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ME/CFS: A disease at war with itself
We can all agree that ME/CFS is a nasty disease, particularly in its severe form, but there are abundant nasty diseases in the world. What is unique and particularly confounding about our disease is that so much controversy surrounds it, and not only surrounds it, but invades it too.
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Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. Sasha

    Sasha Fine, thank you

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    In terms of ME possibly being lots of different diseases caught up under the same set of diagnostic critieria, is it noteworthy that 67% of patients in the Haukeland trial showed moderate to major improvement? If memory serves, all but one had major improvement. The two controls who improved I think were the only two patients in the study who only filled the less specific Fukuda criteria rather than also the tighter Canadian Consensus Criteria, and hence might have been in line for spontaneous remission anyway of whatever they had. So if 67% of Fukuda cases improve with Rituximab, does that suggest there might not be all that many varieties after all?
    ukxmrv likes this.
  2. Kati

    Kati Patient in training

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    Jonathan Edwards I am not sure where you get the information that ME gets better over time. I do not subscribe to this idea. Perhaps patients learn to live with their illness better, through pacing of their activities.

    My experience has been a steady decline in my functionality. The people who are participating in this forum are still here and still sick. Some of them have been at it for 20-30 years. A lot of whom are trying to heal themselves by their own means. They are still here.
    NK17, irwinsturtle, rosie26 and 3 others like this.
  3. Bob

    Bob

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  4. Bob

    Bob

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    I don't think there is enough data for us to know for sure, but I've always understood that the long-term course of ME varies a lot.

    For example as follows...

    1. Long-term improvement leading to stable remission.
    2. Alternating between periods of illness, and periods of remission.
    3. Fluctuating symptoms over the long-term (e.g. vulnerable to regular relapses.)
    4. Relatively steady levels of symptoms over the long-term, possibly because of successful symptom management.
    5. Some will experience steady deterioration.
  5. Esther12

    Esther12 Senior Member

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    Also, it could well depend upon the type of patient being assessed, and when they are measured from. For example, for those patients studied as part of prospective studies on certain specific viral triggers, those who do go on to fulfil a criteria for ME/CFS also tend to continue to see some improvement over time (which is not to say that they all go on to recovery).

    Evidence on all this is complicated by the difficulty of meaningfully and reliably measuring the severity of CFS. When looking back at my own posts on this forum I noticed how I would often talk about my health improving, and a helpful new way of managing my symptoms, but in the long-run it was apparent that this wasn't really the case. I was just tending to view bad periods as unusual blips to be discounted, and periods of improvement as a representation of what was 'really' happening with my health.
    Bob, rosie26, Sasha and 2 others like this.
  6. Kate_UK

    Kate_UK Senior Member

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    How is this measured? At the 2011 Invest in ME conference Dr David Bell talked about his 25 year followup of his patients.

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  7. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Sorry, maybe I was just trying to be a bit upbeat. I realise that the outlook for ME is very variable. Still, my understanding from friends who have had it and from paediatricians is that someone like Andrew who has had it for a year and is 19 does have a decent chance of improving. And I still think Andrew's thoughts about whether ME fits with other autoimmunity are well worth pondering on.

    And yes, Sasha, I agree the Norwegian study does suggest that there may not be so many diseases after all. It would be easy if it is all B cell related disease. However, I think that Fluge and Mella would admit that their cases may come from a subgroup. I think they were referred by neurologists. If we take into account the placebo rate it might be that 7-8 patients out of 15 genuinely responded to rituximab - that is half. That leaves room.

    If I were to guess what percentages would fall into each of several causal groups for a clinical syndrome I would tend to think something like 60, 20, 12, 4, 1, 1, 0.2, 0.1, ... That would seem to fit with the data if B cell related disease is the common one, but it does not exclude there being some other quite common subgroups. There could be big effects from referral pattern though. The trial would not take people under 18 and it might be that ME starting under 20 is a different illness - in the inflammatory arthritis field children have a quite different set of diseases.

