According to legend, celiac research originated with Dr. Willem Dicke. He discovered the cause of celiac during the 1944-’45 Dutch famine under German occupation. He noticed children recovering on a starvation diet, then falling sick after bread was airdropped into Holland. Dicke conducted clinical trials for years, asking parents to remove one food or another from their children’s diets. The famine confirmed what he already knew: something in wheat, barley and rye was the culprit.
“That was one of the huge breakthroughs in celiac disease: identifying an environmental factor that drives the immune disease,” says Ciarán Kelly, MD, medical director of the celiac center at Beth Israel Deaconess Medical Center in Boston. “With most autoimmune diseases, we do not know what the environmental factor is.”
Celiac offers a unique tool to study autoimmunity, explains Daniel Leffler, MD, director of clinical research at the celiac center: “We can control celiac disease by adding and removing gluten in a so-called gluten challenge study, a degree of control we have in very few other diseases.”
Celiac often killed children before Dicke solved the puzzle. Now most patients live full, healthy lives on a gluten-free diet.
However, not everyone recovers well. Strict gluten avoidance affects quality of life. Inability to follow the diet or accidental gluten exposure—getting “glutened”—can cause ongoing symptoms. In refractory celiac disease, intestinal damage persists despite strict adherence.
Unraveling autoimmunity and developing alternative therapies hinge on patients willing to participate in studies. Medical experts say research could move faster if people living with celiac took a more active role. Apparently they tend to suffer in silence even more than people with other diseases. The reason may be that they have frequently been misunderstood in the past.
Silent problem
“The diagnosis of celiac disease is not taken adequately seriously by the medical community,” says Kelly. “There is a false impression that once a patient is diagnosed and told to follow a gluten-free diet, it is a straightforward treatment that almost always works.”
Recent studies uncover a different story. Patients rate their overall health better than people with other chronic diseases but consider their burden of treatment higher. Many fear getting glutened, worry about food costs, avoid eating out and become socially isolated.
In 2014, patient advocacy group Beyond Celiac met leading researchers and asked what they needed to investigate a cure. Experts concluded that the No. 1 gap was a lack of data about people living with celiac.
“We don’t have a good understanding of the burden of the disease,” says Alice Bast, chief executive officer of Beyond Celiac. “We don’t understand the long-term health consequences. At this meeting, we determined that the most important contribution Beyond Celiac could make to accelerate research was to get patients’ participation.”
Leffler says, “Something about the disease, about the treatment thus far, has made people need to be understated, to not complain, to minimize or hide the disorder and not talk about how it affects their lives. I wish I knew the roots of this in celiac disease.”
Marilyn Geller, chief executive officer of Celiac Disease Foundation, explains, “Our community has been told that this is a disease not worth investing in. Congressionally funded medical dollars go to other diseases…. We have to convince policy experts and the biopharmaceutical industry we need treatment alternatives to the gluten-free diet.”
Referral bias
Much research about celiac in North America comes from a handful of major referral centers. Peter Green, MD, director of the Celiac Disease Center at Columbia University Medical Center, New York, says eight doctors there receive 10,000 visits per year, mainly celiac patients.
“This is a very self-empowered patient population seeking specialty expertise,” says Benjamin Lebwohl, MD, a clinician and researcher at Columbia. “A referral center also attracts patients having more difficulty, whether due to recurrent symptoms or a borderline diagnosis.”
Studies of these groups provide skewed data, a problem known as referral bias. Experts know little about the lives of many patients without access to a celiac center. They might rarely even see a doctor regardless of whether they flourish on a gluten-free diet or not.
Lebwohl says, “While we are proud of our research, we are unable to answer seemingly simple questions, such as what proportion of patients with celiac disease still have symptoms despite attempting to adhere to a gluten-free diet.”
Extending the community
To go deeper, celiac advocacy groups have launched patient registries. The Celiac Disease Foundation’s iCureCeliac and Beyond Celiac’s program Go Beyond Celiac have enrolled thousands.
Geller explains, “You go online and create an account. There are a number of questions that you complete regarding your health, from diagnosis to current experiences, not just the medical data points but also your opinion on how difficult it is to exist in this world with celiac disease.”
Participants provide data anonymously. Researchers can peruse the data for clues and patterns. Columbia University used iCureCeliac to investigate whether patients with depression are more likely to have trouble staying gluten free.
Investigators testing a new drug provide a profile of patients who meet criteria such as age or location. The Celiac Disease Foundation does not release contact information but informs everyone in the registry who is eligible to participate, Geller says. Each patient may then choose whether to contact the researcher.
The case for drugs
Registry data may convince larger drug companies to help look for a cure.
Linda Deal, head of patient-centered outcomes for Pfizer, Inc., and a member of Beyond Celiac’s board of directors, says, “Folks in my discipline are interested in understanding insights from the patient’s perspective, what is their journey with their disease.”
Stating she does not speak for Pfizer or Beyond Celiac, Deal says drug companies and the FDA must balance treatment benefits against risks. They must also ensure treatment could be made affordable and available.
“The sooner patients get listed in registries and have their consequences tracked, the sooner we will understand the cost of this disease to society,” Deal says.
No trivial undertaking
“The real bottleneck is patient involvement. If I have patients willing to work with me, I can find funding or ways to partner with industry,” Leffler says. “Participating in a clinical trial, while a rigorous process, gives patients a tremendous amount of information about themselves. Often trial participation involves undergoing measurements of symptom activity and [dietary] adherence, checking in with investigators.”
Kelly says, “While an individual may have a general openness toward participating, to actually take the time and effort may not be a trivial undertaking.”
Filling out a 20-minute survey is far less demanding than a 15-week trial. Patients have an opportunity to ask any and all questions before a trial and can opt out at any time.
“Trials of medications for celiac disease require that patients be exposed to gluten,” Lebwohl warns. “These gluten challenge studies, while critical, are not for everyone. Some people get very ill when exposed even to small amounts of gluten. Those studies can be difficult to recruit for.”
Such trials rely on a small number of volunteers to minimize harm. However, a larger group provides better statistical proof of the findings.
Leffler explains, “We typically err on the side of being a little large, but overpowering a study is not the right thing to do.”
“This is a transformational time for celiac disease,” says Leffler. “Finally, after a period of being stalled, we are getting a critical mass of scientific knowledge, numbers of diagnosed patients and effective advocacy to move celiac disease to a next level where the burden is lower and treatment outcomes are better. If you are in the celiac community and want to be engaged, I see these next five years as critical.”
