Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Jonathan Edwards]

Sandra Kweder of the FDA, in last year's teleconference with patients spoke briefly to the challenge of getting drug companies involved, at least in drug research in the U.S.

"One of the challenges [is] to try and get the companies interested in investing in products to treat a condition.One of the things that we've learned from experience is you've got to be able to define the condition well and they [pharma] need to - they want to know where are the rules about studying it. What am I going to have to show in order to get a drug approved?"​

​

Good definition and agreed upon rules on how to measure the effect of the drug so it can be approved.

There are a few good definitions produced by experts but there are also awful definitions that are more well known, certainly more often used, describe a very different set of patients and have resulted in studies that feed gross misperceptions of the disease

As far as how to measure drug effect, there are a number of ways that could be used. But which ones could pharma use with confidence that the FDA would accept it?

Drug research is very high risk, resulting in many dead failures after years of work. If I am pharma with a choice between this disease and some other disease that is more clearly defined and where the methods to measure effect are agreed, I expect I'd choose the other disease.

Yes, I think it's something like that. The company got interested in RA once I had shown the drug seemed to work. But there are a lot of things different now.

 

[Legendrew]

I'm not sure whether you're aware of the news that has been discussed today regarding Hornig and Lipkins search for pathogens and potential biomarkers: simply put they found little evidence of active infections in 281 patients with ME agaisnt 201 controls (and they did quite a large number of commonly discussed ones in ME/CFS) - believe in 85% they found retroviral sequences but it was made very clear that they do not know whether these are important to ongoing disease and made a comment that they believe this will not be significant, however they found a few interesting leads signalling immune activation.

These include: in Plasma
in patients with less than 3 years of disease, increased Eosinophil in blood - allergy aspect?
General group:
differences in cytokines/chemokines:
decreases in IL17, 2, 8 and TNF
increases in leptin and serpin
less than 3 years specifically: frequent elevation in cytokine IL17 compared to those after 3 years where it appears to then become deficient

Spinal fluid:
very different pattern:
patients elevated IL10, IL 13 (TH2) and 4 generally regarded at TH1
only difference between classic cfs patients those who go on to develop other diseases later (such as lymphoma) was FGH beta increased in those who developed lymphoma.

Fundamentally, after approximately 3 years the profile seems to change quite substantially with regard to this ongoing immune response at least in terms of biomarkers, obviously this work is ongoing but it would be a very interesting part of the disease - is this change something that occurs in any other known autoimmune conditions?

To me these changes seem somewhat non-specific and point towards the general immune dysregulation as would be expected in an autoimmune condition but I wanted to put these to you in case anything jumps out at you.

They concluded that they believe the problems could lie in the gut microbiome and are collecting and looking at fecal samples - from a personal view I don't believe the answer lies here but you never know.

My question here is as to whether these biomarkers are things you would expect to see in an autoimmune disease which ME is being hypothesised to be. For me this virus hunting seems to be leading nowhere again but I know many people believe very strongly in it but I think the biomarkers of active immune response is interesting and could support autoimmunity. Sorry if this doesn't make much sense - I openly admit to not being best informed on this virus stuff and i was making notes while listening to it, but I would be interested to hear your input on the topic!

 

[Jonathan Edwards]

I'm not sure whether you're aware of the news that has been discussed today regarding Hornig and Lipkins search for pathogens and potential biomarkers: simply put they found little evidence of active infections in 281 patients with ME agaisnt 201 controls - however they found a few interesting leads signalling immune activation.

These include: in Plasma in patients with less than 3 years of disease, increased Eosinophil in blood - allergy aspect?
General group:
differences in cytokines/chemokines:
decreases in IL17, 2, 8 and TNF
increases in leptin and serpin
less than 3 years specifically: frequent elevation in cytokine IL17 compared to those after 3 years where it appears to then become deficient

Spinal fluid:
very different pattern:
patients elevated IL10, IL 13 (TH2) and 4 generally regarded at TH1
only difference between classic cfs patients those who go on to develop other diseases later (such as lymphoma) was FGH beta increased in those who developed lymphoma.

Fundamentally, after approximately 3 years the profile seems to change quite substantially - is this change something that occurs in any other known autoimmune conditions?

To me these changes seem somewhat non-specific and point towards the general immune dysregulation as would be expected in an autoimmune condition but I wanted to put these to you in case anything jumps out at you.

