Fluge and Mella on Rituximab and Autoimmunity in ME

A Cambridge University radio series, The Naked Scientists, interviewed Øystein Fluge and Olav Mella on March 24 as part of a program exploring the interface of biology and psychiatry. 

You can listen to the interview HERE. The interview starts at 39:00 and ends at 47:00.

Also interesting is the previous interview with Belinda Lennox, who discovered that 8% of people diagnosed with schizophrenia actually have an autoimmune disease. In these patients, antibodies attack NMDA receptors in the brain, producing hallucinations. Once treated with immunosuppressants, the symptoms of schizophrenia disappear.

How does this apply to ME/CFS? 

ME/CFS, like schizophrenia, is defined as a group of symptoms, which means it is not actually a diagnosis. Pneumonia, tuberculosis, and a chest cold all produce coughing, but they are not the same disease. (And just as those three illnesses are not subsets of "coughing disease" people with ME/CFS are not a subset of "fatiguing illnesses.")

In like fashion, when asked if people with the NMDA receptor antibodies constitute a subset of schizophrenia, Lennox replied that they do not. They have Anti-NMDA Receptor Encephalitis, which is a disease in its own right.

This raises the possibility that the supposed "heterogeneity" of people with ME/CFS is because they actually have different diseases. It is entirely possible that one group of people diagnosed with CFS or ME may have a post-viral illness, another may have poisoning (e.g. Gulf War Illness), another an ongoing bacterial infection (e.g. Lyme), and yet another group an autoimmune disease. While all of these may produce the same symptoms, they do not share the same pathogenesis, would not require the same treatments, and are therefore not the same disease.

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Is ME an autoimmune disease?

Transcript

Øystein Fluge and Olav Mella, Haukeland University Hospital, in Bergen

Chronic Fatigue Syndrome(CFS), also known as ME, affects about 1 person in 500. Sufferers describe symptoms of profound tiredness and lethargy that doesn’t improve with sleep or rest. There’s currently no consensus on what might be causing the condition, there are no tests to confirm the diagnosis, and nor is there a cure. But now we may be closer to understanding what causes at least some of the cases of the condition thanks to research carried out in Norway, as Øystein Fluge and Olav Mella from Haukeland University Hospital, in Bergen, explain to Chris Smith...

Øystein - We are oncologists that work mainly on lymphomas and brain tumours. But in 2004, we observed a patient with longstanding ME who got lymphoma and she experienced a totally unexpected and very marked recovery of ME symptoms after she received lymphoma treatment with cancer chemotherapy. We speculated on this case and when we met new ME patients, it was striking to learn how similar the patients were in symptoms and how they described to be previously completely healthy and often, with an abrupt start of ME after infections. So, we reasoned that B-cells could be important in a subgroup of ME patients.

Chris - When you say, B-cells, these are the white blood cells, the lymphocytes that make say, antibodies and have a memory against infections we’ve seen before, aren't they?

Øystein - Yes, but we did a small pilot case series with a single infusion of the drug rituximab which targets these B-cells to 3 ME patients and they all had a marked but transient clinical response. We published this case series in 2009.

Chris - So, you were giving these people in the course of treating their blood cancer, their lymphoma, the drug rituximab which hits and destroys B-cells in the body which are in these patients, the cancer cells. And as a side effect almost of that treatment, these people who had previously said they had disabling symptoms of ME, chronic fatigue syndrome, they got better.

Øystein - That's correct.

Chris - Olav, I was going to bring you in and say, what actually happened to these people when you did this?

Olav - The 3 pilot patients all had response to treatment and one thing we observed in these 3 patients is that we have a pattern of responses and relapses after the rituximab treatment with a lag time of
several months from initial and rapid B-cell depletion until they start getting clinical responses. Such patients are also seen in established autoimmune diseases after rituximab treatment. We believe that this fits with B-cells not being produced for a period after rituximab which allows a natural degradation of autoantibodies – that is antibodies that have adverse effects on bodily functions, with the symptom improving when the antibody level drops. We really think this points at ME at least in a large subportion is an autoimmune disease.

It’s also spotted that 70% of the patients with ME, they get it immediately after an infection and there's, like in other autoimmune diseases, 3 to 4 times as many women as men who get the disease. And also, a big study from the US has shown a moderate and highly significant risk of B-cell lymphoma in elderly ME CSF patients, showing that the patients may have chronically activated B-cell system. We see the same lymphoma risk also in established autoimmune diseases like rheumatoid arthritis, lupus and Sjogren’s disease.

