From the AGA Journals

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.

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.

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.

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.

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.

Adolescents who undergo metabolic bariatric surgery may require long-term nutrient monitoring and supplementation to prevent nutritional deficiencies, according to investigators.

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.

Adolescents who undergo metabolic bariatric surgery may require long-term nutrient monitoring and supplementation to prevent nutritional deficiencies, according to investigators.

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.

Adolescents who undergo metabolic bariatric surgery may require long-term nutrient monitoring and supplementation to prevent nutritional deficiencies, according to investigators.

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.

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.

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.

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.

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.

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.

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.

For most patients, proton pump inhibitors do not control symptoms of gastroesophageal reflux disease, according to the findings of a large population-based survey study.

In all, 31% of respondents reported gastroesophageal reflux disease (GERD) symptoms within the past week, and 54% of those on proton pump inhibitors (PPIs) had breakthrough symptoms, said Sean D. Delshad, MD, MBA. In all, 54% of patients on PPIs for GERD reported having breakthrough symptoms of heartburn or regurgitation. Novel treatments are needed for patients with PPI-refractory symptoms of GERD, he and his associates wrote in Gastroenterology.

Prior population-based U.S. studies have reported a lower prevalence (16%-28%) of weekly or monthly GERD symptoms, noted Dr. Delshad of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles. However, the study cohorts do not reflect current U.S. demographics — two were 82%-90% white and the third was 43% African American. The most recent data also were collected approximately 15 years ago, the researchers noted.

For the study, they deployed a mobile app that guides users through an automated, online assessment of GI symptoms called AEGIS. Respondents were asked to select any GERD symptoms they had ever experienced and any symptoms they had experienced in the past week. Options included heartburn, acid reflux, gastroesophageal reflux, abdominal pain, bloating or gas, constipation, diarrhea, disrupted swallowing, fecal incontinence, nausea and vomiting, and “no symptoms.” All 71,812 respondents were recruited by a research firm and surveyed during a 3-week period in 2015.

In all, 44% of respondents reported having ever had heartburn, acid reflux, or gastroesophageal reflux, and 31% reported having GERD symptoms in the past week. In all, 55% of respondents who had ever experienced GERD symptoms were on PPIs, 24% were on histamine₂ receptor blockers, and 24% were on antacid agents.

Among more than 3,000 participants on daily PPIs, 54% had persistent symptoms of GERD, which compares with the results of prior community-based studies, the investigators wrote. Current GERD symptoms and PPI-refractory GERD were especially prevalent among women, non-Hispanic whites, and individuals with comorbidities such as irritable bowel syndrome, diabetes, Crohn’s disease, and endometriosis.

In an adjusted analysis, Latinos were 2.44 times more likely to have PPI-refractory GERD ,compared with non-Hispanic whites. “The reason behind this finding is unclear but may be secondary to physiologic or even cultural etiologies,” the researchers wrote.

The more independent and functional middle-aged and older adults are more likely to respond to online surveys. Furthermore, although incentives were used to reduce participation bias, calling the tool a “GI Survey” could have made those with GI symptoms more likely to respond. The survey also did not assess if respondents were taking PPIs correctly or if they had made behavioral changes to mitigate GERD.

This study was sponsored by Ironwood Pharmaceuticals, whose bile acid sequestrant IW-3718 is in late-phase development as an add-on to PPI therapy for patients with persistent GERD. Dr. Delshad reported having no relevant conflicts of interest, but two coinvestigators disclosed consulting relationships with Ironwood Pharmaceuticals.
 

SOURCE: Delshad SD et al. Gastroenterology. 2019 Dec 10. doi: 10.1053/j.gastro.2019.12.014.

For most patients, proton pump inhibitors do not control symptoms of gastroesophageal reflux disease, according to the findings of a large population-based survey study.

In all, 31% of respondents reported gastroesophageal reflux disease (GERD) symptoms within the past week, and 54% of those on proton pump inhibitors (PPIs) had breakthrough symptoms, said Sean D. Delshad, MD, MBA. In all, 54% of patients on PPIs for GERD reported having breakthrough symptoms of heartburn or regurgitation. Novel treatments are needed for patients with PPI-refractory symptoms of GERD, he and his associates wrote in Gastroenterology.

Prior population-based U.S. studies have reported a lower prevalence (16%-28%) of weekly or monthly GERD symptoms, noted Dr. Delshad of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles. However, the study cohorts do not reflect current U.S. demographics — two were 82%-90% white and the third was 43% African American. The most recent data also were collected approximately 15 years ago, the researchers noted.

For the study, they deployed a mobile app that guides users through an automated, online assessment of GI symptoms called AEGIS. Respondents were asked to select any GERD symptoms they had ever experienced and any symptoms they had experienced in the past week. Options included heartburn, acid reflux, gastroesophageal reflux, abdominal pain, bloating or gas, constipation, diarrhea, disrupted swallowing, fecal incontinence, nausea and vomiting, and “no symptoms.” All 71,812 respondents were recruited by a research firm and surveyed during a 3-week period in 2015.