They concluded that they believe the problems could lie in the gut microbiome and are collecting and looking at fecal samples - from a personal view I don't believe the answer lies here but you never know.

My question here is as to whether these biomarkers are things you would expect to see in an autoimmune disease which ME is being hypothesised to be. For me this virus hunting seems to be leading nowhere again but I know many people believe very strongly in it but I think the biomarkers of active immune response is interesting and could support autoimmunity. Sorry if this doesn't make much sense - I openly admit to not being best informed on this virus stuff and i was making notes while listening to it, but I would be interested to hear your input on the topic!

Thanks, and well done, Andrew, this is interesting and encouraging.
You may not be a gardener, but I am, and when I recently walked past some cottages in Walberswick I could tell which gardens were lovingly tended by the owner and which had some chaps in a van come along once a fortnight to make it look pretty. Real gardening has a sort of meaningful messiness and unexpectedness to it. Even in your quick precis these results look like real gardening to me.

The fact that they report what they **did not** find is the hallmark of the spade owner. I agree it looks as if persistent viruses are not going to turn out to be important and that seems good since we are not very good at treating viruses.

Not many autoimmune diseases show eosinophils up, but one group does and it certainly suggests an over-vigorous immune response, if no more. What I find particularly interesting (jumps out) is they found TNF to be decreased. That would fit with the idea that 'inflammation' is too crude a concept for what we are looking for. This suggests some activation of immune pathways that does not involve the 'classical inflammatory cytokine' TNF. I think we should expect that in a real garden. It would explain why people feel awful but the CRP is normal(ish). IL17 looks to be an important cytokine but has not been clear which diseases it is most relevant to. A switch from high to low may be a fluke of these data but again it could be the meaningful messiness of a real lead. The CSF differences also have that quirkiness about them - and I suspect are further evidence that thinking in terms of TH1 and TH2 is a waste of time.

Some autoimmune diseases change with time, but most tend not to switch. But there are other aspects of ME that suggest that it might be a bit unusual in having an early phase and a late phase. I don't think one can draw a hard conclusion from this. And of course we may have two groups here and one may be a bit like a Reiter's T cell response that still might have a B cell loop bound up in it. I don't think we can untangle this yet.

I agree that gut microbes may not be the answer (the old genetics/environment story?) but I am not putting any beer on being right on that. It is well worth looking at.

All in all this seems very plausible support for the idea that in ME the immune system thinks it is fighting infections but is just in an overbusy loop. That might include some people B cell looping with autoimmunity and others T cell looping with something like Reiter's. What I find most encouraging is that within this there begins to look to be a signature - TNF low, IL17 up then down. And for those who feel it is important to establish that there is genuine brain pathology, not just disease beliefs, the CSF findings look promising.

You might say why is this not just another one off set of results that means nothing until repeated? It will need repeating but I have a feeling at least one of these findings may turn out to stand up and be useful because it has that slightly messy meaningfulness we were talking about before.

 

[currer]

Rituximab is highly successful in treating rheumatoid arthritis, some cancers and the profound fatigue experienced by patients with an immune liver disease known as Primary Biliary Cirrhosis." comment taken from here: http://www.ncl.ac.uk/press.office/p...ether-to-discover-biological-causes-of-cfs-me

It's interesting that Rituximab seems to be being used to treat the fatigue in PBC rather than to treat PBC itself, unless I'm reading too much into the wording.

That's odd, I've just discovered that I have a cousin on my fathers side of the family who died from Primary biliary Cirrhosis. I thought it was very rare.

I have another cousin with severe ME and a sister with ME (and me of course). And a brother who has Aspergers syndrome.
All the illness comes from my father's side.

 

[MeSci]

Thanks, and well done, Andrew, this is interesting and encouraging.
You may not be a gardener, but I am, and when I recently walked past some cottages in Walberswick I could tell which gardens were lovingly tended by the owner and which had some chaps in a van come along once a fortnight to make it look pretty. Real gardening has a sort of meaningful messiness and unexpectedness to it. Even in your quick precis these results look like real gardening to me.

The fact that they report what they **did not** find is the hallmark of the spade owner. I agree it looks as if persistent viruses are not going to turn out to be important and that seems good since we are not very good at treating viruses.