Chris - So, putting all of this together, you get these patients who, they happen to have a lymphoma – a cancer of the blood system – but they also have chronic fatigue syndrome. You treat their lymphoma with a drug which takes down their B-cells which are the cause of their cancer. They get this pattern of, their disease recovers when the B-cells go away but with the time lag corresponding to the time it takes the B-cells to go and the antibodies to go. And then when the B-cells come back in these patients, then the symptoms come back which looks like it’s tying the two things together, doesn’t it? So, what do you think that the B-cells are doing in these people to actually make, Olav, the symptoms of chronic fatigue syndrome in those patients?

Olav - Well, we think that it is a kind of an immune response and it obviously affects some very central function in the body. We’re not at all convinced that ME is kind of inflammatory condition in the brain. Probably, more important, I think what is happening in blood vessels, we have indications that the blood vessel do not function as they should, given the dynamic flow to different parts of the body when it is needed.

Øystein - It’s like the patients have a problem in the fine-tuning or regulation of blood flow according to the demands of the tissues for oxygen and nutrients. The patients often describe they feel like running a marathon when they have done a limited exertion and they get brain fog from exertion and so on. So, our hypothesis is that the immune system somehow disturbs the fine-tune regulation of blood flow and tissues including in the brain.

Chris - Øystein, what are you now doing to try to firm this up because your initial results as you published, while very interesting are on very small numbers of patients? Obviously, we’d like to see big numbers of patients in order to make sure that this is not a statistical blip, it’s not happening due to chance, it’s real.

Øystein - To try to convince ourselves, we first did, as you say, a small randomised study which was published in 2011 with 15 patients given two infusions of rituximab and 15 patients given placebo, turn out that the 15 that got rituximab had a clinical response while 2 of the 15 in the placebo group. So, that was some kind of sign of clinical activity to us. So then we did an open label study with no placebo group, further rituximab infusion, prolonging the period with low B-cells.

We gave 6 infusions of rituximab up to 15 months and then followed the patient for 3 years. So, this study is now submitted for publication but we can say that again, 2/3 had a clinical response and the response durations were much prolonged when we gave maintenance treatment. But these two studies are not designed to give a definite answer to whether rituximab works in ME.

So therefore, we are now performing a larger phase III study in Multicentre in Norway with 152 patients. Half of them will receive 6 rituximab infusions during the first year and half of them will receive placebo. And then we will follow the patients for 2 years. And we hope that this study will either verify or refute if rituximab may give benefit to ME patients in a significant proportion.

The UK Rituximab Trial for ME

B-cell Targeted by Rituximab

Source: MEActionUK, August 2, 2013

By Professor Malcolm Hooper and Margaret Williams

The charity Invest in ME has provided a truly remarkable opportunity to address one of the biggest medical scandals in history and to remove what in 2007 Alex Fergusson, Presiding Officer (Speaker) of the Scottish Parliament, referred to as "the cold grip of psychiatry" on myalgic encephalomyelitis (ME), which he said was "still far too deeply rooted in the world of ME"

Now, however, despite the power and control of the psychiatric lobby, thanks to Invest in ME and the invaluable support of Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at University College, London, (world-renowned for his work in B cell immunology and as lead researcher in the clinical trials of rituximab for rheumatoid arthritis), the neuro-immune disease ME is at last about to enter the realm of mainstream medicine in the UK under the guidance of Professor Edwards himself.

Invest in ME are at the forefront of international biomedical research and have by sheer determination and effort managed to put things in place for a trial of rituximab to begin on ME patients in the UK.

They recognise the urgency of the situation and know that many ME patients do not have the luxury of time.

The charity already has the facilities in place, including suitably experienced researchers (Professor Jo Cambridge is now principal researcher at UCL, and the ME trial will involve the same team working under her that carried out the rituximab research in RA).

The Clinical Trials Unit at UCL is already working on the protocol, and Invest in ME have agreed with Professor Edwards that the protocol will be externally reviewed even though the UCL team will make sure it is cast-iron by their own internal reviewers.

Invest in ME have been told this trial could start relatively quickly if the charity had funds available.

