‘The debate over this mysterious disease is suddenly shifting’ | Julie Rehmeyer in ‘Slate’ | 13 November 2015

From Slate, 13 November 2015. Words by Julie Rehmeyer.

Last month, a team of researchers released their latest study on chronic fatigue syndrome. Psychotherapy and a gradual increase in exercise, the researchers claimed, were lasting, effective treatments that could lead to recovery. The study was an update of the largest treatment trial in CFS history, now with longer-term data.

That might sound like good news – but I knew these researchers’ past work very well, and it had only added to the misery of CFS patients like me. Back in 2011, I watched the headlines spread around the world when the team, funded by the British government, published the first results in the Lancet – while I was desperately ill in bed, reading the news on my phone, too weak to sit up to use my computer.

I – and a lot of other people with knowledge of CFS – couldn’t believe what we were reading. Psychotherapy had helped me keep my sanity while my body fell apart, but it had never made me less sick. And the hallmark symptom of the illness is that exertion can make patients much, much worse. I’d learned through hard experience that the only way I could exercise safely was to stop as soon as the thought “I’m a little tired” wafted through my brain. Walking five minutes yesterday was no guarantee I could safely walk six minutes today – and if I misjudged and overdid it, I’d be semi-paralyzed later.

But according to the theory underlying this psychiatric research, my problem was that I was out of shape, afraid of exercise, and obsessed about my symptoms. The path to wellness was to drop the idea that I had a physical disease and steadily increase my exercise, no matter how bad it made me feel.

Patients rapidly discovered serious scientific problems with the 2011 Lancet paper. Despite these errors, the study, known as the PACE trial, went on to inform recommendations from such influential bodies as the Centers for Disease Control and Prevention, the Mayo Clinic, and the British National Health Service. So the new follow-up study, I feared, seemed destined for a warm and uncritical reception from the medical establishment regardless of whether its findings were legitimate.

But just days before the new study was released, on Oct. 21, the San Francisco journalist David Tuller published a major investigation exposing deep methodological flaws in the entire PACE trial that put its validity in serious doubt.

And this time, the new study has been met with intense criticism from outside the world of patients and advocates. On Friday, six researchers, including prominent scientists such as virologist Vincent Racaniello of Columbia University and geneticist Ronald Davis of Stanford University, released an open letter to the Lancet demanding an independent review of the PACE trial.

“The whole study is unbelievably amateur,” says Jonathan Edwards, a biomedical researcher at University College London who signed the letter. “The trial is useless.”

The PACE trial has exerted a strong influence on American physicians: If you ask your doctor about CFS, odds are good you’ll hear that cognitive behavioral therapy (the flavor of psychotherapy used in the trial) and exercise are the only proven treatments for CFS.

The American scientific research community, on the other hand, has rejected the psychiatric model that PACE epitomizes and is instead looking for physiological explanations for the disease. Research efforts have been hamstrung, though, by scarce funding: the National Institutes of Health spends $5 million to $6 million a year on a disease that affects a million Americans. (For comparison, about the same number of people with HIV/AIDS, which receives $3 billion in NIH funding.)

Just two days after the follow-up PACE study was released, the NIH made the stunning announcement that it is starting a program to study CFS (which is also referred to as myalgic encephalomyelitis or ME/CFS) at the NIH Clinical Center in Bethesda, Maryland. Francis Collins, the director of the NIH, has also promised increased funding for universities to research the illness. “It will be substantially greater than the current $5 [million] or $6 million a year,” he told NPR. “We are going to ramp this up.”

After so many years of scarce funding, bad science, and uncritical journalism, the events of the past few weeks have left me feeling something I’ve never felt before about this illness: hope. It almost frightens me to say it, but we may be on the verge of clearing up the massive misunderstandings about this disease—and even of starting to figure the damn thing out.

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Questions about the 2011 Lancet paper emerged soon after the PACE team announced its first results at a press conference. One of the researchers said that, compared with other study subjects, “twice as many people on graded exercise therapy and cognitive behavior therapy got back to normal.” In a follow-up paper two years later, the researchers claimed that 22 percent of participants who received cognitive behavioral therapy or exercise on top of regular medical care “recovered” by the end of the trial.

But patients who analyzed the PACE trial and its follow-up studies discovered that these statements depended on a remarkably weak definition of “recovery”—one so weak that participants could enter the trial, get worse on two out of four criteria, and then be called “recovered.” These supposedly recovered patients could furthermore have poorer physical function than 92 percent of the British working-age population. And 13 percent of participants qualified as “recovered” on at least one of the criteria even before they received treatment.

Peter White, a psychiatrist at Queen Mary University of London and the lead PACE investigator, told me by email in late October that “some small overlap might be expected” between the criteria for entry into the trial and those for recovery, and he pointed out that there were two additional criteria. He didn’t, however, mention that those criteria were also weakened. When I inquired why such an overlap “might be expected,” he declined to answer further questions.

Starting in 2011, patients analyzing the study filed Freedom of Information Act requests to learn what the trial’s results would have been under the original protocol. Those were denied along with many other requests about the trial, some on the grounds that the requests were “vexatious.” The investigators said they considered the requests to be harassment.

The patients found many other problems as well. The study participants hadn’t significantly improved on any of the team’s chosen objective measures: They weren’t able to get back to work or get off welfare, they didn’t get more fit, and their ability to walk barely improved. Though the PACE researchers had chosen these measures at the start of the experiment, once they’d analyzed their data, they dismissed them as irrelevant or not objective after all. In addition, the patients researching the study found statistical errors, actions that might have pumped up the subjective ratings, measurement problems that allowed participants to deteriorate without being detected, conflicts of interest, and more.

