Meeting News

Novel blood test shows promise for parsing celiac vs. gluten sensitivity

Robert P. Anderson, MD
Robert P. Anderson

Measuring circulating cytokines in blood plasma within 6 hours of eating gluten differentiated patients with celiac disease from those with non-celiac gluten sensitivity, according to late-breaking data presented at UEG Week.

Investigators found that a one-off oral gluten challenge caused an increase in interleukin (IL)-8, IL-10 and especially IL-2 in patients with celiac disease. Conversely, patients with non-celiac gluten sensitivity showed no measurable immune response to gluten, but did show a symptom response to FODMAPs — specifically, fructans.

Biotech company ImmusantT plans to develop this as a clinical tool for diagnosing celiac disease, which current diagnostics are unable to do when patients adhere to a strict gluten-free diet.

The results of this study were unexpected, Robert P. Anderson, BMedSc, MB, ChB, PhD, FRACP, ImmusanT’s chief scientific officer, told Healio Gastroenterology and Liver Disease.

“It turns out that the people with celiac disease had an immune activation signature that we could measure in blood, and consistent with our previous research, this pointed to a T-cell effect, with gluten stimulating T-cells very quickly within 2 to 4 hours,” he said. “But there was absolutely nothing that we could measure showing any form of immune activation in patients with non-celiac gluten sensitivity, which was surprising, because the immune activation in this condition is thought to be caused by the innate immune system releasing markers like IL-8.”

Also surprising was that gluten-sensitive patients showed a symptom response to fructans rather than gluten, Anderson added. “It doesn’t appear to be gluten that’s the trigger to the symptoms in these patients, so this is quite a big deal in terms of what gluten does, and who should be on a gluten-free diet,” he said.

To evaluate whether cytokine responses could distinguish between patients with celiac disease and non-celiac gluten sensitivity on a gluten-free diet, Anderson and colleagues, in collaboration with the University of Oslo, evaluated IL-2, IL-8 and IL-10 plasma levels in 19 patients with celiac disease and 49 patients with non-celiac gluten sensitivity who underwent parallel food challenges. They drew blood samples before and 2, 4 and 6 hours after patients consumed breakfast bars containing gluten, FODMAP or placebo free of these ingredients.

Overall, the gluten-containing bars triggered mucosal changes in five of the patients with celiac disease, and induced a T-cell response in 12 of the 15 assessed for this.

In contrast, the gluten-containing bars triggered no symptomatic response vs. placebo in patients with non-celiac gluten sensitivity. Rather, these patients showed significantly higher irritable bowel syndrome symptom scores (P < .05) and bloating (P = .0003) after consuming the FODMAP vs. gluten bars.

Further, Anderson and colleagues found that patients with celiac disease showed significant increases in IL-2 levels after consuming the gluten bars compared with non-celiac gluten sensitivity patients. At 2 hours the median elevations were 1.2-fold higher (P = .0012), at 4 hours they were 10 times higher (P < .0001) and at 6 hours they were 3.6 times higher (P < .001).

Celiac patients also showed significantly higher increases in IL-8 and IL-10 relative to those with non-celiac gluten sensitivity at both 4 and 6 hours (P < .0001), but the median elevations were just between 1.2 to 1.8 times higher.

Using optimized cutoffs, IL-2 identified celiac patients with 74% sensitivity and 98% specificity, while IL-8 performed with 42% sensitivity and 100% specificity, and IL-10 performed with 32% sensitivity and 100% specificity.

Finally, the investigators noted that among 16 celiac patients who were HLA-DQ2.5-positive, the average fold change in IL-2 elevation at 2 to 6 hours correlated with the frequency of gluten-specific cells at baseline (P = .0028), and with overall discomfort at 6 hours in all 19 celiac patients (P = .0446).

Leslie Williams, BS, RN, MBA
Leslie Williams

The availability of such a blood test in primary care would be a game-changer for preventing misdiagnosis of celiac disease in non-celiac gluten sensitive patients, according to Leslie Williams, BS, RN, MBA, founder and CEO of ImmusanT.

“This is the first time ever that data supports the differentiation of non-celiac gluten sensitivity, which affects about 10% of the population, vs. celiac disease, which affects 1% of the population,” she told Healio Gastroenterology and Liver Disease. “This is a simple blood-based diagnostic test for patients who have put themselves on a gluten-free diet, and it will differentiate between these two seemingly similar yet very different clinical presentations.”

In addition to standardizing the gluten challenge required for the test and optimizing the blood markers, the company’s next steps for development include an additional study to test the final version of the diagnostic test, according to Anderson. Williams added that after completing validation studies, they plan to license it to a diagnostic company to rapidly and broadly commercialize it.

