In a setback for Danish drugmaker Genmab, topline results from a Phase 3 study showed combining the company’s drug Arzerra with bendamustine did not improve progression-free survival in indolent non-Hodgkin lymphoma (NHL) compared to bendamustine alone.
Arzerra is marketed under a collaboration agreement between Genmab and Novartis, and is approved for chronic lymphocytic leukemia in the U.S. and Europe. The Phase 3 study testing the drug in NHL was sponsored by Novartis.
A subcutaneous formulation of Arzerra is also under investigation in two Phase 3 clinical studies in relapsing multiple sclerosis. These trials of Arzerra are not affected by the NHL results, Genmab said.
Genmab has sought new indications for Arzerra (ofatumumab), its first marketed product, as the drug is facing increasing competition in the chronic lymphocytic leukemia (CLL) market.
In light of this competition, Genmab’s marketing partner Novartis already has pulled Arzerra from markets outside the U.S. except for compassionate use.
Net sales of Arzerra recorded by Novartis were $36 million in 2017, down 22% from $46 million in the year prior. Genmab’s royalty income on net sales of Arzerra was DKK48 million (approximately $7.5 million) in 2017 compared with DKK63 million (approximately $9.9 million) in 2016.
“We are disappointed that the ofatumumab treatment regimen did not meet the primary endpoint in this trial,” said Jan van de Winkel, CEO, Genmab said in a statement. “The full data will be submitted for publication at a future medical conference and we hope that these will provide a better understanding of this result.”
It’s not clear, however, whether development of Arzerra will continue in NHL.
Genmab has already faced setbacks in Arzerra in NHL and Jefferies equity analyst Peter Welford had only projected $150 million in peak sales.
Elsewhere, in relapsing multiple sclerosis (RMS), recruitment has completed in two Phase 3 trials of a subcutaneous formulation of Arzerra in comparison with teriflunomide. Phase 2 results from the MIRROR study showed the treatment reduced the number of new lesions 12 weeks after starting treatment in people with relapsing multiple sclerosis.
Covered California is putting hospitals on notice to hit specified safety and quality goals or risk losing out in the state’s Affordable Care Act insurance exchange market, WBUR reports.
Specifically, California’s ACA marketplace is telling participating health plans to exclude hospitals that don’t hit certain goals from in-network status. Those goals include performing fewer unnecessary cesarean sections, prescribing fewer opioids and reducing the use of X-rays and other imaging to diagnose and treat back pain.
“We’re saying ‘times’s up,’” Lance Ling, chief medical officer for Covered California, said. “We’ve told health plans that by the end of 2019, we want networks to only include hospitals that have achieved those targets.”
The threat should get hospitals’ attention. Tying quality measures to payment size is one thing, but this links performance on specific metrics with even being in a network.
Unnecessary or inappropriate care is a huge problem. The U.S. wastes about $200 billion a year on excess medical tests and treatment, contributing to some 30,000 deaths due to errors and injuries.
C-sections have been on the radar for years. In the past decade, the U.S. rate of C-section births has climbed by 50%, and today a third of all babies have a surgical birth, according to the California Health Care Foundation. Unnecessary C-sections are a concern not just for their cost, which tends to run about 50% higher than a vaginal delivery, but because there is a greater chance of major complications for the mother and baby.
Covered California’s plan may have been influenced by Smart Care California, which launched the Choosing Wisely program last year to reduce medical waste by promoting safer, more cost-effective care. The coalition is initially focused on reducing elective C-sections, opioid use and treatment for patients with lower back pain.
But despite widespread agreement that unnecessary care is bad for patients and hospitals, change has been slow. An analysis in Health Affairsearlier this year found physicians often resist Choosing Wisely recommendations out of concern about malpractice, patient demand and satisfaction and a desire for more information to reduce uncertainty. In one study, 85% of physicians said they fear of malpractice led to overtreatment.
Clinicians should do more to identify premature infants that are at low risk of developing sepsis to prevent unnecessary antibiotic exposure, which has been associated with increased risks of death, according to a new study.
