(Thanks to Nowegian journalist, Jorgen Jelstad, for allowing us to reproduce his article on Phoenix Rising. The original can be found here. The article first appeared in the InvestinME newsletter covering the 2012 London Conference)
“They soon found that new ideas aren’t always welcome in science – even if the old ones aren’t working.”
Switch off, switch on, The National, 2009.
2004: Patient zero
Anne Katrine walks into the Cancer Department at Haukeland University Hospital in Bergen in 2004 to get treatment against the lymphoma the doctors discovered one year earlier. After four rounds of chemotherapy the cancer seemed to be beaten, but suddenly it came back and she is in for her second treatment regimen.
Anne Katrine also has ME/CFS since she suddenly fell ill with mononucleosis in 1997. For several years she had mostly been housebound with muscle pain, problems with sleep and great cognitive difficulties. An overwhelming fatigue and malaise has made her unable to leave the house for more than short periods of time.
Five weeks after starting the new treatment against lymphoma, something unexpected happens. Suddenly she notices a marked improvement in all the ME/CFS symptoms that she has endured for more than seven years. She has never before experienced anything like this. Her teenage son had one time told her that he was not sure if he could manage to live with someone as sick as his mother. Now, they were able to go to Turkey together for the holidays.
But suddenly it all comes back. The headache, the aching muscles, the cognitive decline and the devastating fatigue and malaise. Back to scratch.
“When you had cancer, mom, we had the best dinners ever,” Anne Katrines daughter tells her after the relapse.
Sitting in his office at Haukeland University Hospital, cancer specialist Øystein Fluge scratches the back of his head, puzzled. What really happened to his patient Anne Katrine?
For years to come he cannot forget what he saw during these months in 2004.
In October 2009 I sat in a small office at Haukeland University Hospital in Bergen, a city on the west coast of Norway. I remember it well. The two doctors enthusiastically telling their surprising tale. I was in the very beginning of researching my book about ME/CFS when I came across a small pilot study from the very same people I was meeting for the first time this day.
Even then, without the extensive knowledge about ME/CFS that I have now, I remember thinking: If this turns out to be true, it will change everything.
It was a beautiful sunny day, with snow covering the peaks around Bergen. On my way to the meeting with professor Olav Mella and doctor Øystein Fluge, I saw signs pointing the public to the mass vaccinations against the swine flu. In a few weeks Norwegian authorities had spent more money on buying vaccines than everything the American government had spent on ME/CFS research for the last 25 years.
I remember seeing that as a telling comparison pointing towards a still grim future for ME/CFS. But now, I was wondering if these two doctors story could be a turning point. After 25 years of controversies, lack of funding, maltreatment, ridicule and dashed hopes. Could this be the game changer?
Dr Fluge was talking about Anne Katrines remarkable story of recovery from most of her ME/CFS symptoms, and after those months she had never let Fluge off the hook. She begged him to find out what had happened. And in the end, Fluge and Olav Mella, the head of the Cancer Departement at the hospital, decides to give it a try even though they have never before worked with ME/CFS and had barely heard of it.
“Our starting point was: Could this be an autoimmune disease? And if so, could it be that it was methotrexate in Anne Katrines treatment that was working on her ME/CFS symptoms”, said Fluge.
Methotrexate is a medication which dampens the immune response. It is used in large doses in some cancer treatments, but it is also used in smaller doses against different autoimmune diseases, for example rheumatoid arthritis. Anne Katrine had gone through three different courses of cancer treatment, but only with one of them did she experience a near resolution of her ME/CFS symptoms. In that treatment she got methotrexate, something she did not get during the other treatments.
“We could not know if this hypothesis was right, but our idea was to try to treat CFS with Rituximab, which is a medication that works directly on the B-cells in the immune system,” said Fluge.
Like methotrexate, Rituximab is a medication that dampens the immune response, but through a different mechanism. It basically wipes the B-cells out for a few months before they slowly grow back. Both of these medications are used in the treatment of cancer and autoimmune diseases. In 2007, Fluge and Mella decided to do a small pilot study on three ME/CFS patients. One of the three patients they contacted was Svein.
“Before Olav Mella called me, I remember I discussed with my wife how long I would manage to go on with this disease,” said Svein when I asked his story in a phone interview.
He worked at the local hospital, but after a serious viral infection ten years earlier he never recovered. For a long time he tried to stay at work, but in the end had to give it up.
“I have been so ill that I was bedridden and had to get help to get to the toilet. But of course, I still hope to get back to work some day,” Svein said.
Six weeks after his first infusion with Rituximab something happened. In just a few days Svein experienced major improvement in all ME/CFS symptoms.
“My father in law has a cabin, and it is situated just a hundred meters from the road from where we had to walk. Usually my stay at that cabin had been just managing to get there, and then I had to lie on the couch or the bed during the whole stay. Now I went skiing with my kids,” said Svein.