Nexvax2 ‘gluten vaccine’ data

In two additional oral presentations at UEG Week, researchers shared new data on Nexvax2, ImmusanT’s investigational therapeutic vaccine for protecting HLA-DQ2.5-positive celiac patients against the effects of gluten exposure. As Healio Gastroenterology and Liver Disease previously reported, this is an “epitope-specific immunotherapy consisting of three peptides with immunodominant epitopes for gluten-specific CD4-positive T cells.”

In one presentation, Anderson shared new clinical trial data showing that both gluten ingestion and intradermal injection with Nexvax2 resulted in a plasma cytokine signature dominated by IL-2 within 2 to 6 hours in patients with celiac disease.

“These findings suggest ingestion of gluten or injection of peptides activate T cells rapidly, and could account for symptoms triggered by gluten,” Anderson and colleagues wrote in the study abstract.

The second presentation included new data showing that higher doses of Nexvax2 for maintenance are safe and well tolerated when dosing is gradually escalated in celiac patients.

“The key here is that we were able to develop a dosing regimen which was very effective in terms of shutting down the clinical effects of the stimulation of the gluten T cells,” Anderson told Healio Gastroenterology and Liver Disease. “This study showed we could administer Nexvax2 as injections, gradually increasing from a very low dose to a high dose that prevented symptoms associated with the targeting of those T cells, so it’s showing that we’ve shut down the T cells’ ability to react to the most important parts of gluten.”

In this double-blind trial, Anderson and colleagues randomly assigned 38 HLA-DQ2.5-positive adults with celiac disease on a gluten-free diet to receive twice-weekly escalating doses of Nexvax2 or placebo. They showed that dosing up to 900 g was generally well tolerated, and did not cause immune activation based on levels of 38 cytokines evaluated 4 hours after dosing. This supports further studies of Nexvax2 at these high doses, which Anderson and colleagues predict will be more effective.

“This provides us with a regimen that can be used in phase 2, and it overcomes the activation and symptoms we saw with giving a one-off dose in our earlier phase 1 studies, so it’s a very important study for us in the field because it’s showing how to administer this new kind of therapeutic vaccine,” Anderson said.

Their preliminary work on this new class of drug, called epitope specific immunotherapy (ESIT), will inform similar efforts to develop new therapies for diseases like type 1 diabetes, multiple sclerosis and rheumatoid arthritis, he added. – by Adam Leitenberger

References:

Daveson A, et al. Abstract OP118. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Lundin K, et al. Abstract LB18. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Tye-Din J, et al. Abstract OP060. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Disclosures: Anderson and Williams are employed by ImmusanT.

Robert P. Anderson, MD
Robert P. Anderson

Measuring circulating cytokines in blood plasma within 6 hours of eating gluten differentiated patients with celiac disease from those with non-celiac gluten sensitivity, according to late-breaking data presented at UEG Week.

Investigators found that a one-off oral gluten challenge caused an increase in interleukin (IL)-8, IL-10 and especially IL-2 in patients with celiac disease. Conversely, patients with non-celiac gluten sensitivity showed no measurable immune response to gluten, but did show a symptom response to FODMAPs — specifically, fructans.

Biotech company ImmusantT plans to develop this as a clinical tool for diagnosing celiac disease, which current diagnostics are unable to do when patients adhere to a strict gluten-free diet.

The results of this study were unexpected, Robert P. Anderson, BMedSc, MB, ChB, PhD, FRACP, ImmusanT’s chief scientific officer, told Healio Gastroenterology and Liver Disease.

“It turns out that the people with celiac disease had an immune activation signature that we could measure in blood, and consistent with our previous research, this pointed to a T-cell effect, with gluten stimulating T-cells very quickly within 2 to 4 hours,” he said. “But there was absolutely nothing that we could measure showing any form of immune activation in patients with non-celiac gluten sensitivity, which was surprising, because the immune activation in this condition is thought to be caused by the innate immune system releasing markers like IL-8.”

Also surprising was that gluten-sensitive patients showed a symptom response to fructans rather than gluten, Anderson added. “It doesn’t appear to be gluten that’s the trigger to the symptoms in these patients, so this is quite a big deal in terms of what gluten does, and who should be on a gluten-free diet,” he said.

To evaluate whether cytokine responses could distinguish between patients with celiac disease and non-celiac gluten sensitivity on a gluten-free diet, Anderson and colleagues, in collaboration with the University of Oslo, evaluated IL-2, IL-8 and IL-10 plasma levels in 19 patients with celiac disease and 49 patients with non-celiac gluten sensitivity who underwent parallel food challenges. They drew blood samples before and 2, 4 and 6 hours after patients consumed breakfast bars containing gluten, FODMAP or placebo free of these ingredients.

Overall, the gluten-containing bars triggered mucosal changes in five of the patients with celiac disease, and induced a T-cell response in 12 of the 15 assessed for this.

In contrast, the gluten-containing bars triggered no symptomatic response vs. placebo in patients with non-celiac gluten sensitivity. Rather, these patients showed significantly higher irritable bowel syndrome symptom scores (P < .05) and bloating (P = .0003) after consuming the FODMAP vs. gluten bars.