    So I guess nothing is certain, but it does quite look as if there might be a major B cell related group. It also suggests, interestingly, that if there are other groups then the response rate for B cell related disease, if we can identify it, might be consistently high.
    NK17, Battery Muncher, Svenja and 3 others like this.
  8. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Several people have commented that the current proposal for a trial seems too small. However, trials only need to be large if the statistical analysis needs it because you are looking for a small change or one that shows up in a small proportion of cases (like for preventing stroke with blood pressure drugs). Large multicentre trials actually have a Catch 22. With big trials (especially international ones) quality control of recruiting and assessment drops so you need an even bigger trial to get an answer. On the face of it what we want to see is whether quite a big change in 60% of cases can be repeated. The only worry is that we may start treating people with a different sort of disease and only get an effect in a few cases. If so, I think a big trial first off would be a waste of resources. If only one person in ten is going to respond we only need to treat a small number to discover we are not in the same ball park. On the other hand if 60% respond in a small study there is a strong case to do further studies. Even these may not need to be big. I think there is a requirement for a certain number of cases to be treated for licensing but I don't think we are that far ahead just yet. Moreover, I do not think that the UK is obliged to foot the bill for all of that.
  9. lansbergen

    lansbergen Senior Member

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    Would you include patiens who's disease process responses to a a7nAchR modulator?
  10. Sasha

    Sasha Fine, thank you

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    When I got sick in the mid-1980s, the prevalent wisdom was that the natural course of ME was to improve to full recovery within 18 months and if it didn't, you didn't fully recover. The younger you were, the better your chances. I think a figure I saw was that 80% were in that first category. Where those numbers came from, I've no idea.

    I think we're hamstrung on this issue by lack of data and, of course, poor diagnostic criteria in the US and UK where 'CFS' is basically unexplained chronic fatigue with knobs on.
    Bob and rosie26 like this.
  11. Sasha

    Sasha Fine, thank you

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    That's interesting - I didn't know that Fluge and Mella got their cases referred by neurologists. However, ME (properly defined by the CCC or ICC) is a neuroendocrine-immune disorder and all of us could probably request and get a neurological referral if we asked, based on our neurological symptoms (we often don't ask for all the appropriate referrals because we won't get treated). We could also probably get a referral to an endocrinologist, a rheumatologist, an immunologist, infectious diseases specialist, gastroenterologist...

    The placebo rate is interesting. Many clinicians have noted that ME seems to be (more's the pity) fairly immune to placebo effects. In any trial, any improvement in a 'placebo' group is often interpreted as a 'placebo' effect but it is impossible to distinguish between a placebo response and a natural remission. With people with long-term ME, a placebo response seems unlikely and so more likely that those two people in the placebo group had a natural remission - in turn made more likely by the fact that they may not have had ME proper, given that they only (I think) fulfilled the Fukuda 'chronic fatigue with knobs on' criteria, not the CCC like all the other patients.
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  12. alex3619

    alex3619 Senior Member

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    The impression I have with ME and recovery is that patients who are younger and have been sick less than five years have a good chance of recovery. However this is the same pattern and time frame for post viral fatigue syndrome. I suspect ME and PVFS are not the same thing. Both ME and PVFS do however fit within a spectrum of fatigue conditions.

    What Maes showed is an extremely high antibody load, but many antibodies to each of six targets. He did not go looking for a specific antibody, but presented ME blood with six possible targets. Each was heavily attacked by the immune system. This is not autoimmune disease as classically understood, but its not normal either. There was some speculation though that these were low affinity antibodies.

    While B cells do use genetic recombination to create antibodies, and these are first selected against by the body to ensure they are not responding to self-antigens, and then by the immune system which amplifies those which target presented antigens, I would not call this trial and error. Its more random selection. The system is also imperfect. Possible self-antigens that are isolated from B cells maturation do not select against responses to self-antigens. This is probably true of the brain, eyes and gonads, which are considered immunologically privileged. I think that is probably true of fetuses as well. However immune cells have restricted migration into these areas.
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  13. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I do not see any reason to exclude them. An AChR modulator response might perhaps be a marker for an antibody related (B cell related) subset but then again it might be the opposite. I suspect judging response might be difficult to quantify. But it's an interesting thought.
  14. Kate_UK

    Kate_UK Senior Member

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    The other thing I wonder about is sudden onset versus gradual onset, I wonder if that makes a difference?

    Also the subgroups in the Light/Bateman post-exertional study, the graphs are in the ICC.

    10/15 in the Fluge Mella study is great, even if that went down to 20-25% it would still mean a lot of help for a lot of people.

