Will Pass

For patients with recurrent, high-grade glioblastoma, localized, drug-inducible gene therapy could unlock the anticancer potential of interleukin-12, based on a phase 1 trial.

In 31 patients who had their tumors excised, intraoperative site injection with an IL-12 vector followed by postoperative administration of veledimex, an oral activator of the transgene, increased IL-12 levels in the brain and appeared to improve overall survival, reported E. Antonio Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Boston, and colleagues. Although some serious adverse events were encountered, the investigators noted that these were less common with lower doses of veledimex and were reversible upon discontinuation. These findings mark a turning point in IL-12 cancer research, which previously encountered prohibitive safety obstacles.

“There was interest in the use of recombinant IL-12 in humans with cancer, and clinical trials of systemic IL-12 were undertaken but had to be stopped because the cytokine, administered as a recombinant soluble protein, was poorly tolerated,” the investigators wrote in Science Translational Medicine.

To overcome this issue, a novel treatment approach was developed. “With the objective of minimizing systemic toxicity, a ligand-inducible expression switch [RheoSwitch Therapeutic System] was developed to locally control production of IL-12 in the tumor microenvironment. In this system, transcription of the IL-12 transgene occurs only in the presence of the activator ligand, veledimex,” they noted.

The primary aim of the study was to evaluate safety and determine the optimal dose of veledimex; four dose levels were tested: 10, 20, 30, and 40 mg. Survival outcomes also were reported.

The protocol-defined maximum tolerated dose was not reached; however, the 20-mg dose was chosen, based on observed tolerability. At this dose level, the most common grade 3 or higher adverse events were lymphopenia (20.3%), thrombocytopenia (13.3%), and hyponatremia (13.3%). Specifically for grade 3 or higher neurologic adverse events, headache was most common, occurring in 13.3% of patients. Grade 2 cytokine release syndrome occurred in about one-fourth of patients (26.7%), whereas grade 3 cytokine release syndrome occurred about half as frequently (13.3%). All adverse events, including cytokine release syndrome, were reversible upon discontinuation of veledimex.

After a mean follow-up of 13.1 months, the median overall survival among patients receiving the 20-mg dose was 12.7 months. The investigators pointed out that this compared favorably with historical controls, who had a weighted median overall survival of 8.1 months. Those who received 30- or 40-mg doses had the poorest survival, which the investigators attributed to intolerability and other subgroup factors.

Data analysis also revealed a negative correlation between dexamethasone use and survival. Among patients in the 20-mg veledimex group who received 20 mg or less of dexamethasone during active veledimex dosing, median overall survival was extended to 17.8 months. The investigators speculated that this was because of reduced immune suppression, although dexamethasone could have induced cytochrome P450 3A4, which may have increased elimination of veledimex.

“In summary, this phase 1 trial reports the use of a transcriptional switch to safely control dosing of [IL-12], highlighting that this can be accomplished across the [blood-brain barrier] to remodel the tumor microenvironment with an influx of activated immune cells,” the investigators wrote.

They noted that this strategy could potentially be applied to other types of cancer, particularly those that are immunologically cold. “These data contribute to our understanding of IL-12 as a ‘master regulator’ of the immune system and highlight that even the transient production of this cytokine may function as a match to turn tumors from cold to hot.”

The study was funded by Ziopharm Oncology and the National Institutes of Health. The investigators reported additional relationships with Advantagene, Stemgen, Sigilon Therapeutics, and others.

SOURCE: Chiocca EA et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aaw5680.

For patients with recurrent, high-grade glioblastoma, localized, drug-inducible gene therapy could unlock the anticancer potential of interleukin-12, based on a phase 1 trial.

In 31 patients who had their tumors excised, intraoperative site injection with an IL-12 vector followed by postoperative administration of veledimex, an oral activator of the transgene, increased IL-12 levels in the brain and appeared to improve overall survival, reported E. Antonio Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Boston, and colleagues. Although some serious adverse events were encountered, the investigators noted that these were less common with lower doses of veledimex and were reversible upon discontinuation. These findings mark a turning point in IL-12 cancer research, which previously encountered prohibitive safety obstacles.

“There was interest in the use of recombinant IL-12 in humans with cancer, and clinical trials of systemic IL-12 were undertaken but had to be stopped because the cytokine, administered as a recombinant soluble protein, was poorly tolerated,” the investigators wrote in Science Translational Medicine.

To overcome this issue, a novel treatment approach was developed. “With the objective of minimizing systemic toxicity, a ligand-inducible expression switch [RheoSwitch Therapeutic System] was developed to locally control production of IL-12 in the tumor microenvironment. In this system, transcription of the IL-12 transgene occurs only in the presence of the activator ligand, veledimex,” they noted.

The primary aim of the study was to evaluate safety and determine the optimal dose of veledimex; four dose levels were tested: 10, 20, 30, and 40 mg. Survival outcomes also were reported.

The protocol-defined maximum tolerated dose was not reached; however, the 20-mg dose was chosen, based on observed tolerability. At this dose level, the most common grade 3 or higher adverse events were lymphopenia (20.3%), thrombocytopenia (13.3%), and hyponatremia (13.3%). Specifically for grade 3 or higher neurologic adverse events, headache was most common, occurring in 13.3% of patients. Grade 2 cytokine release syndrome occurred in about one-fourth of patients (26.7%), whereas grade 3 cytokine release syndrome occurred about half as frequently (13.3%). All adverse events, including cytokine release syndrome, were reversible upon discontinuation of veledimex.

After a mean follow-up of 13.1 months, the median overall survival among patients receiving the 20-mg dose was 12.7 months. The investigators pointed out that this compared favorably with historical controls, who had a weighted median overall survival of 8.1 months. Those who received 30- or 40-mg doses had the poorest survival, which the investigators attributed to intolerability and other subgroup factors.

Data analysis also revealed a negative correlation between dexamethasone use and survival. Among patients in the 20-mg veledimex group who received 20 mg or less of dexamethasone during active veledimex dosing, median overall survival was extended to 17.8 months. The investigators speculated that this was because of reduced immune suppression, although dexamethasone could have induced cytochrome P450 3A4, which may have increased elimination of veledimex.

“In summary, this phase 1 trial reports the use of a transcriptional switch to safely control dosing of [IL-12], highlighting that this can be accomplished across the [blood-brain barrier] to remodel the tumor microenvironment with an influx of activated immune cells,” the investigators wrote.

They noted that this strategy could potentially be applied to other types of cancer, particularly those that are immunologically cold. “These data contribute to our understanding of IL-12 as a ‘master regulator’ of the immune system and highlight that even the transient production of this cytokine may function as a match to turn tumors from cold to hot.”

The study was funded by Ziopharm Oncology and the National Institutes of Health. The investigators reported additional relationships with Advantagene, Stemgen, Sigilon Therapeutics, and others.

SOURCE: Chiocca EA et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aaw5680.

For patients with recurrent, high-grade glioblastoma, localized, drug-inducible gene therapy could unlock the anticancer potential of interleukin-12, based on a phase 1 trial.

In 31 patients who had their tumors excised, intraoperative site injection with an IL-12 vector followed by postoperative administration of veledimex, an oral activator of the transgene, increased IL-12 levels in the brain and appeared to improve overall survival, reported E. Antonio Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Boston, and colleagues. Although some serious adverse events were encountered, the investigators noted that these were less common with lower doses of veledimex and were reversible upon discontinuation. These findings mark a turning point in IL-12 cancer research, which previously encountered prohibitive safety obstacles.

“There was interest in the use of recombinant IL-12 in humans with cancer, and clinical trials of systemic IL-12 were undertaken but had to be stopped because the cytokine, administered as a recombinant soluble protein, was poorly tolerated,” the investigators wrote in Science Translational Medicine.

To overcome this issue, a novel treatment approach was developed. “With the objective of minimizing systemic toxicity, a ligand-inducible expression switch [RheoSwitch Therapeutic System] was developed to locally control production of IL-12 in the tumor microenvironment. In this system, transcription of the IL-12 transgene occurs only in the presence of the activator ligand, veledimex,” they noted.

The primary aim of the study was to evaluate safety and determine the optimal dose of veledimex; four dose levels were tested: 10, 20, 30, and 40 mg. Survival outcomes also were reported.