PAGE BREAK

Further, Anderson and colleagues found that patients with celiac disease showed significant increases in IL-2 levels after consuming the gluten bars compared with non-celiac gluten sensitivity patients. At 2 hours the median elevations were 1.2-fold higher (P = .0012), at 4 hours they were 10 times higher (P < .0001) and at 6 hours they were 3.6 times higher (P < .001).

Celiac patients also showed significantly higher increases in IL-8 and IL-10 relative to those with non-celiac gluten sensitivity at both 4 and 6 hours (P < .0001), but the median elevations were just between 1.2 to 1.8 times higher.

Using optimized cutoffs, IL-2 identified celiac patients with 74% sensitivity and 98% specificity, while IL-8 performed with 42% sensitivity and 100% specificity, and IL-10 performed with 32% sensitivity and 100% specificity.

Finally, the investigators noted that among 16 celiac patients who were HLA-DQ2.5-positive, the average fold change in IL-2 elevation at 2 to 6 hours correlated with the frequency of gluten-specific cells at baseline (P = .0028), and with overall discomfort at 6 hours in all 19 celiac patients (P = .0446).

Leslie Williams, BS, RN, MBA
Leslie Williams

The availability of such a blood test in primary care would be a game-changer for preventing misdiagnosis of celiac disease in non-celiac gluten sensitive patients, according to Leslie Williams, BS, RN, MBA, founder and CEO of ImmusanT.

“This is the first time ever that data supports the differentiation of non-celiac gluten sensitivity, which affects about 10% of the population, vs. celiac disease, which affects 1% of the population,” she told Healio Gastroenterology and Liver Disease. “This is a simple blood-based diagnostic test for patients who have put themselves on a gluten-free diet, and it will differentiate between these two seemingly similar yet very different clinical presentations.”

In addition to standardizing the gluten challenge required for the test and optimizing the blood markers, the company’s next steps for development include an additional study to test the final version of the diagnostic test, according to Anderson. Williams added that after completing validation studies, they plan to license it to a diagnostic company to rapidly and broadly commercialize it.

Nexvax2 ‘gluten vaccine’ data

In two additional oral presentations at UEG Week, researchers shared new data on Nexvax2, ImmusanT’s investigational therapeutic vaccine for protecting HLA-DQ2.5-positive celiac patients against the effects of gluten exposure. As Healio Gastroenterology and Liver Disease previously reported, this is an “epitope-specific immunotherapy consisting of three peptides with immunodominant epitopes for gluten-specific CD4-positive T cells.”

PAGE BREAK

In one presentation, Anderson shared new clinical trial data showing that both gluten ingestion and intradermal injection with Nexvax2 resulted in a plasma cytokine signature dominated by IL-2 within 2 to 6 hours in patients with celiac disease.

“These findings suggest ingestion of gluten or injection of peptides activate T cells rapidly, and could account for symptoms triggered by gluten,” Anderson and colleagues wrote in the study abstract.

The second presentation included new data showing that higher doses of Nexvax2 for maintenance are safe and well tolerated when dosing is gradually escalated in celiac patients.

“The key here is that we were able to develop a dosing regimen which was very effective in terms of shutting down the clinical effects of the stimulation of the gluten T cells,” Anderson told Healio Gastroenterology and Liver Disease. “This study showed we could administer Nexvax2 as injections, gradually increasing from a very low dose to a high dose that prevented symptoms associated with the targeting of those T cells, so it’s showing that we’ve shut down the T cells’ ability to react to the most important parts of gluten.”

In this double-blind trial, Anderson and colleagues randomly assigned 38 HLA-DQ2.5-positive adults with celiac disease on a gluten-free diet to receive twice-weekly escalating doses of Nexvax2 or placebo. They showed that dosing up to 900 g was generally well tolerated, and did not cause immune activation based on levels of 38 cytokines evaluated 4 hours after dosing. This supports further studies of Nexvax2 at these high doses, which Anderson and colleagues predict will be more effective.

“This provides us with a regimen that can be used in phase 2, and it overcomes the activation and symptoms we saw with giving a one-off dose in our earlier phase 1 studies, so it’s a very important study for us in the field because it’s showing how to administer this new kind of therapeutic vaccine,” Anderson said.

Their preliminary work on this new class of drug, called epitope specific immunotherapy (ESIT), will inform similar efforts to develop new therapies for diseases like type 1 diabetes, multiple sclerosis and rheumatoid arthritis, he added. – by Adam Leitenberger

References:

Daveson A, et al. Abstract OP118. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Lundin K, et al. Abstract LB18. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Tye-Din J, et al. Abstract OP060. Presented at: UEG Week; Oct. 28 to Nov. 1, 2017; Barcelona.

Disclosures: Anderson and Williams are employed by ImmusanT.