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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. lansbergen

    lansbergen Senior Member

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  2. natasa778

    natasa778 Senior Member

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    @Jonathan Edwards Could the world of HIV research and clinical practice teach us anything about autoimmune diseases in general, including ME (if indeed autoimmune)?


    Is it possible that an acute infection, or immune stress through vaccination, could lead to a temporary dip in immune competence, to be followed by a sudden restoration of immune competence, which then leads to autoimmune disease? Same setting as above, but in the absence of HIV proper and happening in a shorter time span?


    btw various autoimmune diseases, including RA, appear to be quite common in HTLV, another human retroviral infection, although unfortunately it is not clear from papers whether staging/phasing of autoimmune resurgence correlates to that seen in HIV patients.
    NK17 likes this.
  3. Jonathan Edwards

    Jonathan Edwards Board Member

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    The problem I see with that explanation is the time course. If rituximab stopped B cells making inflammatory cytokines then people should get better in a few days because B cells are removed more or less overnight. The other point on cytokines is that B cells do not actually occur at inflammatory sites, with the exception of very gross types of inflammation like in RA (even then they are not always around). Unlike T cells they are not inflammatory effector cells per se. B cells hang out in lymph node and spleen. The cytokines they make are involved in talking to other cells getting educated - like T cells. These are likely to operate at very short range so not very likely to make you feel ill I guess. And if the idea is that T cells are not doing much anyway that does not seem a good line to pursue.

    If on the other hand rituximab reduced inflammation by reducing antibodies to viruses - which can indeed contribute to inflammation at virus infected sites - you would expect the effect to occur when antibody levels reduced. We have no specific evidence on anti-virus antibodies but what we know about antibodies to foreign organisms (and just the total level) is that in most people they do not really go down at all, even after many months. It is only autoantibodies that go down significantly.

    So it does not seem to fit the kinetics so far.
  4. lansbergen

    lansbergen Senior Member

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    Sorry, no luck. Anybody else found something?
  5. lansbergen

    lansbergen Senior Member

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    Would it not be a good idea to test this in the Rituximab trial?


    NK17 likes this.
  6. olliec

    olliec

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    Prof Edwards, thank you so much for your interest, curiosity and support. If you don't mind I wanted to ask a few broader questions.

    What do you think is required in order for this illness to get much more funding, from governments, pharma, and charitable organisations, and do you think a (successful) Rituximab trial could move things a little way down that path? Is a biomarker the ideal?

    Do you see a space for so-called "Big Data" in ME research? e.g. some patients have accounts with 23andme so a little of their DNA has been sequenced, and others carry Fitbits that measure their activity and sleep. There are also web sites like CureTogether and PatientLikeMe that have quite a lot of patient data. Perhaps 23andme provides a lower cost way to acquire more data, and trial participants carrying Fitbits provides additional objective activity data at a low cost. There are also low-energy Bluetooth heart rate, HRV and breathing monitors that collect data and send it to a mobile (e.g. the Zephyr BioHarness).

    What can patients do to help, aside from fundraising? Are there any successful models we can learn from?
    Kati, Ritto, Marco and 2 others like this.
  7. Jonathan Edwards

    Jonathan Edwards Board Member

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    I certainly think it would be worth looking at other populations for NK receptor ligands. I am not sure how it would be linked to a rituximab trial. Rituximab kills B cells through several mechanisms, including NK killing but I think it would be a mistake to think this has any relevance to the relation of NK function to ME. In the doses rituximab is given in it basically kills all B cells, at least in circulation, and there is no evidence that it matters what NK receptor types you have. The experiments recently reported on the killing mechanism are of technical interest to those making antibody-based drugs but not much else I think.
  8. Jonathan Edwards

    Jonathan Edwards Board Member

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    I am a bit doubtful that HIV research will tell as much. There has been a history of anecdotal reports related to HIV but as far as I know there is no real link to autoimmunity proper (with autoantibodies). There is a link to things like psoriasis, which are probably best called something else. As indicated before, I doubt that infections trigger autoimmunity because there isn't actually a mechanism that makes sense that would work like that, even if for fifty years immunologists have assumed there was!

