From the AGA Journals

When patients with inflammatory bowel disease report persistent gastrointestinal symptoms, clinicians should perform a thorough clinical assessment and then take a stepwise approach to rule out ongoing inflammation, according to a clinical practice update from the American Gastroenterological Association.

A fecal calprotectin test can be useful because values under 50 mcg/mL may suggest endoscopic remission, which may, in turn, point to another etiology of gastrointestinal symptoms, wrote Jean-Frederic Colombel, MD, of the Icahn School of Medicine at Mount Sinai, New York, together with his associates in Clinical Gastroenterology and Hepatology.

However, a result between 50 and 250 mcg/mL is harder to interpret because the upper limit of normal varies and mild increases can occur secondary to nonspecific low-grade inflammation, according to the experts. For mild gastrointestinal symptoms, they suggested testing fecal calprotectin every 3-6 months to identify flares as early as possible. If a flare is suspected, they advised considering cross-sectional imaging or endoscopy with biopsy.

Imaging also is indicated for patients with obstructive symptoms such as abdominal pain, obstipation, or constipation, the practice update states. Such symptoms can indicate fecal stasis proximal to distal colitis in patients with ulcerative colitis, or intestinal stenosis in patients with Crohn’s disease.

Other pathophysiologies of gastrointestinal symptoms also should be considered based on constellations of symptoms. For example, steatorrhea with chronic abdominal pain may indicate pancreatic exocrine insufficiency, which fecal elastase testing can help confirm. Symptoms of diarrhea-predominant irritable bowel syndrome can result from bile acid diarrhea, for which several screening tests are available. Diarrhea, abdominal pain, and bloating may indicate carbohydrate malabsorption or small-intestinal bacterial overgrowth, which can be evaluated with breath testing.

If patients with inflammatory bowel disease have persistent gastrointestinal symptoms but lack objective evidence of ongoing inflammation or another etiology, then clinicians should increase their suspicion of an overlapping functional gastrointestinal disorder. These conditions actually “share many common pathophysiologic disturbances that, in some inflammatory bowel disease patients, may be a consequence of prior structural and functional bowel damage,” the experts wrote.

For patients with chronic constipation who do not have an underlying obstruction, they suggest osmotic or stimulant laxatives. For chronic diarrhea, they recommend hypomobility agents or bile-acid sequestrants. Patients with fecal symptoms of irritable bowel syndrome also should be evaluated for pelvic floor disorders, which may improve with biofeedback therapy, the experts state.

A low-FODMAP diet (a diet low in lactose, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) also can improve symptoms of irritable bowel syndrome, including patients with inflammatory bowel disease. However, a dietitian always should deliver this restrictive diet because patients with inflammatory bowel disease already are at increased risk for undernutrition.

Patients with functional gastrointestinal pain may benefit from antispasmodics, neuropathic-directed agents, and antidepressants, but they should not receive opiates, the experts emphasized. Anxiety and depression are common in both inflammatory bowel disease and irritable bowel syndrome, and patients may benefit from psychotherapy (cognitive-behavioral therapy, hypnotherapy, and mindfulness therapy), antidepressants, anxiolytics, or combinations of these treatments. The practice update also recommends physical exercise, which has been shown to decrease the risk of recurrent active disease in the setting of inflammatory bowel disease.

Finally, persistent gut symptoms can indicate intestinal barrier dysfunction, even if endoscopy shows mucosal healing. Barrier dysfunction is a potential therapeutic target that needs further study in this setting, the experts noted. They also called for studies of the potential benefits and risks of probiotics and other alternative approaches, such as herbal treatments and supplements, yoga, acupuncture, and moxibustion. Until further evidence, however, they have recommended against complementary or alternative medicine or fecal microbiota transplantation.

Dr. Colombel has served as consultant, advisory board member, or speaker for AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, and many other pharmaceutical companies. He has received research grants from AbbVie, Takeda, and Janssen and Janssen.

SOURCE: Colombel J-F et al. Clin Gastroenterol Hepatol. 2018 Aug 9. doi: 10.1016/j.cgh.2018.08.001.

When patients with inflammatory bowel disease report persistent gastrointestinal symptoms, clinicians should perform a thorough clinical assessment and then take a stepwise approach to rule out ongoing inflammation, according to a clinical practice update from the American Gastroenterological Association.

A fecal calprotectin test can be useful because values under 50 mcg/mL may suggest endoscopic remission, which may, in turn, point to another etiology of gastrointestinal symptoms, wrote Jean-Frederic Colombel, MD, of the Icahn School of Medicine at Mount Sinai, New York, together with his associates in Clinical Gastroenterology and Hepatology.

However, a result between 50 and 250 mcg/mL is harder to interpret because the upper limit of normal varies and mild increases can occur secondary to nonspecific low-grade inflammation, according to the experts. For mild gastrointestinal symptoms, they suggested testing fecal calprotectin every 3-6 months to identify flares as early as possible. If a flare is suspected, they advised considering cross-sectional imaging or endoscopy with biopsy.

Imaging also is indicated for patients with obstructive symptoms such as abdominal pain, obstipation, or constipation, the practice update states. Such symptoms can indicate fecal stasis proximal to distal colitis in patients with ulcerative colitis, or intestinal stenosis in patients with Crohn’s disease.

Other pathophysiologies of gastrointestinal symptoms also should be considered based on constellations of symptoms. For example, steatorrhea with chronic abdominal pain may indicate pancreatic exocrine insufficiency, which fecal elastase testing can help confirm. Symptoms of diarrhea-predominant irritable bowel syndrome can result from bile acid diarrhea, for which several screening tests are available. Diarrhea, abdominal pain, and bloating may indicate carbohydrate malabsorption or small-intestinal bacterial overgrowth, which can be evaluated with breath testing.

If patients with inflammatory bowel disease have persistent gastrointestinal symptoms but lack objective evidence of ongoing inflammation or another etiology, then clinicians should increase their suspicion of an overlapping functional gastrointestinal disorder. These conditions actually “share many common pathophysiologic disturbances that, in some inflammatory bowel disease patients, may be a consequence of prior structural and functional bowel damage,” the experts wrote.

For patients with chronic constipation who do not have an underlying obstruction, they suggest osmotic or stimulant laxatives. For chronic diarrhea, they recommend hypomobility agents or bile-acid sequestrants. Patients with fecal symptoms of irritable bowel syndrome also should be evaluated for pelvic floor disorders, which may improve with biofeedback therapy, the experts state.

A low-FODMAP diet (a diet low in lactose, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) also can improve symptoms of irritable bowel syndrome, including patients with inflammatory bowel disease. However, a dietitian always should deliver this restrictive diet because patients with inflammatory bowel disease already are at increased risk for undernutrition.

Patients with functional gastrointestinal pain may benefit from antispasmodics, neuropathic-directed agents, and antidepressants, but they should not receive opiates, the experts emphasized. Anxiety and depression are common in both inflammatory bowel disease and irritable bowel syndrome, and patients may benefit from psychotherapy (cognitive-behavioral therapy, hypnotherapy, and mindfulness therapy), antidepressants, anxiolytics, or combinations of these treatments. The practice update also recommends physical exercise, which has been shown to decrease the risk of recurrent active disease in the setting of inflammatory bowel disease.

Finally, persistent gut symptoms can indicate intestinal barrier dysfunction, even if endoscopy shows mucosal healing. Barrier dysfunction is a potential therapeutic target that needs further study in this setting, the experts noted. They also called for studies of the potential benefits and risks of probiotics and other alternative approaches, such as herbal treatments and supplements, yoga, acupuncture, and moxibustion. Until further evidence, however, they have recommended against complementary or alternative medicine or fecal microbiota transplantation.