The patients wrote detailed letters to the Lancet and other journals describing PACE’s scientific shortcomings. In responding, the researchers either didn’t address the core problems, dismissed them as unimportant, or accused the critics of being prejudiced against psychiatry.

Richard Horton, the editor of the Lancet, aggressively defended the trial. In a radio interview, he called the critics “a fairly small, but highly organized, very vocal and very damaging group of individuals who have, I would say, actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients.” He didn’t address the substance of the criticisms.

In the United States, ME/CFS researchers largely dismissed the PACE trial findings. Their research on the role of exercise in the illness has instead focused on unraveling the physiology of patients’ abnormal response to it. Multiple teams found that when patients exercise to exhaustion two days in a row, their performance drops dramatically the second day, as shown by physiological indicators that can’t be faked. Other researchers documented changes in how genes function in patients after moderate exercise.

Still, each time the PACE team publishes a new follow-up study, a flurry of ill-informed news coverage follows, including after the release last month. The Telegraph front page blared “Chronic Fatigue Syndrome Sufferers ‘Can Overcome Symptoms of [Myalgic Encephalomyelitis] with Positive Thinking and Exercise’: Oxford University has found ME is not actually a chronic illness.”

When I read the study itself, I quickly found that this headline went far beyond even the researchers’ claims – but I also saw that the researchers’ claims went far beyond their own data.

According to the researchers, their work proved that the purported improvements from cognitive behavioral therapy and exercise stood up over time. But what the data actually showed was that after 2½ years, the benefits of CBT and exercise had entirely vanished. The patients who hadn’t been assigned to those therapies had by then improved as much as those who had, though all groups were still sick.

The PACE researchers acknowledged this but discounted the significance of the improvement of the patients who hadn’t received therapy or exercise. They pointed out that some of these patients had received CBT or exercise after the trial had ended, and they argued that this might explain the improvement. However, their data showed that the additional therapy didn’t help these patients at all.

The reception of this new study among researchers was very different from in the past, in part because Tuller, a public health and journalism lecturer at the University of California–Berkeley, published his long story on the site Virology Blog just days before this latest study came out. His work persuaded researchers outside the ME/CFS community to scrutinize the study for the first time—and they condemned it. For example, James Coyne, a psychologist at the University Medical Center Groningen in the Netherlands, who was previously uninvolved in ME/CFS research, wrote a blog post for the Public Library of Science calling the researchers’ interpretation of their new study “unsubstantiated spin in favor of the investigators’ preferred intervention.”

And now researchers and patients are demanding that the PACE team release its data (with any patient-identifying information made anonymous), either publicly or to a team of highly qualified independent investigators, for re-analysis.

The PACE researchers have refused to release the data in the past, arguing that “activists seeking to discredit the PACE trial and its researchers” would somehow decrypt the anonymous details in the data and publish the names of participants. And White told me that the changes to the original protocol “improved the science and interpretation. We see no reason why we should do a further analysis based on an inferior method.” Horton, editor of the Lancet, didn’t respond to my request for comment.

“The Lancet needs to stop circling the wagons and be open,” says Bruce Levin, a biostatistician at Columbia University who signed the open letter. “One of the tenets of good science is transparency.”

Davis, the Stanford geneticist, has a son with ME/CFS so severe that he can’t walk, talk, or eat. Davis goes even further: “The Lancet should step up to the plate and pull that paper,” he says. “It has lots of flaws, and I worry that it hurts patients.” Davis has now started his own effort to find a cure for the disease, called the End ME/CFS Project. He is collecting a vast amount of data on severe patients like his son, who have almost never been included in studies because they are too frail to go to a doctor or clinic.

As encouraging as the public criticism of the PACE trial has been, only one thing is likely to excise the notion from the minds of doctors and the public that ME/CFS is a psychiatric condition: a truly effective treatment for the disease. My condition has improved remarkably after I pursued a treatment that has hardly been researched at all: taking extreme measures to avoid mold. But there hasn’t been the money to follow up on promising leads like that one and others.

That makes the NIH announcement of its research plans for the disease a huge step in undoing the damage PACE has caused. The NIH plans to analyze 40 patients whose illness began suddenly with an apparent infection, using big data methods. And if the NIH follows through on its promises for increased funding for research at universities, scientists like Davis will have new opportunities.

Just a year ago, both the public criticism of the PACE trial and the moves by the NIH were nearly unimaginable. But to me, these events feel like the fruits of change that’s been cultivated over years. When the PACE trial first came out in 2011, few journalists took serious interest in the disease, and much of the coverage was dreadful. Now, several journalists, in addition to Tuller, have been producing great work. In 2011, the cadre of dedicated researchers was tiny and isolated. Now, giants in their own fields have become fascinated by the illness. The patient community has long been divided and fractious, but now, platforms like #MEAction are supporting more united action, and patients are developing recommendations for research priorities, modeling their efforts on AIDS and breast cancer activists’ methods to earn respect and influence in the scientific community.

Coyne, the psychology researcher whose interest was sparked by the controversy over PACE, suggested on Twitter that PACE might be the ME/CFS Stonewall, and it does feel like I’m watching the emergence of a new movement.

Of course, there’s still a long way to go. Patients are still suffering, derided, and without treatment. But it no longer seems quixotic to anticipate the day when patients as sick as I was in 2011 won’t have their misery exacerbated by prejudice and bad science.

Julie Rehmeyer is a contributing editor to Discover who is writing a memoir on the science and politics of chronic fatigue syndrome and other poorly understood illnesses.