Shorter gluten challenges in celiac disease clinical trials also possible with new testing technology
By Amy Ratner, Director Scientific Affairs
New ways of measuring how those with celiac disease respond to gluten could lead to less invasive, lower-dose and shorter gluten challenges for diagnosis and in clinical trials, a new study has found.
Currently, both diagnosis and evaluation of how well a celiac disease drug under study works are based on symptoms reported by patients, blood tests for celiac disease antibodies and results of intestinal biopsies, the study, published in the journal Gastroenterology, notes. But all three methods present challenges, the authors wrote.
In clinical trials investigating new treatments for celiac disease, study participants are often given some amount of gluten to induce signs of active celiac disease. Then they receive doses of the drug under study and researchers measure whether it is effective in treating celiac disease. The gluten challenge can involve both significant doses and duration, making it a burden for study participants.
Likewise, if someone starts a gluten-free diet before being diagnosed, a gluten challenge is needed to determine whether that person has celiac disease. Many people are reluctant to consume gluten and get sick again and don’t ever get definitively diagnosed.
The study was done at two celiac disease centers in Boston as researchers set out to determine whether several “modern” blood-based biomarkers that are more sensitive and responsive to gluten could reduce the amount and duration of the gluten challenge and make studies less invasive by reducing the need for biopsies. The study was funded by Takeda Pharmaceuticals, which is currently developing two drugs to treat celiac disease. Several of the researchers involved in the study have associations with Takeda.
“Modern research tools are being brought to bear in celiac disease, and this is giving us much better understanding of the chain reaction that occurs in the body when you are exposed to gluten,” said Daniel Leffler, MD, a study author and medical director of clinical science at Takeda. In addition to increased understanding, the study could lead to better ways to diagnose and monitor celiac disease and evaluate new treatments, he said.
Researchers investigated newer blood biomarkers that measure celiac disease activity, as well as patients’ symptom reports, video capsule endoscopy and biopsy results after two different doses of gluten were given to study participants. The study included 14 adults with biopsy proven celiac disease, half who got 3 grams of gluten daily for 14 days and half who got 10 grams of gluten. It was a randomized, double-blind study, which means participants were indiscriminately assigned to a dose group without either they or researchers knowing which group they were in.
In celiac disease, specific immune cells incorrectly react to gluten and cause damage, but for a long time researchers did not have the technology to measure these cells because only a few of them are floating around in your blood even when celiac disease is not controlled, Leffler explained. “These tests use modern technology to sift through the millions of white blood cells you have in every drop of blood and find the few that are actually involved in celiac disease,” he said
In the study, all the methods of measuring the reaction to a gluten challenge showed changes resulting from the higher dose of gluten, but only symptoms and Interleukin-2 (IL-2) levels also increased significantly at the lower 3 gram level. IL-2, one of the immune cells, is a cytokine secreted in the blood by the immune system when it is activated by gluten in those who have celiac disease.
After a gluten challenge, IL-2 increases rapidly in patients with celiac disease, but not in controls, according to the study, which found a response in four hours. “The increase is associated with symptom severity and is one of the earliest and most dynamic soluble blood biomarkers of gluten exposure to date,” the authors wrote. They noted that use of IL-2 is feasible for large studies, reducing the burden on patients because only a single-dose gluten challenge and minimal amounts of blood for testing are needed.
Overall, the study provides “a preliminary framework for rational design of a gluten challenge for celiac disease research,” the study says.
Results demonstrated that each of the biomarkers showed responses dependent on the amount of gluten and the time frame used, giving researchers a range of options based on the design of a clinical trial.
“Different research focuses on different aspects of celiac disease,” Leffler said. “Some [studies] look at intestinal damage, some at symptoms, some at white blood cells. This provides data to guide how to most efficiently study these issues so that we are asking patients who participate in research to have the minimal amount of gluten necessary for the study to be successful and help us better understand celiac disease.”
While the main study conclusion was related to celiac disease research, the biomarkers evaluated could also be used for diagnosing patients, the authors noted. For example, the study says, those who have already started a gluten-free diet could first be tested for the genes associated with celiac disease.
If the test is positive, they could be given a single-dose gluten challenge, followed by measurement of IL-2 four hours later. Patients with no IL-2 response would be unlikely to have celiac disease. If IL-2 is positive, further confirmatory testing for gluten-specific response by T-cells could be done in six days or a 14-day gluten challenge followed by a biopsy could be used.
Currently, use of IL-2 for diagnosis is most promising in people who are already gluten-free and are given a gluten challenge, Leffler said.
Additionally, the study provided some evidence that video capsule endoscopy could, in some cases, replace the traditional endoscopy with biopsy. In video capsule endoscopy, you swallow a vitamin-size capsule that contains a tiny wireless camera, according to the Mayo Clinic. As the capsule travels through your digestive tract, the camera takes thousands of pictures that are transmitted to a recorder you wear on a belt around your waist. The camera is expelled from the body after a bowel movement.
It is less invasive than an endoscopy, which often requires some sedation to allow your doctor to snake a thin tube through the mouth to the small intestine. There, a small tool is used to take four to eight biopsy samples from the intestinal wall.
Study limitations include the small sample size and the fact that study participants were demographically similar. They also had a significant amount of intestinal damage prior to the gluten challenge. “These issues highlight that confirmation of these results in other populations is important,” the study says. Authors note that including study participants with better treated celiac disease and children are among goals for future confirming research.
You can read more about the study here.