Dr. Colombel has served as consultant, advisory board member, or speaker for AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, and many other pharmaceutical companies. He has received research grants from AbbVie, Takeda, and Janssen and Janssen.

SOURCE: Colombel J-F et al. Clin Gastroenterol Hepatol. 2018 Aug 9. doi: 10.1016/j.cgh.2018.08.001.

When patients with inflammatory bowel disease report persistent gastrointestinal symptoms, clinicians should perform a thorough clinical assessment and then take a stepwise approach to rule out ongoing inflammation, according to a clinical practice update from the American Gastroenterological Association.

A fecal calprotectin test can be useful because values under 50 mcg/mL may suggest endoscopic remission, which may, in turn, point to another etiology of gastrointestinal symptoms, wrote Jean-Frederic Colombel, MD, of the Icahn School of Medicine at Mount Sinai, New York, together with his associates in Clinical Gastroenterology and Hepatology.

However, a result between 50 and 250 mcg/mL is harder to interpret because the upper limit of normal varies and mild increases can occur secondary to nonspecific low-grade inflammation, according to the experts. For mild gastrointestinal symptoms, they suggested testing fecal calprotectin every 3-6 months to identify flares as early as possible. If a flare is suspected, they advised considering cross-sectional imaging or endoscopy with biopsy.

Imaging also is indicated for patients with obstructive symptoms such as abdominal pain, obstipation, or constipation, the practice update states. Such symptoms can indicate fecal stasis proximal to distal colitis in patients with ulcerative colitis, or intestinal stenosis in patients with Crohn’s disease.

Other pathophysiologies of gastrointestinal symptoms also should be considered based on constellations of symptoms. For example, steatorrhea with chronic abdominal pain may indicate pancreatic exocrine insufficiency, which fecal elastase testing can help confirm. Symptoms of diarrhea-predominant irritable bowel syndrome can result from bile acid diarrhea, for which several screening tests are available. Diarrhea, abdominal pain, and bloating may indicate carbohydrate malabsorption or small-intestinal bacterial overgrowth, which can be evaluated with breath testing.

If patients with inflammatory bowel disease have persistent gastrointestinal symptoms but lack objective evidence of ongoing inflammation or another etiology, then clinicians should increase their suspicion of an overlapping functional gastrointestinal disorder. These conditions actually “share many common pathophysiologic disturbances that, in some inflammatory bowel disease patients, may be a consequence of prior structural and functional bowel damage,” the experts wrote.

For patients with chronic constipation who do not have an underlying obstruction, they suggest osmotic or stimulant laxatives. For chronic diarrhea, they recommend hypomobility agents or bile-acid sequestrants. Patients with fecal symptoms of irritable bowel syndrome also should be evaluated for pelvic floor disorders, which may improve with biofeedback therapy, the experts state.

A low-FODMAP diet (a diet low in lactose, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) also can improve symptoms of irritable bowel syndrome, including patients with inflammatory bowel disease. However, a dietitian always should deliver this restrictive diet because patients with inflammatory bowel disease already are at increased risk for undernutrition.

Patients with functional gastrointestinal pain may benefit from antispasmodics, neuropathic-directed agents, and antidepressants, but they should not receive opiates, the experts emphasized. Anxiety and depression are common in both inflammatory bowel disease and irritable bowel syndrome, and patients may benefit from psychotherapy (cognitive-behavioral therapy, hypnotherapy, and mindfulness therapy), antidepressants, anxiolytics, or combinations of these treatments. The practice update also recommends physical exercise, which has been shown to decrease the risk of recurrent active disease in the setting of inflammatory bowel disease.

Finally, persistent gut symptoms can indicate intestinal barrier dysfunction, even if endoscopy shows mucosal healing. Barrier dysfunction is a potential therapeutic target that needs further study in this setting, the experts noted. They also called for studies of the potential benefits and risks of probiotics and other alternative approaches, such as herbal treatments and supplements, yoga, acupuncture, and moxibustion. Until further evidence, however, they have recommended against complementary or alternative medicine or fecal microbiota transplantation.

Dr. Colombel has served as consultant, advisory board member, or speaker for AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, and many other pharmaceutical companies. He has received research grants from AbbVie, Takeda, and Janssen and Janssen.

SOURCE: Colombel J-F et al. Clin Gastroenterol Hepatol. 2018 Aug 9. doi: 10.1016/j.cgh.2018.08.001.

For patients with extensive mild to moderate ulcerative colitis, numerous randomized controlled trials support the use of either standard-dose mesalamine (2-3 grams per day) or diazo-bonded 5-aminosalicylic acid (ASA) instead of low-dose mesalamine, sulfasalazine, or no therapy, state new guidelines from the American Gastroenterological Association, published in Gastroenterology.

©selvanegra/thinkstockphotos.com

Sulfasalazine (2-4 grams per day) is less likely to be tolerated but remains a “reasonable option” for remitted patients who are already on it and for patients with prominent arthritis symptoms, especially if alternative treatments are cost prohibitive, wrote Cynthia W. Ko, MD, MS, of the University of Washington, Seattle, and her associates.

According to the guideline, patients with mild to moderate ulcerative colitis have less than four to six bowel movements per day, only mild or moderate rectal bleeding, no constitutional symptoms, and no high overall inflammatory burden or signs of high inflammatory activity on the Mayo Clinic score and Truelove and Witt’s criteria. These patients usually do not require colectomy, but this outcome is more likely when patients are diagnosed before age 40 years or have extensive disease or deep ulcers, extraintestinal manifestations, or elevated inflammatory markers. These higher-risk patients need more aggressive initial treatment and faster treatment intensification in cases of inadequate response, the guideline emphasizes. Even for cases of mild to moderate ulcerative colitis, treatment intensification is preferable to repeated courses of corticosteroids.

The guideline recommends adding rectal mesalamine to oral 5-ASA if patients have extensive or left-sided mild to moderate ulcerative colitis. In randomized controlled trials, this combination was significantly more likely to induce and maintain remission than was standard-dose oral mesalamine monotherapy, the authors noted. “In the maintenance trials, enemas were used twice per week or for 1 week per month. Both oral and topical mesalamine were well tolerated.”

For patients with moderate disease activity or a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA, the guideline recommends adding rectal mesalamine to high-dose oral mesalamine (more than 3 grams daily). Combination therapy maximizes the delivery of mesalamine to the affected area of the colon, which optimizes the trial of 5-ASA before opting for treatment escalation, the authors noted. They recommend once-daily oral mesalamine dosing, since this is easier to adhere to and studies have found no benefit of more frequent dosing.

For inducing remission of mild to moderate ulcerative colitis, the guideline recommends standard-dose oral mesalamine or diazo-bonded 5-ASA over budesonide. “Overall, the budesonide preparations are not superior to mesalamine for induction of remission,” the authors wrote. Oral 5-ASAs are preferred, especially given the absence of data on the efficacy or safety of maintenance budesonide therapy.

SOURCE: Crocket SD et al.  Gastro 2019;156(2).  doi: org/10.1053/j.gastro.2018.12.009.

For patients with extensive mild to moderate ulcerative colitis, numerous randomized controlled trials support the use of either standard-dose mesalamine (2-3 grams per day) or diazo-bonded 5-aminosalicylic acid (ASA) instead of low-dose mesalamine, sulfasalazine, or no therapy, state new guidelines from the American Gastroenterological Association, published in Gastroenterology.

©selvanegra/thinkstockphotos.com

Sulfasalazine (2-4 grams per day) is less likely to be tolerated but remains a “reasonable option” for remitted patients who are already on it and for patients with prominent arthritis symptoms, especially if alternative treatments are cost prohibitive, wrote Cynthia W. Ko, MD, MS, of the University of Washington, Seattle, and her associates.

