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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.


Results

"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


Mega-responders?


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.​


Safety

“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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Comments

Do you know if there is any methodology being developed that would help determine which patients would be the best candidates for this treatment?
The Phase III trial is collecting lots of data that will help get some preliminary findings on these questions. The UK study has fixed on a B cell metric that they think will be worth following through the UK Rituximab study; my understanding is that the ideal finding would be that it correlates with those who respond to Rituximab. So yes, I think this question is being explored as a priority, and in an entirely appropriate way. It's going to take years to work these things out though. Cyclophosphamide works on a shorter timescale, so the next big clues might come from the research on that.
 
Cyclophosphamide works on a shorter timescale, so the next big clues might come from the research on that.
Shorter timescale in what sense? It wipes out B-cells faster or something (and again, I wasn't the scientist on this paper!).

@Simon?
 
Shorter timescale in what sense? It wipes out B-cells faster or something (and again, I wasn't the scientist on this paper!)
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.
 
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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 Fluga 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.
Thanks, Bob.

This is confusing, because:

Simon said:
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.
So the delay in rituximab's action seems inherent in it working by wiping out B-cells: there's a built-in delay because of how long it takes the plasma cells to die off. So cyclophosphamide doesn't kill B-cells off?

Here's what it says about cyclophosphamide's mechanism of action on Medscape:

Medscape said:
These compounds crosslink DNA by adding an alkyl group (CnH2n+1) to the guanine base of DNA, at the number seven nitrogen atom of the imidazole ring. This induces inhibition of DNA replication, leading to cell death. CYC exerts its cytotoxic effect on both resting and dividing lymphocytes. Its precise mechanisms in treatment of autoimmune diseases are not well established. In patients with rheumatoid arthritis, CYC has been shown to suppress T-helper cell functions with prolonged reduction of B cells due to the slower rate of recovery of B lymphocytes from an alkylating agent.
 
@Sasha, yes, I agree that it's confusing. I asked Jonathan Edwards about this, and he provided a helpful answer. But I can't remember what he said! :ill: I think he might have said that its treatment effect for autoimmunity may work via a b-cell mechanism, but I'm not sure. I'll have a hunt for his post.
 
"The authors finish up by pointing out their new results are further evidence that a subgroup of ME/CFS patients have an autoimmune disease." I think this was attributed to Simon (thank you to both Simon and Sasha for your excellent efforts!), but it's what the study's authors apparently wrote. Regardless it both confuses and concerns me.

I do not think we should say that some ME/CFS patients have an autoimmune disorder, and some don't. It's like we are uncertain about what ME/CFS is - which maybe we are, but this is not nuanced, it's a large mallet striking readers between the eyes. You cannot say some ME/CFSers' symptoms are due to an autoimmune disorder, anymore than you can say some ME/CFS patients symptoms are due to cancer - they either have cancer, or they have an autoimmune disorder, one of which may have the label 'ME/CFS', but that label would have to apply to all who have ME/CFS.

How we each got to ME/CFS may be different, and indeed, those pathways may be heterogeneous, but if ME/CFS is an autoimmune disease triggered by EBV or an enterovirus or Borrelia etc, it is nevertheless an autoimmune disease for all who have ME/CFS.

If my Lyme led to ME/CFS, then I have ME/CFS. But if I what I suffer from is some form of persistent Lyme, then I do not have ME/CFS, any more than someone with a post viral syndrome might. (I understand the two are not mutually exclusive, but for the sake of my point...)

If ME/CFS is an autoimmune disorder, then it is an autoimmune disorder for all. This not a transition; it is the end point. What got us here may be peculiar to each, but the destination is shared. Like cancer.

I think it would be just as odd to state that a subgroup of MS is an autoimmune disorder. This is definitional.

Or am I missing something?
 