Such an opportunity must not be lost. However, this will not happen without substantial funding.

We therefore ask everyone who is able to do so to donate whatever they can afford, in order that the UK rituximab trial can get under way as quickly as possible whilst the excellent facilities and committed staff at UCL and the active support of Professor Edwards remain available, so that ME can finally be recognised as the devastating multi-system neuro-immune disease that it is and - most importantly -- so that sufferers may at last have some hope of alleviation of their suffering.

Invest in ME have assured us that all donations to the rituximab fund will sit in a separate account which is totally ring-fenced, and should the trial not proceed, the following statement on the IiME website will be honoured:

What Happens With These Funds If The Project Does Not Go Ahead:

If the rituximab project does not go ahead for some reason then the funds raised will be transferred to the IiME Biomedical Research Fund to fund other biomedical research projects which are attached to our proposal for an examination and research facility based in Norwich Research park in Norfolk, UK.

These funds will only be used for biomedical research into ME.

Invest in ME: http://bit.ly/18TZN5d

A UK trial of rituximab is essential to move ME out of the realm of psychiatric dogma and into the realm of medical reality.

Information on how to donate can be found on the Invest in ME website: www.investinme.org

Is Chronic Fatigue Syndrome an Autoimmune Disease?

For decades, a heated debate has raged over the nature of the illness known variously as chronic fatigue syndrome (CFS) and/or myalgic encephalomyelitis (ME). Historically, the two warring camps have been divided between “it’s all in their heads” and “we’re still looking.” But while both sides have consistently referred to CFS/ME as an “enigma,” it turns out the source of the illness may very well have been under everyone’s nose the whole time.

In the May 2013 issue of Discover Magazine, an article by Jill Neimark bearing the intriguing title, “Are B-Cells to Blame for Chronic Fatigue Syndrome?,” chronicled a remarkable discovery: wiping out the B-cells of patients with CFS/ME can actually cure the illness.

In 2007 Øystein Fluge and Olav Mella, two Norwegian oncologists at Haukeland University Hospital in Bergen, Norway, accidentally discovered that rituximab, a drug employed to treat Hodgkin’s lymphoma (as well as autoimmune disorders such as rheumatoid arthritis and Wegener's granulomatosis) cured several of their patients with CFS/ME. The news made instant headlines.

Inspired by their success, Fluge and Mella conducted a pilot study of rituximab on three patients with CFS/ME. The patients were given rituximab in an open-label trial (that is, the patients knew they were receiving the drug). All three patients experienced significant improvement; two of them responded within six weeks and the third had a delayed response, occurring six months after treatment. The positive effects lasted for between 16 and 44 weeks. After relapse, the patients were administered another dose of rituximab, with the same positive results. The investigators hypothesized that B-cells of the immune system might play a significant role in CFS, at least for a subset of patients, and that “CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function.”

The positive results of this, as well as a second open-label trial, led Drs. Fluge and Mella to conduct a larger study with a more rigorous design to test the effects of the drug. In 2009 they initiated a double-blind, placebo-controlled phase trial with 30 CFS/ME patients. As in the earlier open-label studies, the responses to rituximab were significant. Sustained overall improvements were noted in 67% of the patients (as opposed to 13% of the control group). Four of the rituximab patients showed improvement past the study period. The authors concluded that the delayed responses starting from 2–7 months after rituximab treatment, in spite of rapid B-cell depletion, “suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.”

The unprecedented success of these small trials has led to a $2.1 million privately funded initiative spearheaded by the Norwegian nonprofit group, ME and You.

This is all very topical, but is it news? Dr. Paul Cheney, an immunologist, and one of the physicians who treated CFS/ME patients during the Incline Village outbreak, stated nearly thirty years ago that CFS/ME was the result of immune system upregulation. In fact, the prevailing theory during the 1980s and 1990s was that the immune systems of people with CFS simply did not shut off after the initial infection, but remained on “high.” This was considered the driving force behind CFS/ME, and, not coincidentally, is the basis for autoimmune disease.

