Science at the UK CMRC Conference, 1-2 Sept 2014

[Sean]

Two or three contributions were out of context and these were just ignored. To my mind that sends the most powerful message.

There is more than one way to skin a cat.

 

[Sean]

I suspect that a high proportion of 'placebo' responses are the patient trying not to offend the therapist. If you think it is important to the therapist's ego that their treatment is appreciated then you will score 'their treatment' higher than 'the ordinary one'. It is worse than that because patients are frightened of upsetting their therapists because they think they may be sent away from the clinic if they do not 'help'.

Or worse.

One of the areas psych medicine really needs to be pinned on is the consequences of having an inappropriate psych diagnosis, especially some form of somatisation or 'uncooperative' label, on your medical records. They are a bastard to get removed or modified, and can seriously mess up your prospects for fair, accurate, and timely clinical treatment, not to mention critical medico-legal assessment.

 

[Jonathan Edwards]

I have one "simply" question - can we say that after this conference (and other ME/CFS conferences of this year) we moved further with understanding, diagnosing, treating,....ME/CFS.

I agree with Charles that the answer is a definite yes. My impression is that ten years ago there were a few individual scientists scattered over the world, each with their own private theory about ME. Now we have a body of scientists, many coming in from careers in other related fields, who are all talking the same language and they pretty much agree on what sort of a problem we are dealing with. There is some sort of persistent problem in the brain and spinal cord, and maybe in many other organ systems, of a sort that can be at least influenced by, and may well in some cases be caused by, a disturbed immune response. Perhaps most importantly we now understand how such a problem can be explained by changes in cells like microglia at a level that would be invisible on traditional tests.

Understanding every step of a disease process is a lot to ask, but it may not be necessary. It may be interesting to ask; do we know as much about ME now as we did about rheumatoid arthritis when we started finding powerful new treatments in the 1990s? The answer may be not quite, but it is not so far off. We have a good idea what processes we might want to target in treatment and as soon as we find a treatment working we will know we were on the right lines. We may already be in that situation.

The last months there were many positive news and enthusiasme from ME/ CFS conferences and I would also like to be optimistic like always but I am not even sure if we are able to diagnose ME/CFS correctly. I just ask myself where we are in our fight - can we expect in a short time at least a propre diagnose? this would be probably my question if I would be at the conference

Interestingly, Professor Holgate and many others at the CMRC conference answered this question by turning it on its head. In other branches of medicine we now realise that 'a proper diagnosis' is not really what we looking for. We want to be able to know exactly what is going wrong for each person individually. The buzz word is personalised medicine but the reality is just common sense.

In the last twenty years I looked after people with rheumatoid arthritis I never bothered to think what the name of their diagnosis was. Each person had a different range of problems and I dealt with them as seemed sensible for that person. If you are in a restaurant you have to order pizza Romana or Fiorentina, but at home you may put anchovy on dad's pizza but not on the kids' pizzas. You may put more cheese of Jack's and no salt on your own. If you know enough about what you are doing in cooking and medicine the labels no longer matter.

But you are right in that we do need some basic agreed categories - you need to know what a pizza is. The scientists at the CMRC meeting seemed to agree that we should allow the category to be quite broad because we do not want to leave anybody out just because they do not tick some box on a form. And I think we have as good an idea of what we mean by ME as we do for 'inflammatory arthritis' which would be the pizza word in my old clinic.

I think ME, or MEs, are a group of processes in which there is some persistent microscopic change in the brain and spinal cord (probably with some common features and some difference between cases) that gives rise to fatigue, myalgia and post-exercise malaise, and which are not covered by other categories (often with more macroscopic structural or inflammatory change) such as lupus or MS. That is all we need to go on to start developing new treatments because we know a lot about the possible mechanisms that might be involved.

My memory is that Charles Shepherd has been quite keen on the term Myalgic Encephalomyelopathy. I would agree but I suspect neither of us would think it something worth arguing over, since disease names are often a bit arbitrary. But with this proviso it seems to me more and more that Ramsay's name of Myalgic Encephalomyelitis was not so bad. It is no worse than osteoarthritis, which is not really an -itis at all.

