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Never Ask Us if We're Hungry -- The Answer's Always No
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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. Jonathan Edwards

    Jonathan Edwards Board Member

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    I think this may be a case of not seeing the wood for the trees. If rituximab did not kill B cells nobody with B cell lymphoma would have got better - and an awful lot of people have. And they quote a 51% reduction in CD19 count in their blood analysis but when rituximab is used for autoimmune disease we like to see more than 98% depletion of CD19 positive cells. Moreover, that depletion can last long after rituximab levels have sunk away, in rare cases for years. And autoantibodies go down and the B cell growth factor that regulates B cell numbers goes way up, as if there are no B cells. There is no reason to think that rituximab does anything to any other cells, except perhaps a tiny strange population of T cells that have CD20, so I think this looks like a laboratory artefact.
    ukxmrv, Countrygirl and Valentijn like this.
  2. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    If we had decent GPs, perhaps! I have been refused referral to both neurologists and infectious disease specialists.
    irwinsturtle likes this.
  3. Marco

    Marco Old blackguard

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    Many thanks:)

    Would it be accurate then, if simplistic, to say that with both approaches result in reduced levels of TNF-a?
  4. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    As the paper I linked to on how leaky gut can lead to autoimmunity states, autoimmunity is not a once-and-for-all event but an ongoing process. Auto-antibodies can stop being produced for various reasons, which will produce remission in autoimmune disease. There is info about the processes involved here for example:

    http://www.birmingham.ac.uk/Documents/college-mds/facilities/cis/Essentialimmunology/Chapter4.pdf

    So if we have an autoimmune disease, we are looking to achieve self-tolerance. There may be various ways to achieve this, and it can happen spontaneously. The Holy Grail is of course for such self-tolerance to be permanent. This may require more than one type of intervention, and perhaps some lifelong lifestyle changes.
  5. Kate_UK

    Kate_UK Senior Member

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    What about families where the mother and the children have ME? Does that mean the children could have ME because their B-cells learned wrong from the mother?
    Bob likes this.
  6. Roy S

    Roy S former DC ME/CFS lobbyist

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  7. lilpink

    lilpink

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    Thank you so much for this very interesting reply. I must say that's the most supportive response I've ever had to this query over the last 26 years since I noticed the effect during my two pregnancies in 1987 and 1988. I'm very glad that my own notions of cause and effect (if only theoretical) might indeed have a biological basis. It's such a change to be able to have this sort of interaction with someone who doesn't only reply in terms of 'probably not' or 'we just don't know'. Many thanks indeed!
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  8. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, although measuring it may not be that easy.
    What I forgot to add is that the pathway from antibody to TNF is important in rheumatoid arthritis but may not figure at all in other conditions. In lupus the antibodies may deposit in blood vessel walls. In thrombocytopenia they cause phagocytosis of platelets. In thyroid disease they may stimulate hormones. In some neurological diseases they interfere with neurotransmission. On the other hand there are diseases that involve TNF but not antibodies - like psoriasis.
  9. Jonathan Edwards

    Jonathan Edwards Board Member

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    Brilliant thought Kate. I would need to think hard about that but I think the answer is probably no, judging by other autoimmune diseases (assuming we can extrapolate). When mothers have autoimmune disease their babies can get sick in the womb because the mother's antibodies cross the placenta - it happens in lupus, myasthenia and Sjogren's. It does not happen in rheumatoid because complexes do not cross the placenta I think. However, the effect wears off in a matter of days or weeks. And as far as I know there is no evidence that the baby's immune system then starts making its own autoantibodies. You might then ask why, considering the story I told a while ago, and I don't think anybody knows. Maybe its because the mother's antibodies are not actually being produced in the baby's bone marrow where the B cells are developing. That would be a neat answer but I would like to think about it more. Not that many scientists ask these interesting questions, in my experience. I will have to see if Jo Cambridge or Amolak Bansal have a neater answer!
  10. Esther12

    Esther12 Senior Member

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    Thanks for all your responses. I tend to avoid reading research involving the immune system because it all seems so complicated, but the Samurai training story was right on my level!

    re concerns about a small trial: My concerns are largely in light of the report that the larger Norwegian trial is no longer being held up, and is under-way (I'm not sure if this has been officially confirmed or not, if this is wrong, most of this post will be redundant). I don't want to talk down this proposed trial, as it seems like a more worthwhile area of research than most CFS studies that end up being funded, but I don't think I really understand why you think a small trial is the right way to go at the moment, so hoped you could respond and expand on this.