In their pilot study, published in BMC Neurology in early 2009, Mella and Fluge writes:
He could take one-hour walks and started to do carpentry on his house. Myalgic pain was markedly reduced. Cognitive functions improved remarkably, and he could now read a whole book without interruption. The hypersensitivity to noise decreased. He and his wife confirmed that family life had improved considerably.
“After my first treatment I finished two books in a weekend. Before treatment I could not even read two pages,” said Svein.
But after ten weeks of major improvement Svein crashed. Back to a life within the four walls of his house. All the symptoms came back as fast as they had gone away. He received a second treatment course, and the same thing happened. Major improvement after six weeks, then ten weeks with maintained improvement, and then a crash.
In February 2009 he got a new infusion.
“Then I had the best effect so far, and it lasted even longer. I started doing carpentry on the house, made a new roof and new walls, put down cables. I throw myself at these kinds of projects when I feel better, because I feel there is so much I have undone. As soon as my body functions again, I’m ready,” said Svein.
Before treatment with Rituximab, Svein had only been able to watch pictures of his kid’s activities outside the house.
“That feels terrible. When I get this treatment I manage to participate. It is like being brought back to life again,” said Svein.
The two other patients in the pilot study, one of them Anne Katrine, and the other a woman in her early twenties, had similar major improvements after Rituximab treatment. Mella and Fluge were themselves surprised when they saw the astounding pilot results, where the patients at times experienced near resolution of all of their symptoms.
“Then we felt that we were touching a central mechanism in the disease,” said Fluge back in 2009.
They started a double blinded, placebo controlled and randomized study on Rituximab in 30 ME/CFS patients – what is called a RCT. Placebo controlled means that the patients are divided into two groups – 15 got placebo (salt water) and 15 got Rituximab. Double blinded means that neither the patients, nor the researchers, know who gets real drugs and who does not. Randomized means that it is random which group the 30 patients end up in. This is considered the gold standard in medical research on drugs.
At my first meeting with the two doctors that day in 2009 none of them knew if their study would turn out positive. They did not yet know which patients got the drug and who got placebo.
I followed Mella and Fluge closely the next two years. Ups and downs. Uncertainty and promise. And now we all know: new hope. Let us take a leap to October 2011.
“It’s the most encouraging drug result so far in the history of this disease. Although it’s a small trial, it’s produced dramatic results,” said Charles Shepherd, MD and medical advisor to Britains biggest patient association for ME/CFS, to New Scientist in October 2011.
The Norwegian Rituximab study had just been published in PLoS ONE, and it generated a massive amount of media coverage. “Immune system defect may cause ME” reported BBC. “Cancer drug can help chronic fatigue” was the headline in Europes leading news magazine Der Spiegel.
Never before had a study on a drug in ME/CFS had such promising results.
The study on 30 patients showed that 10 out of 15 patients (67 %) got a significant improvement from the cancer drug Rituximab which wipes out most of the B-cells in the immune system. 9 out of the 10 responders got a “major improvement” according to the paper. In the placebo group only 2 out of 15 (13 %) got a significant improvement. The result was 10-2 between the groups. Or 9-1 if you only look at “major improvers”.
It turned out that most of the responders, unlike two out of three pilot patients who were early responders, started their improvement as late as 3-7 months after the infusion with the drug. Another significant finding was that most patients relapsed when the effect of the B-cell depletion wore off, which is consistent with the effect of such treatment in some autoimmune disesases. “Thus, we believe that B-cell depletion targets a central player in the pathogenesis of the CFS disease, directly or indirectly”, the study authors wrote in their paper.
The director of Haukeland University hospital, Stener Kvinnsland, who was not directly involved in the study, said to the Norwegian broadcaster TV2 that he “had a strong feeling that this was a breakthrough”. Dr. Kvinnsland is one of Norways most respected cancer researchers with a solid track record, and to a Norwegian newspaper he said that the Rituximab finding was one of the most exciting things he had followed in his professional career.
Professor Carmen Scheibenbogen, Deputy Director of the Institute of Medical Immunology at the Charité University Hospital in Berlin, described the results of the study as a possible breakthrough. “This is a very important first step. For the first time, a therapeutic study has been conducted with medication that was originally applied to the immune system, and which proved effective for a majority of the patients”.
In Norway, a country where ME/CFS has generated a lot of media attention the last few years, the Rituximab study led to a media blitz. For several days the media reported on the study, the lack of good care for the patients and all the broken promises about better services for ME/CFS patients from the government and the responsible health care providers.
It was like Rituximab was a tipping point for not longer being able to give the impression that this disease was not real, or that it was mainly a psychosomatic problem. Because how do you argue against a big gun cancer drug? In a way, Rituximab did not just heal some of the study participants, it also healed the self-respect of thousands of Norwegian ME/CFS patients who finally experienced something else than suspicion and disbelief.
In a rare public statement the National Institutes of Health in Norway even apologized to the patients for the lack of services and years of mismanagement.
