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Bold Beyond Research Symposium experts focus on need for participation in celiac disease studies 

 By Amy Ratner, Medical and Science News Analyst

Patients who would like to see something more than the gluten-free diet to treat celiac disease have been looking to researchers for answers for years.

But at the recent Beyond Celiac Research Symposium experts said patients themselves hold the key to developing a drug, vaccine or other option that can halt symptoms and intestinal damage suffered when those who have the disease consume gluten.

“If those who have celiac disease don’t participate in research, we will go nowhere. We can’t do research in celiac disease if we don’t have co-operation across the spectrum of individuals who have celiac disease,” Ciaran Kelly, M.D., director of the Celiac Center at Beth Israel Deaconess Medical Center, told a symposium audience of 1,700. “It’s an absolute essential. Without it we might as well go home.”

The symposium audience included those who attended the event at Drexel University in Philadelphia and those who tuned in from five continents via live webcast.  Alice Bast, Beyond Celiac CEO, moderated.

Watch the Bold Beyond Research Symposium webcast

“You can have all the money in the world and the smartest people (working on celiac disease), but if people don’t show up you aren’t going to go anywhere,” agreed Daniel Leffler, M.D., medical director, clinical science, gastroenterology, Takeda Pharmaceuticals, USA Inc.

Kelly, a member of the Beyond Celiac Board of Directors, and Leffler, a member of the organization’s Scientific/Medical Advisory Council, were participants in the symposium panel along with advisory council members Anthony J. DiMarino, Jr., M.D., chief, division of gastroenterology & hepatology, Thomas Jefferson University Hospital, and Ritu Verma, M.D., section chief, gastroenterology, The Children's Hospital of Philadelphia. They tackled issues in celiac disease treatment that ranged from misconceptions about how complete a treatment the gluten-free diet really is, to lack of funding for research, to the path research is taking to find treatment targets.

Why me?

The symposium started by addressing a question posed by celiac disease patients, “Why me?”

Celiac disease has a genetic requirement of immune molecules that  present gluten to the body as if it is a threat, and the body reacts to the threat by causing inflammation, Kelly explained.  Still, only about 1 in 40 people with the genetic predisposition ever develop the disease. A key unknown is what activates the immune system and makes it respond to gluten. The answer to that question would enable researchers to develop targets for treatment that would prevent or block the reaction, Kelly added.  

Parents who ask why their children get celiac disease often feel guilty, Verma said. “They wonder, 'Did I do something wrong during pregnancy,'" she said. “'And can I prevent it so my next child won’t get celiac disease.'”

Leffler said everyone goes through a lifetime of insults to their intestinal system, and in those who have the genes for celiac disease, that “roulette” may eventually lead to development of the disease. “It may not be one thing,” he said.

What the future holds

Panelists were optimistic that this and other questions are getting closer to being answered. And they offered their vision of the future for those who have celiac disease.

DiMarino said he is optimistic one of the approaches now being investigated by scientists, including breaking gluten down before it’s ingested, keeping it from being absorbed by the digestive system, and modifying the  immune system, will be successful as a treatment in addition to the gluten-free diet.

Although Kelly acknowledged that researchers have been saying a treatment will be available in five years for about 10 years, he predicted an agent that treats celiac disease in addition to the diet will become a reality in the 2020s.

Beyond that, he said it’s likely scientists will discover an intervention that prevents celiac disease from occurring in children and young adults or, if it has already occurred, turns around the mistake made by the immune system and stops it from “getting so annoyed with gluten.”

“I’d like to see people with celiac disease live a life as healthy and unburdened as someone who does not have it,” Leffler said. “It does not have to be fancy science to make that happen. It’s a goal we should share and feel is realistic.”

His hope is that celiac disease will be treated much like thyroid disease is treated now. Every doctor knows to test for it. There are not a lot of undiagnosed cases and it is treated effectively without impacting the rest of a patient’s life, he explained.

Verma, whose focus is pediatrics, emphasized the importance of family screening for children. “Screening has to be done because there is a higher risk for other autoimmune diseases,” she said. “If we diagnose celiac disease earlier in young children we will cut down on other autoimmune diseases.”

Gluten-free diet misconceptions

Meanwhile, researchers studying celiac disease today are challenged by the misconception that the gluten-free diet is all patients need, lack of National Institutes of Health (NIH) funding and patients’ decreased willingness to participate in research.