According to the guideline, patients with mild to moderate ulcerative colitis have less than four to six bowel movements per day, only mild or moderate rectal bleeding, no constitutional symptoms, and no high overall inflammatory burden or signs of high inflammatory activity on the Mayo Clinic score and Truelove and Witt’s criteria. These patients usually do not require colectomy, but this outcome is more likely when patients are diagnosed before age 40 years or have extensive disease or deep ulcers, extraintestinal manifestations, or elevated inflammatory markers. These higher-risk patients need more aggressive initial treatment and faster treatment intensification in cases of inadequate response, the guideline emphasizes. Even for cases of mild to moderate ulcerative colitis, treatment intensification is preferable to repeated courses of corticosteroids.

The guideline recommends adding rectal mesalamine to oral 5-ASA if patients have extensive or left-sided mild to moderate ulcerative colitis. In randomized controlled trials, this combination was significantly more likely to induce and maintain remission than was standard-dose oral mesalamine monotherapy, the authors noted. “In the maintenance trials, enemas were used twice per week or for 1 week per month. Both oral and topical mesalamine were well tolerated.”

For patients with moderate disease activity or a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA, the guideline recommends adding rectal mesalamine to high-dose oral mesalamine (more than 3 grams daily). Combination therapy maximizes the delivery of mesalamine to the affected area of the colon, which optimizes the trial of 5-ASA before opting for treatment escalation, the authors noted. They recommend once-daily oral mesalamine dosing, since this is easier to adhere to and studies have found no benefit of more frequent dosing.

For inducing remission of mild to moderate ulcerative colitis, the guideline recommends standard-dose oral mesalamine or diazo-bonded 5-ASA over budesonide. “Overall, the budesonide preparations are not superior to mesalamine for induction of remission,” the authors wrote. Oral 5-ASAs are preferred, especially given the absence of data on the efficacy or safety of maintenance budesonide therapy.

SOURCE: Crocket SD et al.  Gastro 2019;156(2).  doi: org/10.1053/j.gastro.2018.12.009.

For patients with extensive mild to moderate ulcerative colitis, numerous randomized controlled trials support the use of either standard-dose mesalamine (2-3 grams per day) or diazo-bonded 5-aminosalicylic acid (ASA) instead of low-dose mesalamine, sulfasalazine, or no therapy, state new guidelines from the American Gastroenterological Association, published in Gastroenterology.

©selvanegra/thinkstockphotos.com

Sulfasalazine (2-4 grams per day) is less likely to be tolerated but remains a “reasonable option” for remitted patients who are already on it and for patients with prominent arthritis symptoms, especially if alternative treatments are cost prohibitive, wrote Cynthia W. Ko, MD, MS, of the University of Washington, Seattle, and her associates.

According to the guideline, patients with mild to moderate ulcerative colitis have less than four to six bowel movements per day, only mild or moderate rectal bleeding, no constitutional symptoms, and no high overall inflammatory burden or signs of high inflammatory activity on the Mayo Clinic score and Truelove and Witt’s criteria. These patients usually do not require colectomy, but this outcome is more likely when patients are diagnosed before age 40 years or have extensive disease or deep ulcers, extraintestinal manifestations, or elevated inflammatory markers. These higher-risk patients need more aggressive initial treatment and faster treatment intensification in cases of inadequate response, the guideline emphasizes. Even for cases of mild to moderate ulcerative colitis, treatment intensification is preferable to repeated courses of corticosteroids.

The guideline recommends adding rectal mesalamine to oral 5-ASA if patients have extensive or left-sided mild to moderate ulcerative colitis. In randomized controlled trials, this combination was significantly more likely to induce and maintain remission than was standard-dose oral mesalamine monotherapy, the authors noted. “In the maintenance trials, enemas were used twice per week or for 1 week per month. Both oral and topical mesalamine were well tolerated.”

For patients with moderate disease activity or a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA, the guideline recommends adding rectal mesalamine to high-dose oral mesalamine (more than 3 grams daily). Combination therapy maximizes the delivery of mesalamine to the affected area of the colon, which optimizes the trial of 5-ASA before opting for treatment escalation, the authors noted. They recommend once-daily oral mesalamine dosing, since this is easier to adhere to and studies have found no benefit of more frequent dosing.

For inducing remission of mild to moderate ulcerative colitis, the guideline recommends standard-dose oral mesalamine or diazo-bonded 5-ASA over budesonide. “Overall, the budesonide preparations are not superior to mesalamine for induction of remission,” the authors wrote. Oral 5-ASAs are preferred, especially given the absence of data on the efficacy or safety of maintenance budesonide therapy.

SOURCE: Crocket SD et al.  Gastro 2019;156(2).  doi: org/10.1053/j.gastro.2018.12.009.

Aluminum ingested in small amounts causes visceral hypersensitivity in rats, suggesting that dietary levels of aluminum may trigger irritable bowel syndrome (IBS) in humans, according to a study published in Cellular and Molecular Gastroenterology and Hepatology.

Rats given oral aluminum exhibited dose-dependent visceral pain along with activation of proteinase-activated receptor-2 (PAR2) and mast cell degranulation, a combination of events that mirror clinical signs and molecular mechanisms of IBS in humans, reported lead author, Nicolas Esquerre, PhD, of Lille Inflammation Research International Center at Université Lille in France, and his colleagues. The study contributes to ongoing research surrounding causes and mechanisms of IBS, which may vary among patients because of disease subsets. These findings suggest that some patients with IBS may benefit from dietary aluminum restriction or chelation therapy.

“[T]he question of the initial trigger [of IBS] still remains unresolved,” the investigators wrote. “A more precise link between food and IBS has been demonstrated for gluten and other wheat proteins, lactose, and nickel, highlighting particular subsets of IBS patients now diagnosed as nonceliac gluten/wheat sensitivity, lactose intolerance, and nickel-allergic contact mucositis,” they added. “Here, we evaluated the effect of aluminum, a common contaminant of food and water, on abdominal pain.”

Aluminum may enter the diet as a food additive, or it may contaminate foods grown in aluminum-rich soil. Other sources of oral exposure include packaging and kitchenware. A previous study showed that most Americans ingest 0.01-1.4 mg/kg of aluminum daily, and 5% ingest 1.58 mg/kg daily (i.e., 95 mg per day for a 60-kg person).

Based on these statistics, rats in the present study received oral aluminum citrate (AlCi) corresponding with three doses of aluminum: 0.5 mg/kg, 1.5 mg/kg, or 3.0 mg/kg. Treatment continued for 30 days, with colorectal distension (CRD) measured on days 2, 4, 8, 15, and 30.

Results showed a dose-dependent relationship between aluminum ingestion and visceral hypersensitivity. Within 2 days, rats receiving 3.0 mg/kg of aluminum exhibited a significantly lower pain threshold, and within 8 days, rats receiving 0.5 mg/kg and 1.5 mg/kg also showed increased visceral hypersensitivity.

After 1 month of treatment, rats receiving 1.5 mg/kg per day demonstrated a 30% increase in pain compared with control animals. In the same group, visceral hypersensitivity began to wane 7 days after cessation of treatment; 4 more weeks were needed to return to baseline. When treatment was restarted, visceral hypersensitivity occurred within 2 days, compared with 8 days upon initial administration. These findings are particularly relevant to some people, as the 1.5-mg/kg dose corresponds with the daily amount of aluminum ingested by 5% of Americans. Similar patterns of response and sensitization were observed in rats ingesting 0.5 mg/kg and 3.0 mg/kg. Female rats were more sensitive to aluminum than were male rats, a sex pattern that mimics human IBS.