One in 90 very-low-birth-weight infants develop sepsis, and it can kill up to 50% of the babies born between 22 and 24 weeks that develop the infection. But an analysis published Friday in JAMA Network Open found many infants receive antibiotics without evidence of an infection, which can put them at risk for a host of adverse health outcomes, including acquiring antimicrobial-resistant infections, chronic lung disease, necrotizing enterocolitis or death.
“Although very-low-birth-weight premature infants are at higher risk of early-onset infection compared with term-born infants, we found an overall rate of antibiotic initiation that was an order of magnitude higher than the actual incidence of infection,” the study concluded.
The study authors analyzed more than 40,000 inpatient encounters involving premature infants at nearly 300 academic and community hospitals between January 2009 and September 2015.
More than 61% of the centers studied started antibiotic therapy for more than three-quarters of infants who weighed less than 3.3 pounds at birth.
But physicians didn’t change their prescribing patterns from January 2009 through September 2015 despite increased hospital efforts to improve antibiotic stewardship, according to the study. Providers administered antibiotics to 78% of very-low-birth-weight infants within 3 days of birth and 87% of infants with extremely low birth weight, defined as being under 2.2 pounds. More than a quarter of very-low-birth-weight infants and more than one-third of extremely-low-birth-weight infants were exposed to antibiotics for more than five days, which is considered prolonged.
In an accompanying editorial, Dr. Matthew Bizzarro, medical director of the Neonatal Intensive Care Unit at Yale University School of Medicine, wrote that the analysis’ findings and other studies seem to show clinicians aren’t identifying and treating premature infants at high risk for developing sepsis accurately.
“It is therefore the responsibility of individuals who prescribe antibiotics to premature infants to ensure, to the best of their ability that treatment is only administered to those who need it,” Bizzarro wrote.
Study author Dr. Dustin Flannery, a Perinatal-Neonatal Medicine fellow at The Children’s Hospital of Philadelphia, said there is little guidance on early antibiotic use in premature infants. He said more research is needed to “refine the approach” to early onset sepsis risk assessment in premature babies.
Many clinicians preemptively administer antibiotics to premature infants as a means of staving off infections such as sepsis, pneumonia; infection of the fluid that surrounds the brain, meningitis, skin and urinary tract infections because they have underdeveloped immune systems that make them susceptible to a number of pathogens.
But questions have been raised about whether that practice may do more harm than good. A 2016 study published in the journal Nature Microbiology found evidence of antimicrobial-resistant bacteria residing in the gut of premature infants that has raised calls for shorter courses of antibiotic treatment and limiting the number of antibiotics given to premature infants.
In 2001, 8% of the 4.6 million infant stays nationwide were for pre-term birth or low birth weight, according to a 2017 study published in the journal Pediatrics. The costs associated with admissions totaled $5.8 billion, representing 47% of the costs for all infant hospitalizations and 27% for all pediatric stays.
Blue Cross & Blue Shield of Illinois plans to cut Medicaid reimbursement rates by 35% for medical suppliers—apparently an effort to win back business after new enrollees were blocked from the state’s revamped Medicaid managed care program.
The proposed cuts, starting Jan. 1, 2019, cover durable medical equipment—wheelchairs, ventilators and oxygen tanks, for example.
According to a letter this month seeking an amended agreement from providers by June 1, Blue Cross is asking for a payment cap equal to no more than 65% of the state’s Medicaid reimbursement rate.
Blue Cross wouldn’t discuss the letter’s details, but in a statement today it said, “We’re looking to evolve our provider network to better serve our members and realign provider reimbursements to bring us more in line with industry standards.”
Last month Medicaid overseer Illinois Department of Healthcare & Family Services barred enrollment to Blue Cross just as Medicaid recipients are choosing providers under a revamped managed care system called HealthChoice Illinois. It debuted Jan. 1 and rolled out statewide three months later.
Blue Cross was displaced as the insurer with the largest number of enrollees in HealthChoice Illinois as of April 1. Its enrollment increased 8.5%, to 469,384, while regional carrier Meridian Health Plan’s soared by 27.5% to 546,663.
Total enrollment was up even more, by 30%, to 2,249,704, according to state enrollment data, buttressed by a 67% surge in IlliniCare’s numbers to 341,300. CountyCare, owned and operated by the Cook County Health & Hospitals System, reported flat enrollment, at 332,243.