The protocol-defined maximum tolerated dose was not reached; however, the 20-mg dose was chosen, based on observed tolerability. At this dose level, the most common grade 3 or higher adverse events were lymphopenia (20.3%), thrombocytopenia (13.3%), and hyponatremia (13.3%). Specifically for grade 3 or higher neurologic adverse events, headache was most common, occurring in 13.3% of patients. Grade 2 cytokine release syndrome occurred in about one-fourth of patients (26.7%), whereas grade 3 cytokine release syndrome occurred about half as frequently (13.3%). All adverse events, including cytokine release syndrome, were reversible upon discontinuation of veledimex.

After a mean follow-up of 13.1 months, the median overall survival among patients receiving the 20-mg dose was 12.7 months. The investigators pointed out that this compared favorably with historical controls, who had a weighted median overall survival of 8.1 months. Those who received 30- or 40-mg doses had the poorest survival, which the investigators attributed to intolerability and other subgroup factors.

Data analysis also revealed a negative correlation between dexamethasone use and survival. Among patients in the 20-mg veledimex group who received 20 mg or less of dexamethasone during active veledimex dosing, median overall survival was extended to 17.8 months. The investigators speculated that this was because of reduced immune suppression, although dexamethasone could have induced cytochrome P450 3A4, which may have increased elimination of veledimex.

“In summary, this phase 1 trial reports the use of a transcriptional switch to safely control dosing of [IL-12], highlighting that this can be accomplished across the [blood-brain barrier] to remodel the tumor microenvironment with an influx of activated immune cells,” the investigators wrote.

They noted that this strategy could potentially be applied to other types of cancer, particularly those that are immunologically cold. “These data contribute to our understanding of IL-12 as a ‘master regulator’ of the immune system and highlight that even the transient production of this cytokine may function as a match to turn tumors from cold to hot.”

The study was funded by Ziopharm Oncology and the National Institutes of Health. The investigators reported additional relationships with Advantagene, Stemgen, Sigilon Therapeutics, and others.

SOURCE: Chiocca EA et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aaw5680.

CD4+ T-cell reactivation and interleukin (IL)–2 release are responsible for acute gastrointestinal symptoms when patients with celiac disease are exposed to gluten, according to investigators.

designer491/Thinkstock

Although T cells have been well studied in previous celiac disease research, clinical symptoms after acute gluten exposure have never been linked with specific cytokine changes, reported lead author Gautam Goel, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“If treated [celiac disease] patients, i.e., those following a strict [gluten-free diet], are exposed to gluten-containing food, they typically suffer from gastrointestinal reactions occurring 1 to 2 hours after the gluten exposure,” the investigators wrote in Science Advances. “There is currently no explanation for the acute gluten-induced symptoms seen in treated [celiac disease] patients.”

The current study was prompted by two phase 1 trials involving the therapeutic vaccine Nexvax2, which uses peptide fragments of gluten proteins to desensitize celiac patients to gluten, the investigators explained. During those trials, intradermal injections of Nexvax2 above a certain dose threshold led to gastrointestinal symptoms within 2-5 hours, but not injection site reactions, which would have been indicative of a cutaneous response to recall antigen.

“Our observations from these phase 1 studies led us to hypothesize that cytokine release occurs following natural gluten exposure and could be used to implicate which arms of the immune system drive early symptoms.”

Of the 28 patients in the two trials, all underwent intradermal testing, while 19 also participated in an oral gluten challenge. Following intradermal injection of gluten peptides, patients exhibited gastrointestinal symptoms, along with coordinated elevations of least 15 plasma cytokines; most significantly IL-2, MCP-1, IL-8, IL-10, MIP-1beta, IP-10, and eotaxin. The first cytokines to respond to injection were IL-2 and IL-8, rising within 2 hours, prior to symptoms. At 4 hours, when symptoms were present, peak IL-2 elevations were most dramatic, with a 272-fold elevation, followed by IL-8 (11-fold) and IL-10 (1.2-fold).

“IL-2 is both the earliest and most sensitive marker for the coordinated cytokine release that was almost universal in HLA-DQ2.5 + [celiac disease] patients administered gluten peptides,” the investigators wrote.

Similar to intradermal testing, oral challenge with gluten caused IL-2, IL-8, and IL-10 to elevate within 2 hours, and peak within 4-6 hours. Again, IL-2 was most sensitive, with a 15-fold increase at 4 hours. This increase in IL-2 correlated with IL-8 and IL-10 elevations, although IL-2 increases were at least six times greater than the other two cytokines.

“Together, the serum cytokine profile following gluten ingestion is less prominent but qualitatively similar and over a corresponding time course to that after injecting gluten peptides, which is consistent with activated CD4+ T cells being the driver of cytokine release in both scenarios,” the investigators wrote.

Further testing showed that, after gluten challenge, plasma levels of IL-2, IL-8, and IL-10 negatively correlated with duodenal villous height-to-crypt depth ratios. In addition, high levels of IL-2 correlated with severe nausea and vomiting, adding to the evidence that celiac symptoms were linked with specific cytokine elevations.

“The link between immune activation and symptoms was further strengthened by showing that postdose symptoms and cytokine release were both lessened after three weekly doses and absent after 16 twice-weekly injections of gluten peptides,” the investigators wrote. “These findings are consistent with the difference in severity of symptoms after gluten ingestion compared to gluten peptide injection being related to potency of the antigen challenge and T-cell activation measured by circulating IL-2 concentration at 4 hours.”

Even though IL-2 elevations appeared to drive celiac symptoms, the source of IL-2 was initially unknown. “Activated T cells are the primary source of IL-2, but [dendritic cells] can also secrete IL-2 following ligation of specific pathogen recognition receptors; mast cells also secrete IL-2 following exposure to IL-33 or IL-9,” the investigators explained. Still, CD4+ T cells are known to be key players in celiac disease, and the timing and magnitude of IL-2 release made T cells the most likely candidates. To test this hypothesis, the investigators collected blood from patients 6 days after gluten food challenge and incubated these samples for 24 hours with gluten peptides. Results of this test suggested that gluten-specific CD4+ T cells were the most likely source of IL-2.

The connection between particular cytokines and gastrointestinal symptoms is now supported with evidence; however, the investigators pointed out that a relationship between cytokines and other symptoms of celiac disease remains to be seen. “Whether cytokines elevated in blood after injecting gluten peptides or ingesting gluten have any direct extraintestinal effects is unclear,” the investigators wrote. “Fatigue, headache, and ‘brain fog’ are the commonly reported extraintestinal symptoms in [celiac disease] patients. However, symptoms being focused on the upper gastrointestinal tract suggest that cytokines increased in blood have clinical and immunological effects that selectively affect the tissue from which they originate.”

“Future studies should test whether cytokine concentrations are substantially higher in gut mucosal tissue than in blood after gluten challenge or injection of gluten peptides and determine whether alterations in local cytokine levels are matched by immune and inflammatory cell infiltration,” the investigators wrote.

The study was supported by the University of Chicago Celiac Disease Center and the University of Oslo KG Jebsen Coeliac Disease Research Centre. The investigators reported additional relationships The investigators reported additional relationships with several government and nonprofit organizations. Multiple investigators are employees of ImmusanT, which is developing Nexvax2.

SOURCE: Goel G et al. Science Advances. 2019 Aug 7. doi: 10.1126/sciadv.aaw7756.

CD4+ T-cell reactivation and interleukin (IL)–2 release are responsible for acute gastrointestinal symptoms when patients with celiac disease are exposed to gluten, according to investigators.

designer491/Thinkstock

Although T cells have been well studied in previous celiac disease research, clinical symptoms after acute gluten exposure have never been linked with specific cytokine changes, reported lead author Gautam Goel, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“If treated [celiac disease] patients, i.e., those following a strict [gluten-free diet], are exposed to gluten-containing food, they typically suffer from gastrointestinal reactions occurring 1 to 2 hours after the gluten exposure,” the investigators wrote in Science Advances. “There is currently no explanation for the acute gluten-induced symptoms seen in treated [celiac disease] patients.”

The current study was prompted by two phase 1 trials involving the therapeutic vaccine Nexvax2, which uses peptide fragments of gluten proteins to desensitize celiac patients to gluten, the investigators explained. During those trials, intradermal injections of Nexvax2 above a certain dose threshold led to gastrointestinal symptoms within 2-5 hours, but not injection site reactions, which would have been indicative of a cutaneous response to recall antigen.

“Our observations from these phase 1 studies led us to hypothesize that cytokine release occurs following natural gluten exposure and could be used to implicate which arms of the immune system drive early symptoms.”