Leffler said celiac disease is evolving from the days when physicians didn’t think celiac disease existed in the America, to a point where they acknowledged it’s as common here as in other parts of the world, but also believed that if someone were put on a gluten-free diet they were perfectly fine.

Now that view is changing as a result of studies that show patients are unwell enough that it compromises their daily lives.  “Outside of living in a bubble, it is impossible to be gluten-free enough to have full health as someone living with celiac disease in the modern world,” he said. “The falsehood that the gluten-free diet is all you need…is the next part of the story that needs to be told.”

Early on, physicians were the ones being asked if the diet was all that was needed, not patients, Kelly added. “That was the sea change,” he said. “You stopped asking the experts if it was enough and started asking the people who were self treating if it was enough, and they said, ‘No, we would actually like something more.’”

One of the reasons the diet is so hard to follow is that there is “no such thing” as 100 percent gluten-free diet, Leffler said, noting that a focus on trying to achieve a completely gluten-free diet is misplaced. “The goal is to make the patient well, not to make the diet strict,” he said. That’s best achieved by setting targets, including intestinal healing, normal growth, being nutritionally complete and avoiding osteopenia and osteoporosis. “If we are hitting those targets, that’s the goal,” he said.

DiMarino said the initial dramatic improvement that many patients experience when they are diagnosed and begin the diet contributes to the belief that the diet is a complete treatment. Still, he said, 30 percent of patients continue to have symptoms or intestinal damage. And 30 to 40 percent of patients drop the diet because it is too difficult, with more men giving up than women.

When the first company interested in developing a drug for celiac disease launched a clinical trial and was seeking a financial partner, the reaction it received was, ‘Why are you asking for money when you already have a great cure and it’s all about the gluten-free diet?’” DiMarino said.

Squeaky wheel gets funding

“Celiac disease has been the poor step child” among gastrointestinal diseases when it comes to funding by the NIH, Leffler said, pointing to a review of NIH data that he recently published. He found that celiac disease gets the lowest number of NIH grants among gastrointestinal conditions, typically being awarded only one or two in a good year. “It was a little depressing. There was no trend it was going to change,” he said. He urged the celiac disease community to get involved in pushing for more NIH dollars.

“Funding is not all based on science. Some funding is based on being the squeaky wheel. This is a stoic community that does not like to complain,” he said. “The celiac disease community could benefit by being more vocal about the struggles of everyday life living with celiac disease to everyone from your primary care physician to your senator.”

Inflammatory bowel disease (IBD) is an example of the way an active patient community can impact funding and consequent treatment options, according to Kelly. He said the IBD community has built strong philanthropy and research networks that are used to leverage funding from NIH.  “They have a plethora of new drugs to treat inflammatory bowel disease,” he said. “There is a lesson to be learned that we can all do better in putting our case forward for research in our disease.”

Despite low levels of federal funding, there has been an increased interest in clinical research of celiac disease from academic scientists, which has drawn investment from pharmaceutical companies, Kelly said.

“Pharma has realized there is a need for new approaches to the management of celiac disease and has begun to devote resources,” Kelly noted, calling this a very important development in celiac disease research in the past five years.

Path to new treatment

Additionally, there has been progress both in the Food and Drug Administration’s (FDA) understanding of the needs of celiac disease patients and in researchers’ understanding of what the FDA requires for approval of the first drug or drugs to treat a disease.

“For a pharmaceutical company to invest, they have to see a way they can actually get approval for an agent.,” Kelly said. The FDA has been forthcoming in finding a pathway that everyone can agree upon for research and testing.”

DiMarino said meetings with the FDA have resolved issues with the stringent and difficult requirements the FDA had set for a drug for celiac disease treatment. Researchers can now use new parameters that will be useful in achieving drug approval, he said.

Meanwhile, researchers have learned how to do good clinical trials, Leffler said, having gone through the necessary process of trial and error of in earlier investigations. “We can now do good, robust therapeutic studies,” he said.

Symposium panelists acknowledged that patients worry about the risks of participating in clinical trials.

They noted that even as the number of diagnosed patients has grown, it’s become more difficult to find those willing to volunteer because a completely gluten-free diet has been widely promoted and studies often involve consuming some amount of gluten.