HFS, which also fined Blue Cross $150,000, said the insurer failed through its network of doctors and hospitals to provide enough patient access, while inadequately addressing a backlog of grievances and appeals from its enrollees.
In a statement at the time Blue Cross said it was “committed to making the necessary investments and improvements in technology, process, staffing and training to provide long-term solutions to meet the needs of all our (Medicaid) members.”
The letter to providers from Christa Mitchem, manager of auxiliary contracting, said that Blue Cross seeks to ensure that reimbursement amounts for member services “promote a stable and sustainable Medicaid program.”
In a statement in November IlliniCare said the carrier works “with our providers and vendors to align with the Medicaid program and be good stewards within its financial structure.”
After years of unquestioning praise, Theranos was exposed due to WSJ reporter Carreyrou’s dogged reporting. His new book, Bad Blood, tells the full story.
The Theranos story got everyone’s attention because it involved all the ingredients for a classic drama—hubris, greed, big personalities, and fraud. The blood-testing tech startup’s rise and fall, from a $9 billion valuation and CEO Elizabeth Holmes posing for magazine covers to revelations that its technology didn’t work and being targeted with multiple federal and state investigations, is by now legendary. But the story wouldn’t have been told without the reporting of the Wall Street Journal‘s investigative dynamo John Carreyrou, who doggedly asked the tough questions that punctured the unicorn’s facade and exposed Holmes’s lies.
Carreyrou tells the tale in his new book, Bad Blood: Secrets and Lies in a Silicon Valley Startup, which goes on sale on Monday, May 21, and has been optioned for a feature film starring Jennifer Lawrence and helmed by The Big Short director Adam McKay. I talked with Carreyrou about how he first suspected that Theranos might not live up to the hype and what he advises journalists and investors in approaching Silicon Valley’s freshest and shiniest startups. Fast Company: What made you first suspect that something might be a little fishy about Theranos? John Carreyrou: The absolute first tip-off was reading the Ken Auletta profile in the New Yorker. Even though [Elizabeth Holmes] had risen to fame six months prior, she only got on my radar screen with that story.
I read it with interest and some of the details struck me as off—one of them was that she’d dropped out of Stanford after only a year and a half to start a medical startup. And I thought that was weird. You can do that with computer stuff but not really with science and medical research. And another thing was the absence of peer review publications, which Ken Auletta to his credit pointed out. And also her quote summarizing how the technology worked. I thought that was ham-handed.
But to be fair, I probably wouldn’t have done anything if I hadn’t been approached by Adam Clapper, a blogger who’d written a short skeptical item pegged to the New Yorker story. And [inventor-entrepreneur] Richard Fuisz got in touch with him and the Fuiszes had him talk to [Stanford professor of medicine] Phyllis Gardner and he was like, “Wow! This is indeed interesting but it seems kind of second-hand.”
I had the same reaction—this is all interesting but I need a primary source. The game was to get to the lab director who had just left the company, and getting him to talk to me on deep background was hard. He was terrified, and then it was all about getting corroboration.
FC: What is your advice for journalists covering Silicon Valley, where there is so much cheerleading by the media? JC: Everyone out there covering the Valley should have some healthy skepticism and not fall into the trap of cheerleading all the time. I think that Silicon Valley has become one of the most fascinating beats in the country. If you’re a journalist today, it’s really become an important part of the American economy—all this innovation but all this pretending and rule-breaking and these larger-than-life personalities. It’s a fascinating beat. I would love, if I were a young reporter in the early part of my career, I would really be happy to cover Silicon Valley. FC: What questions should investors be asking of startups like Theranos? JC: People like Larry Ellison and Tim Draper invested in companies like Theranos when they’re just starting out. The odds are that most will fail and maybe a few will do okay and one will really hit it big. That equation isn’t going to change.
The Theranos story is a lesson for investing when startups are at a later stage. Theranos raised most of hits money when it was over 10 years old. You need to do due diligence: What happened in the previous 10 years? What are the revenues and profits and the CFS [consolidated financial statement]. Investors didn’t ask for the CFS or asked for it and were rebuffed. FC: That’s amazing that some didn’t ask for something as basic as the CFS.