    We have to get the funding somehow to make this happen, the UK rituximab trial is the best chance we've seen in decades.
  15. Purple

    Purple Bundle of purpliness

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    It is my opinion that the biological mechanisms behind short(ish) term completely recoverable from and non-relapsing post viral (or post infectious) fatigue are different than the mechanisms behind chronic crippling disease I personally know as ME. (and had there been enough funds invested over the last few decades, we would probably know by now at least some of the biological mechanisms)

    As an example, a relative of mine had nearly a year of tiredness following a near-fatal case of pneumonia. They were tired and slept a lot more and got out of breath climbing stairs but they managed to work and take care of their family (though had to slow down on hobbies for a while) and they gradually got better and their tiredness was similar to normal tiredness, just more of it. So: tiredness, sleepiness, loss of some fitness following a bad infectious illness. All of which completely went away on its own and was never disabling enough to have to stop working.

    My case of ME was a steep descent from fully functional and fit to not being able to work, walk, sit, do basics of self-care within a few months. The first 3 years or so, I felt distinctly this was an infectious disease - I had daily fevers, flu-like symptoms, stomach flu type nausea and diarhea, UTIs, sore throat, extreme weight loss and of course post exertional crashes. After about 3 years, the illness changed in nature. The infectious manifestations went away suddenly and the illness became much more neurological and systemic in nature with pain, extreme sensitivities to everything (e.g. light would send my body into jerking involuntary movements), cognitive issues, nausea now resulting from vertigo/dizziness, blackouts, extreme muscle weakness with transient paralysis, insomnia from another world, autonomic problems, heart problems, I won't go into all of it... but no fever and the weight came back. During a crash, I can be in a semi-conscious state passing out with pain and too weak to move or talk and gasp for breath for weeks/months after the 'activity' that put me in a crash (e.g. a necessary trip to a doctor in a wheelchair).


    I wonder if there was a point of my own illness when it changed from predominantly infectious to predominantly autoimmune (as this what it 'feels' like to me... not the best evidence, I know!) and if the point of this occurred when the fever went away and the neuro symptoms started in earnest. (From the limited tests I have been given, at the start of my illness autoimmune markers ANA and anti-DNA came back positive, then only anti-DNA and as my illness changed nature from flu-like infectious feel-illness to more neurological illness, all autoimmune markers came back normal. So as I got worse, my basic autoimmune markers improved and normalised.)

    Also, these days I suspect many doctors would likely diagnose both my relative and myself as the same illness: CFS which in the UK most take to be equivalent to ME. And THIS is a big problem: not being able to separate short term PVFS from the long term chronic ME - the only way we can tell the difference now (as far as I know) is if someone with PVFS has recovered and those with ME have not... a very unsatisfactory way to distinguish between illnesses, in my opinion.
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  16. Sasha

    Sasha Fine, thank you

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    Agreed. The fastest way to get that done is to get all the UK ME charities on board. The MEA's pledge (subject to their peer review process) of nearly £60k, plus the £20k already raised by IiME, gets us to £80k so we're nearly a quarter of the way there already. If AfME's board approves their donation that will be another big chunk and I hope that ME Research UK would be seriously considering this now, and possibly the CFS Research Foundation (they're very quiet and perhaps not well known but every now and again they drop big bucks on a biomedical research project).

    That kind of cooperation between charities is going to be hugely important in getting this done fast and I'd like to see those donations warmly welcomed when they happen. That's going to encourage cooperation, get more donations, and help get everyone on board. Between them, the UK ME charities have the potential to get a very large chunk of this trial funded and these donations are a hugely positive move.

    I agree this is the best thing to happen in the UK in decades and we've got to do everything we can to encourage donations and make it happen.
    Battery Muncher likes this.
  17. Marco

    Marco Old blackguard

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    I've just caught up on this thread and wish to add how great it is that Professor Edwards is taking so much time to answer our questions (and ask some of his own which is equally welcome).

    Could I ask Prof Edwards if he could briefly explain the differences between treatment of RA using TNF-a inhibitors v B cell depletion using Rituximab as relates to the underlying disease mechanism(s) in RA.

    I guess the question I'm asking is do the two treatment approaches overlap or are they addressing two different disease pathways?
    NK17 likes this.
  18. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Yes, things are complicated but this is roughly the idea. In the version that Jo Cambridge and I work with it is not so much that anything mounts an attack on gating cells, and T cells do not really come in to this part of the story (we think they are really just innocent dupes in all this) but the cycling idea is on the right lines.

