“The recent study of Drs. Øystein Fluge and Olav Mella demonstrating significant improvement in ME/CFS patients treated with the B cell depleting agent Rituximab is a key study for our field.”
Nancy Klimas, professor in medicine at Nova University, bto.no October 2011
Everybody in Norway now knows the word Rituximab and everybody knows that something exciting has been going on in the hallways of Haukeland University hospital in Bergen. One of Norways two major TV-channels, TV2, has given the Rituximab-study just published in PLoS ONE a massive amount of coverage. It has also been reported in BBC, Der Spiegel (the biggest and leading news magazine in Europe), the respected scientific magazine New Scientist and others.
I’m a journalist and I have a mother with a diagnosis of ME/CFS. The last two and a half years I have been working on a book about the disease: “The Hidden – and how ME/CFS became the most controversial disease of our time”. It’s a book about the history, politics and controversies and what consequences all of this has had for the patients trying to live with this disease in health care and society. The book was just published by one of Norways biggest publishers Cappelen Damm (it is only available in Norwegian language).
I have done hundreds of hours with interviews with ME/CFS-researchers and clinicians in Norway and in the international scientific community, I have been to several ME/CFS-conferences, I have met loads of patients and carers, advocates and politicians, lawyers and nurses – and I have been reading thousands of pages in research papers, reports, public documents, books etc.
I have also been following closely the work of dr. Øystein Fluge and dr. Olav Mella since late 2009 – long before they even knew if their study on Rituximab would be positive. A big part of the book documents the whole story behind this research.
From all my work, I know that the Rituximab-study could turn out to be something special in the 25 year long research history in ME/CFS. Yes, it’s a small study, but never before has a study on a medication in ME/CFS had these kind of promising results. If it turns out to be true in bigger studies, this is definitely a game changer.
The study on 30 patients showed that 10 out of 15 patients gets a significant improvement from the cancer drug Rituximab who wipes out most of the B-cells in the immune system. 9 out of the 10 responders get a “major improvement” according to the paper. In the placebo group only 2 out of 10 got a significant improvement. The result is then 10-2 between the groups. Or 9-1 if you only look at “major improvers”.
The director of Haukeland University hospital, Stener Kvinnsland, who was not directly involved in the study, said to 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, but to the newspaper Bergens Tidende he said that the Rituximab finding is one of the most exciting things he has been allowed to follow in his professional career.
Charles Shepherd, MD and medical advisor to Britains biggest patient association, said to New Scientist that: “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.” Recently I attended the IACFS/ME research conference in Ottawa, and I had the opportunity to interview three of the major ME/CFS-experts about their thoughts on Rituximab and ME/CFS. At this time the study in PLoS ONE was not yet published, so the following interviews are based on thoughts and theories they shared without knowing the data yet.
Nancy Klimas, professor in immunology at the University of Miami, has worked on the immune system in ME/CFS for 25 years, and she was very excited about the upcoming study results.
– I think they’re doing fabulous work. I first heard about their work when that first report came out a couple of years ago. I was in London, and I was all excited, I couldn’t wait for them to do this, Klimas said.
She said she wanted to leap right in and do her own study, but she didn’t want to step on the Norwegian researchers toes.
– I decided that I needed to let them do what they did, because they did it right, and they deserve all the credit for all the work that they’re doing – it’s very exciting and very innovative, Klimas said.
But she points out that Rituximab is a “big gun”.
– You’re wiping out all of the B-cell population. So the question in my head about this is – why would it work?
She then presented two possible theories. One is that a big subgroup of ME/CFS-patients has an autoimmune disease that is antibody mediated.
– So this could be, if Rituximab works, an autoimmune disease that is specifically and entirely by an antibody mediated autoantibody. We know that Rituximab is being used in autoimmune diseases like RA, Klimas said.
According to Klimas another possibility is that the B-cell is a reservoir for a virus that really matters. The B-cells are the major reservoir for Epstein Barr Virus, a virus that has been linked to ME/CFS several times in the research literature. It is well established in research that mononucleosis trigger ME/CFS in many cases.