JC: What Holmes did very successfully was that she positioned Theranos as a classic tech company and investors allowed her to do that. In tech, maybe you need to do less digging and less forensic due diligence because it comes down to programming and coding. But actually, Theranos was first and foremost a medical technology company—that involves medical research and science.
Those investors who came in after 2013 allowed her to make them forget that. They should have been asking those questions, hiring scientific consultants to ask how she had solved problems in physics and chemistry that thousands of researchers had struggled to do. FC: Have investors learned their lesson? Are they asking those questions now? JC: Right now, there’s a convergence of traditional tech and medicine in the Valley and that’s a trend that will only increase.
The medical industry can only benefit from the boldness and imagination of Silicon Valley. But people need to always remember that as soon as you enter the medical realm you have the lives of patients at stake. You have to be transparent with your science.
There is no science without peer review. People who know a thing or two about science need to be able to verify.
And regulation—there’s a reason that the medical industry is the most tightly regulated industry in the country.
https://bit.ly/2LfXwuh
The discovery of the first human retrovirus in 1980 was a minor scientific sensation. Researchers knew retroviruses—which transcribe their RNA genome into DNA and integrate it into a host cell’s genome—existed in animals. But until Robert Gallo, then at the National Cancer Institute in Bethesda, Maryland, found the human T-cell leukemia virus-1 (HTLV-1), some doubted that retroviruses infect humans. HTLV-1 was soon eclipsed, however, by another retrovirus that would go on to kill more than 35 million people and keep generations of scientists busy: HIV. “If you were working on retroviruses you switched to HIV,” says epidemiologist Antoine Gessain of the Pasteur Institute in Paris.
But in a 10 May open letter to World Health Organization (WHO) Director-General Tedros Adhanom Ghebreyesus, Gallo and 59 other virologists, epidemiologists, and patient advocates call for a global effort to eradicate HTLV-1, which infects millions and causes cancer and several other diseases. Just like HIV, HTLV-1 spreads through blood, semen, and breast milk, and the letter argues that the testing and prevention strategies used against HIV should be employed to stop HTLV-1.
HTLV-1 is nowhere to be found among the many dozens of diseases on fact sheets on WHO’s website; it’s not recognized as a neglected tropical disease and isn’t on WHO’s list of sexually transmitted diseases either. “I still scratch my head about how we managed to stay on the margins of HIV and of sexual health,” says Graham Taylor, who studies HTLV-1 at Imperial College London.
The virus probably jumped from monkeys to humans somewhere in Africa tens of thousands of years ago; the slave trade helped spread it around the world. Today, scientists estimate that 5 million to 10 million people are infected, but the real number is probably much higher, Taylor says. One hot spot is southern Japan, where up to 6% of pregnant women have been found to carry the virus. But poor countries are most affected, which partly explains the neglect, Gallo says. In Jamaica and other Caribbean islands, about 6% of the entire population may carry the virus. Parts of Brazil have high rates, millions are infected in Africa, and in some aboriginal communities in Australia, almost half the people over age 50 are infected, a recent study found. Europe and the United States can’t rest easy, Taylor says: “If we are not careful, this could become more prevalent in our communities without us being aware. … As other infections like HIV come under control, people’s behavior may change.”
Most people infected with HTLV-1 never have symptoms, but about 3% to 5% develop adult T-cell leukemia, a cancer that kills patients after 8 to 10 months on average and for which treatment has not improved in the past quarter-century. Another 4% develop tropical spastic paraparesis, a disease similar to multiple sclerosis. Other inflammatory diseases and immune deficiency have also been reported, and an Australian study published in March showed that those infected with HTLV-1 are more likely to develop bronchiectasis, a disease in which parts of the airways are enlarged, and to die from it.
Yet HTLV-1’s modest death toll, and the decades that often go by between infection and disease, have kept it out of the limelight. In response to the letter, a WHO spokesperson pointed out that another virus, hepatitis B, causes more than 400,000 cancers each year worldwide. In contrast, the International Agency for Research on Cancer estimates that only 3000 cancer diagnoses annually are directly linked to HTLV-1. Taylor thinks the real number is higher, but he says, “I really don’t think this should turn into a ‘my disease is more important than your disease’ competition.”
