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Fluge & Mella's pre-trial study highlights life-changing potential of rituximab

Sasha submitted a new blog post:

Fluge & Mella's pre-trial study highlights life-changing potential of rituximab

Professor Olav Mella (left) and Dr Oystein Fluge

Sasha gives the background and Simon gives the interpretation of the latest study from Haukeland, published today...

It’s out! Dr Øystein Fluge and Professor Olav Mella have published their new study in PLoS ONE. And though the study was not a blinded, placebo-controlled trial, the results are further evidence that rituximab is beneficial in some ME/CFS patients, and potentially life-changing for a substantial minority. The findings also give important new insights into the optimum dosing schedule to maintain those benefits in the long run.

We all know the story that led up to this study: cancer specialists Fluge and Mella treated an ME patient for cancer with the immune-system drug rituximab. The patient’s ME symptoms improved markedly. The effect was confirmed in two additional patients and so Fluge and Mella set up a 30-patient, double-blind, randomised, placebo-controlled trial of rituximab in ME/CFS.

The results, when published in October 2011, were striking: although there were no differences between the two groups at the pre-defined endpoint of three months, 67% of patients receiving rituximab had moderate to major improvement during follow-up, compared to only 13% of placebo patients (p=0.003).

And not only that: there was a tell-tale delay of several months in the improvement. This time-lag suggested that it was rituximab’s B-cell destroying capabilities that were responsible. That, in turn suggested that rituximab was switching off an autoimmune process (some B-cells produce antibodies that attack the body’s own tissues).

The findings took the ME/CFS world by storm and started a sea-change in attitudes to the disease. The Norwegian Health Directorate apologised for how ME patients had been treated. Researchers and clinicians outside the ME/CFS community began to focus on autoimmunity as a hypothesis rather than psychology. Fundraising efforts for more rituximab trials started up all over the world, including MEandYou’s successful crowdfund in Norway and the ongoing fundraising for Invest in ME’s UK rituximab trial and B-cell studies.

Meanwhile, Fluge and Mella set up a small study – this newly published study – to inform the design of a larger trial. In their original placebo-controlled study, most of the patients who benefited from rituximab had a transient response and then relapsed. Fluge and Mella needed to investigate the best dosing schedule, and other aspects of rituximab’s use.

The large multi-centre rituximab trial is now underway in Norway, led by Fluge and Mella and funded by MEandYou, the Norwegian government, and others. It’s another double-blind, placebo-controlled, randomised study and has 152 patients, who will be followed up for 24 months post-treatment: results won’t be available until 2017 or 2018.

Meanwhile, this new study has much to tell us. Over to Simon, to take a look at it.

Haukeland University Hospital, the site of the initial pilot and ongoing rituximab studies

The science

Thanks, Sasha...
In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses.

Dr Fluge, Professor Mella and colleagues

The study findings are very encouraging. 64% of patients showed a clinical response, similar to the 67% seen in the original trial. Half were classed as major responders. And at the end of the study a quarter of patients were doing exceptionally well: in my opinion the data suggests they were close to recovery.

Some limitations
This was an ‘open label’ trial, in which all patients and medical staff knew the patients were on rituximab, and there was no control group. Some of the improvements recorded might have been down to placebo response, and/or ‘response bias’, in which patients subconsciously overstate their improvements (all outcomes were self-reported). Some patients may have simply improved naturally, regardless of the rituximab treatment.

Most of these patients had featured in the earlier trials: nine from the trial placebo group, nine from the rituximab group and one pilot patient.

Only ten patients were new, so response rates for this and the previous trial are largely based on a small and highly overlapping group of patients. The response rates seen here might not be replicated in a wider group of patients (leaving aside that this and the earlier trial are small studies).

The only way to remove such problems is to conduct a randomised, double-blind, placebo-controlled trial – which is exactly what Fluge and Mella have organised, with a large multi-centre trial under way in Norway. This latest study was set up to help plan that large trial..​

A word of caution

I want to point out the limitations of this study – limitations the authors note in their paper – before I enthuse about how good some of these results seem to me.