In all, 44% of respondents reported having ever had heartburn, acid reflux, or gastroesophageal reflux, and 31% reported having GERD symptoms in the past week. In all, 55% of respondents who had ever experienced GERD symptoms were on PPIs, 24% were on histamine₂ receptor blockers, and 24% were on antacid agents.

Among more than 3,000 participants on daily PPIs, 54% had persistent symptoms of GERD, which compares with the results of prior community-based studies, the investigators wrote. Current GERD symptoms and PPI-refractory GERD were especially prevalent among women, non-Hispanic whites, and individuals with comorbidities such as irritable bowel syndrome, diabetes, Crohn’s disease, and endometriosis.

In an adjusted analysis, Latinos were 2.44 times more likely to have PPI-refractory GERD ,compared with non-Hispanic whites. “The reason behind this finding is unclear but may be secondary to physiologic or even cultural etiologies,” the researchers wrote.

The more independent and functional middle-aged and older adults are more likely to respond to online surveys. Furthermore, although incentives were used to reduce participation bias, calling the tool a “GI Survey” could have made those with GI symptoms more likely to respond. The survey also did not assess if respondents were taking PPIs correctly or if they had made behavioral changes to mitigate GERD.

This study was sponsored by Ironwood Pharmaceuticals, whose bile acid sequestrant IW-3718 is in late-phase development as an add-on to PPI therapy for patients with persistent GERD. Dr. Delshad reported having no relevant conflicts of interest, but two coinvestigators disclosed consulting relationships with Ironwood Pharmaceuticals.
 

SOURCE: Delshad SD et al. Gastroenterology. 2019 Dec 10. doi: 10.1053/j.gastro.2019.12.014.

For most patients, proton pump inhibitors do not control symptoms of gastroesophageal reflux disease, according to the findings of a large population-based survey study.

In all, 31% of respondents reported gastroesophageal reflux disease (GERD) symptoms within the past week, and 54% of those on proton pump inhibitors (PPIs) had breakthrough symptoms, said Sean D. Delshad, MD, MBA. In all, 54% of patients on PPIs for GERD reported having breakthrough symptoms of heartburn or regurgitation. Novel treatments are needed for patients with PPI-refractory symptoms of GERD, he and his associates wrote in Gastroenterology.

Prior population-based U.S. studies have reported a lower prevalence (16%-28%) of weekly or monthly GERD symptoms, noted Dr. Delshad of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles. However, the study cohorts do not reflect current U.S. demographics — two were 82%-90% white and the third was 43% African American. The most recent data also were collected approximately 15 years ago, the researchers noted.

For the study, they deployed a mobile app that guides users through an automated, online assessment of GI symptoms called AEGIS. Respondents were asked to select any GERD symptoms they had ever experienced and any symptoms they had experienced in the past week. Options included heartburn, acid reflux, gastroesophageal reflux, abdominal pain, bloating or gas, constipation, diarrhea, disrupted swallowing, fecal incontinence, nausea and vomiting, and “no symptoms.” All 71,812 respondents were recruited by a research firm and surveyed during a 3-week period in 2015.

In all, 44% of respondents reported having ever had heartburn, acid reflux, or gastroesophageal reflux, and 31% reported having GERD symptoms in the past week. In all, 55% of respondents who had ever experienced GERD symptoms were on PPIs, 24% were on histamine₂ receptor blockers, and 24% were on antacid agents.

Among more than 3,000 participants on daily PPIs, 54% had persistent symptoms of GERD, which compares with the results of prior community-based studies, the investigators wrote. Current GERD symptoms and PPI-refractory GERD were especially prevalent among women, non-Hispanic whites, and individuals with comorbidities such as irritable bowel syndrome, diabetes, Crohn’s disease, and endometriosis.

In an adjusted analysis, Latinos were 2.44 times more likely to have PPI-refractory GERD ,compared with non-Hispanic whites. “The reason behind this finding is unclear but may be secondary to physiologic or even cultural etiologies,” the researchers wrote.

The more independent and functional middle-aged and older adults are more likely to respond to online surveys. Furthermore, although incentives were used to reduce participation bias, calling the tool a “GI Survey” could have made those with GI symptoms more likely to respond. The survey also did not assess if respondents were taking PPIs correctly or if they had made behavioral changes to mitigate GERD.

This study was sponsored by Ironwood Pharmaceuticals, whose bile acid sequestrant IW-3718 is in late-phase development as an add-on to PPI therapy for patients with persistent GERD. Dr. Delshad reported having no relevant conflicts of interest, but two coinvestigators disclosed consulting relationships with Ironwood Pharmaceuticals.
 

SOURCE: Delshad SD et al. Gastroenterology. 2019 Dec 10. doi: 10.1053/j.gastro.2019.12.014.

Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.

“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.

Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.

To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.

After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).

Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.

The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.

SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.

Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.

“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.

Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.

To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.

After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).

Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.

The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.

SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.

Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.

“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.

Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.

To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.

After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).

Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.

The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.

SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.