Routine testing for HTLV-1 should be available in sexual health clinics everywhere, the researchers write in the letter, and mothers in endemic regions should routinely be screened for HTLV-1 and advised not to breastfeed if they are infected. Since antenatal testing was introduced in Japan’s Nagasaki region in 1987, the infection rate in the population has dropped from 7.2% to 1%. The letter also calls for universal HTLV-1 testing of blood and organ donors, because transplants have transmitted the virus, albeit rarely. “I honestly believe that nobody should have a transplant where the donor has not been tested for HTLV-1,” Taylor says. (Until 2009, the United States did screen organ donors, but the practice was stopped because false positive results were disqualifying too many healthy organs.)
Gallo believes renewed attention to HTLV-1 could have broader benefits. In the early 1980s, the virus sped up the discovery of HIV, he says, because it alerted scientists to the possibility that a retrovirus might be causing the mysterious new syndrome called AIDS. Today, a better understanding of HTLV-1’s powerful carcinogenic properties may lead researchers to new insights about cancer, Gallo says.
The patients weren’t crazy—Knut Lundin was sure of that. But their ailment was a mystery. They were convinced gluten was making them sick. Yet they didn’t have celiac disease, an autoimmune reaction to that often-villainized tangle of proteins in wheat, barley, and rye. And they tested negative for a wheat allergy. They occupied a medical no man’s land.
About a decade ago, gastroenterologists like Lundin, based at the University of Oslo, came across more and more of those enigmatic cases. “I worked with celiac disease and gluten for so many years,” he says, “and then came this wave.” Gluten-free choices began appearing on restaurant menus and creeping onto grocery store shelves. By 2014, in the United States alone, an estimated 3 million people without celiac disease had sworn off gluten. It was easy to assume that people claiming to be “gluten sensitive” had just been roped into a food fad.
“Generally, the reaction of the gastroenterologist [was] to say, ‘You don’t have celiac disease or wheat allergy. Goodbye,’” says Armin Alaedini, an immunologist at Columbia University. “A lot of people thought this is perhaps due to some other [food] sensitivity, or it’s in people’s heads.”
But a small community of researchers started searching for a link between wheat components and patients’ symptoms—commonly abdominal pain, bloating, and diarrhea, and sometimes headaches, fatigue, rashes, and joint pain. That wheat really can make nonceliac patients sick is now widely accepted. But that’s about as far as the agreement goes.
As data trickle in, entrenched camps have emerged. Some researchers are convinced that many patients have an immune reaction to gluten or another substance in wheat—a nebulous illness sometimes called nonceliac gluten sensitivity (NCGS).
Others believe most patients are actually reacting to an excess of poorly absorbed carbohydrates present in wheat and many other foods. Those carbohydrates—called FODMAPs, for fermentable oligosaccharides, disaccharides, monosaccharides, and polyols—can cause bloating when they ferment in the gut. If FODMAPs are the primary culprit, thousands of people may be on gluten-free diets with the support of their doctors and dietitians but without good reason.
Those competing theories were on display in a session on wheat sensitivity at a celiac disease symposium held at Columbia in March. In back-to-back talks, Lundin made the case for FODMAPs, and Alaedini for an immune reaction. But in an irony that underscores how muddled the field has become, both researchers started their quests believing something completely different.
Known wheat-related illnesses have clear mechanisms and markers. People with celiac disease are genetically predisposed to launch a self-destructive immune response when a component of gluten called gliadin penetrates their intestinal lining and sets off inflammatory cells in the tissue below. People with a wheat allergy respond to wheat proteins by churning out a class of antibodies called immunoglobulin E that can set off vomiting, itching, and shortness of breath. The puzzle, for both doctors and researchers, is patients who lack both the telltale antibodies and the visible damage to their intestines but who feel real relief when they cut out gluten-containing food.
Some doctors have begun to approve and even recommend a gluten-free diet. “Ultimately, we’re here not to do science, but to improve quality of life,” says Alessio Fasano, a pediatric gastroenterologist at Massachusetts General Hospital in Boston who has studied NCGS and written a book on living gluten-free. “If I have to throw bones on the ground and look at the moon to make somebody better, even if I don’t understand what that means, I’ll do it.”