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@Sasha, it seems that Jonathan Edwards has had quite a bit of discussion on the forum re cyclophosphamide, which he confirms is a proper 'chemotherapy' type of drug, unlike rituximab. Below is a list of some of his most relevant posts that you can peruse at your leisure, if it interests you. He suggests that cyclophosphamide may work as a treatment for ME partly via a b-cell modulating mechanism, but also possibly by other additional mechanisms, such as knocking out plasma cells:
http://forums.phoenixrising.me/inde...rtx-might-be-working.37669/page-2#post-601787
http://forums.phoenixrising.me/inde...archers-at-haukeland.34262/page-7#post-554235
http://forums.phoenixrising.me/inde...archers-at-haukeland.34262/page-7#post-554240
http://forums.phoenixrising.me/inde...archers-at-haukeland.34262/page-8#post-554515
http://forums.phoenixrising.me/inde...archers-at-haukeland.34262/page-9#post-561066
http://forums.phoenixrising.me/inde...archers-at-haukeland.34262/page-9#post-561360
 
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A label based on symptoms does not have to be the same disease/disorder for all.

I think they mean there are enough indications for a subgroup to call it autoimmune, the rest has to wait till there is revealed more by the research..
 
@lansbergen , agreed, a label based on symptoms does not have to be the same.

But autoimmune is not based on symptoms, it is defined by lab signs, no? I mean, yes, there are symptoms, but it is known by its lab signs - in this case, reactions to B cell depletion.

Aach, my brain is misfiring probably.
 
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[Re Megaresponders]
What can account for this dramatic change? Is the only difference the maintenance doses every three months?
Not sure if you mean dramatic change from baseline, or from original trial?

Vs orginal trial:
There were almost certainly similar huge (but transient) gains in their placebo-controlled trial, but you had to look very hard at the data in the paper to work it out (though I think they presented such data in private at an IiME conference). For a few patients these gains were maintained beyond that trial, even without further rtx doses: this paper says that 4 out of ten responders in that original study maintained some responde beyond the 12 months of the study itself - but didn't say how much beyond the 12 months, or how big a response.

Compared with baseline
, well, yes, you'd think it was the rituximab and the repeat dosing. Apart from the huge gains being most unlike a placebo response (or spontaneous recovery on that scale), the time lag before clinical response (average of 23 weeks for major responders), and the relapse for some after rtx dosing ended suggests it was rtx driving the changes. If the improvements were all by chance or placebo, you'd expect a more random distribution of change.

Intriguingly, they included 9 patients who received placebo in the first trial and didn't show any response then, or in the following twelve months. And they compared the first 12 months for those patients in the new study (ie on rtx) with their data for 12 months in the placebo group. There is a huge difference - take a look at Fig 4

That is pretty damn amazing, Simon, especially considering that some of these were non-responders in the original trial.
In a way, that works the other way around. Of ten who'd had rtx in previous studies, 7 had shown a transient response. 5 responded well in this study (looking at the data in more detail, it looks like these include 3-4 of the 7 megaresponders (ah, think that's important). While only 1 of the three non-responders did well in this study.

So the delay in rituximab's action seems inherent in it working by wiping out B-cells: there's a built-in delay because of how long it takes the plasma cells to die off. So cyclophosphamide doesn't kill B-cells off?
Shorter timescale in what sense? It wipes out B-cells faster or something (and again, I wasn't the scientist on this paper!). @Simon?
In the paper F&M point out rituximab works in ways other than wiping out B-cells, including effects on T-cells.
 
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A label based on symptoms does not have to be the same disease/disorder for all.

I think they mean there are enough indications for a subgroup to call it autoimmune, the rest has to wait till there is revealed more by the research..
If a patient has a no positive reaction to one autoimmune treatment, it doesn't mean that this patient doesn't suffer from an autoimmune disease. They could be resistant to this specific treatment. There is no autoimmune treatment out there that works for ALL patients suffering from a particular autoimmune disease.

To absolutely label patients whether they suffer from the same disease by their reaction to one specific drug is lunacy.
 
Just want to make clear before I begin that I am not making a personal criticism of doctors who are making an honest effort to deal with a confusing disease in a terrible social and historical context. This research is like a breath of fresh air. It is a beginning, not an end.

I'm still pushing for a better explanation of what Rituximab is doing, which can lead to better targeting of malfunctioning immune cells. The talk about cyclophosphamide disturbs me in this regard because it is less selective in action. When doctors treating rheumatoid arthritis "fall back" to a drug like methotrexate after a crisis with cyclophosphamide, considering all the known problems with methotrexate, I remain wary. We are dealing with drugs that cause extensive damage to immune systems on the simplistic theory the problem is "too much" immune response. Most questions about how immune systems reconstitute themselves after successful treatment remain unanswered.

