into the cost of caring for the complications of NASH progression, including liver disease clinical decompensations and transplant.
Maya Balakrishnan, MD, MPH, is an assistant professor, department of medicine, section of gastroenterology & hepatology, Baylor College of Medicine, Houston, and director of hepatology at Ben Taub General Hospital, Houston. She has no conflicts of interest.
The possibility of FDA approval of NASH-modifying drugs later this year brings the hope of improving outcomes for patients with NAFLD. Inevitably, the cost effectiveness of those drugs also will be scrutinized as we evaluate their impact in the coming years. To that end, Hagstrom et al. provide useful insight regarding the real-world costs of medical care among patients with histologically staged NAFLD in Sweden.
Their main finding is that medical costs for a patient with NAFLD over 20 years is double that for a random control patient from the general population.
It is worth taking a deeper dive into the factors that drove the cost differential. First, higher inpatient and outpatient specialty care costs accounted for the incremental cost of NAFLD care; drug costs were materially similar in the two groups, albeit examined over a very short time period in the study due to limited national registry data. Second, the cost differential was largest in the first year of diagnosis and attributed to the cost of liver biopsy and related expenses. Last, as one would expect, the cost differential was largest between patients who had stage 3-4 fibrosis, possibly explained by the costs of NASH-related complications.
While we hope that NASH-modifying drugs will reduce the risk of liver-specific complications, the cumulative financial impact of such therapies remains to be seen. On the one hand, short-term costs may increase because of the direct expense of the NASH-modifying drugs plus additional expenses related to management of side effects. In addition, it is likely patients treated with NASH-modifying drugs will need more frequent assessments of liver disease severity to evaluate whether the medication is working, which even if done noninvasively, is likely the add to medical costs. In the long term however, NASH-modifying treatments may reduce the risk of NAFLD complications over time, mitigating the cumulative cost of NAFLD care. The true net effect remains to be seen. In the meantime, we need further studies that quantify costs of NAFLD care - ideally by disease severity and that provide greater insight into the cost of caring for the complications of NASH progression, including liver disease clinical decompensations and transplant.
Maya Balakrishnan, MD, MPH, is an assistant professor, department of medicine, section of gastroenterology & hepatology, Baylor College of Medicine, Houston, and director of hepatology at Ben Taub General Hospital, Houston. She has no conflicts of interest.
The possibility of FDA approval of NASH-modifying drugs later this year brings the hope of improving outcomes for patients with NAFLD. Inevitably, the cost effectiveness of those drugs also will be scrutinized as we evaluate their impact in the coming years. To that end, Hagstrom et al. provide useful insight regarding the real-world costs of medical care among patients with histologically staged NAFLD in Sweden.
Their main finding is that medical costs for a patient with NAFLD over 20 years is double that for a random control patient from the general population.
It is worth taking a deeper dive into the factors that drove the cost differential. First, higher inpatient and outpatient specialty care costs accounted for the incremental cost of NAFLD care; drug costs were materially similar in the two groups, albeit examined over a very short time period in the study due to limited national registry data. Second, the cost differential was largest in the first year of diagnosis and attributed to the cost of liver biopsy and related expenses. Last, as one would expect, the cost differential was largest between patients who had stage 3-4 fibrosis, possibly explained by the costs of NASH-related complications.
While we hope that NASH-modifying drugs will reduce the risk of liver-specific complications, the cumulative financial impact of such therapies remains to be seen. On the one hand, short-term costs may increase because of the direct expense of the NASH-modifying drugs plus additional expenses related to management of side effects. In addition, it is likely patients treated with NASH-modifying drugs will need more frequent assessments of liver disease severity to evaluate whether the medication is working, which even if done noninvasively, is likely the add to medical costs. In the long term however, NASH-modifying treatments may reduce the risk of NAFLD complications over time, mitigating the cumulative cost of NAFLD care. The true net effect remains to be seen. In the meantime, we need further studies that quantify costs of NAFLD care - ideally by disease severity and that provide greater insight into the cost of caring for the complications of NASH progression, including liver disease clinical decompensations and transplant.
Maya Balakrishnan, MD, MPH, is an assistant professor, department of medicine, section of gastroenterology & hepatology, Baylor College of Medicine, Houston, and director of hepatology at Ben Taub General Hospital, Houston. She has no conflicts of interest.
The health care costs of patients with nonalcoholic fatty liver disease (NAFLD) were nearly twice that of matched population controls, according to the results of a longitudinal cohort study.
Patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were hospitalized an average of 0.27 times per year versus 0.16 times for controls (P < .001), for an annual incremental cost of $635, reported Hannes Hagström, MD, PhD, of Karolinska University Hospital in Stockholm. Patients with NAFLD also made significantly more outpatient care visits than controls (P < .001), he said. “Patients with advanced fibrosis [had] the highest costs, suggesting that reducing fibrosis progression is important to reduce future health care costs” among patients with NASH, Dr. Hagström and his associates wrote in Clinical Gastroenterology and Hepatology.
The retrospective longitudinal cohort study included all 646 patients diagnosed with biopsy-confirmed NAFLD at two hospitals in Sweden between 1971 and 2019. Patients with other liver diseases were excluded, as were heavy drinkers: men who drank more than 30 g of alcohol (just under four units) daily and women who drank more than 20 g daily. Each patient with NAFLD was matched with 10 population controls matched by age, sex, and county of residence.
Over a mean of 19.9 years of follow-up (range, 0-40 years), patients with NASH were hospitalized a total of 3,478 times, an average of 5.4 hospitalizations per patient. Controls were hospitalized an average of 3.2 times during the same time period (P < .001 vs. NASH patients). “This corresponded to a higher incremental cost in NAFLD patients of $635 per year (95% confidence interval, $407-$864; P < .001),” the researchers reported.
Between 2001 and 2009, patients with NAFLD averaged 5.4 more outpatient visits than controls (P < .001), with annual averages of 1.46 versus 0.86 visits (P < .001). Consequently, patient with NASH incurred $255 more per year in annual outpatient care costs. Liver disease accounted for 6% of outpatient care costs among NASH patients versus 0.2% of costs among controls.
“Cumulative costs in the [fibrosis stage 3 and 4] subgroup were relatively matched with the control population until around year 4 after biopsy, when costs diverged,” the researchers said. “This could possibly be an effect of the larger F3 population developing cirrhosis and increasing costs due to decompensation events.”
They noted that the rising prevalence of NAFLD will further burden health care budgets. “Costs [among patients with NASH] were higher in conjunction with liver biopsy, which is why using noninvasive diagnostic methods (e.g., transient elastography) is likely to reduce total costs,” they added. Of note, although patients with NAFLD also incurred somewhat more per year in prescription costs, the difference was not statistically significant.
The study was supported by Stockholm City Council, the Bengt Ihre Foundation, the County Council of Östergötland, and Gilead. The researchers reported having no conflicts of interest.
SOURCE: Kim H et al. Clin Gastroenterol Hepatol. 2019 Sep 12. doi: 10.1016/j.cgh.2019.10.023.
The health care costs of patients with nonalcoholic fatty liver disease (NAFLD) were nearly twice that of matched population controls, according to the results of a longitudinal cohort study.
Patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were hospitalized an average of 0.27 times per year versus 0.16 times for controls (P < .001), for an annual incremental cost of $635, reported Hannes Hagström, MD, PhD, of Karolinska University Hospital in Stockholm. Patients with NAFLD also made significantly more outpatient care visits than controls (P < .001), he said. “Patients with advanced fibrosis [had] the highest costs, suggesting that reducing fibrosis progression is important to reduce future health care costs” among patients with NASH, Dr. Hagström and his associates wrote in Clinical Gastroenterology and Hepatology.
The retrospective longitudinal cohort study included all 646 patients diagnosed with biopsy-confirmed NAFLD at two hospitals in Sweden between 1971 and 2019. Patients with other liver diseases were excluded, as were heavy drinkers: men who drank more than 30 g of alcohol (just under four units) daily and women who drank more than 20 g daily. Each patient with NAFLD was matched with 10 population controls matched by age, sex, and county of residence.
Over a mean of 19.9 years of follow-up (range, 0-40 years), patients with NASH were hospitalized a total of 3,478 times, an average of 5.4 hospitalizations per patient. Controls were hospitalized an average of 3.2 times during the same time period (P < .001 vs. NASH patients). “This corresponded to a higher incremental cost in NAFLD patients of $635 per year (95% confidence interval, $407-$864; P < .001),” the researchers reported.
Between 2001 and 2009, patients with NAFLD averaged 5.4 more outpatient visits than controls (P < .001), with annual averages of 1.46 versus 0.86 visits (P < .001). Consequently, patient with NASH incurred $255 more per year in annual outpatient care costs. Liver disease accounted for 6% of outpatient care costs among NASH patients versus 0.2% of costs among controls.
“Cumulative costs in the [fibrosis stage 3 and 4] subgroup were relatively matched with the control population until around year 4 after biopsy, when costs diverged,” the researchers said. “This could possibly be an effect of the larger F3 population developing cirrhosis and increasing costs due to decompensation events.”
They noted that the rising prevalence of NAFLD will further burden health care budgets. “Costs [among patients with NASH] were higher in conjunction with liver biopsy, which is why using noninvasive diagnostic methods (e.g., transient elastography) is likely to reduce total costs,” they added. Of note, although patients with NAFLD also incurred somewhat more per year in prescription costs, the difference was not statistically significant.
The study was supported by Stockholm City Council, the Bengt Ihre Foundation, the County Council of Östergötland, and Gilead. The researchers reported having no conflicts of interest.
SOURCE: Kim H et al. Clin Gastroenterol Hepatol. 2019 Sep 12. doi: 10.1016/j.cgh.2019.10.023.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Guideline: Management of eosinophilic esophagitis
Patients with eosinophilic esophagitis should receive topical steroids instead of oral steroids or no treatment, according to new recommendations from the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters.
In a pooled analysis of eight double-blind clinical trials, monotherapy with topical budesonide or topical fluticasone was about 61% more likely than placebo to produce histologic remissions in patients with eosinophilic esophagitis (relative risk of failure to achieve remission, 0.39; 95% confidence interval, 0.26-0.58), wrote Ikuo Hirano, MD, of Northwestern University, Chicago. Although these trials differed methodologically, the results were robust enough to warrant a strong recommendation for topical steroids, wrote Dr. Hirano and coauthors of the guidelines, published in Gastroenterology (doi: 10.1053/j.gastro.2020.02.038). “[T]he same inhaled steroid agents are considered very safe for use in children and adults with asthma and are routinely used in [its] primary management,” they noted.
All other recommendations in the guidelines are graded as conditional, reflecting a lack of high-quality supporting evidence. For example, one only study to date has compared topical and oral steroids for patients with eosinophilic esophagitis. In this pediatric trial, children benefited similarly from fluticasone (two puffs four times daily) and oral prednisone (1 mg/kg twice daily), but prednisone caused side effects (weight gain and cushingoid appearance) in 40% of patients, while topical steroids caused oral candidiasis (thrush) in only 15% of patients. Similarities between pediatric and adult eosinophilic esophagitis support the use of topical versus oral steroids in both groups, the guidelines conclude.
Eosinophilic esophagitis tends to be chronic and can progress to recurrent dysphagia, esophageal impactions, and stricture if left untreated. For this reason, the guidelines call for remitted patients to stay on topical steroids as maintenance therapy despite “very low confidence in the estimated benefits of [any type of] long-term therapy.” In a very small trial, 1 year of low-dose budesonide maintenance therapy (0.25 mg twice daily) outperformed placebo, but only 36% of patients maintained less than 5 eosinophils per high power field. Other studies have produced mixed results. Pending more data, the guidelines call maintenance treatment with topical steroids, proton pump inhibitors, and elimination diets “reasonable options” that comprise “a preference-sensitive area of management.”
Dietary interventions for eosinophilic esophagitis include the elemental diet (amino acid–based formulas), the empiric six-food elimination diet, and eliminating foods based on allergy testing. The guidelines cite moderate-quality evidence for the elemental diet, which induced histologic remissions (less than than 15 eosinophils per high power field) in nearly 94% of patients in six single-arm observational studies (in contrast, the rate of histologic failure with placebo is nearly 87%). However, patients may struggle to adhere to both the elemental diet and the six-food elimination diet, which has less supporting evidence. Hence, patients “may reasonably decline” these treatment options and “may prefer alternative medical or dietary therapies” to a diet exclusively based on food allergens, tests for which are potentially inaccurate, the guidelines state.