Like many doctors, Lundin believed that (fad dieters and superstitious eaters aside) some patients have a real wheat-related ailment. His group helped dispel the notion that NCGS was purely psychosomatic. They surveyed patients for unusual levels of psychological distress that might express itself as physical symptoms. But the surveys showed no differences between those patients and people with celiac disease, the team reported in 2012. As Lundin bluntly puts it: “We know they are not crazy.”
Still, skeptics worried that the field had seized on gluten with shaky evidence that it was the culprit. After all, nobody eats gluten in isolation. “If we did not know about the specific role of gluten in celiac disease, we would never have thought gluten was responsible for [NCGS],” says Stefano Guandalini, a pediatric gastroenterologist at the University of Chicago Medical Center in Illinois. “Why blame gluten?”
Defenders of NCGS generally acknowledge that other components of wheat might contribute to symptoms. In 2012, a group of proteins in wheat, rye, and barley called amylase trypsin inhibitors emerged as a potential offender, for example, after a team led by biochemist Detlef Schuppan of Johannes Gutenberg University Mainz in Germany (then at Harvard Medical School in Boston) reported that those proteins can provoke immune cells.
Against the grain
Data from the National Health and Nutrition Examination Survey show the rising tide of gluten avoidance by people without celiac disease. Celiac diagnoses also rose, but probably not its actual prevalence.
But without biological markers to identify people with NCGS, researchers have relied on self-reported symptoms measured through a “gluten challenge”: Patients rate how they feel before and after cutting out gluten. Then doctors reintroduce gluten or a placebo—ideally disguised in indistinguishable pills or snacks—to see whether the symptoms tick back up.
Alaedini has recently hit on a more objective set of possible biological markers—much to his own surprise. “I entered this completely as a skeptic,” he says. Over his career, he has gravitated toward studying spectrum disorders, in which diverse symptoms have yet to be united under a clear biological cause—and where public misinformation abounds. His team published a study in 2013, for example, that debunked the popular suggestion that children with autism had high rates of Lyme disease. “I do studies [where] there is a void,” he says.
In NCGS, Alaedini saw another poorly defined spectrum disorder. He did accept that patients without celiac disease might somehow be sensitive to wheat, on the basis of several trials that measured symptoms after a blinded challenge. But he was not convinced by previous studies claiming that NCGS patients were more likely than other people to have certain antibodies to gliadin. Many of those studies lacked a healthy control group, he says, and relied on commercial antibody kits that gave murky and inconsistent readings.
In 2012, he contacted researchers at the University of Bologna in Italy to obtain blood samples from 80 patients their team had identified as gluten sensitive on the basis of a gluten challenge. He wanted to test the samples for signs of a unique immune response—a set of signaling molecules different from those in the blood of healthy volunteers and celiac patients. He wasn’t optimistic. “I thought if we were going to see something, like with a lot of spectrum conditions that I have looked at, we would see small differences.”
The results shocked him. Compared with both healthy people and those with celiac, these patients had significantly higher levels of a certain class of antibodies against gluten that suggest a short-lived, systemic immune response. That didn’t mean gluten itself was causing disease, but the finding hinted that the barrier of those patients’ intestines might be defective, allowing partially digested gluten to get out of the gut and interact with immune cells in the blood. Other elements—such as immune response–provoking bacteria—also might be escaping. Sure enough, the team found elevated levels of two proteins that indicate an inflammatory response to bacteria. And when 20 of the same patients spent 6 months on a gluten-free diet, their blood levels of those markers declined.
For Alaedini, the beginnings of a mechanism emerged: Some still-unidentified wheat component prompts the intestinal lining to become more permeable. (An imbalance in gut microbes might be a predisposing factor.) Components of bacteria then seem to sneak past immune cells in the underlying intestinal tissue and make their way to the bloodstream and liver, prompting inflammation.
“This is a real condition, and there can be objective, biological markers for it,” Alaedini says. “That study changed a lot of minds, including my own.”
The study also impressed Guandalini, a longtime skeptic about the role of gluten. It “opens the way to finally reach an identifiable marker for this condition,” he says.