The goal was to help establish the therapeutic effect of repeated maintenance doses of rituximab on long-term response, and to help guide the design of the large clinical trial now under way in Norway. However, it wasn’t a gold-standard placebo-controlled randomised trial, and wasn’t meant to be, and that means we have to be careful about interpreting the results.

First, the study was unblinded – patients and clinicians knew they were dealing with a drug with great potential. That can artificially boost results, to a modest degree.

Second, there was no control group (ideally a placebo group to see how patients would have responded to a dummy treatment), and some of the observed gains might have occurred even if no drug had been given.

And finally, 20 out of the 29 patients had been in previous rituximab studies.

More details are in the box.

How the study worked
All patients met both Fukuda and Canadian consensus criteria. The average age of patients was 40, and 69% were women. They’d been ill for an average of nine years, and 20 (two-thirds) were at least housebound, including three who were mainly bedbound.

The main measure of success was change in fatigue from baseline (see box below). For clinical response, patients needed six consecutive weeks of improvement, and to average at least a slight-to-moderate improvement, including at least one week better than moderate (so at least one of the fatigue symptoms had to be rated as a major improvement). This could be at any time during the 36 months of the study.

Patients received an initial two doses of rituximab two weeks apart and then maintenance infusions at 3, 6, 10 and 15 months. They were followed up for a total 36 months.

How fatigue was measured
Patients scored four different aspects of fatigue (fatigue, malaise after exertion, need for rest, and lack of daily functioning) on a scale of 0 to 6. The overall fatigue score was the average of the scores for the four different aspects.
On the 0-6 scale, 3 was the midpoint, meaning there was no difference from baseline. 4, 5 and 6 corresponded to slight, moderate and major improvement from baseline, respectively. 2, 1 and 0 meant slight, moderate and major worsening, respectively.
This was the same scale as used in the small placebo-controlled trial. Although this scale hasn't been formally validated, the authors also used the validated and widely used SF-36 health scale, and the SF-36 results told the same story as the fatigue scale.


"Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years," says Fluge. "Suddenly, their limbs started to work again and their hands were no longer cold or sweaty." (From an interview in the New Scientist)

Of the 28 patients who received any maintenance doses, 18 (64%) showed a clinical response, similar to the 67% seen in the initial trial. 14 were classed as major responders and four as ‘moderate responders’.

Thus, half of the patients showed a ‘major’ response, with an average response period of 105 weeks (out of 156 weeks in the study). Typically, patients didn’t start improving until 23 weeks after the first dose of rituximab.

Peak response, and relapse for some
The results for patients overall peaked at 20 to 24 months, which was 5 to 9 months after most patients had had their final dose. (Some patients who were responding slowly received more, but these additional doses didn’t seem to make much difference.)

During this peak response time, the average SF-36 scores for major responders matched average population scores (though some were well below average, at levels typically seen in people who have long-term illness). That’s a big improvement from baseline when the scores showed they were all well and truly sick.

However, some patients declined after this peak period, including four major responders who, after doing extremely well, relapsed severely – almost back to baseline levels.

Even so, nine out of 14 major responders (32% of patients) were still showing a clinical response, of various levels, at the end of the study. Including moderate responders, eleven were still in response at the end of the study, showing that repeated rituximab dosing had given a sustained response, right to the end of the study for some.