Of the 28 patients in the two trials, all underwent intradermal testing, while 19 also participated in an oral gluten challenge. Following intradermal injection of gluten peptides, patients exhibited gastrointestinal symptoms, along with coordinated elevations of least 15 plasma cytokines; most significantly IL-2, MCP-1, IL-8, IL-10, MIP-1beta, IP-10, and eotaxin. The first cytokines to respond to injection were IL-2 and IL-8, rising within 2 hours, prior to symptoms. At 4 hours, when symptoms were present, peak IL-2 elevations were most dramatic, with a 272-fold elevation, followed by IL-8 (11-fold) and IL-10 (1.2-fold).

“IL-2 is both the earliest and most sensitive marker for the coordinated cytokine release that was almost universal in HLA-DQ2.5 + [celiac disease] patients administered gluten peptides,” the investigators wrote.

Similar to intradermal testing, oral challenge with gluten caused IL-2, IL-8, and IL-10 to elevate within 2 hours, and peak within 4-6 hours. Again, IL-2 was most sensitive, with a 15-fold increase at 4 hours. This increase in IL-2 correlated with IL-8 and IL-10 elevations, although IL-2 increases were at least six times greater than the other two cytokines.

“Together, the serum cytokine profile following gluten ingestion is less prominent but qualitatively similar and over a corresponding time course to that after injecting gluten peptides, which is consistent with activated CD4+ T cells being the driver of cytokine release in both scenarios,” the investigators wrote.

Further testing showed that, after gluten challenge, plasma levels of IL-2, IL-8, and IL-10 negatively correlated with duodenal villous height-to-crypt depth ratios. In addition, high levels of IL-2 correlated with severe nausea and vomiting, adding to the evidence that celiac symptoms were linked with specific cytokine elevations.

“The link between immune activation and symptoms was further strengthened by showing that postdose symptoms and cytokine release were both lessened after three weekly doses and absent after 16 twice-weekly injections of gluten peptides,” the investigators wrote. “These findings are consistent with the difference in severity of symptoms after gluten ingestion compared to gluten peptide injection being related to potency of the antigen challenge and T-cell activation measured by circulating IL-2 concentration at 4 hours.”

Even though IL-2 elevations appeared to drive celiac symptoms, the source of IL-2 was initially unknown. “Activated T cells are the primary source of IL-2, but [dendritic cells] can also secrete IL-2 following ligation of specific pathogen recognition receptors; mast cells also secrete IL-2 following exposure to IL-33 or IL-9,” the investigators explained. Still, CD4+ T cells are known to be key players in celiac disease, and the timing and magnitude of IL-2 release made T cells the most likely candidates. To test this hypothesis, the investigators collected blood from patients 6 days after gluten food challenge and incubated these samples for 24 hours with gluten peptides. Results of this test suggested that gluten-specific CD4+ T cells were the most likely source of IL-2.

The connection between particular cytokines and gastrointestinal symptoms is now supported with evidence; however, the investigators pointed out that a relationship between cytokines and other symptoms of celiac disease remains to be seen. “Whether cytokines elevated in blood after injecting gluten peptides or ingesting gluten have any direct extraintestinal effects is unclear,” the investigators wrote. “Fatigue, headache, and ‘brain fog’ are the commonly reported extraintestinal symptoms in [celiac disease] patients. However, symptoms being focused on the upper gastrointestinal tract suggest that cytokines increased in blood have clinical and immunological effects that selectively affect the tissue from which they originate.”

“Future studies should test whether cytokine concentrations are substantially higher in gut mucosal tissue than in blood after gluten challenge or injection of gluten peptides and determine whether alterations in local cytokine levels are matched by immune and inflammatory cell infiltration,” the investigators wrote.

The study was supported by the University of Chicago Celiac Disease Center and the University of Oslo KG Jebsen Coeliac Disease Research Centre. The investigators reported additional relationships The investigators reported additional relationships with several government and nonprofit organizations. Multiple investigators are employees of ImmusanT, which is developing Nexvax2.

SOURCE: Goel G et al. Science Advances. 2019 Aug 7. doi: 10.1126/sciadv.aaw7756.

CD4+ T-cell reactivation and interleukin (IL)–2 release are responsible for acute gastrointestinal symptoms when patients with celiac disease are exposed to gluten, according to investigators.

designer491/Thinkstock

Although T cells have been well studied in previous celiac disease research, clinical symptoms after acute gluten exposure have never been linked with specific cytokine changes, reported lead author Gautam Goel, PhD, of Massachusetts General Hospital in Boston, and colleagues.

“If treated [celiac disease] patients, i.e., those following a strict [gluten-free diet], are exposed to gluten-containing food, they typically suffer from gastrointestinal reactions occurring 1 to 2 hours after the gluten exposure,” the investigators wrote in Science Advances. “There is currently no explanation for the acute gluten-induced symptoms seen in treated [celiac disease] patients.”

The current study was prompted by two phase 1 trials involving the therapeutic vaccine Nexvax2, which uses peptide fragments of gluten proteins to desensitize celiac patients to gluten, the investigators explained. During those trials, intradermal injections of Nexvax2 above a certain dose threshold led to gastrointestinal symptoms within 2-5 hours, but not injection site reactions, which would have been indicative of a cutaneous response to recall antigen.

“Our observations from these phase 1 studies led us to hypothesize that cytokine release occurs following natural gluten exposure and could be used to implicate which arms of the immune system drive early symptoms.”

Of the 28 patients in the two trials, all underwent intradermal testing, while 19 also participated in an oral gluten challenge. Following intradermal injection of gluten peptides, patients exhibited gastrointestinal symptoms, along with coordinated elevations of least 15 plasma cytokines; most significantly IL-2, MCP-1, IL-8, IL-10, MIP-1beta, IP-10, and eotaxin. The first cytokines to respond to injection were IL-2 and IL-8, rising within 2 hours, prior to symptoms. At 4 hours, when symptoms were present, peak IL-2 elevations were most dramatic, with a 272-fold elevation, followed by IL-8 (11-fold) and IL-10 (1.2-fold).

“IL-2 is both the earliest and most sensitive marker for the coordinated cytokine release that was almost universal in HLA-DQ2.5 + [celiac disease] patients administered gluten peptides,” the investigators wrote.

Similar to intradermal testing, oral challenge with gluten caused IL-2, IL-8, and IL-10 to elevate within 2 hours, and peak within 4-6 hours. Again, IL-2 was most sensitive, with a 15-fold increase at 4 hours. This increase in IL-2 correlated with IL-8 and IL-10 elevations, although IL-2 increases were at least six times greater than the other two cytokines.

“Together, the serum cytokine profile following gluten ingestion is less prominent but qualitatively similar and over a corresponding time course to that after injecting gluten peptides, which is consistent with activated CD4+ T cells being the driver of cytokine release in both scenarios,” the investigators wrote.

Further testing showed that, after gluten challenge, plasma levels of IL-2, IL-8, and IL-10 negatively correlated with duodenal villous height-to-crypt depth ratios. In addition, high levels of IL-2 correlated with severe nausea and vomiting, adding to the evidence that celiac symptoms were linked with specific cytokine elevations.

“The link between immune activation and symptoms was further strengthened by showing that postdose symptoms and cytokine release were both lessened after three weekly doses and absent after 16 twice-weekly injections of gluten peptides,” the investigators wrote. “These findings are consistent with the difference in severity of symptoms after gluten ingestion compared to gluten peptide injection being related to potency of the antigen challenge and T-cell activation measured by circulating IL-2 concentration at 4 hours.”

Even though IL-2 elevations appeared to drive celiac symptoms, the source of IL-2 was initially unknown. “Activated T cells are the primary source of IL-2, but [dendritic cells] can also secrete IL-2 following ligation of specific pathogen recognition receptors; mast cells also secrete IL-2 following exposure to IL-33 or IL-9,” the investigators explained. Still, CD4+ T cells are known to be key players in celiac disease, and the timing and magnitude of IL-2 release made T cells the most likely candidates. To test this hypothesis, the investigators collected blood from patients 6 days after gluten food challenge and incubated these samples for 24 hours with gluten peptides. Results of this test suggested that gluten-specific CD4+ T cells were the most likely source of IL-2.