Further testing showed that rats treated with zinc citrate (ZnCi) did not exhibit changes to pain threshold, thereby excluding citrate as an aggravating factor. Rat models of noninflammatory and inflammatory colonic hypersensitivity (butyrate enema or intrathecal injection of 25%-50% ethanol in combination with 2,4,6-trinitrobenzenesulfonic acid, respectively) had visceral hypersensitivity similar to that of rats in the 1.5-mg/kg AlCi group.

Testing of colonic tissue from AlCi-treated rats did not reveal inflammatory changes according to a variety of qualifiers, including histology, myeloperoxidase activity, mRNA expression of several inflammatory cytokines, or infiltration of eosinophils or macrophages. Noninflammatory effects of aluminum, however, were found. For instance, treated rats had lower serotonin levels in enteroendocrine cells.

“Enteroendocrine cells are specialized epithelial cells that respond to luminal stimuli by releasing various biologically active compounds,” the investigators wrote. “They regulate several physiological and homeostatic functions of the gastrointestinal tract, such as postprandial secretion, motility, immune responses, and sensory functions. A reduced number of enteroendocrine cells has been observed in the duodenum, ileum, and colon of some patients with IBS.”

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.

Aluminum ingested in small amounts causes visceral hypersensitivity in rats, suggesting that dietary levels of aluminum may trigger irritable bowel syndrome (IBS) in humans, according to a study published in Cellular and Molecular Gastroenterology and Hepatology.

Rats given oral aluminum exhibited dose-dependent visceral pain along with activation of proteinase-activated receptor-2 (PAR2) and mast cell degranulation, a combination of events that mirror clinical signs and molecular mechanisms of IBS in humans, reported lead author, Nicolas Esquerre, PhD, of Lille Inflammation Research International Center at Université Lille in France, and his colleagues. The study contributes to ongoing research surrounding causes and mechanisms of IBS, which may vary among patients because of disease subsets. These findings suggest that some patients with IBS may benefit from dietary aluminum restriction or chelation therapy.

“[T]he question of the initial trigger [of IBS] still remains unresolved,” the investigators wrote. “A more precise link between food and IBS has been demonstrated for gluten and other wheat proteins, lactose, and nickel, highlighting particular subsets of IBS patients now diagnosed as nonceliac gluten/wheat sensitivity, lactose intolerance, and nickel-allergic contact mucositis,” they added. “Here, we evaluated the effect of aluminum, a common contaminant of food and water, on abdominal pain.”

Aluminum may enter the diet as a food additive, or it may contaminate foods grown in aluminum-rich soil. Other sources of oral exposure include packaging and kitchenware. A previous study showed that most Americans ingest 0.01-1.4 mg/kg of aluminum daily, and 5% ingest 1.58 mg/kg daily (i.e., 95 mg per day for a 60-kg person).

Based on these statistics, rats in the present study received oral aluminum citrate (AlCi) corresponding with three doses of aluminum: 0.5 mg/kg, 1.5 mg/kg, or 3.0 mg/kg. Treatment continued for 30 days, with colorectal distension (CRD) measured on days 2, 4, 8, 15, and 30.

Results showed a dose-dependent relationship between aluminum ingestion and visceral hypersensitivity. Within 2 days, rats receiving 3.0 mg/kg of aluminum exhibited a significantly lower pain threshold, and within 8 days, rats receiving 0.5 mg/kg and 1.5 mg/kg also showed increased visceral hypersensitivity.

After 1 month of treatment, rats receiving 1.5 mg/kg per day demonstrated a 30% increase in pain compared with control animals. In the same group, visceral hypersensitivity began to wane 7 days after cessation of treatment; 4 more weeks were needed to return to baseline. When treatment was restarted, visceral hypersensitivity occurred within 2 days, compared with 8 days upon initial administration. These findings are particularly relevant to some people, as the 1.5-mg/kg dose corresponds with the daily amount of aluminum ingested by 5% of Americans. Similar patterns of response and sensitization were observed in rats ingesting 0.5 mg/kg and 3.0 mg/kg. Female rats were more sensitive to aluminum than were male rats, a sex pattern that mimics human IBS.

Further testing showed that rats treated with zinc citrate (ZnCi) did not exhibit changes to pain threshold, thereby excluding citrate as an aggravating factor. Rat models of noninflammatory and inflammatory colonic hypersensitivity (butyrate enema or intrathecal injection of 25%-50% ethanol in combination with 2,4,6-trinitrobenzenesulfonic acid, respectively) had visceral hypersensitivity similar to that of rats in the 1.5-mg/kg AlCi group.

Testing of colonic tissue from AlCi-treated rats did not reveal inflammatory changes according to a variety of qualifiers, including histology, myeloperoxidase activity, mRNA expression of several inflammatory cytokines, or infiltration of eosinophils or macrophages. Noninflammatory effects of aluminum, however, were found. For instance, treated rats had lower serotonin levels in enteroendocrine cells.

“Enteroendocrine cells are specialized epithelial cells that respond to luminal stimuli by releasing various biologically active compounds,” the investigators wrote. “They regulate several physiological and homeostatic functions of the gastrointestinal tract, such as postprandial secretion, motility, immune responses, and sensory functions. A reduced number of enteroendocrine cells has been observed in the duodenum, ileum, and colon of some patients with IBS.”

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.

Aluminum ingested in small amounts causes visceral hypersensitivity in rats, suggesting that dietary levels of aluminum may trigger irritable bowel syndrome (IBS) in humans, according to a study published in Cellular and Molecular Gastroenterology and Hepatology.

Rats given oral aluminum exhibited dose-dependent visceral pain along with activation of proteinase-activated receptor-2 (PAR2) and mast cell degranulation, a combination of events that mirror clinical signs and molecular mechanisms of IBS in humans, reported lead author, Nicolas Esquerre, PhD, of Lille Inflammation Research International Center at Université Lille in France, and his colleagues. The study contributes to ongoing research surrounding causes and mechanisms of IBS, which may vary among patients because of disease subsets. These findings suggest that some patients with IBS may benefit from dietary aluminum restriction or chelation therapy.

“[T]he question of the initial trigger [of IBS] still remains unresolved,” the investigators wrote. “A more precise link between food and IBS has been demonstrated for gluten and other wheat proteins, lactose, and nickel, highlighting particular subsets of IBS patients now diagnosed as nonceliac gluten/wheat sensitivity, lactose intolerance, and nickel-allergic contact mucositis,” they added. “Here, we evaluated the effect of aluminum, a common contaminant of food and water, on abdominal pain.”

Aluminum may enter the diet as a food additive, or it may contaminate foods grown in aluminum-rich soil. Other sources of oral exposure include packaging and kitchenware. A previous study showed that most Americans ingest 0.01-1.4 mg/kg of aluminum daily, and 5% ingest 1.58 mg/kg daily (i.e., 95 mg per day for a 60-kg person).

Based on these statistics, rats in the present study received oral aluminum citrate (AlCi) corresponding with three doses of aluminum: 0.5 mg/kg, 1.5 mg/kg, or 3.0 mg/kg. Treatment continued for 30 days, with colorectal distension (CRD) measured on days 2, 4, 8, 15, and 30.

Results showed a dose-dependent relationship between aluminum ingestion and visceral hypersensitivity. Within 2 days, rats receiving 3.0 mg/kg of aluminum exhibited a significantly lower pain threshold, and within 8 days, rats receiving 0.5 mg/kg and 1.5 mg/kg also showed increased visceral hypersensitivity.

After 1 month of treatment, rats receiving 1.5 mg/kg per day demonstrated a 30% increase in pain compared with control animals. In the same group, visceral hypersensitivity began to wane 7 days after cessation of treatment; 4 more weeks were needed to return to baseline. When treatment was restarted, visceral hypersensitivity occurred within 2 days, compared with 8 days upon initial administration. These findings are particularly relevant to some people, as the 1.5-mg/kg dose corresponds with the daily amount of aluminum ingested by 5% of Americans. Similar patterns of response and sensitization were observed in rats ingesting 0.5 mg/kg and 3.0 mg/kg. Female rats were more sensitive to aluminum than were male rats, a sex pattern that mimics human IBS.