    So, if we ask 'why are the B cells dysfunctional?' the answer may be because B cells are dysfunctional - or to be a bit clearer B cells coming along today will be dysfunctional because yesterdays B cells were dysfunctional. If B cells are not right at the transitional stage the problem must be in bone marrow. What looks tricky about bone marrow is that not only does it grow up young B cells but it is the permanent residence of the fully mature plasma cells that actually make most of the antibodies - cells that a while back were themselves transitional cells coming out of bone marrow.

    For this reason I would actually disagree with Amolak Bansal - in a friendly debating way - and say that it is far from clear that we need to get rid of any viruses, which are probably endemic anyway and would cause no trouble if the immune system was working smoothly. If the reason the B cells are misbehaving is because B cells are misbehaving then all we need to do is deal with misbehaving B cells.

    But, as people have mentioned, this may need a bit of organising. I tend to think of B cells as a bit like Samurai cadets at the Kyoto Bone Marrow School of Martial Arts. (B cells themselves make hardly any antibody, they are learner cells; it is the plasma cells they turn into that make the antibodies.) They are supposed to learn the art of killing enemies by throwing enemy shaped knives into the Japanese circulation. They are taught their art by venerable plasma cell masters who give them bits of enemy with knives in to practice on. (In order to start making antibodies B cells rely heavily on other B cells having made antibodies before. For babies it is mother's antibodies from the placenta and in milk. If a B cell is shown a protein that already has an antibody attached to it, together with complement, it will start making antibodies. If it is shown a protein without antibody attached it tends to roll over and die.) It is a tough school, because any cadet that has not been given a bit of enemy that fits their knives to practice on after a week is taken by matron to the kitchen, put through the mincer and served up for dinner.

    Unfortunately autoimmunity has set in and some master plasma cells are going around killing innocent citizens of Kyoto. Worse, they are handing bits of citizen to cadets with citizen shaped knives so that these are no longer put in matron's mincer. What can be done? Nobody can kill a schoolmaster Samurai, they are too clever, and they can live for ten years. Fortunately, it seems that most of the killing in town is being done by newly trained plasma cells, who, unlike the masters that live in the Bone Marrow School, live in the crowded Spleen camp and mostly only survive for a few months. So if we prevent any new cadets arriving at the School for six months by removing B cells for that time most of the carnage will settle down. The trouble is if we then reopen the doors the rogue masters will get up to their tricks again. We have been waiting for a safe effective anti-plasma cell drug for fifteen years now, although using one would require care, because we don't really want to get rid of all the masters.

    Of course if it was only some plasma cells in Spleen that were leading new recruits astray on field days, as might be true of immune thrombocytopenia, then closing the School for six months would do the trick. The problem is that now we have studied this for ten years we have come to realise how hideously complicated the detail is. For almost every rule there is a group of B cells that is exempt. General patterns emerge but there are exceptions.

    A key point of this story is that there need be no mention of infections at all. The problem starts with a B cell getting away with making an autoantibody that, by definition, it will have generated at random, and, once it has become a plasma cell, teaching other B cells to follow suit. The epidemiology of autoimmune disease is actually very against any infective trigger. Lots of doctors still just talk of genetic and environmental factors in disease and forget that the epidemiology textbooks mention another class of factor - stochastic or random. Antibody generation is entirely random. But for ME it does look as if, at least in one form, infection is a trigger. That need not mean that it matters much which infection it is. The idea that there is a cross reactivity between a microbe and a self protein has never had much evidence to support it. But it might mean that viruses need to be thought about. The only thing is that the one virus that one would obviously suspect is EBV and rituximab clears away the EBV with the B cells.

    I hope that makes some sense.
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  19. lansbergen

    lansbergen Senior Member

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  20. Jonathan Edwards

    Jonathan Edwards Senior Member

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    As I understand it they address two steps in the same chain. B cells make autoantibodies that bind to antigens to form complexes that then bind to IgG Fc receptors on macrophages that trigger TNF production. Tiny Maini and Marc Feldman who were the first to try anti-TNF thought the macrophages were being activated by T cells but there are various reasons for doubting that, including the way patients respond to rituximab.

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