The connection between particular cytokines and gastrointestinal symptoms is now supported with evidence; however, the investigators pointed out that a relationship between cytokines and other symptoms of celiac disease remains to be seen. “Whether cytokines elevated in blood after injecting gluten peptides or ingesting gluten have any direct extraintestinal effects is unclear,” the investigators wrote. “Fatigue, headache, and ‘brain fog’ are the commonly reported extraintestinal symptoms in [celiac disease] patients. However, symptoms being focused on the upper gastrointestinal tract suggest that cytokines increased in blood have clinical and immunological effects that selectively affect the tissue from which they originate.”

“Future studies should test whether cytokine concentrations are substantially higher in gut mucosal tissue than in blood after gluten challenge or injection of gluten peptides and determine whether alterations in local cytokine levels are matched by immune and inflammatory cell infiltration,” the investigators wrote.

The study was supported by the University of Chicago Celiac Disease Center and the University of Oslo KG Jebsen Coeliac Disease Research Centre. The investigators reported additional relationships The investigators reported additional relationships with several government and nonprofit organizations. Multiple investigators are employees of ImmusanT, which is developing Nexvax2.

SOURCE: Goel G et al. Science Advances. 2019 Aug 7. doi: 10.1126/sciadv.aaw7756.

Vitamin D supplementation may lead to significant improvements in ulcerative colitis (UC), based on a placebo-controlled trial involving 60 patients with active disease.

Those who achieved vitamin D levels greater than 40 ng/mL were most likely to benefit, reported lead author Rizwan Ahamed Z, MD, of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues. They noted that the findings contribute much-needed clinical data to a largely theoretical subject area.

“[T]he discovery of vitamin D receptors on lymphocytes, monocytes, and dendritic cells initiated various studies which have highlighted the role of vitamin D in regulating gut mucosal immunity and gut barrier,” the investigators wrote in Journal of Clinical Gastroenterology. “In experimental interleukin (IL)-10 knockout mice models, vitamin D deficiency was found to result in severe colitis, progressive wasting, and high mortality. However, vitamin D supplementation not only prevented but also ameliorated symptoms of colitis in the mice model.”

Human studies have revealed similar associations between vitamin D supplementation and inflammatory bowel disease, such as a study by Jørgensen and colleagues that found a lower risk of relapse in Crohn’s disease, and another by Sharifi and colleagues that showed injectable vitamin D could reduce erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with UC. Still, the investigators suggested that more clinical data are needed, particularly for outcomes after vitamin D therapy. In addition to providing such data, the present trial was also the first of its kind to test oral nano vitamin D₃, which may have better bioavailability than conventional supplements.

The investigators initially recruited 110 patients with active UC who had an ulcerative colitis disease activity index (UCDAI) of at least 3. After screening, 50 patients were excluded because they had vitamin D levels greater than 40 ng/mL, were already taking a vitamin D supplement, had severe UC requiring hospitalization, or exhibited severe systemic illness. The remaining 60 patients were randomized in a 1:1 ratio to receive either 60,000 IU nano vitamin D₃ once daily for 8 days, or placebo. Disease parameters, which were measured at baseline and then again at 4 weeks, included UCDAI, ESR, CRP, and fecal calprotectin. The primary outcome was response, defined as a UCDAI reduction of at least 3 points. Secondary outcome measures included stool frequency, stool consistency, and remission (UCDAI less than 3); in addition, the investigators evaluated histologic, endoscopic, fecal, and serum inflammatory markers.

The majority of patients in the study were men (60%), with a mean age of 36 years. Most patients had moderate UC (73.3%), while smaller proportions had severe (18%) or mild (8%) disease. All patients were taking a 5-aminosalicylic acid oral compound and some (16.6%) were also taking azathioprine. At baseline, the mean vitamin D level was 14 ng/mL. Most patients (70%) were diagnosed with vitamin D deficiency, based on measurements below 20 ng/mL. The remaining patients were diagnosed with insufficiency (13%; 20-30 ng/mL) or suboptimal levels (17%; 30-40 ng/mL).

From baseline to 4-week follow-up, median vitamin D level in the supplement group increased from 15.4 to 40.83 ng/mL, compared with a much smaller increase in the placebo group, from 13.45 to 18.85 ng/mL. Compared with the placebo group, significantly more patients given nano vitamin D₃ achieved a UCDAI 3-point reduction (53% vs 13%; P = .001); this translated to a Pearson correlation coefficient (rho) of –0.713, between vitamin D level and UCDAI. Similar, albeit less strong, inverse relationships were detected between vitamin D level and CRP (rho = −0.603) and calprotectin (rho = −0.368).

Benefits observed in the supplement group also extended to stool frequency, stool consistency, and histologic measures. Those who achieved a vitamin D level greater than 40 ng/mL were 4 times more likely to have a UCDAI 3-point reduction than those who did not meet the same criteria (80% vs 20%; P = .038). Independent predictors of response included baseline histologic activity (odds ratio, 1.92), and to a greater extent, vitamin D supplementation (OR, 9.17). No patients achieved remission, which the investigators attributed to the relatively short study duration.

Minor, self-limiting side effects occurred in 13.3% and 10% of patients given the vitamin D supplement and placebo, respectively.

“[T]he present study showed significant improvement in all inflammatory parameters of the disease including clinical, endoscopic, histopathologic, and serum and fecal markers of inflammation, all of which paralleled each other in showing [the benefit of] oral nano vitamin D supplementation,” the investigators concluded. They advised that larger, longer-term studies are needed before the findings can be generalized to all patients with active UC.

The investigators disclosed no external funding or conflicts of interest.

SOURCE: Ahamed R et al. J Clin Gastroenterol. 2019 Jul 24. doi: 10.1097/MCG.0000000000001233.

Vitamin D supplementation may lead to significant improvements in ulcerative colitis (UC), based on a placebo-controlled trial involving 60 patients with active disease.

Those who achieved vitamin D levels greater than 40 ng/mL were most likely to benefit, reported lead author Rizwan Ahamed Z, MD, of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues. They noted that the findings contribute much-needed clinical data to a largely theoretical subject area.

“[T]he discovery of vitamin D receptors on lymphocytes, monocytes, and dendritic cells initiated various studies which have highlighted the role of vitamin D in regulating gut mucosal immunity and gut barrier,” the investigators wrote in Journal of Clinical Gastroenterology. “In experimental interleukin (IL)-10 knockout mice models, vitamin D deficiency was found to result in severe colitis, progressive wasting, and high mortality. However, vitamin D supplementation not only prevented but also ameliorated symptoms of colitis in the mice model.”

Human studies have revealed similar associations between vitamin D supplementation and inflammatory bowel disease, such as a study by Jørgensen and colleagues that found a lower risk of relapse in Crohn’s disease, and another by Sharifi and colleagues that showed injectable vitamin D could reduce erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with UC. Still, the investigators suggested that more clinical data are needed, particularly for outcomes after vitamin D therapy. In addition to providing such data, the present trial was also the first of its kind to test oral nano vitamin D₃, which may have better bioavailability than conventional supplements.

The investigators initially recruited 110 patients with active UC who had an ulcerative colitis disease activity index (UCDAI) of at least 3. After screening, 50 patients were excluded because they had vitamin D levels greater than 40 ng/mL, were already taking a vitamin D supplement, had severe UC requiring hospitalization, or exhibited severe systemic illness. The remaining 60 patients were randomized in a 1:1 ratio to receive either 60,000 IU nano vitamin D₃ once daily for 8 days, or placebo. Disease parameters, which were measured at baseline and then again at 4 weeks, included UCDAI, ESR, CRP, and fecal calprotectin. The primary outcome was response, defined as a UCDAI reduction of at least 3 points. Secondary outcome measures included stool frequency, stool consistency, and remission (UCDAI less than 3); in addition, the investigators evaluated histologic, endoscopic, fecal, and serum inflammatory markers.

The majority of patients in the study were men (60%), with a mean age of 36 years. Most patients had moderate UC (73.3%), while smaller proportions had severe (18%) or mild (8%) disease. All patients were taking a 5-aminosalicylic acid oral compound and some (16.6%) were also taking azathioprine. At baseline, the mean vitamin D level was 14 ng/mL. Most patients (70%) were diagnosed with vitamin D deficiency, based on measurements below 20 ng/mL. The remaining patients were diagnosed with insufficiency (13%; 20-30 ng/mL) or suboptimal levels (17%; 30-40 ng/mL).