Verma said this is especially true in pediatrics, where it is difficult for parents to dive into research participation. She said parents themselves might agree to consume a little gluten, but to give gluten to a child is “a different ballgame.”

Pediatric gastroenterologists have to be brought on board first and educated about safety in research, according to Verma. Additionally, researchers need to find out what children, particularly teenagers, want from research compared to what parents want. “When you talk to the teenagers they want that pill, but the parents say, ‘Oh, no. We don’t need that for you.’”

It’s important for patients to know that safety is built into clinical studies, which require approval from an Institutional Review Board, DiMarino said. While study participants sometimes do have to consume gluten, and some get a placebo instead of the drug designed to prevent symptoms and intestinal damage, its usually a relatively low amount for a limited amount of time.

“There is a risk you will feel uncomfortable, but it won’t do long-term harm,” he explained.

Leffler noted it was not too long ago that a gluten challenge was a routine part of confirming diagnosis of celiac disease. The challenge sometimes involved eating gluten for months. In the end, even children who had been sick at diagnosis and later went through the challenge were fine, he said. Leffler calculated that the risk for an adult to go on a gluten-containing diet for a few weeks under close monitoring is “virtually zero.”

A break-through in celiac disease research also has the potential to impact other autoimmune diseases. “Celiac disease is special because we know the environmental trigger, which is gluten,” Kelly said. “We know a lot about how celiac disease develops. If we can identify the targets, we can work to break the sequence of the disease.” Other diseases in which the processes are not as well understood can benefit from advances in celiac disease," he said.

Risks of undiagnosed celiac disease

The most controversial topic of panel discussion was whether there should be screening to detect undiagnosed celiac disease in those who don’t have symptoms, particularly first-degree family members who are at greater risk of developing the condition.

Panelists agreed that for children screening is needed because it is harder to be sure of symptoms and because undiagnosed celiac disease can cause irreversible changes as the child grows and develops.

But Kelly questioned whether screening is always needed in asymptomatic adults who have risk factors.

On one hand, those patients could develop nutritional deficiencies, osteoporosis and cancer, he said. On the other, a positive result means “you give someone who thought they were healthy a chronic, incurable, autoimmune disease, and they have to decide what to do about the diet," Kelly noted. “You have to balance what is the proven benefit versus the known negative of giving someone a disease,” he explained. “The jury is out on that balance, and there is no point to screening if the patient has already decided they are not going on the diet.”

Even those who feel fine and question why they should follow the gluten-free diet may reconsider when they think about any related increased risk for certain kinds of cancer, Kelly noted, saying its often the deal breaker.

The best study has shown that while there is an increased cancer risk in untreated patients, it is relatively small, he said. In the general population, the risk is 10 percent compared to 13 percent for those who have undiagnosed celiac disease. “That 3 percent difference is enough for some people to say, 'I will follow the diet,' and for others to say, 'I will take my chances,'” Kelly said.   

Bone health is a concern when celiac disease goes undetected, DiMarino said. “If you are a man and you have osteoporosis at 40, as far as I’m concerned you have celiac disease until proven otherwise,” he said. If you have one autoimmune disease you are at risk of others, he added.

Likewise, the weight of evidence shows that undiagnosed women have an increased risk of pre-term delivery and spontaneous miscarriages, according to DiMarino.

Unexplained infertility can also be associated with undiagnosed celiac disease, Leffler said. He called for routine celiac disease testing for all women who have unexplained infertility. “It’s a cheap test. Even if celiac disease is  not the cause of infertility, in a young woman’s life, because of bone density and anemia, why would you not take the opportunity to figure that out? If does not make clinical sense,” he said. “It’s the perfect opportunity to catch a high-risk population and make a huge impact for the rest of their lives. Let’s not wait for another study. Let’s just do it.”

Bold Beyond Symposium and Go Beyond Celiac

The Bold Beyond Research Symposium was the first presented by Beyond Celiac as part of its mission to advance research to find a treatment and, eventually, a cure for celiac disease. The Go Beyond Celiac platform and patient registry was designed to further that mission by capturing celiac disease patients’ stories and data and connecting patients with scientists studying celiac disease. You can participate by signing up at Go Beyond Celiac.

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