But others see the immune-response explanation as a red herring. To them, the primary villain is FODMAPs. The term, coined by gastroenterologist Peter Gibson at Monash University in Melbourne, Australia, and his team, encompasses a smorgasbord of common foods. Onions and garlic; legumes; milk and yogurt; and fruits including apples, cherries, and mangoes are all high in FODMAPs. So is wheat: Carbs in wheat called fructans can account for as much as half of a person’s FODMAP intake, dietitians in Gibson’s group have estimated. The team found that those compounds ferment in the gut to cause symptoms of irritable bowel syndrome, such as abdominal pain, bloating, and gas.
Gibson has long been skeptical of studies implicating gluten in such symptoms, arguing that those findings are hopelessly clouded by the nocebo effect, in which the mere expectation of swallowing the dreaded ingredient worsens symptoms. His team found that most patients couldn’t reliably distinguish pure gluten from a placebo in a blinded test. He believes that many people feel better after eliminating wheat not because they have calmed some intricate immune reaction, but because they’ve reduced their intake of FODMAPs.
Lundin, who was firmly in the immune-reaction camp, didn’t believe that FODMAPs could explain away all his patients. “I wanted to show that Peter was wrong,” he says. During a 2-week sabbatical in the Monash lab, he found some quinoa-based snack bars designed to disguise the taste and texture of ingredients. “I said, ‘We’re going to take those muesli bars and we’re going to do the perfect study.’”
His team recruited 59 people on self-instituted gluten-free diets and randomized them to receive one of three indistinguishable snack bars, containing isolated gluten, isolated FODMAP (fructan), or neither. After eating one type of bar daily for a week, they reported any symptoms. Then they waited for symptoms to resolve and started on a different bar until they had tested all three.
Before analyzing patient responses, Lundin was confident that gluten would cause the worst symptoms. But when the study’s blind was lifted, only the FODMAP symptoms even cleared the bar for statistical significance. Twenty-four of the 59 patients had their highest symptom scores after a week of the fructan-laced bars. Twenty-two responded most to the placebo, and just 13 to gluten, Lundin and his collaborators—who included Gibson—reported last November in the journal Gastroenterology. Lundin now believes FODMAPs explain the symptoms in most wheat-avoiding patients. “My main reason for doing that study was to find out a good method of finding gluten-sensitive individuals,” he says. “And there were none. And that was quite amazing.”
At the Columbia meeting, Alaedini and Lundin went head to head in consecutive talks titled “It’s the Wheat” and “It’s FODMAPS.” Each has a list of criticisms of the other’s study. Alaedini contends that by recruiting broadly from the gluten-free population, instead of finding patients who reacted to wheat in a challenge, Lundin likely failed to include people with a true wheat sensitivity. Very few of Lundin’s subjects reported symptoms outside the intestines, such as rash or fatigue, that might point to a widespread immune condition, Alaedini says. And he notes that the increase in patients’ symptoms in response to the FODMAP snacks was just barely statistically significant.
Lundin, meanwhile, points out that the patients in Alaedini’s study didn’t go through a blinded challenge to check whether the immune markers he identified really spiked in response to wheat or gluten. The markers may not be specific to people with a wheat sensitivity, Lundin says.
Despite the adversarial titles of their talks, the two researchers find a lot of common ground. Alaedini agrees that FODMAPs explain some of the wheat-avoidance phenomenon. And Lundin acknowledges that some small population may really have an immune reaction to gluten or another component of wheat, though he sees no good way to find them.
After the meeting, Elena Verdù, a gastroenterologist at McMaster University in Hamilton, Canada, puzzled over the polarization of the field. “I don’t understand why there is this need to be so dogmatic about ‘it is this, it is not that,’” she says.
She worries that the scientific confusion breeds skepticism toward people who avoid gluten for medical reasons. When she dines with celiac patients, she says, waiters sometimes meet requests for gluten-free food with smirks and questions. Meanwhile, the conflicting messages may send nonceliac patients down a food-avoidance rabbit hole. “Patients are withdrawing gluten first, then lactose, and then FODMAPs—and then they are on a really, really poor diet,” she says.
But Verdù believes careful research will ultimately break through the superstitions. She is president of the North American Society for the Study of Celiac Disease, which this year awarded its first grant to study nonceliac wheat sensitivity. She’s hopeful that the search for biomarkers like those Alaedini has proposed will show that inside the monolith of gluten avoidance lurk multiple, nuanced conditions. “It will be difficult,” she says, “but we are getting closer.”