Not many autoimmune diseases show eosinophils up, but one group does and it certainly suggests an over-vigorous immune response, if no more. What I find particularly interesting (jumps out) is they found TNF to be decreased. That would fit with the idea that 'inflammation' is too crude a concept for what we are looking for. This suggests some activation of immune pathways that does not involve the 'classical inflammatory cytokine' TNF. I think we should expect that in a real garden. It would explain why people feel awful but the CRP is normal(ish). IL17 looks to be an important cytokine but has not been clear which diseases it is most relevant to. A switch from high to low may be a fluke of these data but again it could be the meaningful messiness of a real lead. The CSF differences also have that quirkiness about them - and I suspect are further evidence that thinking in terms of TH1 and TH2 is a waste of time.

Some autoimmune diseases change with time, but most tend not to switch. But there are other aspects of ME that suggest that it might be a bit unusual in having an early phase and a late phase. I don't think one can draw a hard conclusion from this. And of course we may have two groups here and one may be a bit like a Reiter's T cell response that still might have a B cell loop bound up in it. I don't think we can untangle this yet.

I agree that gut microbes may not be the answer (the old genetics/environment story?) but I am not putting any beer on being right on that. It is well worth looking at.

All in all this seems very plausible support for the idea that in ME the immune system thinks it is fighting infections but is just in an overbusy loop. That might include some people B cell looping with autoimmunity and others T cell looping with something like Reiter's. What I find most encouraging is that within this there begins to look to be a signature - TNF low, IL17 up then down. And for those who feel it is important to establish that there is genuine brain pathology, not just disease beliefs, the CSF findings look promising.

You might say why is this not just another one off set of results that means nothing until repeated? It will need repeating but I have a feeling at least one of these findings may turn out to stand up and be useful because it has that slightly messy meaningfulness we were talking about before.

I wonder whether this thread about viruses that become incorporated into DNA may be significant to some of these points?

I've noticed that many people report different symptoms at the beginning of the illness from those which develop later, and it is certainly my own experience. This could fit with the biochemical changes.

 

[MeSci]

Rituximab is highly successful in treating rheumatoid arthritis, some cancers and the profound fatigue experienced by patients with an immune liver disease known as Primary Biliary Cirrhosis." comment taken from here: http://www.ncl.ac.uk/press.office/p...ether-to-discover-biological-causes-of-cfs-me

It's interesting that Rituximab seems to be being used to treat the fatigue in PBC rather than to treat PBC itself, unless I'm reading too much into the wording.

That's odd, I've just discovered that I have a cousin on my fathers side of the family who died from Primary biliary Cirrhosis. I thought it was very rare.

I have another cousin with severe ME and a sister with ME (and me of course). And a brother who has Aspergers syndrome.
All the illness comes from my father's side.

and my father had RA. There have been threads and at least one blog about connections with autism, which has often been linked to gut problems (floral imbalance, acidosis) as has ME/CFS. Some of us did online questionnaires for autism and found that we were actual or borderline Aspie. I come out borderline on two different ones. Of course it may just mean that Aspies like using internet forums and/or are particularly drawn to PR!

 

[Marco]

Jonathan Edwards

Earlier in the thread you stated that the onset of autoimmunity is essentially a random event which would seem to imply that at some point in time you move from being well to unwell.

From what I've read of stiff person syndrome (which I believe is considered an autoimmune condition) patients may have a period before the onset of the characteristic symptoms where anxiety and vague stiffness is the only problem with the result that many are treated for 'mood disorders' and once the muscle spasms become debilitating they are also often diagnosed with kinesiophobia. I don't know how long this 'pro-dromal' period can last.

Is it possible for an autoimmune disease to have a 'slow burn' trajectory with certain symptoms experienced - perhaps not even those cardinal symptoms of the disease' - for some time (maybe even decades) before the full onset of physical symptoms?

In other words 'onset' may seem sudden but is really just a transition in the level of severity?

 

[Legendrew]

Jonathan Edwards

Earlier in the thread you stated that the onset of autoimmunity is essentially a random event which would seem to imply that at some point in time you move from being well to unwell.

From what I've read of stiff person syndrome (which I believe is considered an autoimmune condition) patients may have a period before the onset of the characteristic symptoms where anxiety and vague stiffness is the only problem with the result that many are treated for 'mood disorders' and once the muscle spasms become debilitating they are also often diagnosed with kinesiophobia. I don't know how long this 'pro-dromal' period can last.