Nonetheless, the idea that CFS/ME was an autoimmune disease languished for decades, even though the on-the-ground evidence has been apparent all along. The waxing and waning symptoms that are typical of CFS/ME are also typical of autoimmune diseases. Frequent comorbidities of CFS/ME with autoimmune diseases - e.g. Sjögren’s Syndrome and Hashimoto’s disease - were tip-offs that an autoimmune process was involved. And even if researchers didn’t care to take symptoms and comorbidity into account, there were dozens of studies documenting immune system abnormalities, particularly increased inflammatory cytokines, as well as a high incidence of markers such as antinuclear antibodies (ANA), and anti-cardiolipin antibodies (ACA), both of which are associated with autoimmunity.

The sad fact is that although the evidence was there, it was ignored. In a recent review of the accumulated evidence for autoimmunity in CFS/ME (in a chapter titled “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Parallels with Autoimmune Disorders”) Ekua Brenu and associates site over 180 related articles. Their conclusion? "CFS/ME may have a potential to be described as autoimmune, as this is the only consistent immunological abnormality associated with CFS/ME.”

Given the thorough nature of the review, Brenu's conclusion, however cautious, is warranted. And, bearing out Brenu's review, as well as the rituximab studies, in March 2013 a UK study by Bradley et al found an increased number of naïve B-cells in patients with CFS/ME. An increase in naïve B-cells is a hallmark of autoimmune disease.  In short, if it walks like a duck, and it quacks like a duck, it’s a duck.

Apropos of the rituximab studies, and as an excuse for not noticing the duck-like nature of CFS/ME, Neimark quotes rheumatologist Jonathan Edwards as saying, “T-cells were in fashion for a long time. B-cells were just considered boring.” It is hard to imagine that the absence of research on fully half of the immune system could be due to the whims of fashion, but whimsy is only part of the explanation for this exercise in mass denial. The other component is that the major players in our health care system - government agencies, researchers, physicians, insurance companies – have had a vested interest in perpetuating the myth that CFS/ME is an unknown and unknowable entity.

Norwegians, apparently, have less invested in the myth. When the results of Fluge and Mella’s rituximab study were made public, the Norwegian Directorate of Health Deputy Director Bjørn Guldvog was prompted to issue a televised apology. "I think that we have not cared for people with ME to a great enough extent,” he said. “I think it is correct to say that we have not established proper health care services for these people, and I regret that."

We look forward to hearing something similar from the CDC.

References:

1. Neimark, Jill. “Are B-Cells to Blame for Chronic Fatigue Syndrome?” Discover Magazine. May, 2013.

2. Fluge, Øystein, Olav Mella. “Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series.” BMC Neurol. 2009 Jul 1;9:28

3. Fluge, Øystein, Ove Brulan, Kristin Risa, Anette Storstein, Einar K. Kristoffersen, Dipak Sapkota, Halvor Næss, Olav Dahl, Harald Nyland, Olav Mella. “Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study.” PLoS ONE 6(10): e26358. doi:10.1371/journal.pone.0026358

4. “Will MEandYou be the first to crowdfund a clinical trial?” ME and You.

5. Hokama, Yoshitsugi, Cara Empey Campora, Cynthia Hara, Tina Kuribayashi, Diana Le Huynh, and Kenichi Yabusaki. “Anticardiolipin Antibodies in the Sera of Patients with Diagnosed Chronic Fatigue Syndrome.” Journal of Clinical Laboratory Analysis. 23 : 210–212 (2009).

6. Brenu, Ekua W., Lotti Tajouri, Kevin J. Ashton, Donald R. Staines and Sonya M. Marshall-Gradisnik. “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Parallels with Autoimmune Disorders” in Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution. Spaska Angelova Stanilova, ed. InTech. March 2013.

7. Bradley, A. S.,  B. Ford, A. S. Bansal. "Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls". Clinical & Experimental Immunology. Volume 172, Issue 1, pages 73–80, April 2013.

A shorter version of this article was originally published on Blogcritics on April 7, 2013 as "Is Chronic Fatigue Syndrome an Autoimmune Disease?"

Norwegian Group Begins Ambitious Fundraiser for ME/CFS Treatment, Rituximab

The Norwegian group, MEandYou, has begun fundraising for an ambitious study on the cancer drug, rituximab (trade name: Rituxan), for patients with ME/CFS.  Their goal is to raise 7 million kroner, or 1.2 million US dollars in three months to support a study headed by professor Olav Mella and Dr. Øystein Fluge at Haukeland University Hospital, Norway. A total of 140 patients will be involved. Rituximab made headlines when Mella and Fluge reported that several ME/CFS patients who had been treated for cancer using rituximab experienced a remission of ME/CFS. (For an excellent summary of the rituximab studies, read Cort Johnson’s article “A Drug For ME/CFS? The Rituximab Story.”)