    I am intrigued by the constant interest in viruses. I have a theory as to why this should be and may comment on it when I have time, but I suspect virus-hunting is a blind alley. The idea that XMRV might have explained ME seems to me as a scientist completely bonkers - a bit like Benveniste saying homeopathic remedies left a memory in the water or Wakefield's MMR story - they just don't stand up to common sense. I am intrigued but not surprised that it got published in a 'respectable' journal. I know I need to justify these prejudices and will try to soon, but paradoxically I think the virus fixation may be telling us something quite important about the biology of ME - to do with why it is not 'caused by viruses'!!!
    Firestormm, Marco and Legendrew like this.
  9. Jonathan Edwards

    Jonathan Edwards Board Member

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    To the first question the answer is willpower, but willpower seasoned with clear thinking. I think keeping the momentum on the rituximab lead until we know which way it will go is well worth while - enough for me to put my retirement pursuits to one side and try and get something moving. And, yup, the biomarker is the Holy Grail. Once ME has a biomarker the whole game changes. I am hoping there is a whiff of a lead but I am not going to speculate until I have seen something more solid. It would be good to use a rituximab trial to move this forward but I am still trying to get a clear view of this.

    To be honest I never found Big Data much use. When I needed some data to test an idea I had to take the samples afresh and I have a feeling that unless samples are taken afresh in a way carefully suited to the study being done you tend to get a lemon.

    Use your brains. Try to work out what is going on. Be critical. Keep nagging the scientific community, but from a well informed position. Ask me some really tough questions. Don't take my word for it - nullis in verba.
    NK17, aimossy, MeSci and 6 others like this.
  10. Firestormm

    Firestormm Guest

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    OK. So now I gone and spat coffee at my computer screen whilst laughing and choking at the same time :D

    I for one will be most interested to read your further comments in relation to the above. Damn just when I'm all nice and relaxed, you throw another corker at me!

    Thanks Professor :)
    aimossy and Kati like this.
  11. voner

    voner Senior Member

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    Prof. Edwards,

    Can you give some examples of possible biomarkers? Shouldn't they be simple and usable in a clinical setting and hopefully inexpensive? I am especially interested in examples that are not blood tests.

    Here's to hoping that your interest is sparked enough to keep you from pursuing those retirement thoughts...
    Firestormm likes this.
  12. lansbergen

    lansbergen Senior Member

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  13. lansbergen

    lansbergen Senior Member

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    Would you in a Rituximab trial include patients with known low to no seroconversion after vaccination?
  14. garcia

    garcia Aristocrat Extraordinaire

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    Jonathan Edwards
    If as you say the immune system is behaving as though there is a serious infection, but there is no serious infection, then surely things like hydrocortisone would make us feel better (by shutting down an aberrant immune response)? However my experience, and the experience of most patients, is that hydrocortisone makes us feel worse, not better. If it were just a runaway immune response (without a pathogen) then surely shutting down the immune response would make patients universally feel better? (it seems to have the opposite effect).
    Kati likes this.
  15. Legendrew

    Legendrew Content team

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    This is something which I'm also interested in, i've heard many people refuse to believe rituximab will prove a good treatment due to the loss of these memory cells and people being unwilling to have this happen. As i understand it, these memory B cells so provide a form of lasting protection to previously encountered disease however i've also heard of people implying that long-lived plasma cells are also somewhat capable of doing this and since they don't express CD20 (as far as i'm aware anyway!) the risks from losing this supply of circulating memory B-cells isn't as extreme as many people seem to believe. It does however at least concern me given the long length of treatments that could be involved.

    As far as i'm aware hydrocortisone is a corticosteroid and therefore acts by reducing inflammation - in a few previous posts it has been discussed as to whether there is any inflammation involved in ME with the conclusions that there's little evidence of, at least standard, inflammation. I believe there's some debate about whether neuro-inflammation follows the same pathways/course and then there's also the possibility that any autoantibody acts by directly blocking or at least changing the normal function of receptor sites in neurones or other organs, meaning no inflammation need be involved!