Is it possible for an autoimmune disease to have a 'slow burn' trajectory with certain symptoms experienced - perhaps not even those cardinal symptoms of the disease' - for some time (maybe even decades) before the full onset of physical symptoms?

In other words 'onset' may seem sudden but is really just a transition in the level of severity?

Interesting question - especially given that some ME patients experience sudden very severe onset following viruses, vaccinations, stress etc etc while some refer to an incredibly slow decline over years and sometimes even decades. I've read a few times that slow onset is a negative predictor for prognosis while acute onset have a better (albeit still not great) chance of improvement and possibly even recovery - i'm not sure how well researched this is but it does seem unusual. Perhaps in those who progress slowly the process is very slow whereas in sudden onset the sudden intense immune activation drastically increases the progression on the disease. Unfortunately I imagine this to be a very difficult topic - I wouldn't be surprised if we have treatments before the answer to this question becomes apparent.

 

[Marco]

wouldn't be surprised if we have treatments before the answer to this question becomes apparent.

You may be right and fingers crossed - but after nigh on 30 years of this nonsense I'm not overly optimistic of any meaningful treatment in my lifetime.

I'd settle for a few answers though!

 

[Sasha]

Cort Johnson wrote this about last year's XMRV press conference held by Dr Lipkin:

http://www.prohealth.com/library/showarticle.cfm?libid=17220​

​

Looking back at his own 1990 negative Borna Virus/ME/CFS study, Dr. Lipkin emphasized the enormous amount of immune activation he'd uncovered, with two-thirds to three quarters of the patients exhibiting polyclonal B-cell activation. ME/CFS, he said, "is not a psychosomatic disorder.”​

Jonathan Edwards - this discussion is way over my head now but do you think that patients exhibiting polyclonal B-cell activation are the ones that Rituximab might work for? And if so, do you think that 2/3 to 3/4 of patients might be responders?

I'm thinking it's interesting that Fluge & Mella got roughly 2/3 Rituximab responders and Lipkin is talking about a similar proportion of patients with B cell issues, even though they presumably had different selection biases (Fluge & Mella taking referrals from a neurology department, I think).

I'm afraid mine isn't a well-informed questiion - I'm just reacting to the mention of B cells.

 

[Jonathan Edwards]

Jonathan Edwards

Earlier in the thread you stated that the onset of autoimmunity is essentially a random event which would seem to imply that at some point in time you move from being well to unwell.

From what I've read of stiff person syndrome (which I believe is considered an autoimmune condition) patients may have a period before the onset of the characteristic symptoms where anxiety and vague stiffness is the only problem with the result that many are treated for 'mood disorders' and once the muscle spasms become debilitating they are also often diagnosed with kinesiophobia. I don't know how long this 'pro-dromal' period can last.

Is it possible for an autoimmune disease to have a 'slow burn' trajectory with certain symptoms experienced - perhaps not even those cardinal symptoms of the disease' - for some time (maybe even decades) before the full onset of physical symptoms?

In other words 'onset' may seem sudden but is really just a transition in the level of severity?

Yes, there are several situations where it seems that an autoimmune loop is set up months or years before any symptoms. In RA this is thought to be the usual situation. Sometimes rather trivial features are present for years before typical symptoms appear. The loops that I envisage would be able to feed off other loops so over a period of time the disease may evolve and become more complex. This is quite often seen in RA. In lupus all sorts of shifts in symptoms and signs can occur. In a number of conditions Raynaud's phenomenon seems to occur before the major symptoms become apparent. And so on. Hyperthyroidism can change to hypothyroidism and vice versa. I have even seen classical long term RA turn into giant cell arteritis, with the RA disappearing.

 

[Jonathan Edwards]

Cort Johnson wrote this about last year's XMRV press conference held by Dr Lipkin:

http://www.prohealth.com/library/showarticle.cfm?libid=17220​

​

Looking back at his own 1990 negative Borna Virus/ME/CFS study, Dr. Lipkin emphasized the enormous amount of immune activation he'd uncovered, with two-thirds to three quarters of the patients exhibiting polyclonal B-cell activation. ME/CFS, he said, "is not a psychosomatic disorder.”​

Jonathan Edwards - this discussion is way over my head now but do you think that patients exhibiting polyclonal B-cell activation are the ones that Rituximab might work for? And if so, do you think that 2/3 to 3/4 of patients might be responders?