Below is the full statement and call to action taken from MEandYou’s website.

This is MEandYou

Do you want to be a part of making a medical breakthrough? Do you want your families and friends to have an opportunity to be a part? Invite them.

Millions of people suffer from the disease ME, but today there are no medications to treat them. Scientists at Haukeland Hospital in Bergen have found that a drug might make more of them healthy. It was so startling that it made ​​international headlines in BBC, Der Spiegel, and ABC News. If the findings verified, thousands of patients worldwide have a healthier life.

Scientists at Haukeland need only one study to be able to find out if this is the breakthrough you have been waiting for. 140 ME sufferers have to try out the medication in a research project. It cost 7 million. However, the public authorities have refused to grant money.

We are fundraising the cost for 140 ME-sufferers to Haukeland Hospital, cancer ward, to be a part of a clinical trial on Rituxan. The cost is 1,2 million USD,  55 000 Norwegian kroner each. We are going to do it in 90 days.

The Rituxan study at Haukeland Hospital, presented in PlosOne autumn 2011, showed the most promising results worldwide for ME/CFS-sufferers. 2/3 had good or moderate effect. The bigger RCT-study has not had sufficient economical support from the official health care system to continue their research.

ME/CFS is a poorly understood, but debilitating, neuroimmunological illness with none or little treatment, that affects hundreds of thousands of people world wide. Have you ever thought about how much society would save just by getting a few of those sufferers back to work and as participants of the community?

What if it turns out that the research that you, as an individual, support will be a breakthrough in the medical field? What if you are one of those people who in few years can say that, yes, I was a part of it! This might be your chance. The patients, the families, the friends pass those well-established channels and contribute funds directly to the research projects we want to support, so that they become a reality. Do you want to be a part of it?

We can do it. MEandYou.

Rituximab: A Wonder Drug for Severe ME/CFS?

This short video demonstrates the action of rituximab, a drug which shows promise for those with severe CFS/ME. Rituximab (trade names: Rituxan, MabThera) was first approved by the FDA in 1997 for the treatment of non-Hodgkin's lymphoma. It is believed that rituximab destroys tumors by attaching to the CD20 receptor on B cells, causing the tumor cells to disintegrate. In some non-Hodgkin's B-cell lymphomas, rituximab prevents the production of more tumor cells.

Rituximab is also used in the treatment of autoimmune disorders, such as rheumatoid arthritis and Wegener's granulomatosis. In these cases, rituximab works by temporarily depleting the total number of B cells, which are important in promoting inflammation. Rich Van Konynenburg proposed that this is why rituximab works for CFS/ME patients – by reducing B cells, rituximab reduces inflammation.

The effect of rituximab on CFS/ME patients was discovered by accident. Two Norwegian doctors, Øystein Fluge and Olav Mella of Haukeland University Hospital, noticed that after treating a CFS/ME patient for Hodgkin's lymphoma with rituximab, she recovered from CFS/ME. This led the doctors to initiate a small study of rituximab on CFS/ME patients.

Three CFS/ME patients were given rituximab in an open-label trial (that is, the patients knew they were receiving the drug). All three patients experienced significant improvement; two of them responded within six weeks and the third had a delayed response, occurring six months after treatment. The positive effects lasted for between 16 and 44 weeks. After relapse, the patients were administered another dose of rituximab, with the same positive results. The investigators hypothesized that B cells of the immune system might play a significant role in CFS, at least for a subset of patients, and that “CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function.”

The positive results of this, as well as a second open-label trial, led Drs. Fluge and Mella to conduct a larger study with a more rigorous design to test the effects of the drug. In 2009 they initiated a double-blind, placebo-controlled phase trial with 30 CFS/ME patients. As in the earlier open-label studies, the responses to rituximab were significant. Sustained overall improvements were noted in 67% of the patients (as opposed to 13% of the control group). Four of the rituximab patients showed improvement past the study period. The authors concluded that the delayed responses starting from 2–7 months after rituximab treatment, in spite of rapid B-cell depletion, “suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.”

Dr. David Bell, a now retired CFS/ME specialist, says “I've not seen results like this in any medical study in the 25 years that I have been in this field."