    I have to say I'm glad someone is sticking their neck out and saying that they doubt any pathogens such as viruses are involved - in the past 6 months or reading into ME research the sheer number of pathogen studies claiming different viruses, bacteria and fungi present in chronic forms in patient sub-sets is so vast that it is self defeating in the respect that it muddies the waters for anyone looking in from the outside wanting to enter the field and isn't furthering the understanding at all. I don't deny studies which rule out things are just as important as those with prove ideas but after so many years of emphasis on viruses surely it's getting to the point where people should embrace research in a different direction. The number of different infectious and non-infectious triggers implies something amiss in the immune system. I honestly believe that chasing these pathogens is the wrong line entirely; i'm sure if these pathogen studies were done on a general population you'd find the same levels of pathogens anyway!

    (In some people viruses may be the issue but I honestly believe this is not the case in the vast majority of people!)
    aimossy and Firestormm like this.
  16. Forbin

    Forbin Forbin

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    I wonder if the relationship of ME to infection could be somewhat indirect. The Dubbo study found that the sole predictor of developing CFS following an infection was not the particular infectious agent, but rather the severity of the infection.

    If M.E. is caused by a random, stochastic and self-perpetuating error/mutation in immune cells, would such an error be statistically more likely to occur when the immune system is highly active, such as during or just after a viral infection? Might that explain the variety of “triggers?”

    The triggers then would not “cause” the illness, per se, but a highly active immune system would increase the probability that the immune system itself would make a self-perpetuating mistake.

    In other cases, the “error” might more rarely occur in a quiescent immune system, just as a matter of probability.

    Perhaps, there might also be some other factor that sets up the immune system to be more likely to make this kind of mistake when it becomes highly active.

    Just amateur speculation. I really don’t know if what I just said was either extremely naïve or extremely obvious. :)

    [ I also wonder how quickly a single random error could propagate into something like the onset of M.E. I became ill a couple of weeks after a particularly severe case of the flu (and then continued to get worse), but I know that for many people the initial illness simply “becomes” M.E. with no apparent interval.]
    alex3619, Firestormm and Marco like this.
  17. user9876

    user9876 Senior Member

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    I was wondering something along similar lines. If an illness leads to increased antibody production then there would be more chance that some would be bad. However, I'm not convinced that the numbers add up. If there were a hundred fold increase in production then from a simple probablistic perspective then this would be equivalent to 100 normal days hence you would expect a greater mix of infection/non infection related illness. The other thing I was thinking was that maybe the filtering of bad antibodies could become overloaded and hence become less effective on increased antibody production.

    The other thing I was wondering about is there appear to be several epidemics (royal free, LA, lake tahoe) and how do these fit into a model. Of course a population model could perhaps show that we should expect some apparant epidemics by chance?
    alex3619 likes this.
  18. Sasha

    Sasha Fine, thank you

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    Jonathan Edwards - I think that ages ago I read something that said that about half of cases of ME were acute viral onset with a flu-like illness, plus there have been epidemic outbreaks, such as at Lake Tahoe or the Royal Free Hospital, which is why everyone thinks, 'virus'. A lot of us with acute viral onset could tell you what time on what day we got sick. The other cases were 'insidious onset'.

    So any model would need to address why a virus would at least trigger the illness, even if it doesn't maintain it. In the US, patients with ME with high antibody titres to EBV, CMV and/or HHV-6 get treated with antivirals by specialists such as Peterson, Enlander, Klimas and so on and many have very significant improvement, though there haven't been any RCTs (lack of money) apart from one by Montoya that we're all waiting for to be published.
    aimossy and Bob like this.
  19. rosie26

    rosie26 Senior Member

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    I think whatever causes our ME, catching a virus like flu is like "the last straw". I had mild symptoms of ME for years before complete collapse into ME. It was a nasty flu that finally took me down completely. In my case.
    aimossy and Sasha like this.
  20. lansbergen

    lansbergen Senior Member

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    I had no health problems before what seemed the worse flu ever, knocked me down. I never completly recovered from it but in the beginning it was not to bad. Pushing made it worse and worse till the point I was dying. Then I had no choice but to take the risk using levamisole. That was the turning point. Back then it was freely available.

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