I'm thinking it's interesting that Fluge & Mella got roughly 2/3 Rituximab responders and Lipkin is talking about a similar proportion of patients with B cell issues, even though they presumably had different selection biases (Fluge & Mella taking referrals from a neurology department, I think).

I'm afraid mine isn't a well-informed questiion - I'm just reacting to the mention of B cells.

It does look as if one could reasonably expect that. I have tended to think Fluge and Mella would have been lucky to have more than 50% B cell related cases and maybe the extra two patients were the matching placebo responders for the two controls that responded. But then even diseases where we know everyone's symptoms are B cell related we do not get 100% response rates. I think there is actually quite a lot of evidence around suggesting that the majority of ME is B cell related but I want to err on the side of caution. I certainly hope that in a year or two we will have a much clearer idea on that.

 

[bertiedog]

This was definitely what I experienced having had what I thought was flu for 2 weeks in 1979 but I never fully recovered. After this the frequent vertigo and migraines started which were so bad I was housebound for days on end. Over time I wasn't housebound but never lost these sort of attacks.

From then onwards I seemed to pick up every virus that was going round and it often turned into an infection in my case. As I was teaching in a school it was far from ideal and meant that for the majority of time there was always something wrong with me. Things went on like this with me only able to work part time until I got some really bad infections either of my respiratory tract or gut during the mid 90s and I finally crashed in 2000 and was unable to work any longer. In my case the fatigue didn't really hit until around 1997 and then it would only come in bouts and I would recover but this changed in 2000.

When I look back it feels as if it was some sort of progressive problem I had. No matter what I did in trying to live a healthy lifestyle nothing worked and I just got sicker and sicker.
Thankfully I am now a lot better due to lots of things like thyroid/adrenal meds, methylation support and also breathing oxygen 3 times daily from my oxygen concentrator.

I am hoping that there will be a much better future for everyone with ME/CFs because the past has been dire and I consider myself one of the lucky ones who could afford some private treatment here in the UK.

Finally I am very grateful to Professor Edwards for all the time he is putting into this research.

Pam

 

[user9876]

Interesting question - especially given that some ME patients experience sudden very severe onset following viruses, vaccinations, stress etc etc while some refer to an incredibly slow decline over years and sometimes even decades. I've read a few times that slow onset is a negative predictor for prognosis while acute onset have a better (albeit still not great) chance of improvement and possibly even recovery - i'm not sure how well researched this is but it does seem unusual. Perhaps in those who progress slowly the process is very slow whereas in sudden onset the sudden intense immune activation drastically increases the progression on the disease. Unfortunately I imagine this to be a very difficult topic - I wouldn't be surprised if we have treatments before the answer to this question becomes apparent.

Rather than a sudden or slow onset what I've observed is an initial mild level following being ill which is followed by a series of relapses after over doing things till the ME is severe.

 

[Marco]

Rather than a sudden or slow onset what I've observed is an initial mild level following being ill which is followed by a series of relapses after over doing things till the ME is severe.

Or in my case a series of step changes (down) followed by the same level of illness for a number of years followed by another step change down. Not at all relapsing and remitting.

 

[Snow Leopard]

You might say why is this not just another one off set of results that means nothing until repeated? It will need repeating but I have a feeling at least one of these findings may turn out to stand up and be useful because it has that slightly messy meaningfulness we were talking about before.

There have been more than a handful of prior CSF studies and at least two of them measured cytokines. Potentially interesting for data mining were the Natelson/Baranaiuk proteome studies, those studies generate a lot of data, but I don't really think anyone knew what the data really meant. It is hard to know what to look for until you have a lead.

One of the first ones was in 1991 and had a limited panel only, and found elevated IL-10.
http://jid.oxfordjournals.org/content/164/5/1023.extract

A more comprehensive study was done by Natelson and colleagues and found elevated IL-8 in one subgroup and elevated IL-10 in another.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC540195/

One of the claimed functions of IL-10 is:
"IL-10 is released by cytotoxic T-cells to inhibit the action of NK cells during the immune response to viral infection".
http://en.wikipedia.org/wiki/Interleukin_10

It seems to make sense in light of the consistently replicated findings of reduced NK cell activity.

Not a specific finding, but it looks to be a potentially consistent one.

A side note, Theo Theoharides has put forth a hypothesis involving increased Mast cell activity and was presenting again at recent conferences in the USA.
http://cfids-cab.org/cfs-inform/Hypotheses/theoharides.etal05.pdf

 

[Snow Leopard]

Jonathan Edwards, an often unappreciated aspect of CFS is the fact that many, dare I say most patients can no longer fully tolerate foods that they were formerly able to eat.