Further testing showed that rats treated with zinc citrate (ZnCi) did not exhibit changes to pain threshold, thereby excluding citrate as an aggravating factor. Rat models of noninflammatory and inflammatory colonic hypersensitivity (butyrate enema or intrathecal injection of 25%-50% ethanol in combination with 2,4,6-trinitrobenzenesulfonic acid, respectively) had visceral hypersensitivity similar to that of rats in the 1.5-mg/kg AlCi group.

Testing of colonic tissue from AlCi-treated rats did not reveal inflammatory changes according to a variety of qualifiers, including histology, myeloperoxidase activity, mRNA expression of several inflammatory cytokines, or infiltration of eosinophils or macrophages. Noninflammatory effects of aluminum, however, were found. For instance, treated rats had lower serotonin levels in enteroendocrine cells.

“Enteroendocrine cells are specialized epithelial cells that respond to luminal stimuli by releasing various biologically active compounds,” the investigators wrote. “They regulate several physiological and homeostatic functions of the gastrointestinal tract, such as postprandial secretion, motility, immune responses, and sensory functions. A reduced number of enteroendocrine cells has been observed in the duodenum, ileum, and colon of some patients with IBS.”

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.

Children who developed inflammatory bowel disease before the age of 18 had a three- to fivefold increase in risk of death, compared with others in a large, retrospective registry study.

The study, which spanned a recent 50-year period, found “no evidence that [these] hazard ratios have changed since the introduction of immunomodulators and biologics,” wrote Ola Olén, MD, PhD, of Karolinska University Hospital in Sola, Sweden, together with her associates. Malignancy was the most frequent cause of death among patients with childhood-onset inflammatory bowel disease, followed by digestive diseases and infections. Absolute numbers of premature deaths were low, but the increase in relative risk was highest among patients with childhood-onset ulcerative colitis with primary sclerosing cholangitis and patients who had a first-degree relative with ulcerative colitis. The findings were published in the February issue of Gastroenterology.

Inflammatory bowel disease is thought to be more severe when it begins in childhood, but data on mortality for these patients are lacking. Using national Swedish health registries, Dr. Olén and her associates compared deaths among 9,442 children and adolescents with inflammatory bowel disease with those among 93,180 others matched by sex, age, and place of residence. Both groups were typically followed through age 30 years, and the study covered 1964 through 2014.

In all, there were 294 deaths among patients with childhood-onset inflammatory bowel disease (2.1 deaths per 1,000 person-years) and 940 deaths among matched individuals (0.7 deaths per 1,000 person-years), for a statistically significant adjusted hazard ratio of 3.2 (95% confidence interval, 2.8-3.7). For every 694 patients with childhood-onset inflammatory bowel disease who were followed through adulthood, there was one additional death per year, compared with a demographically similar population, the researchers determined.

SOURCE: Olén O et al. Gastroenterology. 2018 Oct 17. doi: 10.1053/j.gastro.2018.10.028.

Children who developed inflammatory bowel disease before the age of 18 had a three- to fivefold increase in risk of death, compared with others in a large, retrospective registry study.

The study, which spanned a recent 50-year period, found “no evidence that [these] hazard ratios have changed since the introduction of immunomodulators and biologics,” wrote Ola Olén, MD, PhD, of Karolinska University Hospital in Sola, Sweden, together with her associates. Malignancy was the most frequent cause of death among patients with childhood-onset inflammatory bowel disease, followed by digestive diseases and infections. Absolute numbers of premature deaths were low, but the increase in relative risk was highest among patients with childhood-onset ulcerative colitis with primary sclerosing cholangitis and patients who had a first-degree relative with ulcerative colitis. The findings were published in the February issue of Gastroenterology.

Inflammatory bowel disease is thought to be more severe when it begins in childhood, but data on mortality for these patients are lacking. Using national Swedish health registries, Dr. Olén and her associates compared deaths among 9,442 children and adolescents with inflammatory bowel disease with those among 93,180 others matched by sex, age, and place of residence. Both groups were typically followed through age 30 years, and the study covered 1964 through 2014.

In all, there were 294 deaths among patients with childhood-onset inflammatory bowel disease (2.1 deaths per 1,000 person-years) and 940 deaths among matched individuals (0.7 deaths per 1,000 person-years), for a statistically significant adjusted hazard ratio of 3.2 (95% confidence interval, 2.8-3.7). For every 694 patients with childhood-onset inflammatory bowel disease who were followed through adulthood, there was one additional death per year, compared with a demographically similar population, the researchers determined.

SOURCE: Olén O et al. Gastroenterology. 2018 Oct 17. doi: 10.1053/j.gastro.2018.10.028.

Children who developed inflammatory bowel disease before the age of 18 had a three- to fivefold increase in risk of death, compared with others in a large, retrospective registry study.

The study, which spanned a recent 50-year period, found “no evidence that [these] hazard ratios have changed since the introduction of immunomodulators and biologics,” wrote Ola Olén, MD, PhD, of Karolinska University Hospital in Sola, Sweden, together with her associates. Malignancy was the most frequent cause of death among patients with childhood-onset inflammatory bowel disease, followed by digestive diseases and infections. Absolute numbers of premature deaths were low, but the increase in relative risk was highest among patients with childhood-onset ulcerative colitis with primary sclerosing cholangitis and patients who had a first-degree relative with ulcerative colitis. The findings were published in the February issue of Gastroenterology.

Inflammatory bowel disease is thought to be more severe when it begins in childhood, but data on mortality for these patients are lacking. Using national Swedish health registries, Dr. Olén and her associates compared deaths among 9,442 children and adolescents with inflammatory bowel disease with those among 93,180 others matched by sex, age, and place of residence. Both groups were typically followed through age 30 years, and the study covered 1964 through 2014.

In all, there were 294 deaths among patients with childhood-onset inflammatory bowel disease (2.1 deaths per 1,000 person-years) and 940 deaths among matched individuals (0.7 deaths per 1,000 person-years), for a statistically significant adjusted hazard ratio of 3.2 (95% confidence interval, 2.8-3.7). For every 694 patients with childhood-onset inflammatory bowel disease who were followed through adulthood, there was one additional death per year, compared with a demographically similar population, the researchers determined.

SOURCE: Olén O et al. Gastroenterology. 2018 Oct 17. doi: 10.1053/j.gastro.2018.10.028.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For adults with eosinophilic esophagitis, maintenance treatment with swallowed topical steroids was associated with significantly higher remission rates when compared with “steroid holidays” in a single-center retrospective observational study presented in the February issue of Clinical Gastroenterology and Hepatology.

At a median follow-up time of 5 years, the rate of complete (including clinical, endoscopic, and histologic) remission was 16.1% when patients were receiving swallowed topical steroids but only 1.3% when they were not on these or other maintenance therapies (that is, on “drug holidays”), reported Thomas Greuter, MD, of University Hospital Zürich and the Mayo Clinic in Rochester, Minn., and his associates. Swallowed topical steroids also were associated with significantly higher rates of each individual endpoint (P less than .001). Swallowed topical steroid therapy did not appear to cause dysplasia or mucosal atrophy, although esophageal candidiasis was confirmed in 2.7% of visits when patients were on treatment. “Given the good safety profile of low-dose swallowed topical steroid therapy, we advocate for prolonged treatment. Dose-finding trials are needed to achieve higher remission rates,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Several studies have confirmed the efficacy of short-term swallowed topical steroids for treating eosinophilic esophagitis, but only one small randomized trial has evaluated longer-term treatment, and participants were followed for only 1 year. Dr. Greuter and his associates therefore analyzed retrospective data from 229 adults in Switzerland who received swallowed topical steroids for eosinophilic esophagitis between 2000 and 2014. Induction therapy consisted of 1 mg swallowed topical steroids twice daily, allowing 2-4 weeks for a clinical response. Patients then received infinite maintenance therapy with 0.25 mg swallowed topical steroids twice daily. Patients tended to be male and diagnosed in their late 30s. Endoscopy commonly showed corrugated rings, white exudates, edema, and furrows, and 35% of patients had strictures. Peak eosinophil count typically was 25 cells per high-power frame.