The "hand-waving" argument about unknown autoantibodies could actually be modeled quite well to predict response. Antibody production by CD20 B-cells themselves would stop immediately when they were depleted, while there would be a predictable fall-off in antibody production by plasma cells which were already in existence. This would follow a steady decreasing curve over time, starting at the time of treatment. To get the pattern of response seen here you would need to postulate an additional factor: a threshold at which these unknown antibodies become ineffective. Talk about other factors changed by these drugs takes us even deeper into postulating unknowns.

On the other hand, if I assume some of the depleted B-cells are defective, and, in the case of responders, those generated from precursors in bone marrow are not defective, the idea that the benefits of treatment depend on actions of the population of B-cells without defects works very well. This might be the case if the problem is not an autoantibody but some positive action by undamaged B-cells like production of a peptide which limits recruitment of cytotoxic T-cells.
 
To absolutely label patients whether they suffer from the same disease by their reaction to one specific drug is lunacy.
Couldn't agree more. We'd better not see all the focus shifting to the 2/3 patients who respond to rituximab with the rest being labelled as "psychiatric".
 
Couldn't agree more. We'd better not see all the focus shifting to the 2/3 patients who respond to rituximab with the rest being labelled as "psychiatric".
I agree. Luckily Drs Fluge and Mella aren't giving up on the non-responders to rituximab. They just keep looking for answers. I expect we don't even know the half of what they're doing.
 
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.
 
I'm still pushing for a better explanation of what Rituximab is doing, which can lead to better targeting of malfunctioning immune cells.
On the other hand, if I assume some of the depleted B-cells are defective, and, in the case of responders, those generated from precursors in bone marrow are not defective, the idea that the benefits of treatment depend on actions of the population of B-cells without defects works very well. This might be the case if the problem is not an autoantibody but some positive action by undamaged B-cells like production of a peptide which limits recruitment of cytotoxic T-cells.
Interesting, but think would be helpful to have @Jonathan Edwards input here, and I think he's doing other things

Did anyone else see this -- or was there any mention of actimeter use in the study paper itself?
Yes brief, and not quite in the context you mention i.e. just worn as a one off (no comparison with baseline)

study said:
After 15–20 months follow-up, we had available Sensewear electronic armbands that continuously measured physical activity in the home setting. No data from baseline before intervention were available. The analyses were not preplanned, and were performed only in some patients (mainly in responders). They were performed in order to gain experience with the armbands for design of the protocol for the now ongoing randomized phase III-study. However, 12 out of 14 major responders in this study measured physical activity for 4–6 consecutive days in the time interval 15–20 months follow-up, with a mean value for “mean number of steps per 24h” 9829 (range 5794–18177), and a mean value for “maximum number of steps per 24h” 14623 (range 9310–23407).

These activity data are not valid for formal response characterization, but the counted number of steps per day for major responders corresponded with the level found in the normal population, and thus support the SF-36 data also showing that major responders in the time interval 15–30 months follow-up report SF-36 subdimensions at the mean level of the general population (Table 1, Table 4, Fig 5, Fig 6, S7 Fig).
btw, the Sensewear device looks pretty good at measuring real world activity (previous CBT studies have used unvalidated ones built in university departments, that may work better on treadmill activity than real world functioning).
 
Also, wouldn't it be great to have pre and post 2-day CPET tests results. That would be fascinating.
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'm not sure if I answered pre- and post-fatigue questionnaires the results would look dramatic even if my activity level skyrocketed because I could do much more without PEM. Surely some patients in the research cohort are also pacing well enough not be to constantly fatigued. Maybe I don't understand the fatigue questionnaires they're using. :confused:

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.

Love the quality of this research, and the results, though. :thumbsup:
 
Has anyone else noticed that Pubmed is down? Do you think the study caused such a sensation the servers couldn't handle it, or do you think the psychosomatic brigade are resorting to cyber warfare now?
 
I hate it when my computer does this, it's like it's censoring me.