 

[Sasha]

@Jonathan Edwards - this is hugely encouraging. Do you have a sense of how many years before patients will be able to go to an NHS clinic and get one of these new treatments, given your experience with how things went with RA?

I realise that with Rituximab, we've got some years to go before enough trials have been done for approval but my impression is that you think that other drugs might come online for us earlier that might be more suitable but for which the Rituximab work will have helped make a case.

Also, given the new understanding of what seems to be going on and the wish for diagnostic criteria to be appropriately broad (as opposed to bin-bag broad), did you get the impression that people at the conference wanted to broaden out from the CCC or narrow in from the Oxford, or work with what there is or start again? I'm wondering whether people want to work with existing criteria or modify them. There is of course work ongoing with Lenny Jason in the US on the diagnostic criteria - he thinks that consensus criteria don't make sense and that you need to get at sensible criteria empirically and statistically.

 

[Jonathan Edwards]

@Jonathan Edwards - this is hugely encouraging. Do you have a sense of how many years before patients will be able to go to an NHS clinic and get one of these new treatments, given your experience with how things went with RA?

Also, given the new understanding of what seems to be going on and the wish for diagnostic criteria to be appropriately broad (as opposed to bin-bag broad), did you get the impression that people at the conference wanted to broaden out from the CCC or narrow in from the Oxford, or work with what there is or start again?

I think the time line for new treatments is impossible to predict. Sometimes it seems things take forever and sometimes one is amazed how much things have changed in a few years. The main thing is that the momentum seems to be gathering.

I don't think criteria matter. I know this seems strange to patients but in my RA research I never bothered with any criteria. I followed the biological processes I could measure and the patients' symptoms and signs. Strictly speaking you need a different set of criteria for every experiment because each experiment asks a different question. What matters is that we all know who needs help and that we need to find out which people might be helped one way and which people another way. A key point made at the conference is that criteria for research have nothing whatever to do with criteria for patient care. I know it sounds odd but it is a basic truth about medical research.

 

[ukxmrv]

@Jonathan Edwards

Was there anything at the conference that would help the ME group who have viral symptoms as a primary onset and as a ongoing problem? Also frequent infections rather than fatigue. I can see how teasing apart fatigue and seeing how different parts of fatigue could help people with that symptom as their primary one but that feels as if the my group is being left out in the cold by the conference.

I'm one of the lucky ME patients who does better with antiviral drugs and immune modulators. Plus antibiotic treatment for the repeat infections. Obtaining this on the NHS is next to impossible for me.

We there any presentations or doctors present who would have experience with my group and any clues as to theories or help for us in the future?

 

[Sasha]

I think the time line for new treatments is impossible to predict. Sometimes it seems things take forever and sometimes one is amazed how much things have changed in a few years. The main thing is that the momentum seems to be gathering.

Thanks - hard not to be like a kid in the back of a car saying "Are we nearly there yet?"!

I don't think criteria matter. I know this seems strange to patients but in my RA research I never bothered with any criteria. I followed the biological processes I could measure and the patients' symptoms and signs. Strictly speaking you need a different set of criteria for every experiment because each experiment asks a different question. What matters is that we all know who needs help and that we need to find out which people might be helped one way and which people another way. A key point made at the conference is that criteria for research have nothing whatever to do with criteria for patient care. I know it sounds odd but it is a basic truth about medical research.

I'm having some trouble getting my head around this one. One of the CFS criteria used in the US (the Fukuda?) diagnosed ten times as many people with the disease than another set (my memory's gone - I'm sure someone can help me out). With the Oxford (?) criteria being used by the NHS, Julia Newton found that 40% of those patients referred to her clinic didn't have ME/CFS but undiagnosed primary depression or other disorders (which I appreciate is a question of misdiagnosis rather than broad definition but suggests that the diagnostic criteria might not be doing their job).

I understand that you might want specific subsets of PWME for specific studies but just in terms of being a patient looking to get a diagnosis so that you can get medical care, I wonder if the new research consensus has implications for diagnostic criteria in a clinical setting. And it's from a clinical setting that researchers recruit for trials, so I think it's an important issue for both.

 

[lansbergen]

@Jonathan Edwards

Two strange things I noticed with the fatique in my disease.