Among 819 follow-up visits, 336 (41%) occurred when patients were on maintenance swallowed topical steroid therapy. The median duration of maintenance therapy prior to a follow-up visit was 347 days (interquartile range, 90-750 days) or 677 doses (IQR, 280-1413 doses). The rate of clinical remission was 31% when patients were on maintenance treatment but only 4.5% when they were not (P less than .001). Respective rates of endoscopic and histologic remission were 48.8% versus 17.8% (P less than .001) and 44.8% versus 10.1% (P less than .001). After accounting for numerous demographic and clinical variables, the only significant predictors of clinical remission were treatment with swallowed topical steroids (odds ratio, 16.98; 95% confidence interval, 6.69-43.09) and a negative family history of esophageal eosinophilia (OR, 4.02; 95% CI, 1.41-11.47).

This study excluded patients whose eosinophilic esophagitis had responded to proton pump inhibitor therapy. Also, the maintenance dose of swallowed topical steroid dose (0.25 mg twice daily) probably was too low to achieve efficacious drug levels in the esophageal mucosa, which could explain the high proportion of treatment-refractory cases, according to the researchers. Evaluating a higher maintenance dose “would be of particular interest in the future,” they added.

The Swiss National Science Foundation provided partial funding. Dr. Greuter disclosed a travel grant from Falk Pharma GmbH and Vifor and an unrestricted research grant from Novartis.

SOURCE: Greuter T et al. Clin Gastroenterol Hepatol. 2018 Jun 11.

For adults with eosinophilic esophagitis, maintenance treatment with swallowed topical steroids was associated with significantly higher remission rates when compared with “steroid holidays” in a single-center retrospective observational study presented in the February issue of Clinical Gastroenterology and Hepatology.

At a median follow-up time of 5 years, the rate of complete (including clinical, endoscopic, and histologic) remission was 16.1% when patients were receiving swallowed topical steroids but only 1.3% when they were not on these or other maintenance therapies (that is, on “drug holidays”), reported Thomas Greuter, MD, of University Hospital Zürich and the Mayo Clinic in Rochester, Minn., and his associates. Swallowed topical steroids also were associated with significantly higher rates of each individual endpoint (P less than .001). Swallowed topical steroid therapy did not appear to cause dysplasia or mucosal atrophy, although esophageal candidiasis was confirmed in 2.7% of visits when patients were on treatment. “Given the good safety profile of low-dose swallowed topical steroid therapy, we advocate for prolonged treatment. Dose-finding trials are needed to achieve higher remission rates,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Several studies have confirmed the efficacy of short-term swallowed topical steroids for treating eosinophilic esophagitis, but only one small randomized trial has evaluated longer-term treatment, and participants were followed for only 1 year. Dr. Greuter and his associates therefore analyzed retrospective data from 229 adults in Switzerland who received swallowed topical steroids for eosinophilic esophagitis between 2000 and 2014. Induction therapy consisted of 1 mg swallowed topical steroids twice daily, allowing 2-4 weeks for a clinical response. Patients then received infinite maintenance therapy with 0.25 mg swallowed topical steroids twice daily. Patients tended to be male and diagnosed in their late 30s. Endoscopy commonly showed corrugated rings, white exudates, edema, and furrows, and 35% of patients had strictures. Peak eosinophil count typically was 25 cells per high-power frame.

Among 819 follow-up visits, 336 (41%) occurred when patients were on maintenance swallowed topical steroid therapy. The median duration of maintenance therapy prior to a follow-up visit was 347 days (interquartile range, 90-750 days) or 677 doses (IQR, 280-1413 doses). The rate of clinical remission was 31% when patients were on maintenance treatment but only 4.5% when they were not (P less than .001). Respective rates of endoscopic and histologic remission were 48.8% versus 17.8% (P less than .001) and 44.8% versus 10.1% (P less than .001). After accounting for numerous demographic and clinical variables, the only significant predictors of clinical remission were treatment with swallowed topical steroids (odds ratio, 16.98; 95% confidence interval, 6.69-43.09) and a negative family history of esophageal eosinophilia (OR, 4.02; 95% CI, 1.41-11.47).

This study excluded patients whose eosinophilic esophagitis had responded to proton pump inhibitor therapy. Also, the maintenance dose of swallowed topical steroid dose (0.25 mg twice daily) probably was too low to achieve efficacious drug levels in the esophageal mucosa, which could explain the high proportion of treatment-refractory cases, according to the researchers. Evaluating a higher maintenance dose “would be of particular interest in the future,” they added.

The Swiss National Science Foundation provided partial funding. Dr. Greuter disclosed a travel grant from Falk Pharma GmbH and Vifor and an unrestricted research grant from Novartis.

SOURCE: Greuter T et al. Clin Gastroenterol Hepatol. 2018 Jun 11.

For adults with eosinophilic esophagitis, maintenance treatment with swallowed topical steroids was associated with significantly higher remission rates when compared with “steroid holidays” in a single-center retrospective observational study presented in the February issue of Clinical Gastroenterology and Hepatology.

At a median follow-up time of 5 years, the rate of complete (including clinical, endoscopic, and histologic) remission was 16.1% when patients were receiving swallowed topical steroids but only 1.3% when they were not on these or other maintenance therapies (that is, on “drug holidays”), reported Thomas Greuter, MD, of University Hospital Zürich and the Mayo Clinic in Rochester, Minn., and his associates. Swallowed topical steroids also were associated with significantly higher rates of each individual endpoint (P less than .001). Swallowed topical steroid therapy did not appear to cause dysplasia or mucosal atrophy, although esophageal candidiasis was confirmed in 2.7% of visits when patients were on treatment. “Given the good safety profile of low-dose swallowed topical steroid therapy, we advocate for prolonged treatment. Dose-finding trials are needed to achieve higher remission rates,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Several studies have confirmed the efficacy of short-term swallowed topical steroids for treating eosinophilic esophagitis, but only one small randomized trial has evaluated longer-term treatment, and participants were followed for only 1 year. Dr. Greuter and his associates therefore analyzed retrospective data from 229 adults in Switzerland who received swallowed topical steroids for eosinophilic esophagitis between 2000 and 2014. Induction therapy consisted of 1 mg swallowed topical steroids twice daily, allowing 2-4 weeks for a clinical response. Patients then received infinite maintenance therapy with 0.25 mg swallowed topical steroids twice daily. Patients tended to be male and diagnosed in their late 30s. Endoscopy commonly showed corrugated rings, white exudates, edema, and furrows, and 35% of patients had strictures. Peak eosinophil count typically was 25 cells per high-power frame.

Among 819 follow-up visits, 336 (41%) occurred when patients were on maintenance swallowed topical steroid therapy. The median duration of maintenance therapy prior to a follow-up visit was 347 days (interquartile range, 90-750 days) or 677 doses (IQR, 280-1413 doses). The rate of clinical remission was 31% when patients were on maintenance treatment but only 4.5% when they were not (P less than .001). Respective rates of endoscopic and histologic remission were 48.8% versus 17.8% (P less than .001) and 44.8% versus 10.1% (P less than .001). After accounting for numerous demographic and clinical variables, the only significant predictors of clinical remission were treatment with swallowed topical steroids (odds ratio, 16.98; 95% confidence interval, 6.69-43.09) and a negative family history of esophageal eosinophilia (OR, 4.02; 95% CI, 1.41-11.47).