Esophageal dilation is recommended for patients with stricture based on a systematic review in which 87% of patients improved with this therapy. However, dilation “does not address the esophageal inflammation associated with eosinophilic esophagitis,” and the “assumption that no clinical improvement would occur if dilation was not performed likely overestimates [its] treatment benefit, given the reported symptom-placebo response noted in controlled trials,” according to the guidelines. Moreover, the evidence for dilation “was considered low quality due to the retrospective, single-arm design of all but one of the reports, and the lack of a standard definition for what constitutes clinical improvement.”
Anti-IgE therapy is not recommended – it failed to improve symptoms or esophageal eosinophilia in the only trial conducted to date. Because of a lack of evidence, the guidelines state that patients should receive only montelukast, cromolyn sodium, immunomodulators, anti–tumor necrosis factor (anti-TNF) therapies, or therapies targeting interleukin (IL)-5, IL-13, or IL-4 in the context of a clinical trial.
Eosinophilic esophagitis is triggered by exposure to food antigens and often overlaps with other atopic conditions, such as asthma, eczema, and allergic rhinitis. It has no approved treatments in the United States, although in 2018, the European Medicines Agency approved a budesonide tablet formulation.
The guideline authors disclosed no conflicts of interest.
SOURCE: Hirano I et al. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.02.038.
Patients with eosinophilic esophagitis should receive topical steroids instead of oral steroids or no treatment, according to new recommendations from the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters.
In a pooled analysis of eight double-blind clinical trials, monotherapy with topical budesonide or topical fluticasone was about 61% more likely than placebo to produce histologic remissions in patients with eosinophilic esophagitis (relative risk of failure to achieve remission, 0.39; 95% confidence interval, 0.26-0.58), wrote Ikuo Hirano, MD, of Northwestern University, Chicago. Although these trials differed methodologically, the results were robust enough to warrant a strong recommendation for topical steroids, wrote Dr. Hirano and coauthors of the guidelines, published in Gastroenterology (doi: 10.1053/j.gastro.2020.02.038). “[T]he same inhaled steroid agents are considered very safe for use in children and adults with asthma and are routinely used in [its] primary management,” they noted.
All other recommendations in the guidelines are graded as conditional, reflecting a lack of high-quality supporting evidence. For example, one only study to date has compared topical and oral steroids for patients with eosinophilic esophagitis. In this pediatric trial, children benefited similarly from fluticasone (two puffs four times daily) and oral prednisone (1 mg/kg twice daily), but prednisone caused side effects (weight gain and cushingoid appearance) in 40% of patients, while topical steroids caused oral candidiasis (thrush) in only 15% of patients. Similarities between pediatric and adult eosinophilic esophagitis support the use of topical versus oral steroids in both groups, the guidelines conclude.
Eosinophilic esophagitis tends to be chronic and can progress to recurrent dysphagia, esophageal impactions, and stricture if left untreated. For this reason, the guidelines call for remitted patients to stay on topical steroids as maintenance therapy despite “very low confidence in the estimated benefits of [any type of] long-term therapy.” In a very small trial, 1 year of low-dose budesonide maintenance therapy (0.25 mg twice daily) outperformed placebo, but only 36% of patients maintained less than 5 eosinophils per high power field. Other studies have produced mixed results. Pending more data, the guidelines call maintenance treatment with topical steroids, proton pump inhibitors, and elimination diets “reasonable options” that comprise “a preference-sensitive area of management.”
Dietary interventions for eosinophilic esophagitis include the elemental diet (amino acid–based formulas), the empiric six-food elimination diet, and eliminating foods based on allergy testing. The guidelines cite moderate-quality evidence for the elemental diet, which induced histologic remissions (less than than 15 eosinophils per high power field) in nearly 94% of patients in six single-arm observational studies (in contrast, the rate of histologic failure with placebo is nearly 87%). However, patients may struggle to adhere to both the elemental diet and the six-food elimination diet, which has less supporting evidence. Hence, patients “may reasonably decline” these treatment options and “may prefer alternative medical or dietary therapies” to a diet exclusively based on food allergens, tests for which are potentially inaccurate, the guidelines state.
Esophageal dilation is recommended for patients with stricture based on a systematic review in which 87% of patients improved with this therapy. However, dilation “does not address the esophageal inflammation associated with eosinophilic esophagitis,” and the “assumption that no clinical improvement would occur if dilation was not performed likely overestimates [its] treatment benefit, given the reported symptom-placebo response noted in controlled trials,” according to the guidelines. Moreover, the evidence for dilation “was considered low quality due to the retrospective, single-arm design of all but one of the reports, and the lack of a standard definition for what constitutes clinical improvement.”
Anti-IgE therapy is not recommended – it failed to improve symptoms or esophageal eosinophilia in the only trial conducted to date. Because of a lack of evidence, the guidelines state that patients should receive only montelukast, cromolyn sodium, immunomodulators, anti–tumor necrosis factor (anti-TNF) therapies, or therapies targeting interleukin (IL)-5, IL-13, or IL-4 in the context of a clinical trial.
Eosinophilic esophagitis is triggered by exposure to food antigens and often overlaps with other atopic conditions, such as asthma, eczema, and allergic rhinitis. It has no approved treatments in the United States, although in 2018, the European Medicines Agency approved a budesonide tablet formulation.
The guideline authors disclosed no conflicts of interest.
SOURCE: Hirano I et al. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.02.038.
Patients with eosinophilic esophagitis should receive topical steroids instead of oral steroids or no treatment, according to new recommendations from the American Gastroenterological Association and the Joint Task Force on Allergy-Immunology Practice Parameters.
In a pooled analysis of eight double-blind clinical trials, monotherapy with topical budesonide or topical fluticasone was about 61% more likely than placebo to produce histologic remissions in patients with eosinophilic esophagitis (relative risk of failure to achieve remission, 0.39; 95% confidence interval, 0.26-0.58), wrote Ikuo Hirano, MD, of Northwestern University, Chicago. Although these trials differed methodologically, the results were robust enough to warrant a strong recommendation for topical steroids, wrote Dr. Hirano and coauthors of the guidelines, published in Gastroenterology (doi: 10.1053/j.gastro.2020.02.038). “[T]he same inhaled steroid agents are considered very safe for use in children and adults with asthma and are routinely used in [its] primary management,” they noted.
All other recommendations in the guidelines are graded as conditional, reflecting a lack of high-quality supporting evidence. For example, one only study to date has compared topical and oral steroids for patients with eosinophilic esophagitis. In this pediatric trial, children benefited similarly from fluticasone (two puffs four times daily) and oral prednisone (1 mg/kg twice daily), but prednisone caused side effects (weight gain and cushingoid appearance) in 40% of patients, while topical steroids caused oral candidiasis (thrush) in only 15% of patients. Similarities between pediatric and adult eosinophilic esophagitis support the use of topical versus oral steroids in both groups, the guidelines conclude.
Eosinophilic esophagitis tends to be chronic and can progress to recurrent dysphagia, esophageal impactions, and stricture if left untreated. For this reason, the guidelines call for remitted patients to stay on topical steroids as maintenance therapy despite “very low confidence in the estimated benefits of [any type of] long-term therapy.” In a very small trial, 1 year of low-dose budesonide maintenance therapy (0.25 mg twice daily) outperformed placebo, but only 36% of patients maintained less than 5 eosinophils per high power field. Other studies have produced mixed results. Pending more data, the guidelines call maintenance treatment with topical steroids, proton pump inhibitors, and elimination diets “reasonable options” that comprise “a preference-sensitive area of management.”
Dietary interventions for eosinophilic esophagitis include the elemental diet (amino acid–based formulas), the empiric six-food elimination diet, and eliminating foods based on allergy testing. The guidelines cite moderate-quality evidence for the elemental diet, which induced histologic remissions (less than than 15 eosinophils per high power field) in nearly 94% of patients in six single-arm observational studies (in contrast, the rate of histologic failure with placebo is nearly 87%). However, patients may struggle to adhere to both the elemental diet and the six-food elimination diet, which has less supporting evidence. Hence, patients “may reasonably decline” these treatment options and “may prefer alternative medical or dietary therapies” to a diet exclusively based on food allergens, tests for which are potentially inaccurate, the guidelines state.
Esophageal dilation is recommended for patients with stricture based on a systematic review in which 87% of patients improved with this therapy. However, dilation “does not address the esophageal inflammation associated with eosinophilic esophagitis,” and the “assumption that no clinical improvement would occur if dilation was not performed likely overestimates [its] treatment benefit, given the reported symptom-placebo response noted in controlled trials,” according to the guidelines. Moreover, the evidence for dilation “was considered low quality due to the retrospective, single-arm design of all but one of the reports, and the lack of a standard definition for what constitutes clinical improvement.”
Anti-IgE therapy is not recommended – it failed to improve symptoms or esophageal eosinophilia in the only trial conducted to date. Because of a lack of evidence, the guidelines state that patients should receive only montelukast, cromolyn sodium, immunomodulators, anti–tumor necrosis factor (anti-TNF) therapies, or therapies targeting interleukin (IL)-5, IL-13, or IL-4 in the context of a clinical trial.
Eosinophilic esophagitis is triggered by exposure to food antigens and often overlaps with other atopic conditions, such as asthma, eczema, and allergic rhinitis. It has no approved treatments in the United States, although in 2018, the European Medicines Agency approved a budesonide tablet formulation.
The guideline authors disclosed no conflicts of interest.
SOURCE: Hirano I et al. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.02.038.
FROM GASTROENTEROLOGY
Biotin may benefit patients with IBD
Patients with inflammatory bowel disease (IBD) may benefit from biotin supplementation, according to a preclinical study.
In mice, biotin supplementation delayed onset of colitis, minimized pathology, and accelerated healing, reported lead author Jonathan Skupsky, MD, of the University of California, Irvine, and colleagues.
“Biotin deficiency often is overlooked in the setting of IBD and there have been several reports of biotin deficiency in patients with IBD,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
In addition to these clinical reports, Dr. Skupsky and colleagues were motivated by their previous research, which showed that, in mice, knockout of the sodium-dependent multivitamin transporter (SMVT) for intestinal biotin uptake led to intestinal inflammation and dysplasia, thereby adding evidence that IBD and biotin could be linked.
In the present study, the investigators first compared mice fed a biotin-deficient diet with those fed a biotin-rich diet. Mice lacking biotin developed alopecia and weight loss within 7 weeks, and over time, stool that was soft and bloody. At week 14, mice fed the biotin-deficient diet had intestinal inflammation, based on elevated fecal calprotectin levels. In contrast, mice fed a biotin-rich diet had no gastrointestinal pathology.
“Although no mouse model entirely recapitulates patients with IBD, this model reproduces many of the findings including weight loss, bloody diarrhea, increased fecal calprotectin, altered crypt architecture, and infiltration of neutrophils and lymphocytes to the mucosa and submucosa,” the investigators wrote.
After this experiment, another group of mice were given drinking water with 3% dextran sodium sulfate (DSS), which induced severe colitis within 7 days. The distal colons of these mice had reduced expression of SMVT, the biotin transporter. This finding was also observed in biopsy samples from patients with ulcerative colitis, suggesting a shared pathway.
“This raises the possibility that [the biotin transport pathway] could be a target for therapy,” the investigators wrote.
Next the investigators tested the effect of prophylactic biotin supplementation in mice receiving 1.5% DSS in drinking water. Compared with mice that went without biotin, those that received a week of supplementation before DSS challenge had delayed, milder colitis, with histologic findings and fecal calprotectin levels that approximated those of healthy controls.
In a similar experiment, two groups of mice were given DSS for 7 days, then water or water plus biotin. Those in the biotin group recovered faster and more completely, again with clinical and histologic findings that was close to controls.
According to the investigators, these findings suggest that biotin may be able to protect against development of colitis and speed healing during early remission.
Further experiments dove deeper into cellular processes and molecular mechanisms, ultimately revealing that biotin supplementation reduced activation of NF-kappaB, which led to decreased intestinal permeability and inflammatory cytokines.
“The specific mechanism(s) linking biotin and NF-kappaB is unclear but could be mediated via the different cellular pathways that are affected by biotin availability,” the investigators wrote.
They noted that IBD is a complex condition, which can make it difficult to accurately model the disease; however, they also suggested that the findings are compelling enough to prompt further investigation in human patients because biotin could be a convenient therapeutic add-on.
“We are optimistic that the data presented here will serve as the foundation for future clinical studies to determine if biotin supplementation should be used as adjunct therapy in IBD,” the investigators wrote. “Biotin is available over the counter, is affordable, and it has minimal side effects, making it an ideal therapeutic if clinical trials can show similar efficacy to what we have seen in this preclinical model.
The study was funded by the Veteran’s Administration and the National Institutes of Health. The investigators reported no conflicts of interest.
SOURCE: Skupsky J et al. Cell Mol Gastroenterol Hepatol. 2019 Nov 28. doi: 10.1016/j.jcmgh.2019.11.011.