1 lying on the couch doing nothing suddenly fatique starts at one spot ( yes you read it right: one spot ) and then spreads fast to surrouding tissue.

2 With imporvement I noticed the fatique goes from the place I think inflammation is active to the perifere. It does not involve the area's I think have been cleared.

When I was sure of the pattern I said: in the end it will come out through my big toe.

 

[Nielk]

I think the time line for new treatments is impossible to predict. Sometimes it seems things take forever and sometimes one is amazed how much things have changed in a few years. The main thing is that the momentum seems to be gathering.

I don't think criteria matter. I know this seems strange to patients but in my RA research I never bothered with any criteria. I followed the biological processes I could measure and the patients' symptoms and signs. Strictly speaking you need a different set of criteria for every experiment because each experiment asks a different question. What matters is that we all know who needs help and that we need to find out which people might be helped one way and which people another way. A key point made at the conference is that criteria for research have nothing whatever to do with criteria for patient care. I know it sounds odd but it is a basic truth about medical research.

The fact that criteria are not very important when it comes to medical research is very surprising to me. If one is not researching a specific disease, how could the outcome be meaningful.

For example, if you were to do a study of joint pain in RA but would include patients with osteoarthritis and the flu, what would the result reflect?

If one were to do a study on a broad patient base that suffer from acute fatigue, including patients who suffer from depression, ME and thyroiditis, what would you learn from the results?

 

[Jonathan Edwards]

@Jonathan Edwards
Was there anything at the conference that would help the ME group who have viral symptoms as a primary onset and as a ongoing problem? Also frequent infections rather than fatigue. I can see how teasing apart fatigue and seeing how different parts of fatigue could help people with that symptom as their primary one but that feels as if the my group is being left out in the cold by the conference.

We there any presentations or doctors present who would have experience with my group and any clues as to theories or help for us in the future?

There was lots of stuff on the relation between fatigue and initial infection. That is the main model for studying fatigue. But the problem about trying to connect ME to ongoing infections is that all the studies that look reliable fail to find any specific ongoing infections as far as I can see. Some people with ME may be troubled by viral infections more than healthy individuals but I am not sure that that is part of ME itself. I know that some people have come to view it that way but I don't see hard evidence for it. I think the problem is complicated by the fact that the an oversensitive CNS may well generate more symptoms in the presence of a virus than in a healthy person.

And it is not as if the people at the conference are not interested in infections. Dr Lipkin does nothing else, but the studies from his group so far have not shown more viruses than in controls as I understand it.

 

[Jonathan Edwards]

I'm having some trouble getting my head around this one. One of the CFS criteria used in the US diagnosed ten times as many people with the disease than another set (my memory's gone - I'm sure someone can help me out). With the Oxford (?) criteria being used by the NHS, Julia Newton found that 40% of those patients referred to her clinic didn't have ME/CFS but undiagnosed primary depression or other disorders (which I appreciate is a question of misdiagnosis rather than broad definition but suggests that the diagnostic criteria might not be doing their job).

I understand that you might want specific subsets of PWME for specific studies but just in terms of being a patient looking to get a diagnosis so that you can get medical care, I wonder if the new research consensus has implications for diagnostic criteria in a clinical setting. And it's from a clinical setting that researchers recruit for trials, so I think it's an important issue for both.

As I indicated Sasha, this is hard for patients to get their heads around but disease criteria for research have NOTHING TO DO with diagnostic criteria for clinical care. There are three sets of criteria for rheumatoid arthritis. The vaguest one includes maybe four times as many people as the tightest - it's just the same. Most research is done using the middle one but all three are useful for certain questions. There are huge problems with the fact that research based criteria have crept in to things like NICE guidelines. For instance if you only have one swollen joint you do not have 'definite rheumatoid arthritis' on research criteria. But that is absolutely no reason not to get treatment because the disease has to start in one joint first. Do we say 'oh we will let those two joints rot to pieces - you can only have anti-TNF when a third joint starts rotting because definite RA has to have 3 bad joints'. This is actually happening all the time and it is the main reason I quit being a doctor. I was not prepared to mistreat people in that way.