From baseline to 4-week follow-up, median vitamin D level in the supplement group increased from 15.4 to 40.83 ng/mL, compared with a much smaller increase in the placebo group, from 13.45 to 18.85 ng/mL. Compared with the placebo group, significantly more patients given nano vitamin D₃ achieved a UCDAI 3-point reduction (53% vs 13%; P = .001); this translated to a Pearson correlation coefficient (rho) of –0.713, between vitamin D level and UCDAI. Similar, albeit less strong, inverse relationships were detected between vitamin D level and CRP (rho = −0.603) and calprotectin (rho = −0.368).

Benefits observed in the supplement group also extended to stool frequency, stool consistency, and histologic measures. Those who achieved a vitamin D level greater than 40 ng/mL were 4 times more likely to have a UCDAI 3-point reduction than those who did not meet the same criteria (80% vs 20%; P = .038). Independent predictors of response included baseline histologic activity (odds ratio, 1.92), and to a greater extent, vitamin D supplementation (OR, 9.17). No patients achieved remission, which the investigators attributed to the relatively short study duration.

Minor, self-limiting side effects occurred in 13.3% and 10% of patients given the vitamin D supplement and placebo, respectively.

“[T]he present study showed significant improvement in all inflammatory parameters of the disease including clinical, endoscopic, histopathologic, and serum and fecal markers of inflammation, all of which paralleled each other in showing [the benefit of] oral nano vitamin D supplementation,” the investigators concluded. They advised that larger, longer-term studies are needed before the findings can be generalized to all patients with active UC.

The investigators disclosed no external funding or conflicts of interest.

SOURCE: Ahamed R et al. J Clin Gastroenterol. 2019 Jul 24. doi: 10.1097/MCG.0000000000001233.

Vitamin D supplementation may lead to significant improvements in ulcerative colitis (UC), based on a placebo-controlled trial involving 60 patients with active disease.

Those who achieved vitamin D levels greater than 40 ng/mL were most likely to benefit, reported lead author Rizwan Ahamed Z, MD, of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, and colleagues. They noted that the findings contribute much-needed clinical data to a largely theoretical subject area.

“[T]he discovery of vitamin D receptors on lymphocytes, monocytes, and dendritic cells initiated various studies which have highlighted the role of vitamin D in regulating gut mucosal immunity and gut barrier,” the investigators wrote in Journal of Clinical Gastroenterology. “In experimental interleukin (IL)-10 knockout mice models, vitamin D deficiency was found to result in severe colitis, progressive wasting, and high mortality. However, vitamin D supplementation not only prevented but also ameliorated symptoms of colitis in the mice model.”

Human studies have revealed similar associations between vitamin D supplementation and inflammatory bowel disease, such as a study by Jørgensen and colleagues that found a lower risk of relapse in Crohn’s disease, and another by Sharifi and colleagues that showed injectable vitamin D could reduce erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with UC. Still, the investigators suggested that more clinical data are needed, particularly for outcomes after vitamin D therapy. In addition to providing such data, the present trial was also the first of its kind to test oral nano vitamin D₃, which may have better bioavailability than conventional supplements.

The investigators initially recruited 110 patients with active UC who had an ulcerative colitis disease activity index (UCDAI) of at least 3. After screening, 50 patients were excluded because they had vitamin D levels greater than 40 ng/mL, were already taking a vitamin D supplement, had severe UC requiring hospitalization, or exhibited severe systemic illness. The remaining 60 patients were randomized in a 1:1 ratio to receive either 60,000 IU nano vitamin D₃ once daily for 8 days, or placebo. Disease parameters, which were measured at baseline and then again at 4 weeks, included UCDAI, ESR, CRP, and fecal calprotectin. The primary outcome was response, defined as a UCDAI reduction of at least 3 points. Secondary outcome measures included stool frequency, stool consistency, and remission (UCDAI less than 3); in addition, the investigators evaluated histologic, endoscopic, fecal, and serum inflammatory markers.

The majority of patients in the study were men (60%), with a mean age of 36 years. Most patients had moderate UC (73.3%), while smaller proportions had severe (18%) or mild (8%) disease. All patients were taking a 5-aminosalicylic acid oral compound and some (16.6%) were also taking azathioprine. At baseline, the mean vitamin D level was 14 ng/mL. Most patients (70%) were diagnosed with vitamin D deficiency, based on measurements below 20 ng/mL. The remaining patients were diagnosed with insufficiency (13%; 20-30 ng/mL) or suboptimal levels (17%; 30-40 ng/mL).

From baseline to 4-week follow-up, median vitamin D level in the supplement group increased from 15.4 to 40.83 ng/mL, compared with a much smaller increase in the placebo group, from 13.45 to 18.85 ng/mL. Compared with the placebo group, significantly more patients given nano vitamin D₃ achieved a UCDAI 3-point reduction (53% vs 13%; P = .001); this translated to a Pearson correlation coefficient (rho) of –0.713, between vitamin D level and UCDAI. Similar, albeit less strong, inverse relationships were detected between vitamin D level and CRP (rho = −0.603) and calprotectin (rho = −0.368).

Benefits observed in the supplement group also extended to stool frequency, stool consistency, and histologic measures. Those who achieved a vitamin D level greater than 40 ng/mL were 4 times more likely to have a UCDAI 3-point reduction than those who did not meet the same criteria (80% vs 20%; P = .038). Independent predictors of response included baseline histologic activity (odds ratio, 1.92), and to a greater extent, vitamin D supplementation (OR, 9.17). No patients achieved remission, which the investigators attributed to the relatively short study duration.

Minor, self-limiting side effects occurred in 13.3% and 10% of patients given the vitamin D supplement and placebo, respectively.

“[T]he present study showed significant improvement in all inflammatory parameters of the disease including clinical, endoscopic, histopathologic, and serum and fecal markers of inflammation, all of which paralleled each other in showing [the benefit of] oral nano vitamin D supplementation,” the investigators concluded. They advised that larger, longer-term studies are needed before the findings can be generalized to all patients with active UC.

The investigators disclosed no external funding or conflicts of interest.

SOURCE: Ahamed R et al. J Clin Gastroenterol. 2019 Jul 24. doi: 10.1097/MCG.0000000000001233.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

AGA patient education on GERD can help your patients better understand and manage the disorder. Post this education or your practice website or share you’re your patients at https://www.gastro.org/practice-guidance/gi-patient-center/topic/gastroesophageal-reflux-disease-gerd.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

AGA patient education on GERD can help your patients better understand and manage the disorder. Post this education or your practice website or share you’re your patients at https://www.gastro.org/practice-guidance/gi-patient-center/topic/gastroesophageal-reflux-disease-gerd.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

AGA patient education on GERD can help your patients better understand and manage the disorder. Post this education or your practice website or share you’re your patients at https://www.gastro.org/practice-guidance/gi-patient-center/topic/gastroesophageal-reflux-disease-gerd.

Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.

Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.

“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”

The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.

Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.

A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.

“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.

“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.

The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.

SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.

Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.

Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.

“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”

The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.

Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.

A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.

“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.

“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.

The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.

SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.

Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.

Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.

“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”

The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.

Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.

A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.

“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.

“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.

The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.

SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.

For most patients taking antiplatelet and/or anticoagulant therapies, the proton pump inhibitor (PPI) pantoprazole is unnecessary, based on findings from the prospective COMPASS trial, which involved more than 17,000 participants.

Pantoprazole may reduce the risk of bleeding from gastroduodenal lesions, but it is unlikely to prevent upper-gastrointestinal events, reported lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Canada, and colleagues.

The investigators wrote in Gastroenterology, “Guidelines suggest that patients receiving the combination of antiplatelet and anticoagulant therapy should receive PPIs to reduce the risk of upper-GI bleeding. However … there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin.”