Nutrient deficiency is commonly observed in patients with inflammatory bowel disease (IBD). In fact, over half of IBD patients show deficiency in micronutrients (essential vitamins and minerals). Similarly, there are also reports of the potential negative effect of nutrient deprivation on intestinal epithelium, which could ultimately contribute to IBD. However, to date there is limited evidence supporting the notion of nutrient deficiency as a cause or an effect of IBD.
This study by Skupsky et al. highlights the role of this essential vitamin biotin in IBD pathogenesis and its potential use as a therapeutic modality in colitis. Specifically, the authors first described how biotin deficiency could lead to a colitis-like phenotype in mice and then demonstrated that deficiency of biotin was observed in a mouse model of colitis. Further, it was also shown that biotin supplementation during colitis in mice was capable of alleviating inflammation. The authors also alluded to the potential loss of the biotin transporter, a sodium-dependent multivitamin transporter (SMVT), (which was found to be down-regulated in mice with colitis, as well as in IBD patients) as one of the causative factors for biotin deficiency in IBD. However, to date, biotin deficiency has not been conclusively established in IBD patients and further systematic and well-powered studies are needed.
Since micronutrients have emerged as safe and relatively less explored agents for beneficial effects in IBD, it may be worthwhile to initiate clinical studies to examine the potential beneficial role of biotin supplementation in IBD patients.
Pradeep K. Dudeja, PhD, is professor of physiology and director, divisional scholarly activities, division of gastroenterology and hepatology, department of medicine, University of Illinois at Chicago, as well as senior research career scientist, Jesse Brown VA Medical Center, Chicago.
Nutrient deficiency is commonly observed in patients with inflammatory bowel disease (IBD). In fact, over half of IBD patients show deficiency in micronutrients (essential vitamins and minerals). Similarly, there are also reports of the potential negative effect of nutrient deprivation on intestinal epithelium, which could ultimately contribute to IBD. However, to date there is limited evidence supporting the notion of nutrient deficiency as a cause or an effect of IBD.
This study by Skupsky et al. highlights the role of this essential vitamin biotin in IBD pathogenesis and its potential use as a therapeutic modality in colitis. Specifically, the authors first described how biotin deficiency could lead to a colitis-like phenotype in mice and then demonstrated that deficiency of biotin was observed in a mouse model of colitis. Further, it was also shown that biotin supplementation during colitis in mice was capable of alleviating inflammation. The authors also alluded to the potential loss of the biotin transporter, a sodium-dependent multivitamin transporter (SMVT), (which was found to be down-regulated in mice with colitis, as well as in IBD patients) as one of the causative factors for biotin deficiency in IBD. However, to date, biotin deficiency has not been conclusively established in IBD patients and further systematic and well-powered studies are needed.
Since micronutrients have emerged as safe and relatively less explored agents for beneficial effects in IBD, it may be worthwhile to initiate clinical studies to examine the potential beneficial role of biotin supplementation in IBD patients.
Pradeep K. Dudeja, PhD, is professor of physiology and director, divisional scholarly activities, division of gastroenterology and hepatology, department of medicine, University of Illinois at Chicago, as well as senior research career scientist, Jesse Brown VA Medical Center, Chicago.
Nutrient deficiency is commonly observed in patients with inflammatory bowel disease (IBD). In fact, over half of IBD patients show deficiency in micronutrients (essential vitamins and minerals). Similarly, there are also reports of the potential negative effect of nutrient deprivation on intestinal epithelium, which could ultimately contribute to IBD. However, to date there is limited evidence supporting the notion of nutrient deficiency as a cause or an effect of IBD.
This study by Skupsky et al. highlights the role of this essential vitamin biotin in IBD pathogenesis and its potential use as a therapeutic modality in colitis. Specifically, the authors first described how biotin deficiency could lead to a colitis-like phenotype in mice and then demonstrated that deficiency of biotin was observed in a mouse model of colitis. Further, it was also shown that biotin supplementation during colitis in mice was capable of alleviating inflammation. The authors also alluded to the potential loss of the biotin transporter, a sodium-dependent multivitamin transporter (SMVT), (which was found to be down-regulated in mice with colitis, as well as in IBD patients) as one of the causative factors for biotin deficiency in IBD. However, to date, biotin deficiency has not been conclusively established in IBD patients and further systematic and well-powered studies are needed.
Since micronutrients have emerged as safe and relatively less explored agents for beneficial effects in IBD, it may be worthwhile to initiate clinical studies to examine the potential beneficial role of biotin supplementation in IBD patients.
Pradeep K. Dudeja, PhD, is professor of physiology and director, divisional scholarly activities, division of gastroenterology and hepatology, department of medicine, University of Illinois at Chicago, as well as senior research career scientist, Jesse Brown VA Medical Center, Chicago.
Patients with inflammatory bowel disease (IBD) may benefit from biotin supplementation, according to a preclinical study.
In mice, biotin supplementation delayed onset of colitis, minimized pathology, and accelerated healing, reported lead author Jonathan Skupsky, MD, of the University of California, Irvine, and colleagues.
“Biotin deficiency often is overlooked in the setting of IBD and there have been several reports of biotin deficiency in patients with IBD,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
In addition to these clinical reports, Dr. Skupsky and colleagues were motivated by their previous research, which showed that, in mice, knockout of the sodium-dependent multivitamin transporter (SMVT) for intestinal biotin uptake led to intestinal inflammation and dysplasia, thereby adding evidence that IBD and biotin could be linked.
In the present study, the investigators first compared mice fed a biotin-deficient diet with those fed a biotin-rich diet. Mice lacking biotin developed alopecia and weight loss within 7 weeks, and over time, stool that was soft and bloody. At week 14, mice fed the biotin-deficient diet had intestinal inflammation, based on elevated fecal calprotectin levels. In contrast, mice fed a biotin-rich diet had no gastrointestinal pathology.
“Although no mouse model entirely recapitulates patients with IBD, this model reproduces many of the findings including weight loss, bloody diarrhea, increased fecal calprotectin, altered crypt architecture, and infiltration of neutrophils and lymphocytes to the mucosa and submucosa,” the investigators wrote.
After this experiment, another group of mice were given drinking water with 3% dextran sodium sulfate (DSS), which induced severe colitis within 7 days. The distal colons of these mice had reduced expression of SMVT, the biotin transporter. This finding was also observed in biopsy samples from patients with ulcerative colitis, suggesting a shared pathway.
“This raises the possibility that [the biotin transport pathway] could be a target for therapy,” the investigators wrote.
Next the investigators tested the effect of prophylactic biotin supplementation in mice receiving 1.5% DSS in drinking water. Compared with mice that went without biotin, those that received a week of supplementation before DSS challenge had delayed, milder colitis, with histologic findings and fecal calprotectin levels that approximated those of healthy controls.
In a similar experiment, two groups of mice were given DSS for 7 days, then water or water plus biotin. Those in the biotin group recovered faster and more completely, again with clinical and histologic findings that was close to controls.
According to the investigators, these findings suggest that biotin may be able to protect against development of colitis and speed healing during early remission.
Further experiments dove deeper into cellular processes and molecular mechanisms, ultimately revealing that biotin supplementation reduced activation of NF-kappaB, which led to decreased intestinal permeability and inflammatory cytokines.
“The specific mechanism(s) linking biotin and NF-kappaB is unclear but could be mediated via the different cellular pathways that are affected by biotin availability,” the investigators wrote.
They noted that IBD is a complex condition, which can make it difficult to accurately model the disease; however, they also suggested that the findings are compelling enough to prompt further investigation in human patients because biotin could be a convenient therapeutic add-on.
“We are optimistic that the data presented here will serve as the foundation for future clinical studies to determine if biotin supplementation should be used as adjunct therapy in IBD,” the investigators wrote. “Biotin is available over the counter, is affordable, and it has minimal side effects, making it an ideal therapeutic if clinical trials can show similar efficacy to what we have seen in this preclinical model.
The study was funded by the Veteran’s Administration and the National Institutes of Health. The investigators reported no conflicts of interest.
SOURCE: Skupsky J et al. Cell Mol Gastroenterol Hepatol. 2019 Nov 28. doi: 10.1016/j.jcmgh.2019.11.011.
Patients with inflammatory bowel disease (IBD) may benefit from biotin supplementation, according to a preclinical study.
In mice, biotin supplementation delayed onset of colitis, minimized pathology, and accelerated healing, reported lead author Jonathan Skupsky, MD, of the University of California, Irvine, and colleagues.
“Biotin deficiency often is overlooked in the setting of IBD and there have been several reports of biotin deficiency in patients with IBD,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
In addition to these clinical reports, Dr. Skupsky and colleagues were motivated by their previous research, which showed that, in mice, knockout of the sodium-dependent multivitamin transporter (SMVT) for intestinal biotin uptake led to intestinal inflammation and dysplasia, thereby adding evidence that IBD and biotin could be linked.
In the present study, the investigators first compared mice fed a biotin-deficient diet with those fed a biotin-rich diet. Mice lacking biotin developed alopecia and weight loss within 7 weeks, and over time, stool that was soft and bloody. At week 14, mice fed the biotin-deficient diet had intestinal inflammation, based on elevated fecal calprotectin levels. In contrast, mice fed a biotin-rich diet had no gastrointestinal pathology.
“Although no mouse model entirely recapitulates patients with IBD, this model reproduces many of the findings including weight loss, bloody diarrhea, increased fecal calprotectin, altered crypt architecture, and infiltration of neutrophils and lymphocytes to the mucosa and submucosa,” the investigators wrote.
After this experiment, another group of mice were given drinking water with 3% dextran sodium sulfate (DSS), which induced severe colitis within 7 days. The distal colons of these mice had reduced expression of SMVT, the biotin transporter. This finding was also observed in biopsy samples from patients with ulcerative colitis, suggesting a shared pathway.
“This raises the possibility that [the biotin transport pathway] could be a target for therapy,” the investigators wrote.
Next the investigators tested the effect of prophylactic biotin supplementation in mice receiving 1.5% DSS in drinking water. Compared with mice that went without biotin, those that received a week of supplementation before DSS challenge had delayed, milder colitis, with histologic findings and fecal calprotectin levels that approximated those of healthy controls.
In a similar experiment, two groups of mice were given DSS for 7 days, then water or water plus biotin. Those in the biotin group recovered faster and more completely, again with clinical and histologic findings that was close to controls.
According to the investigators, these findings suggest that biotin may be able to protect against development of colitis and speed healing during early remission.
Further experiments dove deeper into cellular processes and molecular mechanisms, ultimately revealing that biotin supplementation reduced activation of NF-kappaB, which led to decreased intestinal permeability and inflammatory cytokines.
“The specific mechanism(s) linking biotin and NF-kappaB is unclear but could be mediated via the different cellular pathways that are affected by biotin availability,” the investigators wrote.
They noted that IBD is a complex condition, which can make it difficult to accurately model the disease; however, they also suggested that the findings are compelling enough to prompt further investigation in human patients because biotin could be a convenient therapeutic add-on.
“We are optimistic that the data presented here will serve as the foundation for future clinical studies to determine if biotin supplementation should be used as adjunct therapy in IBD,” the investigators wrote. “Biotin is available over the counter, is affordable, and it has minimal side effects, making it an ideal therapeutic if clinical trials can show similar efficacy to what we have seen in this preclinical model.
The study was funded by the Veteran’s Administration and the National Institutes of Health. The investigators reported no conflicts of interest.
SOURCE: Skupsky J et al. Cell Mol Gastroenterol Hepatol. 2019 Nov 28. doi: 10.1016/j.jcmgh.2019.11.011.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
AGA CPU: Screening and surveillance for hepatocellular carcinoma in patients with NAFLD
Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.
Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.
Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.
Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.
Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.
The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”
They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.
It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.
The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.
SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.
Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.
Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.
Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.
Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.
Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.
The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”
They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.
It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.
The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.
SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.
Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.
Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.
Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.
Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.
Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.
The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”
They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.
It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.
The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.
SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.
FROM GASTROENTEROLOGY
Year-long synbiotic regimen fails to improve NAFLD
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
FROM GASTROENTEROLOGY
Genotyping improves accuracy of pancreatic cancer tumor markers
Stratifying diagnostic cut-off values of tumor markers based on genetic variants may improve detection of pancreatic cancer, according to investigators.
Stratification had the greatest positive impact on accuracy of carbohydrate antigen 19-9 (CA19-9), reported lead author Toshiya Abe, MD, PhD, of Johns Hopkins Hospital, Baltimore, and colleagues.
“Despite the evidence that genetic factors influence tumor marker levels, the potential utility of using a genetic test to improve the interpretation of tumor markers has drawn limited attention,” the investigators wrote in Clinical Gastroenterology and Hepatology.
And improvements are needed, the investigators noted, particularly for early cancer detection in high-risk individuals.