What patients need is not a diagnostic label but medical attendants who are interested in finding out what is wrong with them as an individual and trying to deal with it in a way suited to that individual. I agree that labels are important for all sorts of social interactions and for financial support as well. But as we all know, a label without an understanding of what its significance is, gets nobody anywhere. If it is a codeword for 'biopsychosocial' you are worse off than before.

 

[lansbergen]

I think the infections studied are just oportunist and still think the infeciton I suspect is the unddelying cause but that patogen is difficult to harvest. That might change now I found a paper last week about an easy to use methode.. They found the pathogen in the terminal phase at the place I always said the disease starts..

 

[A.B.]

I would say: Just keep telling us what it feels like.

I have some questions about fluctuating symptoms that I hope are not off topic here: I've read that fluctuating symptoms are typical for autoimmune diseases.

How reliable are they as indicator of autoimmune disease?

Why do the symptoms fluctuate? Does the immune system have its own rythms, or are there some subtle triggers, or something else?

And by fluctuating symptoms I mean not merely bad or good days, but sudden worsening for no apparent reason* that takes weeks to resolve fully.

*enough rest, no exertion, no stress, feeling relatively good before, not taking medication that could reasonably have such side effects, no sign of infection, eating healthy food, etc.

 

[Sasha]

As I indicated Sasha, this is hard for patients to get their heads around but disease criteria for research have NOTHING TO DO with diagnostic criteria for clinical care. There are three sets of criteria for rheumatoid arthritis. The vaguest one includes maybe four times as many people as the tightest - it's just the same. Most research is done using the middle one but all three are useful for certain questions. There are huge problems with the fact that research based criteria have crept in to things like NICE guidelines. For instance if you only have one swollen joint you do not have 'definite rheumatoid arthritis' on research criteria. But that is absolutely no reason not to get treatment because the disease has to start in one joint first. Do we say 'oh we will let those two joints rot to pieces - you can only have anti-TNF when a third joint starts rotting because definite RA has to have 3 bad joints'. This is actually happening all the time and it is the main reason I quit being a doctor. I was not prepared to mistreat people in that way.

That's very interesting indeed about RA. I'm not sure that the broadest CFS criteria (fatigue with knobs on) would be the equivalent to the broadest RA criteria, because of the ubiquity of fatigue in diseases of all kinds, but it's interesting all the same.

What patients need is not a diagnostic label but medical attendants who are interested in finding out what is wrong with them as an individual and trying to deal with it in a way suited to that individual. I agree that labels are important for all sorts of social interactions and for financial support as well. But as we all know, a label without an understanding of what its significance is, gets nobody anywhere. If it is a codeword for 'biopsychosocial' you are worse off than before.

I'd agree with that but in practice, NICE is going to influence our treatment according to our diagnostic label (it already does), and the label we're given is going to determine where we get sent in clinical practice - I think it's more than a social issue. Also, until specialist medical ME centres are set up, I don't think we'll get anything like personalised treatment of our ME because GPs simply don't know enough about the condition.

The label isn't unimportant politically, either. The newspapers are full of "ME" patients who have made spectacular "recoveries" within days of doing psychological treatments such as the Lightning Process (which seems to consist of denying your symptoms). As long as that goes on, we've got a problem with public perception of the disease and we continue to carry the huge burden of psychosomatic stigma and to be seen as not worthy of research funding. Although we can hope for more MRC funding, we need to get to a point where the public are donating, because that's where most diseases get most of their research funding from.

Would you say that the conference indicated that we're any closer to biomarkers for diagnosis? I suspect my view of that issue might be oversimplistic and I'd be happy to be educated!

 

[Jonathan Edwards]

I have some questions about fluctuating symptoms that I hope are not off topic here: I've read that fluctuating symptoms are typical for autoimmune diseases.

How reliable are they as indicator of autoimmune disease?

Why do the symptoms fluctuate? Does the immune system have its own rythms, or are there some subtle triggers, or something else?

And by fluctuating symptoms I mean not merely bad or good days, but sudden worsening for no apparent reason* that takes weeks to resolve fully.

*enough rest, no exertion, no stress, feeling relatively good before, not taking medication that could reasonably have such side effects, no sign of infection, eating healthy food, etc.