Rituximab in action: binds to CD20 protein on the B-cell surface, triggering cell death. Credit: NIAID


However, for me, the big story of this study is the substantial group who did exceptionally well, though I should stress this is my interpretation of the data in the paper rather than anything the authors have claimed. There is a wealth of data in the paper, down to the level of individual patients. Seven patients – a quarter of those who had maintenance rituximab doses – showed a response that looks close to recovery at the end of the trial, that is, at 32 to 36 months, which is the final data point on the graph of outcomes. Fatigue, SF-36 Physical Function and self-rated daily functioning scores all look very impressive:
  • Seven patients reported the maximum possible fatigue improvement from baseline, that is, major improvement in all four fatigue symptoms. One patient was actually just shy of the maximum, scoring approximately 5.9 out of 6.0 (Fig 2A).
  • Seven had a SF-36 Physical Function score of 85 or more, which is equal to or better than the population average (Fig 5A).
  • Seven had function levels of 80% or higher (someone at 80%-90% is defined as having "slight restrictions in physical or social functioning, who may perform all activities almost as a completely healthy person, but at a reduced pace or duration"), with two scoring 100% (Fig 6B).
All of the patients in the study started with low scores in each of these three areas, so those highs represent huge progress. There is no guarantee that the same seven patients have top sores in each of those three areas, but it seems very plausible.

While the placebo effect and response-bias may occur, they are relatively modest effects. And with ME/CFS, natural recovery rates are low. So these ‘mega-responder’ results strike me as very impressive, and important. Such life-changing improvements are not a common feature of ME/CFS clinical trials.

In the paper, the authors say:
"One pilot patient is still in complete response with no ME/CFS symptoms even after vigorous exercise, five years after the first, and 3 ½ years after the last rituximab infusion”.​

“Some have now had no symptoms for five years," added Fluge, talking to the New Scientist, which also quoted Nancy Klimas:
"I am very intrigued by the rituximab story," says Nancy Klimas, an authority on CFS at Nova Southeastern University in Fort Lauderdale, Florida. "It's particularly exciting when people seem to have experienced very long periods of remission, and even speak of recovery," she says.​


“There was no unexpected toxicity.”
One patient had an allergic reaction to the initial rituximab dose and took no further part in the trial, leaving 28 patients who passed the ‘induction’ phase. A second had an allergic reaction at the three-month infusion and received no further rituximab doses.

Two patients had an episode of uncomplicated late-onset neutropenia, with recovery after five days. ('Neutropenia' means low levels of neutrophils, which are first-response immune cells that are in the front line of the body’s immune response. Late-onset neutropenia is a known side-effect of rituximab treatment: 9% of patients on rituximab got it in one study, but neutrophil levels normally recover.)

Eight patients experienced one or more transient ME/CFS symptom flares after rituximab infusions. One patient developed breast cancer but this was not judged to be related to rituximab.

As Fluge and Mella state:​
“Rituximab maintenance treatment is generally considered safe [the]. However, even if severe adverse effects are rare, they may occur and include defects in immune reconstitution, and reactivation of chronic viral infections such as hepatitis."​
Safety for ME/CFS will be assessed further in the ongoing large clinical trial. Monitoring of rituximab in other illnesses indicate it is generally safe, but not without some risk.​

How does this compare with the PACE Trial?

Just to put them in some sort of context, it's worth making a rough comparison (given available data) with the PACE Trial, whose cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are often presented as the best treatments currently available to ME/CFS patients.

Obviously, PACE was a randomised trial, was very large, and had a control group – but there was no placebo group and the study was 'unblinded' like this one: that is, patients knew if they were in an active therapy group.

The PACE Trial authors claimed a 22% 'recovery' rate for both CBT and GET (compared with 8% for controls), but the recovery rate was built on the primary outcomes of fatigue and function, including an SF-36 Physical Function score of just 60, compared with the 85 I used above. These recovery criteria have been criticised as too weak, both by patients and at least one proponent of CBT.

On this basis, with a quarter scoring 85 or over on SF36 Physical Function, the new rituximab results look very good compared with PACE. We will, of course, have to wait until the full randomised controlled rituximab trial that is under way in Norway is complete before a proper comparison is possible. But in the meantime I think these results are very promising indeed.

Do not try this at home!
These results are promising but please bear in mind the authors’ caution: “We do not encourage the use of rituximab for ME/CFS outside of approved clinical trials, and this is especially important for the group with very severe disease.”

They also reported trying rituximab on four very severely affected patients, with disappointing results.