“[T]he toughest hurdle for a pancreatic cancer detection blood test is the detection of stage I disease,” the investigators wrote. “Cancers generally shed biomarkers in proportion to their size, and small stage I pancreatic cancers shed fewer diagnostic biomarkers into the circulation, making diagnosis more difficult.”
Although a 2016 study by Dr. Guopei Luo and colleagues demonstrated that diagnostic accuracy of CA19-9 could be improved via genotyping, tumor marker performance was not characterized by high-specificity cut-off values, which the present study aimed to do.
The control group included 504 high-risk individuals who were prospectively enrolled in the Cancer of the Pancreas Screening (CAPS) studies from 2002 to 2018, while the case group included 245 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection at Johns Hopkins from 2010 to 2017.
The control group was randomly divided into discovery and validation sets in order to achieve 99% specificity cut-off values, which were used to measure sensitivity in the case group. According to the investigators, high-specificity cut-off values are necessary for surveillance of asymptomatic high-risk individuals in order to minimize false-positive results.
In all patients, tumor markers and genotype were analyzed. Tumor markers included carcinoembryonic antigen (CEA), CA19-9, and cancer antigen 125 (CA-125). Genotyping included 16 single-nucleotide polymorphisms (SNPs) in 9 genes, including FUT2 and FUT3, which are known to influence levels of CA19-9.
In contrast with previous findings, which identified three relevant subgroups of FUT2/FUT3, the present study found that four distinct subgroups were significantly associated with CA19-9 levels: FUT3-null, FUT3+/-, FUT3+/+, and FUT2-null.
When CA19-9 cut-off levels were stratified by these four subgroups and applied to the 245 patients with pancreatic cancer, the investigators achieved a sensitivity of 60.8%, compared with 52.7% without stratification. The new cut-off values led to reclassification of 28 (11.4%) patients with pancreatic cancer, including 24 who switched from negative to positive, and 4 who switched from positive to negative.
Sensitivity of the SNP-adjusted CA19-9 test was improved to 66.4% when used exclusively in patients with functional FUT3 genes. Conversely, sensitivity was markedly lower, at 36.7%, when the test was used for patients with stage I disease.
While CA19-9 testing was notably improved by SNP-based stratification, results from CEA and CA-125 testing were more modest. Standard CEA testing had a sensitivity of 13.8%, compared with 15.9% when cut-off values were stratified by FUT2 status and ABO blood group. Similarly, modifying CA-125 values based on SNPs in GAL3ST2 raised sensitivity from 15.5% to 17.6%.
Although combining SNP-modified tumor marker results did increase overall sensitivity to as high as 66.1%, this also reduced specificity to as low as 95.4%
Still, Dr. Abe and colleagues suggested that the findings demonstrate proof of concept.
“Our results show that a tumor marker SNP test can improve the diagnostic accuracy of CA19-9 and, to a lesser extent, CEA and CA-125, but further work is needed to improve the diagnostic accuracy of our panel for the detection of early-stage pancreatic cancer,” they concluded.
The investigators also suggested that the technique could have value for surveillance of ovarian cancer; however, again, they emphasized the need for more research.The study was funded by the National Institutes of Health, Susan Wojcicki and Dennis Troper, the Pancreatic Cancer Action Network, and others. The investigators reported no conflicts of interest.
SOURCE: Abe T et al. Clin Gastro Hepatol. 2019 Oct 29. doi: 10.1016/j.cgh.2019.10.036.
Stratifying diagnostic cut-off values of tumor markers based on genetic variants may improve detection of pancreatic cancer, according to investigators.
Stratification had the greatest positive impact on accuracy of carbohydrate antigen 19-9 (CA19-9), reported lead author Toshiya Abe, MD, PhD, of Johns Hopkins Hospital, Baltimore, and colleagues.
“Despite the evidence that genetic factors influence tumor marker levels, the potential utility of using a genetic test to improve the interpretation of tumor markers has drawn limited attention,” the investigators wrote in Clinical Gastroenterology and Hepatology.
And improvements are needed, the investigators noted, particularly for early cancer detection in high-risk individuals.
“[T]he toughest hurdle for a pancreatic cancer detection blood test is the detection of stage I disease,” the investigators wrote. “Cancers generally shed biomarkers in proportion to their size, and small stage I pancreatic cancers shed fewer diagnostic biomarkers into the circulation, making diagnosis more difficult.”
Although a 2016 study by Dr. Guopei Luo and colleagues demonstrated that diagnostic accuracy of CA19-9 could be improved via genotyping, tumor marker performance was not characterized by high-specificity cut-off values, which the present study aimed to do.
The control group included 504 high-risk individuals who were prospectively enrolled in the Cancer of the Pancreas Screening (CAPS) studies from 2002 to 2018, while the case group included 245 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection at Johns Hopkins from 2010 to 2017.
The control group was randomly divided into discovery and validation sets in order to achieve 99% specificity cut-off values, which were used to measure sensitivity in the case group. According to the investigators, high-specificity cut-off values are necessary for surveillance of asymptomatic high-risk individuals in order to minimize false-positive results.
In all patients, tumor markers and genotype were analyzed. Tumor markers included carcinoembryonic antigen (CEA), CA19-9, and cancer antigen 125 (CA-125). Genotyping included 16 single-nucleotide polymorphisms (SNPs) in 9 genes, including FUT2 and FUT3, which are known to influence levels of CA19-9.
In contrast with previous findings, which identified three relevant subgroups of FUT2/FUT3, the present study found that four distinct subgroups were significantly associated with CA19-9 levels: FUT3-null, FUT3+/-, FUT3+/+, and FUT2-null.
When CA19-9 cut-off levels were stratified by these four subgroups and applied to the 245 patients with pancreatic cancer, the investigators achieved a sensitivity of 60.8%, compared with 52.7% without stratification. The new cut-off values led to reclassification of 28 (11.4%) patients with pancreatic cancer, including 24 who switched from negative to positive, and 4 who switched from positive to negative.
Sensitivity of the SNP-adjusted CA19-9 test was improved to 66.4% when used exclusively in patients with functional FUT3 genes. Conversely, sensitivity was markedly lower, at 36.7%, when the test was used for patients with stage I disease.
While CA19-9 testing was notably improved by SNP-based stratification, results from CEA and CA-125 testing were more modest. Standard CEA testing had a sensitivity of 13.8%, compared with 15.9% when cut-off values were stratified by FUT2 status and ABO blood group. Similarly, modifying CA-125 values based on SNPs in GAL3ST2 raised sensitivity from 15.5% to 17.6%.
Although combining SNP-modified tumor marker results did increase overall sensitivity to as high as 66.1%, this also reduced specificity to as low as 95.4%
Still, Dr. Abe and colleagues suggested that the findings demonstrate proof of concept.
“Our results show that a tumor marker SNP test can improve the diagnostic accuracy of CA19-9 and, to a lesser extent, CEA and CA-125, but further work is needed to improve the diagnostic accuracy of our panel for the detection of early-stage pancreatic cancer,” they concluded.
The investigators also suggested that the technique could have value for surveillance of ovarian cancer; however, again, they emphasized the need for more research.The study was funded by the National Institutes of Health, Susan Wojcicki and Dennis Troper, the Pancreatic Cancer Action Network, and others. The investigators reported no conflicts of interest.
SOURCE: Abe T et al. Clin Gastro Hepatol. 2019 Oct 29. doi: 10.1016/j.cgh.2019.10.036.
Stratifying diagnostic cut-off values of tumor markers based on genetic variants may improve detection of pancreatic cancer, according to investigators.
Stratification had the greatest positive impact on accuracy of carbohydrate antigen 19-9 (CA19-9), reported lead author Toshiya Abe, MD, PhD, of Johns Hopkins Hospital, Baltimore, and colleagues.
“Despite the evidence that genetic factors influence tumor marker levels, the potential utility of using a genetic test to improve the interpretation of tumor markers has drawn limited attention,” the investigators wrote in Clinical Gastroenterology and Hepatology.
And improvements are needed, the investigators noted, particularly for early cancer detection in high-risk individuals.
“[T]he toughest hurdle for a pancreatic cancer detection blood test is the detection of stage I disease,” the investigators wrote. “Cancers generally shed biomarkers in proportion to their size, and small stage I pancreatic cancers shed fewer diagnostic biomarkers into the circulation, making diagnosis more difficult.”
Although a 2016 study by Dr. Guopei Luo and colleagues demonstrated that diagnostic accuracy of CA19-9 could be improved via genotyping, tumor marker performance was not characterized by high-specificity cut-off values, which the present study aimed to do.
The control group included 504 high-risk individuals who were prospectively enrolled in the Cancer of the Pancreas Screening (CAPS) studies from 2002 to 2018, while the case group included 245 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent resection at Johns Hopkins from 2010 to 2017.
The control group was randomly divided into discovery and validation sets in order to achieve 99% specificity cut-off values, which were used to measure sensitivity in the case group. According to the investigators, high-specificity cut-off values are necessary for surveillance of asymptomatic high-risk individuals in order to minimize false-positive results.
In all patients, tumor markers and genotype were analyzed. Tumor markers included carcinoembryonic antigen (CEA), CA19-9, and cancer antigen 125 (CA-125). Genotyping included 16 single-nucleotide polymorphisms (SNPs) in 9 genes, including FUT2 and FUT3, which are known to influence levels of CA19-9.
In contrast with previous findings, which identified three relevant subgroups of FUT2/FUT3, the present study found that four distinct subgroups were significantly associated with CA19-9 levels: FUT3-null, FUT3+/-, FUT3+/+, and FUT2-null.
When CA19-9 cut-off levels were stratified by these four subgroups and applied to the 245 patients with pancreatic cancer, the investigators achieved a sensitivity of 60.8%, compared with 52.7% without stratification. The new cut-off values led to reclassification of 28 (11.4%) patients with pancreatic cancer, including 24 who switched from negative to positive, and 4 who switched from positive to negative.
Sensitivity of the SNP-adjusted CA19-9 test was improved to 66.4% when used exclusively in patients with functional FUT3 genes. Conversely, sensitivity was markedly lower, at 36.7%, when the test was used for patients with stage I disease.
While CA19-9 testing was notably improved by SNP-based stratification, results from CEA and CA-125 testing were more modest. Standard CEA testing had a sensitivity of 13.8%, compared with 15.9% when cut-off values were stratified by FUT2 status and ABO blood group. Similarly, modifying CA-125 values based on SNPs in GAL3ST2 raised sensitivity from 15.5% to 17.6%.
Although combining SNP-modified tumor marker results did increase overall sensitivity to as high as 66.1%, this also reduced specificity to as low as 95.4%
Still, Dr. Abe and colleagues suggested that the findings demonstrate proof of concept.
“Our results show that a tumor marker SNP test can improve the diagnostic accuracy of CA19-9 and, to a lesser extent, CEA and CA-125, but further work is needed to improve the diagnostic accuracy of our panel for the detection of early-stage pancreatic cancer,” they concluded.
The investigators also suggested that the technique could have value for surveillance of ovarian cancer; however, again, they emphasized the need for more research.The study was funded by the National Institutes of Health, Susan Wojcicki and Dennis Troper, the Pancreatic Cancer Action Network, and others. The investigators reported no conflicts of interest.
SOURCE: Abe T et al. Clin Gastro Hepatol. 2019 Oct 29. doi: 10.1016/j.cgh.2019.10.036.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Adolescents at risk of nutritional deficiencies after bariatric surgery
In a 5-year prospective study, more than a quarter of the participants who underwent vertical sleeve gastrectomy (VSG) developed two or more nutritional deficiencies, reported lead author Stavra A. Xanthakos, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues.
“Although prevalence of nutritional deficiencies has been estimated largely from adult cohorts, bariatric surgery is an increasingly accepted treatment for severe obesity in youth,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Yet, lower adherence to supplementation and anticipated longer lifespan with altered gastrointestinal physiology may increase risk of adverse nutritional outcomes in these youth.”
Previous research has suggested that teens may be at higher risk for nutritional deficiencies, but these studies were largely retrospective, or when prospective, lacked sufficient long-term follow-up, analysis of comprehensive patient factors, or inclusion of VSG, which is now the predominant technique in the field, the investigators noted.
“Our study is the first to assess comparative nutritional outcomes in adolescents after both VSG and gastric bypass,” they wrote.
The study involved 226 participants aged 13-19 years who underwent either Roux-en-Y gastric bypass (n = 161) or VSG (n = 67) at five tertiary-care centers in the United States during 2007-2012.
Six months after surgery, at 12 months, and on an annual basis thereafter, the investigators gathered clinical data and measured participant serum levels of ferritin; transferrin; albumin; parathyroid hormone; C-reactive protein; and vitamins A, D, B1, B12, and folate. Analyses also included sex, age, ethnicity, race, household demographics, weight, height, comorbidities, and body mass index (BMI).