To fill this knowledge gap, the investigators recruited 17,598 participants from 33 countries who had stable peripheral artery disease and cardiovascular disease. Participants were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or a combination of 2.5-mg rivaroxaban twice daily with 100-mg aspirin once daily. This part of the trial was discontinued before completion because of early cardiovascular advantages associated with combination therapy over aspirin alone, and related findings were reported previously. While combination therapy did reduce cardiovascular risks, it had less favorable effects on gut health, highlighted by an associated increase in major GI bleeding events. Despite early cessation of the cardiovascular portion of the trial, the pantoprazole regimen was continued, offering a look at the effect of long-term PPI use on gut health.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. The primary efficacy outcome was time to first upper-GI clinical event, defined as a composite of the following: upper-GI obstruction, perforation, at least five gastroduodenal erosions with at least 3 days of GI pain, symptomatic gastroduodenal ulcer involving at least 3 days of GI pain, overt upper-GI bleeding of unknown origin, occult bleeding (drop in hemoglobin of at least 2 g/dL), overt bleeding with a gastroduodenal lesion (active bleeding during endoscopy), or a symptomatic gastroduodenal ulcer involving at least 3 days of GI pain. In addition to this measure, the investigators evaluated a post-hoc endpoint with a looser definition of peptic ulcer events, most notably eliminating the requirement that a lesion be actively bleeding during endoscopy.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking a nonsteroidal anti-inflammatory drug (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group, after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis showed that upper-GI events occurred marginally less often in the pantoprazole group than the placebo group, but without statistical significance (1.2% vs. 1.3%; P = .35). Of the outcomes measured, only overt bleeding of gastroduodenal origin detected by radiography or endoscopy was statistically less common in the pantoprazole group than the placebo group, with a 48% reduced rate (0.2% vs. 0.4%; P = .03). No statistical efficacy differences or statistical interactions were detected between population subgroups.

“The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact on clinical upper-GI events or upper-GI bleeding,” the investigators wrote. “This is in contrast to previous systematic reviews of randomized trials reporting that PPIs were associated with a 50%-70% reduction in bleeding and symptomatic peptic ulcers related to nonsteroidal anti-inflammatory drugs, including in the critical care setting.”

Post-hoc analysis, which allowed for a broader definition of upper-GI events related to gastroduodenal ulcers, revealed a slightly greater reduction in risk of bleeding lesions in patients taking pantoprazole, compared with placebo (hazard ratio, 0.45), and additional risk reductions for peptic ulcers (HR, 0.46) and erosions (HR, 0.33). Ultimately, pantoprazole reduced the combined rate of post-hoc events by 56%.

The investigators noted that these ulcer- and erosion-reducing effects of pantoprazole align with previous reports. “It is therefore possible that PPIs might be beneficial for patients at particularly high risk for peptic ulcer disease who are also taking aspirin and/or anticoagulants,” the investigators concluded.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 2. doi: 10.1053/j.gastro.2019.04.041.

For most patients taking antiplatelet and/or anticoagulant therapies, the proton pump inhibitor (PPI) pantoprazole is unnecessary, based on findings from the prospective COMPASS trial, which involved more than 17,000 participants.

Pantoprazole may reduce the risk of bleeding from gastroduodenal lesions, but it is unlikely to prevent upper-gastrointestinal events, reported lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Canada, and colleagues.

The investigators wrote in Gastroenterology, “Guidelines suggest that patients receiving the combination of antiplatelet and anticoagulant therapy should receive PPIs to reduce the risk of upper-GI bleeding. However … there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin.”

To fill this knowledge gap, the investigators recruited 17,598 participants from 33 countries who had stable peripheral artery disease and cardiovascular disease. Participants were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or a combination of 2.5-mg rivaroxaban twice daily with 100-mg aspirin once daily. This part of the trial was discontinued before completion because of early cardiovascular advantages associated with combination therapy over aspirin alone, and related findings were reported previously. While combination therapy did reduce cardiovascular risks, it had less favorable effects on gut health, highlighted by an associated increase in major GI bleeding events. Despite early cessation of the cardiovascular portion of the trial, the pantoprazole regimen was continued, offering a look at the effect of long-term PPI use on gut health.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. The primary efficacy outcome was time to first upper-GI clinical event, defined as a composite of the following: upper-GI obstruction, perforation, at least five gastroduodenal erosions with at least 3 days of GI pain, symptomatic gastroduodenal ulcer involving at least 3 days of GI pain, overt upper-GI bleeding of unknown origin, occult bleeding (drop in hemoglobin of at least 2 g/dL), overt bleeding with a gastroduodenal lesion (active bleeding during endoscopy), or a symptomatic gastroduodenal ulcer involving at least 3 days of GI pain. In addition to this measure, the investigators evaluated a post-hoc endpoint with a looser definition of peptic ulcer events, most notably eliminating the requirement that a lesion be actively bleeding during endoscopy.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking a nonsteroidal anti-inflammatory drug (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group, after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis showed that upper-GI events occurred marginally less often in the pantoprazole group than the placebo group, but without statistical significance (1.2% vs. 1.3%; P = .35). Of the outcomes measured, only overt bleeding of gastroduodenal origin detected by radiography or endoscopy was statistically less common in the pantoprazole group than the placebo group, with a 48% reduced rate (0.2% vs. 0.4%; P = .03). No statistical efficacy differences or statistical interactions were detected between population subgroups.

“The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact on clinical upper-GI events or upper-GI bleeding,” the investigators wrote. “This is in contrast to previous systematic reviews of randomized trials reporting that PPIs were associated with a 50%-70% reduction in bleeding and symptomatic peptic ulcers related to nonsteroidal anti-inflammatory drugs, including in the critical care setting.”

Post-hoc analysis, which allowed for a broader definition of upper-GI events related to gastroduodenal ulcers, revealed a slightly greater reduction in risk of bleeding lesions in patients taking pantoprazole, compared with placebo (hazard ratio, 0.45), and additional risk reductions for peptic ulcers (HR, 0.46) and erosions (HR, 0.33). Ultimately, pantoprazole reduced the combined rate of post-hoc events by 56%.

The investigators noted that these ulcer- and erosion-reducing effects of pantoprazole align with previous reports. “It is therefore possible that PPIs might be beneficial for patients at particularly high risk for peptic ulcer disease who are also taking aspirin and/or anticoagulants,” the investigators concluded.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 2. doi: 10.1053/j.gastro.2019.04.041.

For most patients taking antiplatelet and/or anticoagulant therapies, the proton pump inhibitor (PPI) pantoprazole is unnecessary, based on findings from the prospective COMPASS trial, which involved more than 17,000 participants.

Pantoprazole may reduce the risk of bleeding from gastroduodenal lesions, but it is unlikely to prevent upper-gastrointestinal events, reported lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Canada, and colleagues.

The investigators wrote in Gastroenterology, “Guidelines suggest that patients receiving the combination of antiplatelet and anticoagulant therapy should receive PPIs to reduce the risk of upper-GI bleeding. However … there are no randomized data to support the use of PPI therapy in patients taking oral anticoagulants, and a paucity of data relating to aspirin.”

To fill this knowledge gap, the investigators recruited 17,598 participants from 33 countries who had stable peripheral artery disease and cardiovascular disease. Participants were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or a combination of 2.5-mg rivaroxaban twice daily with 100-mg aspirin once daily. This part of the trial was discontinued before completion because of early cardiovascular advantages associated with combination therapy over aspirin alone, and related findings were reported previously. While combination therapy did reduce cardiovascular risks, it had less favorable effects on gut health, highlighted by an associated increase in major GI bleeding events. Despite early cessation of the cardiovascular portion of the trial, the pantoprazole regimen was continued, offering a look at the effect of long-term PPI use on gut health.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. The primary efficacy outcome was time to first upper-GI clinical event, defined as a composite of the following: upper-GI obstruction, perforation, at least five gastroduodenal erosions with at least 3 days of GI pain, symptomatic gastroduodenal ulcer involving at least 3 days of GI pain, overt upper-GI bleeding of unknown origin, occult bleeding (drop in hemoglobin of at least 2 g/dL), overt bleeding with a gastroduodenal lesion (active bleeding during endoscopy), or a symptomatic gastroduodenal ulcer involving at least 3 days of GI pain. In addition to this measure, the investigators evaluated a post-hoc endpoint with a looser definition of peptic ulcer events, most notably eliminating the requirement that a lesion be actively bleeding during endoscopy.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking a nonsteroidal anti-inflammatory drug (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group, after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis showed that upper-GI events occurred marginally less often in the pantoprazole group than the placebo group, but without statistical significance (1.2% vs. 1.3%; P = .35). Of the outcomes measured, only overt bleeding of gastroduodenal origin detected by radiography or endoscopy was statistically less common in the pantoprazole group than the placebo group, with a 48% reduced rate (0.2% vs. 0.4%; P = .03). No statistical efficacy differences or statistical interactions were detected between population subgroups.