I would not say that fluctuations were hard evidence of autoimmunity but they make sense in terms of autoimmunity. The B cell antibody production system depends on clones of cells gradually taking over from each other over time and 'passing the relay baton'. The ongoing control of antibody production involves both positive and negative feedback so one can expect ups and downs. Because we think the control has got distorted in autoimmunity it is reasonable to expect that to become a bit of a roller coaster rather than a smooth transition. Diseases like RA have 'flares' and remissions. Lupus is a firework display of flares moving from one place to another. Even thyroid autoimmunity can switch from low to high or vice versa. The changes can be over days, weeks or years, all of which are reasonably consistent with turnover of antibody populations I think.

 

[MeSci]

Resveratrol comes from the skins of red grapes and some other fruits and is in red wine and (yippee!) chocolate. You can buy it as a food supplement. I think a few PR members have tried it but I don't know what kind of results they've had.

It has become well-known for alleged cardiovascular benefits but:

http://www.nhs.uk/news/2014/05May/Pages/Resveratrol-red-wine-chemical-overhyped.aspx

I note that your linked article says "Resveratrol is also found in a wide range of foods."

'Natural' resveratrol supplements often also have a high level of a chemical called emodin, which can cause vomiting and diarrhoea. These 'natural' supplements are usually made from Japanese knotweed. So it seems preferable to use a purer - and thus probably more expensive and perhaps less 'natural' - form of resveratrol.

I have some abstracts about resveratrol (and curcumin/turmeric) in my blogpost here.

I'm trying natural anti-inflammatories not for fatigue but in an attempt to reduce solute diuresis, which I suspect is a significant cause of electrolyte deficiency and consequent malaise in at least some of us.

 

[Jonathan Edwards]

I agree with all your points about the importance of diagnostic names for patients, Sasha, but my point is that we are in all this mess because people do not realise that it is crazy to expect disease classification for research to match disease classification for clinical care. The reality of it is plain to see but we are born to 'pigeonhole' things and it is hard to get out of the habit. For instance, look at the indications for anti-rheumatic drugs:

Voltarol - anyone with a painful joint or back
Methotrexate - RA and psoriatic arthritis but not lupus
Steroids - RA, polymyalgia and lupus
Sulphasalzine - RA and Reiter's and Crohn's arthritis but probably not psoriatic and not lupus
Anti-TNF - RA and psoriatic but not lupus
Anti- IL-6 - RA but not psoriatic or lupus

And so it goes on. Each clinical therapeutic tool relates to a different disturbance of physiology and these cut across diagnoses. Even what I have written is grossly simplified. Within each diagnostic group the real reasons for using each drug depend on the individual's problems. NICE is a nonsense but it has got that way because people think that we have to have disease names to base treatment on and that these have to be the names in the disease classification books used for research. The only way to sensible treatment is to throw that idea away.

 

[Sasha]

Thank you - I guess I was hoping for all this new research (including from the conference) to inform disease classification for clinical purposes as well as the role that you've explained for research in informing disease classification (using one or more different sets of criteria) for research purposes. My assumption has been that biomedical research ("Look, Carruthers! All these PWME have high levels of substance X!") would be helping to make clinical diagnosis more sophisticated but it sounds as though the edges of the disease(s) are too fuzzy and that Lenny Jason's approach of looking at symptom clusters is going to be what does that, rather than the biomedical research.

Or perhaps I just don't understand how the creation of diagnostic entities is done. I wish I knew more about that.

Ah well! I don't want to pull the thread off-course with this. Thanks for responding. Always fascinating to hear these parallels with RA with issues that I had thought ME had drawn the unique short-straw on.

 

[MeSci]

I've seen it said by many (surprisingly, also by Prof Wessely) that ME seems to be remarkly resistant to a true placebo effect (biological response in the absence of physical intervention), as opposed to the "misdescription" effect I've just described (I forget its technical name).

Maybe not so surprising. A placebo effect to CBT/GET might reduce the likelihood or perception that the treatments were genuinely effective.

 

[MeSci]

Thanks so much for such a fantastic summary, @Jonathan Edwards - almost as good as being there. I'm sure you can imagine what it's like to be desperate to know what was going on at the conference and yet to be too sick to get there and you've filled that knowledge gap, and so speedily! I'm hugely grateful.

and can I have a cure now, please, so that I can take in all this information without the handicap of brain fog?