Evidence of Autoimmunithy
The authors finish up by pointing out that their new results are further evidence that a subgroup of ME/CFS patients have an autoimmune disease. Rituximab is a proven treatment for several autoimmune diseases. It destroys B-cells, wiping out the supply of autoantibodies. Antibodies are produced in bulk by plasma cells (created from B-cells). These are not affected by rituximab and so continue to produce antibodies for several months before dying off. That could explain the pronounced time-lag seen in the clinical responses: it’s not until plasma cells die off and are not replaced (because B-cells have been wiped out) that autoantibodies decline and symptoms improve.

However, say the authors, other mechanisms than autoimmunity may explain the observed clinical effects of B-cell depletion on ME/CFS symptom maintenance. Rituximab influences other types of immune function, including T-cell functioning.

Winning over sceptics
These impressive new results for rituximab are already having an impact. Professor Sir Simon Wessely, a critic of the original rituximab trial, is impressed by the latest findings: “There is now a strong case to be made for a larger trial”, he told the New Scientist. Happily, just such a trial is in progress.

Disclaimer: my section of the blog was put together in a hurry. The paper is huge and while I think I’ve given a fair (though by no means comprehensive) report of the study there may be errors. If so, please let me know!

And back to Sasha...

An opportunity!

This story may well hit the news and if it does, we should hijack the media with our own messages: that ME/CFS is a serious, organic disease and that people should donate to the biomedical research charities (and in this instance, it would be particularly appropriate to mention Invest in ME’s UK rituximab trial fund). This is a great opportunity to educate, win hearts and minds, and grow our donor base. This recent article explains how.

And of course, we too can donate, including via JustGiving. Let’s get to it!

Further resources

Compilation of Phoenix Rising tweets on Dr Fluge and Professor Mella's rituximab presentation at the 2015 Invest in ME conference

Dr Ros Vallings's summary of the 2015 Invest in ME conference, including an account of Dr Fluge and Professor Mella's rituximab presentation

Simon McGrath blogs about ME/CFS research

There are many ways you can help Phoenix Rising to continue its work. If you feel able to offer your time and talent, we could really use some more authors, proof-readers, fundraisers, technicians etc. We’d also love to expand our Board of Directors. So, if you think you can help in any way then please contact Mark through the Forums.

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Continue reading the Original Blog Post
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Nice work, Simon, Sasha. Great article!

I missed some posts in moving from article replies to forum, here... . 'Hope I didn't miss any discussion
re the following:

FWIW, any known Rituximab references published relative to Ampligen ?

I believe we waited ~20 years for Ampligen and seems to have just poofed, though I see its use
occasionally. It would be a shame to see Ritux get short shrift irrespective of its DBPC efficacy.
(The corollary of a DBPC test is that the result works for 'some n' each time; the problem is identifying
the 'n' and raising the statistical significance vs. risk or cure, albeit for some... .)
I agree. I have to wonder about simple fatigue scales as a measure of effectiveness. For example, I pace well enough now that I'm not constantly fatigued, but PEM keeps my activity level low. ..
I just can't like using fatigue as a measure of success or failure in ME/CFS treatment. It seems to me to be focusing on a single, not necessarily core, symptom of the illness. I'd much rather see some measure that centers around PEM.
I think that's a really important point (because it describes my own situation very well :)). I do think fatigue is a useful measure, but maybe not as a primary outcome as here. Though the SF36 scores eg Physical Function (validated) and their own home-grown daily functioning scale tell much the same story in this study - and in the full trial they are using motion sensors as well as CPET.
More explanation of my reasoning in the previous post concerning possible autoantibodies, which have not been identified.

If we had an identified pathogen, we might in fact explain the long delay before dramatic improvement via a mechanism called quorum sensing. No response would appear until the antibodies dropped below a threshold at which the behavior of pathogens suddenly changed. Unfortunately, we have identified neither pathogens nor antibodies at present. Most papers on quorum sensing you find will be about bacteria or cancer cells.