“The data suggest that routine use of PPI therapy is not warranted for patients receiving low-dose rivaroxaban with or without aspirin for the prevention of atherothrombotic events in patients with stable coronary artery disease or symptomatic peripheral artery disease, as there was no overall impact on clinical upper-GI events or upper-GI bleeding,” the investigators wrote. “This is in contrast to previous systematic reviews of randomized trials reporting that PPIs were associated with a 50%-70% reduction in bleeding and symptomatic peptic ulcers related to nonsteroidal anti-inflammatory drugs, including in the critical care setting.”

Post-hoc analysis, which allowed for a broader definition of upper-GI events related to gastroduodenal ulcers, revealed a slightly greater reduction in risk of bleeding lesions in patients taking pantoprazole, compared with placebo (hazard ratio, 0.45), and additional risk reductions for peptic ulcers (HR, 0.46) and erosions (HR, 0.33). Ultimately, pantoprazole reduced the combined rate of post-hoc events by 56%.

The investigators noted that these ulcer- and erosion-reducing effects of pantoprazole align with previous reports. “It is therefore possible that PPIs might be beneficial for patients at particularly high risk for peptic ulcer disease who are also taking aspirin and/or anticoagulants,” the investigators concluded.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 2. doi: 10.1053/j.gastro.2019.04.041.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

A variety of demographic and disease-related factors contribute to poorer quality of life in patients with nonalcoholic fatty liver disease (NAFLD), based on questionnaires involving 304 European patients.

In contrast with previous research, lobular inflammation, but not hepatic fibrosis, was associated with worse quality of life, reported to lead author Yvonne Huber, MD, of Johannes Gutenberg University in Mainz, Germany, and colleagues. Women and those with advanced disease or comorbidities had the lowest health-related quality of life (HRQL) scores. The investigators suggested that these findings could be used for treatment planning at a population and patient level.

“With the emergence of medical therapy for [nonalcoholic steatohepatitis (NASH)], it will be of importance to identify patients with the highest unmet need for treatment,” the investigators wrote in Clinical Gastroenterology and Hepatology, emphasizing that therapies targeting inflammation could provide the greatest relief.

To determine which patients with NAFLD were most affected by their condition, the investigators used the Chronic Liver Disease Questionnaire (CLDQ), which assesses physical, mental, social, and emotional function, with lower scores indicating poorer health-related quality of life. “[The CLDQ] more specifically addresses symptoms of patients with chronic liver disease, including extrahepatic manifestations, compared with traditional HRQL measures such as the [Short Form–36 (SF-36)] Health Survey Questionnaire,” the investigators explained. Recent research has used the CLDQ to reveal a variety of findings, the investigators noted, such as a 2016 study by Alt and colleagues outlining the most common symptoms in noninfectious chronic liver disease (abdominal discomfort, fatigue, and anxiety), and two studies by Younossi and colleagues describing quality of life improvements after curing hepatitis C virus, and negative impacts of viremia and hepatic inflammation in patients with hepatitis B.

The current study involved 304 patients with histologically confirmed NAFLD who were prospectively entered into the European NAFLD registry via centers in Germany (n = 133), the United Kingdom (n = 154), and Spain (n = 17). Patient data included demographic factors, laboratory findings, and histologic features. Within 6 months of liver biopsy, patients completed the CLDQ.

The mean patient age was 52.3 years, with slightly more men than women (53.3% vs. 46.7%). Most patients (75%) were obese, leading to a median body mass index of 33.3 kg/m². More than two-thirds of patients (69.1%) had NASH, while approximately half of the population (51.4%) had moderate steatosis, no or low-grade fibrosis (F0-2, 58.2%), and no or low-grade lobular inflammation (grade 0 or 1, 54.7%). The three countries had significantly different population profiles; for example, the United Kingdom had an approximately 10% higher prevalence of type 2 diabetes and obesity compared with the entire cohort, but a decreased arterial hypertension rate of a similar magnitude. The United Kingdom also had a significantly lower mean CLDQ score than that of the study population as a whole (4.73 vs. 4.99).

Analysis of the entire cohort revealed that a variety of demographic and disease-related factors negatively impacted health-related quality of life. Women had a significantly lower mean CLDQ score than that of men (5.31 vs. 4.62; P less than .001), more often reporting abdominal symptoms, fatigue, systemic symptoms, reduced activity, diminished emotional functioning, and worry. CLDQ overall score was negatively influenced by obesity (4.83 vs. 5.46), type 2 diabetes (4.74 vs. 5.25), and hyperlipidemia (4.84 vs. 5.24), but not hypertension. Laboratory findings that negatively correlated with CLDQ included aspartate transaminase (AST) and HbA_1c, whereas ferritin was positively correlated.

Generally, patients with NASH reported worse quality of life than that of those with just NAFLD (4.85 vs. 5.31). Factors contributing most to this disparity were fatigue, systemic symptoms, activity, and worry. On a histologic level, hepatic steatosis, ballooning, and lobular inflammation predicted poorer quality of life; although advanced fibrosis and compensated cirrhosis were associated with a trend toward reduced quality of life, this pattern lacked statistical significance. Multivariate analysis, which accounted for age, sex, body mass index, country, and type 2 diabetes, revealed independent associations between reduced quality of life and type 2 diabetes, sex, age, body mass index, and hepatic inflammation, but not fibrosis.

“The striking finding of the current analysis in this well-characterized European cohort was that, in contrast to the published data on predictors of overall and liver-specific mortality, lobular inflammation correlated independently with HRQL,” the investigators wrote. “These results differ from the NASH [Clinical Research Network] cohort, which found lower HRQL using the generic [SF-36 Health Survey Questionnaire] in NASH compared with a healthy U.S. population and a significant effect in cirrhosis only.” The investigators suggested that mechanistic differences in disease progression could explain this discordance.

Although hepatic fibrosis has been tied with quality of life by some studies, the investigators pointed out that patients with chronic hepatitis B or C have reported improved quality of life after viral elimination or suppression, which reduce inflammation, but not fibrosis. “On the basis of the current analysis, it can be expected that improvement of steatohepatitis, and in particular lobular inflammation, will have measurable influence on HRQL even independently of fibrosis improvement,” the investigators concluded.

The study was funded by H2020. The investigators reported no conflicts of interest.

SOURCE: Huber Y et al. CGH. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.016.

A variety of demographic and disease-related factors contribute to poorer quality of life in patients with nonalcoholic fatty liver disease (NAFLD), based on questionnaires involving 304 European patients.

In contrast with previous research, lobular inflammation, but not hepatic fibrosis, was associated with worse quality of life, reported to lead author Yvonne Huber, MD, of Johannes Gutenberg University in Mainz, Germany, and colleagues. Women and those with advanced disease or comorbidities had the lowest health-related quality of life (HRQL) scores. The investigators suggested that these findings could be used for treatment planning at a population and patient level.

“With the emergence of medical therapy for [nonalcoholic steatohepatitis (NASH)], it will be of importance to identify patients with the highest unmet need for treatment,” the investigators wrote in Clinical Gastroenterology and Hepatology, emphasizing that therapies targeting inflammation could provide the greatest relief.

To determine which patients with NAFLD were most affected by their condition, the investigators used the Chronic Liver Disease Questionnaire (CLDQ), which assesses physical, mental, social, and emotional function, with lower scores indicating poorer health-related quality of life. “[The CLDQ] more specifically addresses symptoms of patients with chronic liver disease, including extrahepatic manifestations, compared with traditional HRQL measures such as the [Short Form–36 (SF-36)] Health Survey Questionnaire,” the investigators explained. Recent research has used the CLDQ to reveal a variety of findings, the investigators noted, such as a 2016 study by Alt and colleagues outlining the most common symptoms in noninfectious chronic liver disease (abdominal discomfort, fatigue, and anxiety), and two studies by Younossi and colleagues describing quality of life improvements after curing hepatitis C virus, and negative impacts of viremia and hepatic inflammation in patients with hepatitis B.

The current study involved 304 patients with histologically confirmed NAFLD who were prospectively entered into the European NAFLD registry via centers in Germany (n = 133), the United Kingdom (n = 154), and Spain (n = 17). Patient data included demographic factors, laboratory findings, and histologic features. Within 6 months of liver biopsy, patients completed the CLDQ.