    If there is a 60% response rate, then this will be shown by the larger trial.
    If there is a lower response rate, then this is more likely to be picked up by the larger trial than a small one,and this could also lead to data that would allow for more useful small replications in the future.
    If there is no positive response to rituximab, then the larger trial will be more useful for revealing this.

    Is the benefit of a small trial the speed? That a small study be likely to be completed and published long before the larger study? Is it political?: eg, researchers/doctors/funding bodies seem to have more respect for research from their country that elsewhere. Maybe just having different groups working on this in slightly different ways increases the chances of something useful turning up? Is it just that, as the cost is relatively low and it's thought that there's a good chance of a 60% response rate, it's worth trying to get an independent replication in now?

    When I heard the expected cost of the Norwegian study I did think 'maybe do another smaller study first?', but if the large study is under-way, I'm unsure about the value of running a small study concurrently, while we still have a poor understanding of which patients are most likely to benefit.
    irwinsturtle and Simon like this.
  11. Sasha

    Sasha Fine, thank you

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    Everything I've read says that the Norwegian trial will begin in January 2014 and (I think) would take an estimated two years to complete.

    I assume a UK trial of 30 patients could be completed much faster, especially given that potential patients will be thundering like wildebeest towards UCL so recruitment could be pretty quick.
    ukxmrv and rosie26 like this.
  12. Bob

    Bob

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    They'd better watch out for the Samurai!

    I'm loving the metaphors in this thread! :)
    Sasha and rosie26 like this.
  13. Dolphin

    Dolphin Senior Member

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    Always nice to see optimism.
    However, outside the US, where some people with deep pockets occasionally donate 6- and 7-figure sums, £400,000 is a lot of money to raise in the ME world.

    What the ME and You Foundation did was exceptional.
    Valentijn, ukxmrv and Purple like this.
  14. Sasha

    Sasha Fine, thank you

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    I refer the honourable gentleman to the answer I gave some moments ago: :)

    http://forums.phoenixrising.me/inde...uximab-trial-30-july.24499/page-6#post-376996
  15. Dolphin

    Dolphin Senior Member

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    My guess, could be wrong, is the CFSRF won't give anything: they like to fund studies exclusively.

    Not sure whether AfME have much if any money left currently: the biobank has been expensive and they gave out grants for research fairly recently.

    The MEA have pledged £60,000, but £50,000 of that money was raised over a reasonable period (i.e. only around £10,000 since launching the ring-fenced money).

    Not sure how long it took Invest in ME to raise £100,000 for their first study - maybe 2-3 years? I expect they may well raise money faster than that this time of course.

    Other money may come in also, but just pointing out that grants in the ME world outside the US are usually measured in five figures so I wouldn't expect the money will be raised before January 2014. But who knows. I just don't want anyone to get complacent.
    Sasha likes this.
  16. Sasha

    Sasha Fine, thank you

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    Hard to know. I think IiME raised that £100k in two years.

    I think we're into a new game with being able to donate to specific projects with a clear funding goal rather than the bottomless pit of a charity's general fund. That £8k from a single donor, I believe, came within days of the MEA announcing that they'd ringfenced that £50k. Supporters of the other charities might do similarly.

    I wouldn't underestimate the enthusiasm among patients that this trial is going to generate, especially after the example that Maria set. I think those coffers could get topped up pretty quickly.

    The CFSRF is a dark horse but every now and again, they drop an absolute ton of money on something. They will have people with ME who will want to get well as fast as the rest of us. If they see this opportunity, who knows...

    Of course, there's nothing to stop someone in the US donating or pledging to this trial, if they see an advantage in getting a small trial done quickly rather than (or as well as) a large trial done over a longer timeframe.

    And let's not forget the MRC - this would be chickenfeed to them. And even the feeble £700k or so that ME gets a year from them would more than cover this trial.

    Lots of reason for optimism - and it's optimism that brings the money in! :)
    Valentijn likes this.
  17. Firestormm

    Firestormm Guest

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    I agree with Dolphin I also think that when UCL have confirmed a Trial as being worthwhile and produced a proposal, and said proposal meets the separate charities (or a collaboration thereof) peer review: THEN you might see some momentum.