Before the Rituximab study hit the news, I called Sheba Medical Center in Tel Aviv to talk to the Israeli scientist and world renowned expert on autoimmunity, Yehuda Shoenfeld. He is editor in chief of Autoimmunity Reviews and has written several books and published hundreds of scientific articles on autoimmunity. In a review article in 2009 he wrote that recent findings in ME/CFS “points toward an ongoing autoimmune phenomenon in such patients that, although not fully understood, is likely to be enhanced by the presence of certain infectious agents and other adjuvants”.
“I cannot say for sure that this is an autoimmune disease, but CFS has a lot in common with this group of diseases”, a busy Shoenfeld told me over the phone.
At this time he had only seen Mella and Fluges pilot study on three patients, but he said that what they reported there looks much the same as what you see when you use Rituximab in diseases like rheumatoid arthritis and SLE (lupus). Then he said that if they got positive results in a controlled study, it would indicate that a central mechanism in ME/CFS will be found in the immune system.
I asked him if that would be surprising to him.
“No, not to me, but it depends who you ask. I have the idea that CFS belongs in this group of autoimmune patients”, said Shoenfeld.
I have since talked to several international ME/CFS experts, all of them enthusiastic about the Rituximab results. At last year’s Invest in ME conference I sat down with one of the most respected ME/CFS-clinicians, Daniel Peterson, and asked him his thoughts.
– I think it is a crucial step forward, he told me.
And then he went on to say that he had seen effects of Rituximab himself. Several of his ME/CFS patients had developed lymphoma and therefore got treated with Rituximab, one of them for several years.
– And after starting treatment his ME/CFS symptoms disappeared, said Peterson.
The Future: Persistence
Of course, like everything in ME/CFS, no promising study without controversy. So the study in PLoS ONE also met criticism right away. This is science after all. Controversy is the rule, and more so in ME/CFS than anything else. A group of prominent ME/CFS researchers commented the study at the PLoS ONE pages, implying the results were oversold and with methodological flaws, and they challenged the conclusions.
Then one of the world leading authorities on Rituximab quickly commented on a lot of flaws in the critics own criticism. Professor Jonathan Edwards from University College London said their criticism “contains several errors”, and went on to say that the “trial’s authors give the account that is by far the most consistent with the data”.
“In the end I think we have to find the cause behind the disease, or else no one will believe us. If we are right, which I think we are, we will make it. In a few years I think the scientific community will have the answer”, said Fluge responding to some of the doubting critics.
It is important to acknowledge, like Fluge and Mella themselves have repeatedly said, that there is need for bigger studies before concluding on Rituximab and ME/CFS. And this study, like every innovative scientific study, also needs to be subject for criticism and disagreements to make headway for what we all want in the end – the truth. So why did I mention Jonathan Edwards? I did because he has been here, right where ME/CFS is now with Rituximab, just with a different disease. And Jonathan Edwards won the dispute. No one ridicules his ideas anymore.
In the 1990s Edwards, together with another British scientist, Geraldine Cambridge, came up with a theory about possible B-cell involvement in rheumatoid arthritis (RA). They met a cold shoulder from the rest of the research community. The importance of T-cells was then the only accepted theory in RA, and therefore most in the medical community automatically thought that the theory of Edwards and Cambridge were not worth pursuing.
But Edwards and his colleagues pursued their idea despite the resistance, starting off with a small pilot study on Rituximab in five RA patients.
“When the patients’ B cells disappeared, so did most of their arthritis,” Edwardstold New Scientist in 2001. Three of the five patients remained well for a longer period, while symptoms of the disease came back in two patients once their B cells returned.
After years of unproductive battling trying to get this groundbreaking idea of the importance of B-cells in RA acknowledged in the medical community, Edwards talked to the press, and the story made headlines. Something which of course made some of his critics even more critical, but it worked. Finally they got funding for a big study on Rituximab in RA, and in 2004 the results werepublished in the prestigious New England Journal of Medicine. The result? Rituximab turned out to be a superior treatment in the study, and suddenly B-cells were on everybody’s lips.
An article on the history of RA and Rituximab in The National in 2009 ends by mentioning Mella and Fluges pilot study on Rituximab in three ME/CFS patients, which then had just been published:
“With so few patients, it’s hardly definitive proof of a cure. Yet it is just the situation Prof Edwards and Dr Cambridge found themselves in a decade ago. CFS sufferers must be hoping medical researchers are not about to repeat history by rejecting these intriguing findings out of hand – despite not having any better ideas themselves.”
Against the odds, Jonathan Edwards and his colleagues turned the whole field of RA around through pure persistence. He definitely knows that paradigm shifts do happen in medicine. No stranger from controversy, maybe Edwards gets that old feeling back reading the PLoS ONE study from Mella and Fluge, tempting him to have his say in public. Maybe he knows that the Norwegian scientists are in for a hell of a ride.
And maybe, just maybe, he wants them to win too.
(Jorgen Jelstad is a Norwegian journalist and author of the documentary book “The Hidden Ones: and how ME came to be the most controversial disease of our time”. The book is so far only available in Norwegian – named “De Bortgjemte”. This article was printed in Invest in MEs conference magazine for the 2012 Invest in ME conference. Here is the conference magazine in full.)