– Let us just pretend it’s EBV for a moment. When we’re done with our EBV, when you and I had our mono, we are left with roughly one million latent EBV-infected cells. And our immune system handles that. One of the questions that have never been answered in chronic fatigue syndrome patients is, do they have a bigger reservoir than that? Was their primary infection so intense that they have ten million or a hundred million latently infected cells? Because there’s going to be a threshold where a normal immune system can’t contain latency – and can’t maintain that virus under control. (…) Maybe Rituximab simply knocked down the reservoir so intensely so that we got it down under the threshold, and then the immune system could handle it. And that would make sense to me, Klimas said. She stressed that this is just a hypothetical construct without data to back it up, and then adds that she would love to see some before and after cells and serum plasma be sent off from the Norwegian freezers to “EBV-wizards” like Ron Glasers group.
– Do you think this is a more likely explanation than autoantibodies?
– We don’t know. All we know is that they got better, and it’s not that many yet. To understand the mechanism of why it works is critical to go forward with that kind of investigation. And remember that the ME/CFS population is not homogenous, they’re not all the same, there’s going to be a subgroup this matters for. So I’m also hoping in the laboratory that they are looking for a biomarker, or at least storing enough stuff so that someone else can look at the biomarkers to predict who responded. Because we might very well discover that it’s a viral load phenomena or that it’s only the autoimmune group that responded. And there are markers for things like that, Klimas said.
– Some people in the ME/CFS research community say all the immune findings in ME/CFS are inconsistent, and by that implies that they’re not so important. What are your comments on that?
– I’m so frustrated by that response because it’s been 25 years. Pull out the study that have very large numbers if you want to get some consistency in the data. Throw out all of the studies that have 20 patients and under, and look at the studies that have 100, 200, 300 patients – and they are saying the same thing. It’s not hard. I think the immunology is proven. It’s not controversial. It’s not a hypothesis. It’s proven. There’s immune activation, there’s cellular dysfunction and there is a significant degree of immune dysfunction, Klimas said.
She says increasingly more research are coming out that are backing up this statement.
– Everything is fitting together, the clinical observations, the biological observations and even the more sophisticated genomics that try to understand mechanisms. It’s all fitting together. So I have no trouble saying with great confidence that the immune system in ME/CFS is not working correctly, Klimas said.
The story behind how Rituximab came to be an important treatment in RA, which Klimas mentions, is definitely worth a look in this context. When two scientists in Britain, Jonathan Edwards and Geraldine Cambridge, came up with their theory about possible B-cell involvement in RA in the 1990s, they were mostly met with a cold shoulder from the rest of the research community. T-cells was then the only “accepted” theory in RA, and therefore everybody automatically thought that the theory of Edwards and Cambridge were not worth pursuing. In this article from The National you can find a short version of this interesting story on how these two scientists, against all odds and more or less single handedly, turned the whole field of RA around.
Back to the conference in Ottawa, where I get hold of Harvard-professor Anthony Komaroff for a chat on Rituximab in ME/CFS. He has followed the ME/CFS-field as a clinician and researcher since the very beginning 25 years ago, and he is one of the main authorities in the field.
– The theory makes sense to me, Komaroff said.
But he hopes the researchers are trying to find biomarkers that can be monitored, to understand what mechanisms in the body that responds to the medication. The researchers in Norway has just got a substantial grant for exactly this kind of work from a philanthropic organization. Their hypothesis is that there’s a central autoimmune component in ME/CFS, and that it might be possible to find a specific autoantibody. If they find this, they will have a biomarker, and this will be a major step in researching the mechanisms behind the disease. But finding an undiscovered autoantibody is like looking for a needle in a haystack, so it’s time consuming work.
Anthony Komaroff says there are plenty of examples in medical history that a drug has effects the medical community didn’t yet know it had, and therefore it’s important to also look at alternative explanations for possible mechanisms.
– A good example is statin drugs. They lower cholesterol, we know that, but it’s now clear that in people with perfectly normal cholesterol with heart disease, the statins really reduce the risk of future heart disease even though they don’t change the cholesterol much because it’s already low. Why? Because the statins also reduce the inflammation inside artherosclerotic plaques. So the statin works by at least two mechanisms in heart disease, and cholesterol is only one. Most people thought it was stupid to do a study on the value of statin in people where cholesterol levels were low because you wouldn’t expect it to work, but it does because it has other effects, Komaroff said.