This study excluded patients whose eosinophilic esophagitis had responded to proton pump inhibitor therapy. Also, the maintenance dose of swallowed topical steroid dose (0.25 mg twice daily) probably was too low to achieve efficacious drug levels in the esophageal mucosa, which could explain the high proportion of treatment-refractory cases, according to the researchers. Evaluating a higher maintenance dose “would be of particular interest in the future,” they added.

The Swiss National Science Foundation provided partial funding. Dr. Greuter disclosed a travel grant from Falk Pharma GmbH and Vifor and an unrestricted research grant from Novartis.

SOURCE: Greuter T et al. Clin Gastroenterol Hepatol. 2018 Jun 11.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease (IBD).

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in the January issue of Clinical Gastroenterology and Hepatology.

In UC patients who had not previously received tumor necrosis factor (TNF) antagonists, 22% of vedolizumab recipients, compared with 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported decreases in abdominal pain and loose stools at treatment week 2, compared with 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in the January issue of Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.
 

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer SB et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease (IBD).

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in the January issue of Clinical Gastroenterology and Hepatology.

In UC patients who had not previously received tumor necrosis factor (TNF) antagonists, 22% of vedolizumab recipients, compared with 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported decreases in abdominal pain and loose stools at treatment week 2, compared with 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in the January issue of Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.
 

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer SB et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

Two recent studies highlight the ability of vedolizumab and tofacitinib to rapidly improve symptoms reported by patients with inflammatory bowel disease (IBD).

In a post hoc study of 1,758 patients with ulcerative colitis (UC) or Crohn’s disease (CD) in the phase 3 GEMINI trials, 2 weeks of vedolizumab (Entyvio) therapy effectively improved patient-reported outcomes, and these continued to improve through 6 weeks of treatment, wrote Brian G. Feagan, MD, and his associates in the January issue of Clinical Gastroenterology and Hepatology.

In UC patients who had not previously received tumor necrosis factor (TNF) antagonists, 22% of vedolizumab recipients, compared with 7% of placebo recipients, achieved complete resolution of rectal bleeding together with a meaningful reduction in stool frequency at treatment week 2, the investigators noted. Among CD patients who were naive to TNF antagonists, 15% reported decreases in abdominal pain and loose stools at treatment week 2, compared with 8% of placebo recipients.

Although 2 weeks of vedolizumab also topped placebo for improving patient-reported outcomes among TNF antagonist–exposed patients, the effects were less pronounced, wrote Dr. Feagan, of the University of Western Ontario, London, and his associates. “These data add to the growing evidence that second-generation biologics, such as vedolizumab and ustekinumab, have higher efficacy in TNF antagonist–naive patients in both clinical trials and real-world settings. Recent trends in clinical practice are moving toward incorporating disease-modifying therapy earlier in the treatment of IBD to prevent disease progression and cumulative bowel damage.”

Patient-reported outcomes have become key during both clinical research and regulatory review of claims on proposed drug labels. In the second study, also published in the January issue of Clinical Gastroenterology and Hepatology, Stephen B. Hanauer, MD, of Northwestern University, Chicago, and his associates performed a post hoc analysis of symptoms reported by 1,139 adults with UC who received the oral small-molecule Janus kinase inhibitor tofacitinib (10 g twice daily) or placebo during the 8-week OCTAVE Induction 1 and 2 trials. These were identical phase 3 studies of patients with moderate to severe UC who could not tolerate or had responded inadequately to TNF antagonists, corticosteroids, or thiopurines.

Compared with placebo, 3 days of tofacitinib therapy induced significantly greater reductions from baseline in patient-reported stool frequency and rectal bleeding (P less than .01 for each measure), Dr. Hanauer and his associates reported. The effect was independent of prior treatment for UC or baseline levels of C-reactive protein. These findings reflect the rapid onset of effect of tofacitinib therapy in patients with UC. In contrast, thiopurines (azathioprine and 6-mercaptopurine) can take at least 8 weeks to exhibit steroid-sparing effects.

While corticosteroids can induce UC remission within 5 days, their side effects tend to escalate over time and they “lack maintenance benefits,” the researchers wrote. “In these analyses, onset of tofacitinib efficacy occurred within 3 days, irrespective of concomitant corticosteroid use or prior anti-TNF treatment failure.”

Takeda funded the GEMINI studies. Dr. Feagan reported advisory relationships with Takeda, AbbVie, Amgen, AstraZeneca, and several other pharmaceutical companies. Dr. Hanauer also reported ties to numerous pharmaceutical companies, including Pfizer, which funded the OCTAVE trials.
 

SOURCES: Feagan BG et al. Clin Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.cgh.2018.05.026; Hanauer SB et al. Clin Gastroenterol Hepatol. 2018 Jul 15. doi: 10.1016/j.cgh.2018.07.009.

For patients with early-stage esophageal squamous cell carcinoma, minimally invasive esophageal submucosal dissection (ESD) led to significantly fewer severe adverse perioperative events than esophagectomy and was associated with similar rates of all-cause mortality and cancer recurrence or metastasis, according to the findings of a single-center retrospective cohort study.

After a median of 21 months of follow-up (range, 6-73 months), rates of all-cause mortality were 7% with ESD and 11% with esophagectomy, said Yiqun Zhang of Zhongshan Hospital, Shanghai, China, and his associates. Rates of cancer recurrence or metastasis were 9.1% and 8.9%, respectively, while disease-specific mortality was lower with ESD (3.4% vs. 7.4% with esophagectomy; P = .049). Severe nonfatal adverse perioperative events occurred in 15% of ESD cases versus 28% of esophagectomy cases (P less than .001). The findings justify more studies of ESD in carefully selected patients with early-stage (T1a-m2/m3 or T1b) esophageal squamous cell carcinoma, the researchers wrote in Clinical Gastroenterology and Hepatology.

Esophagectomy is standard for managing early-stage esophageal squamous cell carcinoma but is associated with high rates of morbidity and mortality. While ESD is minimally invasive, it is considered risky because esophageal squamous cell carcinoma so frequently metastasizes to the lymph nodes, the investigators noted. For the study, they retrospectively compared 322 ESDs and 274 esophagectomies performed during 2011-2016 in patients with T1a-m2/m3 or T1b esophageal squamous cell carcinoma. All cases were pathologically confirmed, and none were premalignant (that is, high-grade intraepithelial neoplasias).

Endoscopic submucosal dissection was associated with significantly lower rates of esophageal fistula (0.3% with ESD vs. 16% with esophagectomy; P less than .001) and pulmonary complications (0.3% vs. 3.6%, respectively; P less than .001), which explained its overall superiority in terms of severe adverse perioperative events, the researchers wrote. Perioperative deaths were rare but occurred more often with esophagectomy (four patients) than with ESD (one patient). Depth of tumor invasion was the only significant correlate of all-cause mortality (hazard ratio for T1a–m3 or deeper tumors versus T1a–m2 tumors, 3.54; 95% confidence interval, 1.08-11.62; P = .04) in a Cox regression analysis that accounted for many potential confounders, such as demographic and tumor characteristics, hypertension, chronic obstructive pulmonary disease (COPD), nodal metastasis, chemotherapy, and radiotherapy.