Bacteria are not alone in this behavior, organisms as distant from bacteria as social insects do similar things. (Ever watch bees swarm?) I have doubted that bacteria had such a powerful advantage over immune systems entirely to themselves. What has been missing until now is clear evidence of quorum sensing by immune cells, though the hypothesis has been floated. That paper on a peptide from B-cells limiting recruitment of cytotoxic T-cells to inflamed tissues provides the first clear example I have seen. With healthy B-cells from bone marrow doing local quorum sensing, to break a cycle of diffuse inflammation perpetuated by defective B-cells, both the complete lack of positive response at the time defective cells are depleted, and the dramatic improvement when numbers of healthy cells finally allow them to change quorum sensing behavior of immune cells in damaged tissues, become predictable.
I've no idea what the mechanism of action is for cyclophosphamide in ME patients, because it seems to be a complex drug that works via a variety of immune modulating mechanisms. But Fluge and Mella have reported fast response times. (I'm not sure exactly how fast, but not months like they're seeing with rituximab.) And I think some responders hadn't responded to rituximab. Also, i think I saw someone mention that cyclophosphamide is safer than rituximab, but I don't think that's the case, as it potentially has extreme side effects.
Indeed Cyclophosphaminde presents with quite a few risks which are not present with Rituximab.

1) Bladder toxicity. Bladder cancer risks in the longer term.

2) Febrile neutropenia. Chemo like cyclo kills all cells which are reproducing (mitosis). Blood cells are killed, and there will be a time, usually 7-10 days after the chemo, lasting for approximately 7 days where the neutrophil count will be at its lowest and sometimes not high enough to protect agains any kind of infections including bacteria that lives on your own skin, molds you may have in your home or viruses. This is a common but serious oncology situation which is taken care of efficiently and rapidely if you have cancer but it is a very serious situation which could mean death by sepsis if it is left untreated.

Rituximab's risks are usually infusion related and these reactions usually occur while getting the infusion. While someone had a delayed onset neutropenia while on trial, this is rather rare even in oncology using Rituximab alone.
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Just playing here, comparing responses by type of patient:
  • those who'd had rituximab before, most of whom had shown a transient response
  • those from the placebo group of the previous trial (who'd shown no response)
  • new patients (one of whom was allergic to the first rituximab infusion and took no further part so I excluded from these figures)
I focused on 'mega-responders', those with responses that looked close to recovery as such extraordinary responses are unlikely to be down to placebo respose or response bias (an issue with an open label trial like this). I also included 4 patients who were mega-responders at their peak, but later relapsed, as achieving such a big response at any point is still surprising. Possilby one or two megaresponders were natural recoveries, though the timing of rersponse for all fits with the rituximab dosing (Fig 6D).


The results aren't that different between the three different types of patient - and none of the differences are statistically significant (unsurprising since the samples are small).

Can't remember who made this point (was greeneagledown, here), but three of the seven megaresponders at the end of the trial were patients in their twenties who'd contracted mono (glandular fever) in their teens. In fact there were only three of these teen-mono cases so they all responded. (FWIW, this is statistically significant, p=0.005 for response of teen mono cases vs the rest, but that's a very tweaked post hoc comparision).
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I see that responders who remained well are average age of approx. 35 and started treatment at a score of 33.8 (11 samples). But those who showed response but then declined are average age of approx. 46 (7 samples) and starting score of 19.3 (6 samples).
Does this mean one should start this treatment as young and healthy as possible to stay well ???? and does older people need additional infusions after 24 months to stay well?????
I am 62 and was trying to see if there is any hope for me in this data. Very quick calculations...please correct me if any errors....and please do your own calculations to come to any conclusions.
Not meant to give hope or cause despair to anyone....my apologies in advance.