– What are your thoughts on an autoimmune hypothesis in ME/CFS?
– A number of studies suggest that there are autoantibodies. Autoimmune means that the immune system is confused – that it attacks a tissue that it shouldn’t attack because it is its own self. I think it’s entirely plausible that this attack is mediated because that tissue has within it some foreign infectious agent, and that the attack is perfectly sensible. The immune system is not attacking its own tissue deliberately, it’s attacking its own tissue because it sees something foreign inside that tissue. That’s theoretical, but again there’s some evidence to support it, Komaroff said.
– In addition to finding biomarkers, what’s the next step for this kind of possible treatment in ME/CFS?
– The next question will be, do you have to continue this treatment pretty much for the rest of someones life? And what is the optimal dosing regimen to minimize side effects and still achieve the benefits? But I think it’s a perfectly plausible future form of therapy, Komaroff said.
The findings from Norway in 30 patients are done with the gold standard in medical research on drugs – what is called a double blinded, placebo controlled, randomized study. Placebo controlled means that the patients are divided into two groups – 15 get placebo (salt water) and 15 get Rituximab. Double blinded means that neither the patients, nor the researchers, know who gets real drugs and who doesn’t. Randomized means that it’s random which group the 30 patients end up in.
Of course bigger and better studies on Rituximab in ME/CFS are needed to confirm these findings, but this is a really promising start with a solid study design showing impressive results. The researchers in Norway are already well underway with an open label study to understand more about how the drug works in ME/CFS before they try to design and get a bigger randomized controlled trial up and running.
In Ottawa I also interviewed José Montoya, infectious disease specialist at Stanford University, about this. He’s leading a research initiative at Stanford trying to solve the ME/CFS-enigma, and he’s also part of the massive 10 million dollar Chronic Fatigue Initiative that involves top universities like Harvard, Stanford and Columbia (split second and 12th at the recent World University Rankings). Montoya thinks ME/CFS is the most misunderstood disease of our time, and his goal is no less than eradicating ME/CFS as a problem.
– Are you also looking in the direction of autoimmunity?
– Yes, I’m basically looking for an aberration in the immune system in response to pathogens. My specialty is infectious disease – what infections trigger that abnormal immune response? And I think there is a component of autoimmunity based on the fact that it’s most common in women and many patients get better during pregnancy and often gets worse after birth. And researchers have found autoantibodies in patients with CFS. So I’m expecting an autoimmune component, Montoya said.
– Some people say the immune findings in ME/CFS are inconsistent – what’s your take on that?
– Despite some disagreements, there is a core of findings that are consistent. There is a group of abnormalities that everybody seems to agree on, Montoya said.
He has done interesting findings with the use of antivirals in ME/CFS, and in a pilot study from 2006, 9 out of 12 patients had major improvement in their symptoms.
– I went from the observation that valcyte seems to work, to a double blind that shows that it works in a subgroup of patients. It’s not working on everybody, and now we try to understand why. My hope is to be able to find a marker that will allow me to say “this patient need valcyte, while this patient needs another drug”. So my interest is not valcyte, my interest is helping the patients with CFS through different interventions whatever it takes, Montoya said and adds that the placebo controlled trial he mentions will be published soon.
He says it’s entirely plausible that it’s the immune response to different infections that leads to symptoms, not a virus in itself.
– The thinking behind the pathogen directed therapy we have been doing with valcyte is that we are taking away the excuse for the immune system to attack. Pathogens distort the immune system into overreacting, and I think the solution will be in controlling the pathogen, but also controlling the immune response, Montoya said.
He thinks Rituximab and other immune modulators are candidates for future therapies in ME/CFS.
– The problem is how to identify the patients that would benefit from the intervention. That is the only issue that I have with it, Montoya said and continues:
– There have been autoantibodies that have been found in CFS. What has not been found is the auto antibody or the group of anti autobodies that are exclusive to CFS.
– And this will take time I guess?
– Yes, but what can shorten that time, Montoya asks with a big smile.
– Yes, exactly, he says laughing.
He’s on his way back to the mecca of innovation, Silicon Valley, with Stanford University in the heart of it.
– And in Silicon Valley we have always found a solution. So I have decided to do it the Silicon Valley way.