Perhaps esophagectomy did not improve survival in this retrospective study because follow-up time was too short, because adjuvant therapy compensated for the increased risk of tumor relapse with ESD, or because of the confounding effects of unmeasured variables, such as submucosal stages of T1b cancer, lymphovascular invasion, or tumor morphology, the researchers wrote. “Since a randomized study comparing esophagectomy and ESD alone would not be practical, a potential strategy for future research may include serial treatments – that is, ESD first, followed by esophagectomy, radiotherapy, or chemotherapy, depending on the ESD pathology findings,” they added. “A quality-of-life analysis of ESD would also be helpful because this might be one of the biggest advantages of ESD over esophagectomy and was beyond the scope of this study.”

The study was supported by the National Natural Science Foundation of China, the Shanghai Committee of Science and Technology, and Zhongshan Hospital. The investigators reported having no relevant conflicts of interest.

SOURCE: Zhang Y et al. Clin Gastroenterol Hepatol. 2018 Apr 25. doi: 10.1016/j.cgh.2018.04.038.

For patients with early-stage esophageal squamous cell carcinoma, minimally invasive esophageal submucosal dissection (ESD) led to significantly fewer severe adverse perioperative events than esophagectomy and was associated with similar rates of all-cause mortality and cancer recurrence or metastasis, according to the findings of a single-center retrospective cohort study.

After a median of 21 months of follow-up (range, 6-73 months), rates of all-cause mortality were 7% with ESD and 11% with esophagectomy, said Yiqun Zhang of Zhongshan Hospital, Shanghai, China, and his associates. Rates of cancer recurrence or metastasis were 9.1% and 8.9%, respectively, while disease-specific mortality was lower with ESD (3.4% vs. 7.4% with esophagectomy; P = .049). Severe nonfatal adverse perioperative events occurred in 15% of ESD cases versus 28% of esophagectomy cases (P less than .001). The findings justify more studies of ESD in carefully selected patients with early-stage (T1a-m2/m3 or T1b) esophageal squamous cell carcinoma, the researchers wrote in Clinical Gastroenterology and Hepatology.

Esophagectomy is standard for managing early-stage esophageal squamous cell carcinoma but is associated with high rates of morbidity and mortality. While ESD is minimally invasive, it is considered risky because esophageal squamous cell carcinoma so frequently metastasizes to the lymph nodes, the investigators noted. For the study, they retrospectively compared 322 ESDs and 274 esophagectomies performed during 2011-2016 in patients with T1a-m2/m3 or T1b esophageal squamous cell carcinoma. All cases were pathologically confirmed, and none were premalignant (that is, high-grade intraepithelial neoplasias).

Endoscopic submucosal dissection was associated with significantly lower rates of esophageal fistula (0.3% with ESD vs. 16% with esophagectomy; P less than .001) and pulmonary complications (0.3% vs. 3.6%, respectively; P less than .001), which explained its overall superiority in terms of severe adverse perioperative events, the researchers wrote. Perioperative deaths were rare but occurred more often with esophagectomy (four patients) than with ESD (one patient). Depth of tumor invasion was the only significant correlate of all-cause mortality (hazard ratio for T1a–m3 or deeper tumors versus T1a–m2 tumors, 3.54; 95% confidence interval, 1.08-11.62; P = .04) in a Cox regression analysis that accounted for many potential confounders, such as demographic and tumor characteristics, hypertension, chronic obstructive pulmonary disease (COPD), nodal metastasis, chemotherapy, and radiotherapy.

Perhaps esophagectomy did not improve survival in this retrospective study because follow-up time was too short, because adjuvant therapy compensated for the increased risk of tumor relapse with ESD, or because of the confounding effects of unmeasured variables, such as submucosal stages of T1b cancer, lymphovascular invasion, or tumor morphology, the researchers wrote. “Since a randomized study comparing esophagectomy and ESD alone would not be practical, a potential strategy for future research may include serial treatments – that is, ESD first, followed by esophagectomy, radiotherapy, or chemotherapy, depending on the ESD pathology findings,” they added. “A quality-of-life analysis of ESD would also be helpful because this might be one of the biggest advantages of ESD over esophagectomy and was beyond the scope of this study.”

The study was supported by the National Natural Science Foundation of China, the Shanghai Committee of Science and Technology, and Zhongshan Hospital. The investigators reported having no relevant conflicts of interest.

SOURCE: Zhang Y et al. Clin Gastroenterol Hepatol. 2018 Apr 25. doi: 10.1016/j.cgh.2018.04.038.

For patients with early-stage esophageal squamous cell carcinoma, minimally invasive esophageal submucosal dissection (ESD) led to significantly fewer severe adverse perioperative events than esophagectomy and was associated with similar rates of all-cause mortality and cancer recurrence or metastasis, according to the findings of a single-center retrospective cohort study.

After a median of 21 months of follow-up (range, 6-73 months), rates of all-cause mortality were 7% with ESD and 11% with esophagectomy, said Yiqun Zhang of Zhongshan Hospital, Shanghai, China, and his associates. Rates of cancer recurrence or metastasis were 9.1% and 8.9%, respectively, while disease-specific mortality was lower with ESD (3.4% vs. 7.4% with esophagectomy; P = .049). Severe nonfatal adverse perioperative events occurred in 15% of ESD cases versus 28% of esophagectomy cases (P less than .001). The findings justify more studies of ESD in carefully selected patients with early-stage (T1a-m2/m3 or T1b) esophageal squamous cell carcinoma, the researchers wrote in Clinical Gastroenterology and Hepatology.

Esophagectomy is standard for managing early-stage esophageal squamous cell carcinoma but is associated with high rates of morbidity and mortality. While ESD is minimally invasive, it is considered risky because esophageal squamous cell carcinoma so frequently metastasizes to the lymph nodes, the investigators noted. For the study, they retrospectively compared 322 ESDs and 274 esophagectomies performed during 2011-2016 in patients with T1a-m2/m3 or T1b esophageal squamous cell carcinoma. All cases were pathologically confirmed, and none were premalignant (that is, high-grade intraepithelial neoplasias).

Endoscopic submucosal dissection was associated with significantly lower rates of esophageal fistula (0.3% with ESD vs. 16% with esophagectomy; P less than .001) and pulmonary complications (0.3% vs. 3.6%, respectively; P less than .001), which explained its overall superiority in terms of severe adverse perioperative events, the researchers wrote. Perioperative deaths were rare but occurred more often with esophagectomy (four patients) than with ESD (one patient). Depth of tumor invasion was the only significant correlate of all-cause mortality (hazard ratio for T1a–m3 or deeper tumors versus T1a–m2 tumors, 3.54; 95% confidence interval, 1.08-11.62; P = .04) in a Cox regression analysis that accounted for many potential confounders, such as demographic and tumor characteristics, hypertension, chronic obstructive pulmonary disease (COPD), nodal metastasis, chemotherapy, and radiotherapy.

Perhaps esophagectomy did not improve survival in this retrospective study because follow-up time was too short, because adjuvant therapy compensated for the increased risk of tumor relapse with ESD, or because of the confounding effects of unmeasured variables, such as submucosal stages of T1b cancer, lymphovascular invasion, or tumor morphology, the researchers wrote. “Since a randomized study comparing esophagectomy and ESD alone would not be practical, a potential strategy for future research may include serial treatments – that is, ESD first, followed by esophagectomy, radiotherapy, or chemotherapy, depending on the ESD pathology findings,” they added. “A quality-of-life analysis of ESD would also be helpful because this might be one of the biggest advantages of ESD over esophagectomy and was beyond the scope of this study.”

The study was supported by the National Natural Science Foundation of China, the Shanghai Committee of Science and Technology, and Zhongshan Hospital. The investigators reported having no relevant conflicts of interest.

SOURCE: Zhang Y et al. Clin Gastroenterol Hepatol. 2018 Apr 25. doi: 10.1016/j.cgh.2018.04.038.