Non responders : avg. age 40.5 and starting score of 25.9 (9 samples)
I see that responders who remained well are average age of approx. 35 and started treatment at a score of 33.8 (11 samples). But those who showed response but then declined are average age of approx. 46 (7 samples) and starting score of 19.3 (6 samples).
Does this mean one should start this treatment as young and healthy as possible to stay well ???? and does older people need additional infusions after 24 months to stay well?????
I am 62 and was trying to see if there is any hope for me in this data. Very quick calculations...please correct me if any errors....and please do your own calculations to come to any conclusions.
Not meant to give hope or cause despair to anyone....my apologies in advance.

Non responders : avg. age 40.5 and starting score of 25.9 (9 samples)
There are trends suggesting there is an age effect, but the truth is that the sample sizes are not large enough to form any general conclusions. Secondly, even if there was only, say, a 10-20% chance of remission from the drug (assuming no major risks of side effects), would you still take it?
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Re: the measurements of fatigue, I thought I read somewhere (maybe in one the media reports?) details about one of the study patients reporting on actimeter measuremts.

At baseline, her actimeter averaged 800 or something steps/day. She was a strong responder and this also showed up on her actimeter, which now measures 10,000 steps/day.

Did anyone else see this -- or was there any mention of actimeter use in the study paper itself?

Also, wouldn't it be great to have pre and post 2-day CPET tests results. That would be fascinating.
In the paper, they talked about using pedometers on a small number of subjects to test the equipment and see how they were doing. For those who responded to treatment, the average number of steps daily was 9,000+. That is very good as the daily number of steps recommended for healthy people as exercise is 10,000 steps total. Also, for the average stride length, 10,000 steps is equivalent to 5 miles of walking, which is not a small amount. So not surprising those folks were able to get up to 80%+ functioning levels.

They also mentioned using 2-d CPET and other objective measures in the trial that is ongoing.
Vince Racanienello has commented on the study on his blog:


Interesting comment:

Vince Racaniello said:
These results warrant trials of larger numbers of ME/CFS patients in other countries (this study was carried out in Norway) to determine if ablation of B cells would have a similar effects elsewhere.

It would also be useful to determine the total repertoire of antiviral antibodies produced by ME/CFS patients. Such antibodies can be identified using the newly developedVirScan assay, which requires a small amount of blood and is relatively inexpensive.

The results will indicate whether certain viral infections in a large population of ME/CFS patients predispose to the illness. Furthermore, the results may also be used to guide efforts to determine whether such antibodies react with human cellular proteins.

A similar approach was used to determine that antibodies to an influenza virus protein cross react with a neuropeptide receptor, leading to narcolepsy.
Interesting wording, too.

Is he hinting results may be different along national boundaries? There are certainly many geopolitical and cultural differences between Norway and Spain and Ireland etc. For instance, they all boast different dominant languages. Perhaps whether B cell ablation works is a cultural thing.
Thanks for this blog!

About the timeline: The trial will end 24 months after the date when patient no 152 has received his/hers first infusion. One of the sites in Norway is lagging behind, so it seems patient no 152 won't be included until mid- or late fall this year. That means the study would end fall 2017 – when they will break the code. After that all the analysis and writing-up remains - plus the publishing process...
I realise this is somewhat late now but this is a really great article @Simon and @Sasha ! I've been trying to keep up with the Fluge and Mella story as best I can and this latest trial is certainly very interesting and promising in equal measure! The reporting on both a personal and scientific level is fantastic as usual too which really engages the research and highlights the promise these trials have. It has to be said that I'm very out of the loop now in terms of the cutting edge ME/CFS research and ongoing trials so I very much appreciate articles like this which allow me to try my best to keep up!
@Sasha It is indeed a good sign; I would say I'm 95% of my old self pretty much all the time now. I finished my first year of university in the academic year and managed 81% somehow or other and am currently enjoying a nice relaxing summer before returning in late September - with university, my relationship and other assorted commitments I simply don't get the time to keep up with these exciting new trials and papers so I very much appreciate these articles. To think I'd ever feel like this again 2 years ago would have been impossible, I have to thank PR for getting me through the worst of it! I guess the notion that when people feel better they don't post anymore holds true!
Mella and Fluge are Nobel candidates. Amazing discovery they have accomplished.