The mean patient age was 52.3 years, with slightly more men than women (53.3% vs. 46.7%). Most patients (75%) were obese, leading to a median body mass index of 33.3 kg/m². More than two-thirds of patients (69.1%) had NASH, while approximately half of the population (51.4%) had moderate steatosis, no or low-grade fibrosis (F0-2, 58.2%), and no or low-grade lobular inflammation (grade 0 or 1, 54.7%). The three countries had significantly different population profiles; for example, the United Kingdom had an approximately 10% higher prevalence of type 2 diabetes and obesity compared with the entire cohort, but a decreased arterial hypertension rate of a similar magnitude. The United Kingdom also had a significantly lower mean CLDQ score than that of the study population as a whole (4.73 vs. 4.99).

Analysis of the entire cohort revealed that a variety of demographic and disease-related factors negatively impacted health-related quality of life. Women had a significantly lower mean CLDQ score than that of men (5.31 vs. 4.62; P less than .001), more often reporting abdominal symptoms, fatigue, systemic symptoms, reduced activity, diminished emotional functioning, and worry. CLDQ overall score was negatively influenced by obesity (4.83 vs. 5.46), type 2 diabetes (4.74 vs. 5.25), and hyperlipidemia (4.84 vs. 5.24), but not hypertension. Laboratory findings that negatively correlated with CLDQ included aspartate transaminase (AST) and HbA_1c, whereas ferritin was positively correlated.

Generally, patients with NASH reported worse quality of life than that of those with just NAFLD (4.85 vs. 5.31). Factors contributing most to this disparity were fatigue, systemic symptoms, activity, and worry. On a histologic level, hepatic steatosis, ballooning, and lobular inflammation predicted poorer quality of life; although advanced fibrosis and compensated cirrhosis were associated with a trend toward reduced quality of life, this pattern lacked statistical significance. Multivariate analysis, which accounted for age, sex, body mass index, country, and type 2 diabetes, revealed independent associations between reduced quality of life and type 2 diabetes, sex, age, body mass index, and hepatic inflammation, but not fibrosis.

“The striking finding of the current analysis in this well-characterized European cohort was that, in contrast to the published data on predictors of overall and liver-specific mortality, lobular inflammation correlated independently with HRQL,” the investigators wrote. “These results differ from the NASH [Clinical Research Network] cohort, which found lower HRQL using the generic [SF-36 Health Survey Questionnaire] in NASH compared with a healthy U.S. population and a significant effect in cirrhosis only.” The investigators suggested that mechanistic differences in disease progression could explain this discordance.

Although hepatic fibrosis has been tied with quality of life by some studies, the investigators pointed out that patients with chronic hepatitis B or C have reported improved quality of life after viral elimination or suppression, which reduce inflammation, but not fibrosis. “On the basis of the current analysis, it can be expected that improvement of steatohepatitis, and in particular lobular inflammation, will have measurable influence on HRQL even independently of fibrosis improvement,” the investigators concluded.

The study was funded by H2020. The investigators reported no conflicts of interest.

SOURCE: Huber Y et al. CGH. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.016.

A variety of demographic and disease-related factors contribute to poorer quality of life in patients with nonalcoholic fatty liver disease (NAFLD), based on questionnaires involving 304 European patients.

In contrast with previous research, lobular inflammation, but not hepatic fibrosis, was associated with worse quality of life, reported to lead author Yvonne Huber, MD, of Johannes Gutenberg University in Mainz, Germany, and colleagues. Women and those with advanced disease or comorbidities had the lowest health-related quality of life (HRQL) scores. The investigators suggested that these findings could be used for treatment planning at a population and patient level.

“With the emergence of medical therapy for [nonalcoholic steatohepatitis (NASH)], it will be of importance to identify patients with the highest unmet need for treatment,” the investigators wrote in Clinical Gastroenterology and Hepatology, emphasizing that therapies targeting inflammation could provide the greatest relief.

To determine which patients with NAFLD were most affected by their condition, the investigators used the Chronic Liver Disease Questionnaire (CLDQ), which assesses physical, mental, social, and emotional function, with lower scores indicating poorer health-related quality of life. “[The CLDQ] more specifically addresses symptoms of patients with chronic liver disease, including extrahepatic manifestations, compared with traditional HRQL measures such as the [Short Form–36 (SF-36)] Health Survey Questionnaire,” the investigators explained. Recent research has used the CLDQ to reveal a variety of findings, the investigators noted, such as a 2016 study by Alt and colleagues outlining the most common symptoms in noninfectious chronic liver disease (abdominal discomfort, fatigue, and anxiety), and two studies by Younossi and colleagues describing quality of life improvements after curing hepatitis C virus, and negative impacts of viremia and hepatic inflammation in patients with hepatitis B.

The current study involved 304 patients with histologically confirmed NAFLD who were prospectively entered into the European NAFLD registry via centers in Germany (n = 133), the United Kingdom (n = 154), and Spain (n = 17). Patient data included demographic factors, laboratory findings, and histologic features. Within 6 months of liver biopsy, patients completed the CLDQ.

The mean patient age was 52.3 years, with slightly more men than women (53.3% vs. 46.7%). Most patients (75%) were obese, leading to a median body mass index of 33.3 kg/m². More than two-thirds of patients (69.1%) had NASH, while approximately half of the population (51.4%) had moderate steatosis, no or low-grade fibrosis (F0-2, 58.2%), and no or low-grade lobular inflammation (grade 0 or 1, 54.7%). The three countries had significantly different population profiles; for example, the United Kingdom had an approximately 10% higher prevalence of type 2 diabetes and obesity compared with the entire cohort, but a decreased arterial hypertension rate of a similar magnitude. The United Kingdom also had a significantly lower mean CLDQ score than that of the study population as a whole (4.73 vs. 4.99).

Analysis of the entire cohort revealed that a variety of demographic and disease-related factors negatively impacted health-related quality of life. Women had a significantly lower mean CLDQ score than that of men (5.31 vs. 4.62; P less than .001), more often reporting abdominal symptoms, fatigue, systemic symptoms, reduced activity, diminished emotional functioning, and worry. CLDQ overall score was negatively influenced by obesity (4.83 vs. 5.46), type 2 diabetes (4.74 vs. 5.25), and hyperlipidemia (4.84 vs. 5.24), but not hypertension. Laboratory findings that negatively correlated with CLDQ included aspartate transaminase (AST) and HbA_1c, whereas ferritin was positively correlated.

Generally, patients with NASH reported worse quality of life than that of those with just NAFLD (4.85 vs. 5.31). Factors contributing most to this disparity were fatigue, systemic symptoms, activity, and worry. On a histologic level, hepatic steatosis, ballooning, and lobular inflammation predicted poorer quality of life; although advanced fibrosis and compensated cirrhosis were associated with a trend toward reduced quality of life, this pattern lacked statistical significance. Multivariate analysis, which accounted for age, sex, body mass index, country, and type 2 diabetes, revealed independent associations between reduced quality of life and type 2 diabetes, sex, age, body mass index, and hepatic inflammation, but not fibrosis.

“The striking finding of the current analysis in this well-characterized European cohort was that, in contrast to the published data on predictors of overall and liver-specific mortality, lobular inflammation correlated independently with HRQL,” the investigators wrote. “These results differ from the NASH [Clinical Research Network] cohort, which found lower HRQL using the generic [SF-36 Health Survey Questionnaire] in NASH compared with a healthy U.S. population and a significant effect in cirrhosis only.” The investigators suggested that mechanistic differences in disease progression could explain this discordance.

Although hepatic fibrosis has been tied with quality of life by some studies, the investigators pointed out that patients with chronic hepatitis B or C have reported improved quality of life after viral elimination or suppression, which reduce inflammation, but not fibrosis. “On the basis of the current analysis, it can be expected that improvement of steatohepatitis, and in particular lobular inflammation, will have measurable influence on HRQL even independently of fibrosis improvement,” the investigators concluded.

The study was funded by H2020. The investigators reported no conflicts of interest.

SOURCE: Huber Y et al. CGH. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.016.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

Source: American Gastroenterological Association

Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).

NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.

“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.

“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”

The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.

After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.

“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”

Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.

“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.

“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.

The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.

SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

Source: American Gastroenterological Association

Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).

NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.

“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.

“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”

The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.

After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.

“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”

Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.

“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.

“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.

The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.

SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.

The probiotic Bifidobacterium breve Bif195 could protect patients from aspirin-related gut damage, according to investigators.

Source: American Gastroenterological Association

Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).

NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.

“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.

“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”

The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.

After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.

“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”

Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.

“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.

“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.

The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.

SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.