The majority of participants were female (75%) and white (72%). At baseline, mean BMI and age were 52.7 kg/m2 and 16.5 years, respectively. After 5 years, mean body mass index decreased 23% without a significant difference between procedures.
Generally, nutritional deficiencies occurred earlier and were more common after gastric bypass, although both procedures were ultimately associated with increased risks.
In the gastric bypass group, 59% of participants had two or more nutritional deficiencies at 5 years, and 19% had three more deficiencies, which represented increased rates of fivefold and sixfold, respectively, which the investigators described as “striking.” In the VSG group, 27% of patients had two or more nutritional deficiencies at 5 years; while this fourfold increase was not statistically significant, the investigators suggested that it indicated “a lower, but not negligible, nutritional risk.”
Hypoferritinemia was particularly common in both groups, with rates at year 5 of 71% and 45% among patients who underwent gastric bypass and VSG, respectively.
“Our results now provide critical evidence that VSG does in fact carry significantly lower nutritional risk than Roux-en-Y gastric bypass, but can still worsen iron status,” the investigators wrote.
The investigators also highlighted a nonsignificant increase in the incidence of vitamin B12 deficiency among patients who underwent gastric bypass, with rates increasing from 0.6% at baseline to 11.5% at 5 years.
“Vitamin B12 status likewise worsened disproportionately after [gastric bypass], despite similar trajectories of weight loss after VSG,” the investigators wrote. “This suggests that the differential risk is caused by anatomic and physiological differences between procedures, rather than weight loss alone.”
Beyond surgery type, risk factors for nutritional deficiency included inadequate supplement intake, pregnancy, weight regain, and black race.
“Our findings underscore the importance of long-term nutritional monitoring in adolescents after bariatric surgery and the need to examine impact on health outcomes and quality of life as these youth advance into adulthood, including systematic assessment of anemia and bone health,” the investigators concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Courcoulas reported grant support from Allurion.
SOURCE: Xanthakos SA et al. Clin Gastro Hepatol. 2019 Nov 6. doi: 10.1016/j.cgh.2019.10.048.
The prevalence of obesity in adolescents has ballooned to about 20% of children aged 12-19 years. Prevention with diet and exercise remains the cornerstone of obesity policy in the pediatric population. Once patients develop obesity, however, bariatric surgery increasingly is being recommended as a treatment to achieve durable weight loss. Multiple large studies in adults have shown strong evidence of the efficacy of bariatric surgery; comparable data in pediatric patients has been sparse.
The current study by Xanthakos et al. reports on 5-year prospective data from Teen-LABS specifically addressing the nutritional status of adolescents after Roux-en-Y gastric bypass and sleeve gastrectomy. Their data show deficiency only in iron and vitamin B12 levels after gastric bypass. More importantly, vertical sleeve gastrectomy, now the most common procedure, results in decreased risk of nutritional deficiencies compared with gastric bypass. These data add to the reassurance that surgical treatment in the adolescent population is overall safe and should be considered strongly after appropriate counseling.
Wasif M. Abidi, MD, PhD, is an assistant professor of medicine, section of gastroenterology and hepatology, Baylor College of Medicine, Houston. He has received research support from GI Dynamics.
The prevalence of obesity in adolescents has ballooned to about 20% of children aged 12-19 years. Prevention with diet and exercise remains the cornerstone of obesity policy in the pediatric population. Once patients develop obesity, however, bariatric surgery increasingly is being recommended as a treatment to achieve durable weight loss. Multiple large studies in adults have shown strong evidence of the efficacy of bariatric surgery; comparable data in pediatric patients has been sparse.
The current study by Xanthakos et al. reports on 5-year prospective data from Teen-LABS specifically addressing the nutritional status of adolescents after Roux-en-Y gastric bypass and sleeve gastrectomy. Their data show deficiency only in iron and vitamin B12 levels after gastric bypass. More importantly, vertical sleeve gastrectomy, now the most common procedure, results in decreased risk of nutritional deficiencies compared with gastric bypass. These data add to the reassurance that surgical treatment in the adolescent population is overall safe and should be considered strongly after appropriate counseling.
Wasif M. Abidi, MD, PhD, is an assistant professor of medicine, section of gastroenterology and hepatology, Baylor College of Medicine, Houston. He has received research support from GI Dynamics.
The prevalence of obesity in adolescents has ballooned to about 20% of children aged 12-19 years. Prevention with diet and exercise remains the cornerstone of obesity policy in the pediatric population. Once patients develop obesity, however, bariatric surgery increasingly is being recommended as a treatment to achieve durable weight loss. Multiple large studies in adults have shown strong evidence of the efficacy of bariatric surgery; comparable data in pediatric patients has been sparse.
The current study by Xanthakos et al. reports on 5-year prospective data from Teen-LABS specifically addressing the nutritional status of adolescents after Roux-en-Y gastric bypass and sleeve gastrectomy. Their data show deficiency only in iron and vitamin B12 levels after gastric bypass. More importantly, vertical sleeve gastrectomy, now the most common procedure, results in decreased risk of nutritional deficiencies compared with gastric bypass. These data add to the reassurance that surgical treatment in the adolescent population is overall safe and should be considered strongly after appropriate counseling.
Wasif M. Abidi, MD, PhD, is an assistant professor of medicine, section of gastroenterology and hepatology, Baylor College of Medicine, Houston. He has received research support from GI Dynamics.
In a 5-year prospective study, more than a quarter of the participants who underwent vertical sleeve gastrectomy (VSG) developed two or more nutritional deficiencies, reported lead author Stavra A. Xanthakos, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues.
“Although prevalence of nutritional deficiencies has been estimated largely from adult cohorts, bariatric surgery is an increasingly accepted treatment for severe obesity in youth,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Yet, lower adherence to supplementation and anticipated longer lifespan with altered gastrointestinal physiology may increase risk of adverse nutritional outcomes in these youth.”
Previous research has suggested that teens may be at higher risk for nutritional deficiencies, but these studies were largely retrospective, or when prospective, lacked sufficient long-term follow-up, analysis of comprehensive patient factors, or inclusion of VSG, which is now the predominant technique in the field, the investigators noted.
“Our study is the first to assess comparative nutritional outcomes in adolescents after both VSG and gastric bypass,” they wrote.
The study involved 226 participants aged 13-19 years who underwent either Roux-en-Y gastric bypass (n = 161) or VSG (n = 67) at five tertiary-care centers in the United States during 2007-2012.
Six months after surgery, at 12 months, and on an annual basis thereafter, the investigators gathered clinical data and measured participant serum levels of ferritin; transferrin; albumin; parathyroid hormone; C-reactive protein; and vitamins A, D, B1, B12, and folate. Analyses also included sex, age, ethnicity, race, household demographics, weight, height, comorbidities, and body mass index (BMI).
The majority of participants were female (75%) and white (72%). At baseline, mean BMI and age were 52.7 kg/m2 and 16.5 years, respectively. After 5 years, mean body mass index decreased 23% without a significant difference between procedures.
Generally, nutritional deficiencies occurred earlier and were more common after gastric bypass, although both procedures were ultimately associated with increased risks.
In the gastric bypass group, 59% of participants had two or more nutritional deficiencies at 5 years, and 19% had three more deficiencies, which represented increased rates of fivefold and sixfold, respectively, which the investigators described as “striking.” In the VSG group, 27% of patients had two or more nutritional deficiencies at 5 years; while this fourfold increase was not statistically significant, the investigators suggested that it indicated “a lower, but not negligible, nutritional risk.”
Hypoferritinemia was particularly common in both groups, with rates at year 5 of 71% and 45% among patients who underwent gastric bypass and VSG, respectively.
“Our results now provide critical evidence that VSG does in fact carry significantly lower nutritional risk than Roux-en-Y gastric bypass, but can still worsen iron status,” the investigators wrote.
The investigators also highlighted a nonsignificant increase in the incidence of vitamin B12 deficiency among patients who underwent gastric bypass, with rates increasing from 0.6% at baseline to 11.5% at 5 years.
“Vitamin B12 status likewise worsened disproportionately after [gastric bypass], despite similar trajectories of weight loss after VSG,” the investigators wrote. “This suggests that the differential risk is caused by anatomic and physiological differences between procedures, rather than weight loss alone.”
Beyond surgery type, risk factors for nutritional deficiency included inadequate supplement intake, pregnancy, weight regain, and black race.
“Our findings underscore the importance of long-term nutritional monitoring in adolescents after bariatric surgery and the need to examine impact on health outcomes and quality of life as these youth advance into adulthood, including systematic assessment of anemia and bone health,” the investigators concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Courcoulas reported grant support from Allurion.
SOURCE: Xanthakos SA et al. Clin Gastro Hepatol. 2019 Nov 6. doi: 10.1016/j.cgh.2019.10.048.
In a 5-year prospective study, more than a quarter of the participants who underwent vertical sleeve gastrectomy (VSG) developed two or more nutritional deficiencies, reported lead author Stavra A. Xanthakos, MD, of the Cincinnati Children’s Hospital Medical Center, and colleagues.
“Although prevalence of nutritional deficiencies has been estimated largely from adult cohorts, bariatric surgery is an increasingly accepted treatment for severe obesity in youth,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Yet, lower adherence to supplementation and anticipated longer lifespan with altered gastrointestinal physiology may increase risk of adverse nutritional outcomes in these youth.”
Previous research has suggested that teens may be at higher risk for nutritional deficiencies, but these studies were largely retrospective, or when prospective, lacked sufficient long-term follow-up, analysis of comprehensive patient factors, or inclusion of VSG, which is now the predominant technique in the field, the investigators noted.
“Our study is the first to assess comparative nutritional outcomes in adolescents after both VSG and gastric bypass,” they wrote.
The study involved 226 participants aged 13-19 years who underwent either Roux-en-Y gastric bypass (n = 161) or VSG (n = 67) at five tertiary-care centers in the United States during 2007-2012.
Six months after surgery, at 12 months, and on an annual basis thereafter, the investigators gathered clinical data and measured participant serum levels of ferritin; transferrin; albumin; parathyroid hormone; C-reactive protein; and vitamins A, D, B1, B12, and folate. Analyses also included sex, age, ethnicity, race, household demographics, weight, height, comorbidities, and body mass index (BMI).
The majority of participants were female (75%) and white (72%). At baseline, mean BMI and age were 52.7 kg/m2 and 16.5 years, respectively. After 5 years, mean body mass index decreased 23% without a significant difference between procedures.
Generally, nutritional deficiencies occurred earlier and were more common after gastric bypass, although both procedures were ultimately associated with increased risks.
In the gastric bypass group, 59% of participants had two or more nutritional deficiencies at 5 years, and 19% had three more deficiencies, which represented increased rates of fivefold and sixfold, respectively, which the investigators described as “striking.” In the VSG group, 27% of patients had two or more nutritional deficiencies at 5 years; while this fourfold increase was not statistically significant, the investigators suggested that it indicated “a lower, but not negligible, nutritional risk.”
Hypoferritinemia was particularly common in both groups, with rates at year 5 of 71% and 45% among patients who underwent gastric bypass and VSG, respectively.
“Our results now provide critical evidence that VSG does in fact carry significantly lower nutritional risk than Roux-en-Y gastric bypass, but can still worsen iron status,” the investigators wrote.
The investigators also highlighted a nonsignificant increase in the incidence of vitamin B12 deficiency among patients who underwent gastric bypass, with rates increasing from 0.6% at baseline to 11.5% at 5 years.
“Vitamin B12 status likewise worsened disproportionately after [gastric bypass], despite similar trajectories of weight loss after VSG,” the investigators wrote. “This suggests that the differential risk is caused by anatomic and physiological differences between procedures, rather than weight loss alone.”
Beyond surgery type, risk factors for nutritional deficiency included inadequate supplement intake, pregnancy, weight regain, and black race.
“Our findings underscore the importance of long-term nutritional monitoring in adolescents after bariatric surgery and the need to examine impact on health outcomes and quality of life as these youth advance into adulthood, including systematic assessment of anemia and bone health,” the investigators concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Courcoulas reported grant support from Allurion.
SOURCE: Xanthakos SA et al. Clin Gastro Hepatol. 2019 Nov 6. doi: 10.1016/j.cgh.2019.10.048.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
JAK inhibitors may increase risk of herpes zoster
For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.
Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.
“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.
The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).
Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.
Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.
“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.
Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).
“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.
Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.
“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”
The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.
“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.
The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.
For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.
Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.
“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.
The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).
Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.
Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.
“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.
Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).
“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.
Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.
“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”
The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.
“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.
The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.
Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.
“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.
The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).
Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.
Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.
“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.
Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).
“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.
Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.
“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”
The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.
“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.
The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
FROM GASTROENTEROLOGY
Hospitals muzzle doctors and nurses on PPE, COVID-19 cases
Over the past month, an orthopedic surgeon has watched as the crowd of sick patients at his hospital has grown, while the supply of personal protective equipment (PPE) for staff has diminished. As he prepares for another day of staffing testing tents and places his one and only mask across his face, he also receives a daily reminder from hospital management: Don’t talk about it.
“It’s very clear; no one is allowed to speak for the institution or of the institution,” he said in an interview. “We get a daily warning about being very prudent about posts on personal accounts. They’ve talked about this with respect to various issues: case numbers, case severity, testing availability, [and] PPEs.”
The warnings mean staff at the hospital suffer in silence, unable to share the troubling situation with the public or request assistance with supplies.
“I have one mask. We’re expected to reuse them, unless you were exposed or worked with a known COVID victim,” the surgeon said. “However, with the numbers in our region rapidly increasing, you can’t assume that people don’t have it or that you don’t have particles on your mask, even if you’re not in a known quarantine zone within the institution.”
As the COVID-19 health crisis rages on, online platforms have become a common place for health professionals to lament short supplies, share concerns, tell stories, and plead for help. But at the same time, other physicians, nurses, and health care workers are being muzzled by hospital administrators and threatened with discipline for speaking out about coronavirus caseloads and dwindling supplies. Some worry the gag orders are muddying the picture of how hospitals are faring in the pandemic, while placing the safety of frontline workers at risk.
The silencing of physicians by hospitals about PPE shortages and other COVID-19 issues has become widespread, said Nisha Mehta, MD, a physician advocate and community leader who writes about PPE on social media. Physicians are being warned not to speak or post publicly about their COVID-19 experiences, including PPE shortages, case specifics, and the percentage of full hospital beds, Dr. Mehta said in an interview. In some cases, physicians who have posted have been forced to take down the posts or have faced retribution for speaking out, she said.
“There’s definitely a big fear among physicians, particularly employed physicians, in terms of what the consequences may be for telling their stories,” Dr. Mehta said. “I find that counterproductive. I understand not inducing panic, but these are real stories that are important for people to understand so they do stay home and increase the systemic pressure to get sufficient PPE, so that we can preserve our health care workforce for a problem that is going to get worse before it gets better.”
Meanwhile, an Indiana hospitalist who took to social media to ask for masks for hospitals in his area says he was immediately reprimanded by his management after the posts came to light. The hospitalist posted on a social media platform to request donations of N95 masks after hearing members of the public had purchased such masks. He hoped his plea would aid preparation for the pandemic at local hospitals, explained the physician, who spoke on the condition of anonymity.
Shortly afterward, administrators from his hospital contacted the online forum’s moderator and the posts were removed, he said. During a subsequent conversation, administrators warned the doctor not to make such posts about PPE because it made the hospital appear incompetent.
“I was told, ‘we can handle this, we don’t need the public’s help,’” the physician said. “I was hurt and upset. I was trying to help protect my peers.”
After landing on the management’s radar, the hospitalist said he was reprimanded a second time about posts on a separate personal social media account. The second time, the private posts to friends and family were related to COVID-19 and PPE, but did not include any protected health information, he said. However, administrators did not like the content of the posts, and he was told management was monitoring his activity on social media, he said.
“The larger message is that patients are money,” the hospitalist said. “The corporate side of medicine rules out over the medicine side. Image and making sure there is a consistent cash flow trumps all else.”
Another frontline physician who works at a large New York hospital, said staff have been cautioned not to talk with the media and to be careful what they post on social media regarding COVID-19. The general rule is that only information approved by administrators can be shared, said the physician, who spoke on the condition of anonymity.
“[The health system] is very protective of their public image,” he said. “In the past, people that have posted things that they don’t like get spoken to quickly and/or fired depending on what was written. I could only imagine that would be the situation regarding COVID-19. They are very strict.”
The frontline physician, who has close contact with COVID-19 patients, said he has access to N95 masks at the moment, but when he requested higher-level protective gear, hospital management refused the request and denied that such supplies were needed.
“Safety of frontline workers appears to not be taken seriously,” he said of his hospital. “Everyone is stressed, but at the end of the day, the administration is sitting there, while the rest of us are putting ourselves at risk.”
We reached out to one hospital for comment, but messages were not returned. Other hospitals were not contacted because physicians feared they would face retribution. We also contacted the American Hospital Association but they did not immediately respond.
In Chicago, an email by a nurse to her coworkers about the safety of masks has resulted in a lawsuit after the nurse says she was fired for sharing her concerns with staff. The nurse, Lauri Mazurkiewicz, sent an email to staffers at Northwestern Memorial Hospital stating the surgical masks provided by the hospital were less effective against airborne particles than were N95 masks, according to a lawsuit filed March 23 in Cook County Circuit Court. Ms. Mazurkiewicz was terminated the next day in retaliation for her email, the lawsuit alleges.
Ms. Mazurkiewicz could not be reached for comment by press time.
Christopher King, a spokesman for Northwestern Medicine, said the hospital is reviewing the lawsuit.
“As Northwestern Medicine continues to respond to this unprecedented health care pandemic, the health and well-being of our patients, our staff and our employees is our highest priority,” he said in a statement. “We take these matters seriously and we are currently reviewing the complaint. At this time, we will not be commenting further.”
John Mandrola, MD, a Louisville, Ky.–based cardiologist who has written about the recent muzzling of frontline physicians with respect to the coronavirus, said he is not surprised that some hospitals are preventing physicians from sharing their experiences.
“Before C19, in many hospital systems, there was a culture of fear amongst employed clinicians,” he said. “Employed clinicians see other employed physicians being terminated for speaking frankly about problems. It takes scant few of these cases to create a culture of silence.”
Dr. Mandrola, who is a regular Medscape contributor, said that a number of doctors have reached out to him privately about PPE scarcity and shared that they were explicitly warned by administrators not to talk about the shortfalls. Leadership at Dr. Mandrola’s hospital has not issued the same warnings, he said.
“From the hat of total transparency, I think the public is not getting a full view of the impending potential problems that are going to come by doctors not speaking publicly,” he said. “On the other hand, hospital leadership is doing the best they can. It’s not the hospitals’ fault. Hospital administrators can’t manufacture masks.”
From a public health standpoint, Dr. Mehta said that not allowing health professionals to speak publicly about the situations at their hospitals is “irresponsible.” The public deserves to know what is happening, she said, and the health care workforce needs to prepare for what is to come.
“It’s so important that we hear from our colleagues,” she said. “It’s important to hear those accounts so we can prepare for what we’re about to face. Data is crucial. The more you learn from each other, the better shot we have at successfully treating cases and ultimately beating this.”
With the critical shortage of PPE at his hospital and the inability to speak out about the problem, the orthopedic surgeon foresees the dilemma continuing to worsen.
“It’s not only the lives of front-line health care workers that are at risk, but it’s those that they’re going to spread it to and those that are going to be coming to the hospital requiring our care,” he said. “If we don’t have a fully functioning health care force, our capacity is going to be diminished that much further.”
The American Gastroenterological Association, along with 44 other medical specialty societies representing more than 800,000 physicians, signed onto the Council of Medical Specialty Societies letter stating that all frontline health care professionals must have access to PPEs and be able to speak publicly about the lack of PPEs without retribution while pushing for adequate supply and distribution. Review the statement at https://cmss.org/cmss-statement-ppe.
[email protected]
Over the past month, an orthopedic surgeon has watched as the crowd of sick patients at his hospital has grown, while the supply of personal protective equipment (PPE) for staff has diminished. As he prepares for another day of staffing testing tents and places his one and only mask across his face, he also receives a daily reminder from hospital management: Don’t talk about it.
“It’s very clear; no one is allowed to speak for the institution or of the institution,” he said in an interview. “We get a daily warning about being very prudent about posts on personal accounts. They’ve talked about this with respect to various issues: case numbers, case severity, testing availability, [and] PPEs.”
The warnings mean staff at the hospital suffer in silence, unable to share the troubling situation with the public or request assistance with supplies.
“I have one mask. We’re expected to reuse them, unless you were exposed or worked with a known COVID victim,” the surgeon said. “However, with the numbers in our region rapidly increasing, you can’t assume that people don’t have it or that you don’t have particles on your mask, even if you’re not in a known quarantine zone within the institution.”
As the COVID-19 health crisis rages on, online platforms have become a common place for health professionals to lament short supplies, share concerns, tell stories, and plead for help. But at the same time, other physicians, nurses, and health care workers are being muzzled by hospital administrators and threatened with discipline for speaking out about coronavirus caseloads and dwindling supplies. Some worry the gag orders are muddying the picture of how hospitals are faring in the pandemic, while placing the safety of frontline workers at risk.
The silencing of physicians by hospitals about PPE shortages and other COVID-19 issues has become widespread, said Nisha Mehta, MD, a physician advocate and community leader who writes about PPE on social media. Physicians are being warned not to speak or post publicly about their COVID-19 experiences, including PPE shortages, case specifics, and the percentage of full hospital beds, Dr. Mehta said in an interview. In some cases, physicians who have posted have been forced to take down the posts or have faced retribution for speaking out, she said.
“There’s definitely a big fear among physicians, particularly employed physicians, in terms of what the consequences may be for telling their stories,” Dr. Mehta said. “I find that counterproductive. I understand not inducing panic, but these are real stories that are important for people to understand so they do stay home and increase the systemic pressure to get sufficient PPE, so that we can preserve our health care workforce for a problem that is going to get worse before it gets better.”
Meanwhile, an Indiana hospitalist who took to social media to ask for masks for hospitals in his area says he was immediately reprimanded by his management after the posts came to light. The hospitalist posted on a social media platform to request donations of N95 masks after hearing members of the public had purchased such masks. He hoped his plea would aid preparation for the pandemic at local hospitals, explained the physician, who spoke on the condition of anonymity.
Shortly afterward, administrators from his hospital contacted the online forum’s moderator and the posts were removed, he said. During a subsequent conversation, administrators warned the doctor not to make such posts about PPE because it made the hospital appear incompetent.
“I was told, ‘we can handle this, we don’t need the public’s help,’” the physician said. “I was hurt and upset. I was trying to help protect my peers.”
After landing on the management’s radar, the hospitalist said he was reprimanded a second time about posts on a separate personal social media account. The second time, the private posts to friends and family were related to COVID-19 and PPE, but did not include any protected health information, he said. However, administrators did not like the content of the posts, and he was told management was monitoring his activity on social media, he said.
“The larger message is that patients are money,” the hospitalist said. “The corporate side of medicine rules out over the medicine side. Image and making sure there is a consistent cash flow trumps all else.”
Another frontline physician who works at a large New York hospital, said staff have been cautioned not to talk with the media and to be careful what they post on social media regarding COVID-19. The general rule is that only information approved by administrators can be shared, said the physician, who spoke on the condition of anonymity.
“[The health system] is very protective of their public image,” he said. “In the past, people that have posted things that they don’t like get spoken to quickly and/or fired depending on what was written. I could only imagine that would be the situation regarding COVID-19. They are very strict.”
The frontline physician, who has close contact with COVID-19 patients, said he has access to N95 masks at the moment, but when he requested higher-level protective gear, hospital management refused the request and denied that such supplies were needed.
“Safety of frontline workers appears to not be taken seriously,” he said of his hospital. “Everyone is stressed, but at the end of the day, the administration is sitting there, while the rest of us are putting ourselves at risk.”
We reached out to one hospital for comment, but messages were not returned. Other hospitals were not contacted because physicians feared they would face retribution. We also contacted the American Hospital Association but they did not immediately respond.
In Chicago, an email by a nurse to her coworkers about the safety of masks has resulted in a lawsuit after the nurse says she was fired for sharing her concerns with staff. The nurse, Lauri Mazurkiewicz, sent an email to staffers at Northwestern Memorial Hospital stating the surgical masks provided by the hospital were less effective against airborne particles than were N95 masks, according to a lawsuit filed March 23 in Cook County Circuit Court. Ms. Mazurkiewicz was terminated the next day in retaliation for her email, the lawsuit alleges.
Ms. Mazurkiewicz could not be reached for comment by press time.
Christopher King, a spokesman for Northwestern Medicine, said the hospital is reviewing the lawsuit.
“As Northwestern Medicine continues to respond to this unprecedented health care pandemic, the health and well-being of our patients, our staff and our employees is our highest priority,” he said in a statement. “We take these matters seriously and we are currently reviewing the complaint. At this time, we will not be commenting further.”
John Mandrola, MD, a Louisville, Ky.–based cardiologist who has written about the recent muzzling of frontline physicians with respect to the coronavirus, said he is not surprised that some hospitals are preventing physicians from sharing their experiences.