My personal experience is that I had unexplained eczema that I was convinced was dietary, specifically I thought it was due to eating wheat.
I saw a immunologist that was very helpful, however I found that I wasn't actually allergic to any foods. At the same time, I mentioned hydrogen breath testing and he knew where it could be done in my city and how to get a referral. Now I was interested as DeMeirlier had suggested that a substantial portion of patients have abnormal results during hydrogen breath testing, particularly for fructose. I was surprised therefore when the results came back and said that I had malabsorption of lactose and the lab also noted a 'high background level, which was interesting.

I managed to cut out lactose from my diet over time (eliminating cheese was the hard bit, I've never liked milk). What was interesting what that it had no effect on my CFS related symptoms, but my gut is much more tolerant of foods now and I rarely get eczema now. (usually these days it is due to eating chocolate).

While it might not be the central cause of CFS, there are definitely issues related to the gut that may be uncovered by the study that Ian Lipkin wants to do.

 

[Jonathan Edwards]

Jonathan Edwards, an often unappreciated aspect of CFS is the fact that many, dare I say most patients can no longer fully tolerate foods that they were formerly able to eat.

While it might not be the central cause of CFS, there are definitely issues related to the gut that may be uncovered by the study that Ian Lipkin wants to do.

Yes, it looks as if the CSF IL10 story might hold up and that would make sense both for NK changes and also for B cell involvement. Encouraging.

I agree that gut symptoms may be relevant. I have a mild malabsorption, probably from lactose intolerance, following travel in the Far East. My father in law had the same thing after military duties in Burma. We used to call it tropical sprue. I doubt that there are any specific pathogens there though - I treated myself for the so-called commensal entamoebae I had and that may have helped the midnight tummy ache but not the malabsorption much. Some sort of general gut hypersensitivity would seem to make sense - although in my case for another reason. The gut is full of plasma cells and plasma cells love IL10 - so there's another way to link up.

One problem is we have too many ways to play the story, I think. But trying to put together detailed stories is worthwhile because it can throw up testable predictions. Giving cytokine producing bacteria sounds clever, although maybe not the right thing in this case.

 

[Marco]

In the context of previous discussions about inflammation (or lack of) I found the CSF findings interesting given that these were much more consistent than the serum ones :

I will now talk about spinal fluid. Again, we’re using the bio-sequence strategy, where we are using the Luminex, the same one we used for plasma, to measure levels of cytokines. Now, the pattern in spinal fluid is very different than it was in plasma. And these patients that we’ve received samples from—donated samples—via Dr. Peterson, do not appear to fit this profile of having very different patterns from less than three years and more than three years.

We see these patterns consistently throughout the ____. So what we found was that patients with Chronic Fatigue Syndrome, these are classic cases, had elevated levels of a cytokine called IL-10, another called IL-13. These are typically referred to as Th 2-type cytokines. We also have an elevation in levels of four of what are known Th1-type cytokines: IL-1 Beta, IL-5 TNF-Alpha and IL-17.

Quote taken from this transcript :

http://www.mecfsforums.com/wiki/Lipkin_presentation,_CDC_Conference_Call_9/10/2013

 

[alex3619]

One problem is we have too many ways to play the story, I think. But trying to put together detailed stories is worthwhile because it can throw up testable predictions. Giving cytokine producing bacteria sounds clever, although maybe not the right thing in this case.

Jonathan Edwards
That has been the whole issue with ME and CFS, in a nutshell. Too many possibilities, too few testing opportunities. Model building in medical matters at a molecular level is a minefield, with so many possible pathways involved, and even pathways that are as yet undiscovered. Nailing down pathways step by step is the only way I see it can be done, which is apparently what you and others did with RA? Isn't that why we have a better understanding of many medical disorders?

This does however raise questions about cohort selection and subgrouping. Most groups with CFS are probably highly heterogeneous. Given this issue, and given that classifying the same cohort into separate groups for statistical analysis is not technically that difficult (though it has cost), and ignoring for now clustering methods, I wonder why every new study into CFS (and of course ME) doesn't try to incorporate different definitions for comparison? Perhaps one definition could be shown to be clearly superior, or shown to be clearly inferior. Either would be progress.