    Individual charities are unlikely to invest with IiME fundraising pot until such time as this is produced - their is also the issue of ownership to be resolved or raised. IiME cannot take funds from a separate charity and expect to control them; or to hold onto them in the event of this UCL venture not proceeding for any reason. Their literature thus far produced claims that in such a situation the funding would be reallocated to the general 'biomedical' fund.

    Personally, though, I still think you'll be hard pressed to reach £400k before the Norwegian Trial has been completed. If I had the money, I would I think at this point, hold fire until I saw what that revealed.

    But it depends also on what comes out of UCL by way of a proposal - and if that proposal is good enough - you might see an application to the MRC being honoured; which could change the landscape.

    For me - the interest is in learning how this drug appears to have worked (and not worked) at this point.
  18. Bob

    Bob

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    I'm open minded to the idea that ME is an autoimmune disease, but I wonder if the illness can be as simple as the production of an auto-antibody.

    The main reason that I question it is because of post-exertional malaise.

    Post-exertional malaise is a very specific reaction to exertion. Simply put, when we exert ourselves (i.e. use energy) all of our symptoms increase, often with a delayed reaction of 12 to 24 hours, and our illness deteriorates.

    I wonder how and why the symptoms would increase in reaction to exertion, if it's an autoimmune disease.

    If looking at it from the point of view of autoimmunity, what happens when we use energy, that would provoke an autoimmune response? And then why would the reaction be long-lasting once we stopped exercising?

    Exploring the issue hypothetically, let's say that a unique molecule is produced (or enters our bloodstream) when we use energy, and that provokes an auto-immune response. Then why doesn't the autoimmune response diminish once we stop exerting ourselves, or why is there a long-lasting reaction? Post-exertional malaise can last for months, or longer, after we over-exert ourselves. Symptoms do not increase and decrease in direct proportion to energy used.

    If auto-antibodies are produced in reaction to exertion, how long can they last in the body? Can they last a very long time after they are produced? Could this be an explanation for long-lasting reaction to exertion? Or can dysfunctional B-cells last for a very long time after they are created?

    I'm out of my depth here, scientifically, but I can't help feeling that it's more complex than an auto-antibody at play, and that we have a more complex immune dysfunction.

    Hypothetically, again, perhaps there is some sort of destructive biological loop at play, and an auto-antibody is targeted at a part of the immune system. So that when an auto-immune response is provoked or triggered, by exertion, the auto-antibody attacks a part of the immune system which makes the immune system dysfunctional. And perhaps this immune dysfunction causes, or allows, the auto-immune response to take place in the first place. So it's a destructive feedback loop.

    I'm sure I'm talking absolute nonsense, in terms of actual science, but I'm just trying to get my head around the possibilities.


    Another thought is Julia Newton's recent (as yet unpublished) research in which she found that muscle tissue taken from ME patients produces 20 times as much (lactic?) acid as muscle tissue from healthy people. How would this come about in terms of auto-immunity? I imagine that there might be an interplay between auto-antibodies and something within the cellular mechanism that produces energy (i.e. related to the mitochondria.) Are the mitochondria an integral part of the immune system? Could this explain a possible destructive feedback loop? (Dysfunctional mitochondria could potentially explain both the profound fatigue/exhaustion, and the post-exertional malaise in ME patients.)

    Here's an interesting article about the relationship between the immune system and mitochondria, which discusses how mitochondria can mediate/trigger a systemic inflammatory immune response to 'trauma'. (The article doesn't mention ME, but perhaps ME could be described as a systemic inflammatory immune response to 'trauma' or 'stress'?):
    http://www.nature.com/scitable/topicpage/mitochondria-and-the-immune-response-14266967


    I wonder if Jonathan Edwards has any thoughts about any of this at all, if it makes any sense?
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  19. lansbergen

    lansbergen Senior Member

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    I do not know it is autoimmune but I have no doubt in my case there is an immune reaction when overdoing and it hurts like hell. The immunemodulator I use, helped a lot. It gradually became less severe and at less places.
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  20. Bob

    Bob

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    Yep, I agree that there seems to be an immune reaction when over-exerting.

    Dr Nancy Klimas is supposed to be having some success in her clinic with Imunovir (inosine pranobex), which is an immune modulator or immuno-stimulant (with anti-viral properties).

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