“Before C19, in many hospital systems, there was a culture of fear amongst employed clinicians,” he said. “Employed clinicians see other employed physicians being terminated for speaking frankly about problems. It takes scant few of these cases to create a culture of silence.”
Dr. Mandrola, who is a regular Medscape contributor, said that a number of doctors have reached out to him privately about PPE scarcity and shared that they were explicitly warned by administrators not to talk about the shortfalls. Leadership at Dr. Mandrola’s hospital has not issued the same warnings, he said.
“From the hat of total transparency, I think the public is not getting a full view of the impending potential problems that are going to come by doctors not speaking publicly,” he said. “On the other hand, hospital leadership is doing the best they can. It’s not the hospitals’ fault. Hospital administrators can’t manufacture masks.”
From a public health standpoint, Dr. Mehta said that not allowing health professionals to speak publicly about the situations at their hospitals is “irresponsible.” The public deserves to know what is happening, she said, and the health care workforce needs to prepare for what is to come.
“It’s so important that we hear from our colleagues,” she said. “It’s important to hear those accounts so we can prepare for what we’re about to face. Data is crucial. The more you learn from each other, the better shot we have at successfully treating cases and ultimately beating this.”
With the critical shortage of PPE at his hospital and the inability to speak out about the problem, the orthopedic surgeon foresees the dilemma continuing to worsen.
“It’s not only the lives of front-line health care workers that are at risk, but it’s those that they’re going to spread it to and those that are going to be coming to the hospital requiring our care,” he said. “If we don’t have a fully functioning health care force, our capacity is going to be diminished that much further.”
The American Gastroenterological Association, along with 44 other medical specialty societies representing more than 800,000 physicians, signed onto the Council of Medical Specialty Societies letter stating that all frontline health care professionals must have access to PPEs and be able to speak publicly about the lack of PPEs without retribution while pushing for adequate supply and distribution. Review the statement at https://cmss.org/cmss-statement-ppe.
[email protected]
Over the past month, an orthopedic surgeon has watched as the crowd of sick patients at his hospital has grown, while the supply of personal protective equipment (PPE) for staff has diminished. As he prepares for another day of staffing testing tents and places his one and only mask across his face, he also receives a daily reminder from hospital management: Don’t talk about it.
“It’s very clear; no one is allowed to speak for the institution or of the institution,” he said in an interview. “We get a daily warning about being very prudent about posts on personal accounts. They’ve talked about this with respect to various issues: case numbers, case severity, testing availability, [and] PPEs.”
The warnings mean staff at the hospital suffer in silence, unable to share the troubling situation with the public or request assistance with supplies.
“I have one mask. We’re expected to reuse them, unless you were exposed or worked with a known COVID victim,” the surgeon said. “However, with the numbers in our region rapidly increasing, you can’t assume that people don’t have it or that you don’t have particles on your mask, even if you’re not in a known quarantine zone within the institution.”
As the COVID-19 health crisis rages on, online platforms have become a common place for health professionals to lament short supplies, share concerns, tell stories, and plead for help. But at the same time, other physicians, nurses, and health care workers are being muzzled by hospital administrators and threatened with discipline for speaking out about coronavirus caseloads and dwindling supplies. Some worry the gag orders are muddying the picture of how hospitals are faring in the pandemic, while placing the safety of frontline workers at risk.
The silencing of physicians by hospitals about PPE shortages and other COVID-19 issues has become widespread, said Nisha Mehta, MD, a physician advocate and community leader who writes about PPE on social media. Physicians are being warned not to speak or post publicly about their COVID-19 experiences, including PPE shortages, case specifics, and the percentage of full hospital beds, Dr. Mehta said in an interview. In some cases, physicians who have posted have been forced to take down the posts or have faced retribution for speaking out, she said.
“There’s definitely a big fear among physicians, particularly employed physicians, in terms of what the consequences may be for telling their stories,” Dr. Mehta said. “I find that counterproductive. I understand not inducing panic, but these are real stories that are important for people to understand so they do stay home and increase the systemic pressure to get sufficient PPE, so that we can preserve our health care workforce for a problem that is going to get worse before it gets better.”
Meanwhile, an Indiana hospitalist who took to social media to ask for masks for hospitals in his area says he was immediately reprimanded by his management after the posts came to light. The hospitalist posted on a social media platform to request donations of N95 masks after hearing members of the public had purchased such masks. He hoped his plea would aid preparation for the pandemic at local hospitals, explained the physician, who spoke on the condition of anonymity.
Shortly afterward, administrators from his hospital contacted the online forum’s moderator and the posts were removed, he said. During a subsequent conversation, administrators warned the doctor not to make such posts about PPE because it made the hospital appear incompetent.
“I was told, ‘we can handle this, we don’t need the public’s help,’” the physician said. “I was hurt and upset. I was trying to help protect my peers.”
After landing on the management’s radar, the hospitalist said he was reprimanded a second time about posts on a separate personal social media account. The second time, the private posts to friends and family were related to COVID-19 and PPE, but did not include any protected health information, he said. However, administrators did not like the content of the posts, and he was told management was monitoring his activity on social media, he said.
“The larger message is that patients are money,” the hospitalist said. “The corporate side of medicine rules out over the medicine side. Image and making sure there is a consistent cash flow trumps all else.”
Another frontline physician who works at a large New York hospital, said staff have been cautioned not to talk with the media and to be careful what they post on social media regarding COVID-19. The general rule is that only information approved by administrators can be shared, said the physician, who spoke on the condition of anonymity.
“[The health system] is very protective of their public image,” he said. “In the past, people that have posted things that they don’t like get spoken to quickly and/or fired depending on what was written. I could only imagine that would be the situation regarding COVID-19. They are very strict.”
The frontline physician, who has close contact with COVID-19 patients, said he has access to N95 masks at the moment, but when he requested higher-level protective gear, hospital management refused the request and denied that such supplies were needed.
“Safety of frontline workers appears to not be taken seriously,” he said of his hospital. “Everyone is stressed, but at the end of the day, the administration is sitting there, while the rest of us are putting ourselves at risk.”
We reached out to one hospital for comment, but messages were not returned. Other hospitals were not contacted because physicians feared they would face retribution. We also contacted the American Hospital Association but they did not immediately respond.
In Chicago, an email by a nurse to her coworkers about the safety of masks has resulted in a lawsuit after the nurse says she was fired for sharing her concerns with staff. The nurse, Lauri Mazurkiewicz, sent an email to staffers at Northwestern Memorial Hospital stating the surgical masks provided by the hospital were less effective against airborne particles than were N95 masks, according to a lawsuit filed March 23 in Cook County Circuit Court. Ms. Mazurkiewicz was terminated the next day in retaliation for her email, the lawsuit alleges.
Ms. Mazurkiewicz could not be reached for comment by press time.
Christopher King, a spokesman for Northwestern Medicine, said the hospital is reviewing the lawsuit.
“As Northwestern Medicine continues to respond to this unprecedented health care pandemic, the health and well-being of our patients, our staff and our employees is our highest priority,” he said in a statement. “We take these matters seriously and we are currently reviewing the complaint. At this time, we will not be commenting further.”
John Mandrola, MD, a Louisville, Ky.–based cardiologist who has written about the recent muzzling of frontline physicians with respect to the coronavirus, said he is not surprised that some hospitals are preventing physicians from sharing their experiences.
“Before C19, in many hospital systems, there was a culture of fear amongst employed clinicians,” he said. “Employed clinicians see other employed physicians being terminated for speaking frankly about problems. It takes scant few of these cases to create a culture of silence.”
Dr. Mandrola, who is a regular Medscape contributor, said that a number of doctors have reached out to him privately about PPE scarcity and shared that they were explicitly warned by administrators not to talk about the shortfalls. Leadership at Dr. Mandrola’s hospital has not issued the same warnings, he said.
“From the hat of total transparency, I think the public is not getting a full view of the impending potential problems that are going to come by doctors not speaking publicly,” he said. “On the other hand, hospital leadership is doing the best they can. It’s not the hospitals’ fault. Hospital administrators can’t manufacture masks.”
From a public health standpoint, Dr. Mehta said that not allowing health professionals to speak publicly about the situations at their hospitals is “irresponsible.” The public deserves to know what is happening, she said, and the health care workforce needs to prepare for what is to come.
“It’s so important that we hear from our colleagues,” she said. “It’s important to hear those accounts so we can prepare for what we’re about to face. Data is crucial. The more you learn from each other, the better shot we have at successfully treating cases and ultimately beating this.”
With the critical shortage of PPE at his hospital and the inability to speak out about the problem, the orthopedic surgeon foresees the dilemma continuing to worsen.
“It’s not only the lives of front-line health care workers that are at risk, but it’s those that they’re going to spread it to and those that are going to be coming to the hospital requiring our care,” he said. “If we don’t have a fully functioning health care force, our capacity is going to be diminished that much further.”
The American Gastroenterological Association, along with 44 other medical specialty societies representing more than 800,000 physicians, signed onto the Council of Medical Specialty Societies letter stating that all frontline health care professionals must have access to PPEs and be able to speak publicly about the lack of PPEs without retribution while pushing for adequate supply and distribution. Review the statement at https://cmss.org/cmss-statement-ppe.
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AGA guideline favors biologics for moderate to severe ulcerative colitis
For moderate to severe ulcerative colitis, treatment with any one of the leading biologic agents is superior to no treatment at all. And in treatment-naive patients, infliximab or vedolizumab should be used rather than adalimumab for inducing remission. These are key recommendations from the American Gastroenterological Association guideline for patients with moderate to severe ulcerative colitis (UC), published in Gastroenterology (doi: 10.1053/j.gastro.2020.01.006).
In all, the guideline comprises 11 recommendations for using immunomodulators, biologics, and small-molecule agents to induce and maintain remission in outpatients with moderate to severe UC and to decrease the need for colectomy in hospitalized patients with acute severe UC. The latest guideline follows a guideline for mild to moderate UC published last year (Gastroenterology. 2019;156[3]:748-64). A technical review accompanied the most recent publication (Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.007).
An updated guideline was long overdue, lead author Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. “The care of patients with inflammatory bowel disease – both ulcerative colitis and Crohn’s – has become increasingly complicated with many newer drugs becoming available,” he said. “The paradigm of how we are treating the disease is evolving, but we haven’t had updated, evidence-based guidelines.” Dr. Feuerstein is the lead author of this guideline.
The guideline can also aid in influencing payers’ policies that now require step-up therapy – that is, failing with the least costly drug before moving onto newer and more effective but costlier agents – Dr. Feuerstein said. “These guidelines show now that we should be treating people based on the evidence and not based on just an insurance company’s preferred policy,” he said.
The strongest recommendation is to use the tumor necrosis factor–alpha (TNF-alpha) antagonists infliximab, adalimumab, and golimumab, the anti-integrin agent vedolizumab, or the anti-interleukin 12/23 agent ustekinumab — all biologics — or the synthetic JAK inhibitor tofacitinib rather than not treating the UC. This is the only recommendation labeled as “strong,” based on “moderate quality evidence.” The relative risk profiles the committee analyzed all favored the biologics over the JAK inhibitor.
Also based on moderate evidence is the recommendation to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who had taken biologic agents before. The other recommendations are based on evidence listed at “low” or “very low” quality, or citing a “knowledge gap.”
“The quality of the evidence available is variable, and we can only make our recommendations based on the quality of the evidence there, but it doesn’t negate the effects of the guideline itself,” Dr. Feuerstein said. The strong recommendation is based on randomized clinical trials that led to the Food and Drug Administration approvals, said Aline Charabaty-Pishvaian, MD, AGAF, associate professor at Johns Hopkins University, Baltimore, and director of the Inflammatory Bowel Disease Center at Sibley Memorial Hospital, Washington. “For everything else, we do not have randomized controlled trials to help make a decision, and the recommendations are made based on the interpretation of different RCTs [randomized controlled trials], knowing that these trials have different designs, patient populations, and endpoints, as well as on experts’ opinions,” she said in an interview.
The only other recommendation based on moderate quality evidence is to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who haven’t previously used biologic agents. The guideline also recommends using tofacitinib in these patients in the confines of a clinical trial; and using ustekinumab or tofacitinib rather than vedolizumab or adalimumab in patients who’ve already been on infliximab, particularly if they haven’t responded to treatment.
The guideline also recommends against thiopurine monotherapy to induce remission, but, for maintenance of remission, recommends such treatment vs. none. However, the guideline suggests against methotrexate monotherapy to induce or maintain remission. And biologic monotherapy is preferred to thiopurine to induce remission, but the guideline makes no recommendation for biologic vs. thiopurine monotherapy to maintain remission. Likewise, combining vedolizumab or ustekinumab with thiopurines or methotrexate is preferred to monotherapy with either a biologic or thiopurine.
The guideline also addresses step-up therapy. It suggests biologics as a first treatment, either as monotherapy or in combination with an immunomodulator, rather than a step-up after failure with 5-aminosalicylates. Also, it recommends against continuing 5-aminosalicylates to induce or maintain remission after a patient has achieved remission with biologics as monotherapy or in combination with immunomodulators or tofacitinib.
The guideline also offers four recommendations for hospitalized patients with acute severe ulcerative colitis: use of intravenous 40-60 mg/d methylprednisolone rather than higher dose IV corticosteroids, no adjunctive antibiotics in the absence of infection; use of infliximab or cyclosporine when IV corticosteroids fail, and no recommendation on the use of intensive vs. standard infliximab dosing when IV corticosteroids fail and the patient is already on infliximab.
The guideline will be meaningful in closing the evidence gap going forward because it can help direct the design of clinical trials, Dr. Charabaty-Pishvaian said. “The guideline highlights areas of need in terms of randomized clinical trials,” she said. “We need these trials to answer the questions we ask ourselves in our daily practice when managing patients with UC: Which drug to choose as the first-line agent? Which drug is the second-line therapy when the disease doesn’t respond or loses response to the first-line agent? Do we need to use combination therapy with all biologics, or only with anti-TNF-alpha agents? For how long? Can we use vedolizumab or ustekinumab as monotherapy when used as a first-line agent? And is there any advantage in adding an immunomodulator when these agents are used as third- or fourth-line therapy?”
Dr. Feuerstein has no relevant financial relationships to disclose. Guideline author Kim Isaacs, MD, disclosed relationships with AbbVie, Takeda, UCB, Janssen and Hoffmann-Laroche. All other committee members have no relevant disclosures.
*This story was updated on 5/7/2020.
SOURCE: Feuerstein JD et al. on behalf of the AGA Institute Clinical Guidelines Committee. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.006.
For moderate to severe ulcerative colitis, treatment with any one of the leading biologic agents is superior to no treatment at all. And in treatment-naive patients, infliximab or vedolizumab should be used rather than adalimumab for inducing remission. These are key recommendations from the American Gastroenterological Association guideline for patients with moderate to severe ulcerative colitis (UC), published in Gastroenterology (doi: 10.1053/j.gastro.2020.01.006).
In all, the guideline comprises 11 recommendations for using immunomodulators, biologics, and small-molecule agents to induce and maintain remission in outpatients with moderate to severe UC and to decrease the need for colectomy in hospitalized patients with acute severe UC. The latest guideline follows a guideline for mild to moderate UC published last year (Gastroenterology. 2019;156[3]:748-64). A technical review accompanied the most recent publication (Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.007).
An updated guideline was long overdue, lead author Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. “The care of patients with inflammatory bowel disease – both ulcerative colitis and Crohn’s – has become increasingly complicated with many newer drugs becoming available,” he said. “The paradigm of how we are treating the disease is evolving, but we haven’t had updated, evidence-based guidelines.” Dr. Feuerstein is the lead author of this guideline.
The guideline can also aid in influencing payers’ policies that now require step-up therapy – that is, failing with the least costly drug before moving onto newer and more effective but costlier agents – Dr. Feuerstein said. “These guidelines show now that we should be treating people based on the evidence and not based on just an insurance company’s preferred policy,” he said.
The strongest recommendation is to use the tumor necrosis factor–alpha (TNF-alpha) antagonists infliximab, adalimumab, and golimumab, the anti-integrin agent vedolizumab, or the anti-interleukin 12/23 agent ustekinumab — all biologics — or the synthetic JAK inhibitor tofacitinib rather than not treating the UC. This is the only recommendation labeled as “strong,” based on “moderate quality evidence.” The relative risk profiles the committee analyzed all favored the biologics over the JAK inhibitor.
Also based on moderate evidence is the recommendation to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who had taken biologic agents before. The other recommendations are based on evidence listed at “low” or “very low” quality, or citing a “knowledge gap.”
“The quality of the evidence available is variable, and we can only make our recommendations based on the quality of the evidence there, but it doesn’t negate the effects of the guideline itself,” Dr. Feuerstein said. The strong recommendation is based on randomized clinical trials that led to the Food and Drug Administration approvals, said Aline Charabaty-Pishvaian, MD, AGAF, associate professor at Johns Hopkins University, Baltimore, and director of the Inflammatory Bowel Disease Center at Sibley Memorial Hospital, Washington. “For everything else, we do not have randomized controlled trials to help make a decision, and the recommendations are made based on the interpretation of different RCTs [randomized controlled trials], knowing that these trials have different designs, patient populations, and endpoints, as well as on experts’ opinions,” she said in an interview.
The only other recommendation based on moderate quality evidence is to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who haven’t previously used biologic agents. The guideline also recommends using tofacitinib in these patients in the confines of a clinical trial; and using ustekinumab or tofacitinib rather than vedolizumab or adalimumab in patients who’ve already been on infliximab, particularly if they haven’t responded to treatment.
The guideline also recommends against thiopurine monotherapy to induce remission, but, for maintenance of remission, recommends such treatment vs. none. However, the guideline suggests against methotrexate monotherapy to induce or maintain remission. And biologic monotherapy is preferred to thiopurine to induce remission, but the guideline makes no recommendation for biologic vs. thiopurine monotherapy to maintain remission. Likewise, combining vedolizumab or ustekinumab with thiopurines or methotrexate is preferred to monotherapy with either a biologic or thiopurine.
The guideline also addresses step-up therapy. It suggests biologics as a first treatment, either as monotherapy or in combination with an immunomodulator, rather than a step-up after failure with 5-aminosalicylates. Also, it recommends against continuing 5-aminosalicylates to induce or maintain remission after a patient has achieved remission with biologics as monotherapy or in combination with immunomodulators or tofacitinib.
The guideline also offers four recommendations for hospitalized patients with acute severe ulcerative colitis: use of intravenous 40-60 mg/d methylprednisolone rather than higher dose IV corticosteroids, no adjunctive antibiotics in the absence of infection; use of infliximab or cyclosporine when IV corticosteroids fail, and no recommendation on the use of intensive vs. standard infliximab dosing when IV corticosteroids fail and the patient is already on infliximab.
The guideline will be meaningful in closing the evidence gap going forward because it can help direct the design of clinical trials, Dr. Charabaty-Pishvaian said. “The guideline highlights areas of need in terms of randomized clinical trials,” she said. “We need these trials to answer the questions we ask ourselves in our daily practice when managing patients with UC: Which drug to choose as the first-line agent? Which drug is the second-line therapy when the disease doesn’t respond or loses response to the first-line agent? Do we need to use combination therapy with all biologics, or only with anti-TNF-alpha agents? For how long? Can we use vedolizumab or ustekinumab as monotherapy when used as a first-line agent? And is there any advantage in adding an immunomodulator when these agents are used as third- or fourth-line therapy?”
Dr. Feuerstein has no relevant financial relationships to disclose. Guideline author Kim Isaacs, MD, disclosed relationships with AbbVie, Takeda, UCB, Janssen and Hoffmann-Laroche. All other committee members have no relevant disclosures.
*This story was updated on 5/7/2020.
SOURCE: Feuerstein JD et al. on behalf of the AGA Institute Clinical Guidelines Committee. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.006.
For moderate to severe ulcerative colitis, treatment with any one of the leading biologic agents is superior to no treatment at all. And in treatment-naive patients, infliximab or vedolizumab should be used rather than adalimumab for inducing remission. These are key recommendations from the American Gastroenterological Association guideline for patients with moderate to severe ulcerative colitis (UC), published in Gastroenterology (doi: 10.1053/j.gastro.2020.01.006).
In all, the guideline comprises 11 recommendations for using immunomodulators, biologics, and small-molecule agents to induce and maintain remission in outpatients with moderate to severe UC and to decrease the need for colectomy in hospitalized patients with acute severe UC. The latest guideline follows a guideline for mild to moderate UC published last year (Gastroenterology. 2019;156[3]:748-64). A technical review accompanied the most recent publication (Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.007).
An updated guideline was long overdue, lead author Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. “The care of patients with inflammatory bowel disease – both ulcerative colitis and Crohn’s – has become increasingly complicated with many newer drugs becoming available,” he said. “The paradigm of how we are treating the disease is evolving, but we haven’t had updated, evidence-based guidelines.” Dr. Feuerstein is the lead author of this guideline.
The guideline can also aid in influencing payers’ policies that now require step-up therapy – that is, failing with the least costly drug before moving onto newer and more effective but costlier agents – Dr. Feuerstein said. “These guidelines show now that we should be treating people based on the evidence and not based on just an insurance company’s preferred policy,” he said.
The strongest recommendation is to use the tumor necrosis factor–alpha (TNF-alpha) antagonists infliximab, adalimumab, and golimumab, the anti-integrin agent vedolizumab, or the anti-interleukin 12/23 agent ustekinumab — all biologics — or the synthetic JAK inhibitor tofacitinib rather than not treating the UC. This is the only recommendation labeled as “strong,” based on “moderate quality evidence.” The relative risk profiles the committee analyzed all favored the biologics over the JAK inhibitor.
Also based on moderate evidence is the recommendation to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who had taken biologic agents before. The other recommendations are based on evidence listed at “low” or “very low” quality, or citing a “knowledge gap.”
“The quality of the evidence available is variable, and we can only make our recommendations based on the quality of the evidence there, but it doesn’t negate the effects of the guideline itself,” Dr. Feuerstein said. The strong recommendation is based on randomized clinical trials that led to the Food and Drug Administration approvals, said Aline Charabaty-Pishvaian, MD, AGAF, associate professor at Johns Hopkins University, Baltimore, and director of the Inflammatory Bowel Disease Center at Sibley Memorial Hospital, Washington. “For everything else, we do not have randomized controlled trials to help make a decision, and the recommendations are made based on the interpretation of different RCTs [randomized controlled trials], knowing that these trials have different designs, patient populations, and endpoints, as well as on experts’ opinions,” she said in an interview.
The only other recommendation based on moderate quality evidence is to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who haven’t previously used biologic agents. The guideline also recommends using tofacitinib in these patients in the confines of a clinical trial; and using ustekinumab or tofacitinib rather than vedolizumab or adalimumab in patients who’ve already been on infliximab, particularly if they haven’t responded to treatment.
The guideline also recommends against thiopurine monotherapy to induce remission, but, for maintenance of remission, recommends such treatment vs. none. However, the guideline suggests against methotrexate monotherapy to induce or maintain remission. And biologic monotherapy is preferred to thiopurine to induce remission, but the guideline makes no recommendation for biologic vs. thiopurine monotherapy to maintain remission. Likewise, combining vedolizumab or ustekinumab with thiopurines or methotrexate is preferred to monotherapy with either a biologic or thiopurine.
The guideline also addresses step-up therapy. It suggests biologics as a first treatment, either as monotherapy or in combination with an immunomodulator, rather than a step-up after failure with 5-aminosalicylates. Also, it recommends against continuing 5-aminosalicylates to induce or maintain remission after a patient has achieved remission with biologics as monotherapy or in combination with immunomodulators or tofacitinib.
The guideline also offers four recommendations for hospitalized patients with acute severe ulcerative colitis: use of intravenous 40-60 mg/d methylprednisolone rather than higher dose IV corticosteroids, no adjunctive antibiotics in the absence of infection; use of infliximab or cyclosporine when IV corticosteroids fail, and no recommendation on the use of intensive vs. standard infliximab dosing when IV corticosteroids fail and the patient is already on infliximab.
The guideline will be meaningful in closing the evidence gap going forward because it can help direct the design of clinical trials, Dr. Charabaty-Pishvaian said. “The guideline highlights areas of need in terms of randomized clinical trials,” she said. “We need these trials to answer the questions we ask ourselves in our daily practice when managing patients with UC: Which drug to choose as the first-line agent? Which drug is the second-line therapy when the disease doesn’t respond or loses response to the first-line agent? Do we need to use combination therapy with all biologics, or only with anti-TNF-alpha agents? For how long? Can we use vedolizumab or ustekinumab as monotherapy when used as a first-line agent? And is there any advantage in adding an immunomodulator when these agents are used as third- or fourth-line therapy?”
Dr. Feuerstein has no relevant financial relationships to disclose. Guideline author Kim Isaacs, MD, disclosed relationships with AbbVie, Takeda, UCB, Janssen and Hoffmann-Laroche. All other committee members have no relevant disclosures.
*This story was updated on 5/7/2020.
SOURCE: Feuerstein JD et al. on behalf of the AGA Institute Clinical Guidelines Committee. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.006.
FROM GASTROENTEROLOGY