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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 Senior Member

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    A proportion of people who are diagnosed with RA have no autoantibodies. In general they do not respond to rituximab, which makes sense. We have always known that it is not always possible to distinguish RA from other sorts of inflammatory arthritis like psoriatic arthritis, especially when there is no psoriasis to see so it seems likely that a proportion of 'RA non-responders' do not have a B cell related disease.

    Then there are people whose joints are so badly damaged that they do not get much benefit from any drugs.

    Of the remainder with autoantibodies most respond well but there also seems to be a small group with a lot of inflammation whose disease responds very slowly and is hard to get fully under control. This is not actually that surprising. Remember that rituximab does not kill the cells that actually make the autoantibodies (i.e. plasma cells), it kills younger B cells that might one day become plasma cells, so there is a lag in the effect. If the plasma cells making autoantibodies live long enough, and we know that some can live for up to ten years, then repeated courses of rituximab for several years may not reduce antibody levels enough to control inflammation. We tend to see rheumatoid factor levels dropping to about a half the original level in responders, which often seems to be enough, but clearly it might not always be. Even for B cells we have reason to think that some can hide away in lymph nodes and survive rituximab.

    So it is not that difficult to explain non-responses. What is needed is a something that actually kills all autoantibody producing plasma cells. The problem with that is that it needs to be specific for autoantibody producing plasma cells rather than useful plasma cells and we do not know how to do that.
    NK17, aimossy, beaker and 12 others like this.
  2. Kati

    Kati Patient in training

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    Thank you so much for your answer.
    aimossy likes this.
  3. Firestormm

    Firestormm Senior Member

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    @Jill thank you. I missed those :)
  4. Bob

    Bob

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    aimossy, Snow Leopard, beaker and 2 others like this.
  5. Marco

    Marco Old blackguard

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  6. Bob

    Bob

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    @Jonathan Edwards

    I wonder if you have seen this paper, and if you think it has any merit, and if you think it might have any potential as a plausible hypothesis for ME?

    Immunological trigger events have often been associated with ME. Reported trigger events have included: receiving vaccinations (e.g. Hep B); travel abroad esp after vaccination; and having an illness or infection.

    The full paper is accessible.


    Self-Organized Criticality Theory of Autoimmunity
    Tsumiyama K, Miyazaki Y, Shiozawa S
    Published: December 31, 2009
    PLoS ONE 4(12): e8382.
    doi:10.1371/journal.pone.0008382
    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008382

    PDF format:
    http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0008382&representation=PDF

    Abstract

    Background

    The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune ‘system’, to explain the cause of autoimmunity.

    Methodology/Principal Findings

    Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8+ T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).

    Conclusions/Significance

    Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host's immune ‘system’ by repeated immunization with antigen, to the levels that surpass system's self-organized criticality.
  7. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I am afraid that I can say from the abstract that this is a very bad piece of science. The conclusion is totally unjustified. The experiments are just irrelevant. As I mentioned a while ago, the cause of a disease in mice caused by researchers injecting masses of foreign material is not the cause of human autoimmunity - it is researchers injecting antigens. This sort of nonsense has been going on since the 1960s and looks as if it will not change. We have a pretty good idea of how autoimmunity comes about. It is not through being a small rodent in a cage in a lab! It occurs very unpredictably over a period of decades in Homo sapiens. maybe sometimes there is a trigger but not the sort they are describing. What is worrying is that this sort of work, with this sort of lazy conclusion, is now taken as being respectable. Science has been dumbed down by the commercialisation of journals and various other things.

    In other words: 'Nul points' as they say on Eurovision.

    maybe I'm getting old, but I don't think so yet.
    NK17, beaker, Jill and 8 others like this.
  8. Bob

    Bob

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    Thanks for your views. We patients have noticed that a lot of dodgy stuff gets published, despite it being allegedly peer reviewed.
    aimossy and Kati like this.
  9. Bob

    Bob

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    I thought this article might be of interest to folk following this thread, and to Prof Edwards:
    http://www.theguardian.com/society/2013/nov/17/alzheimers-arthritis-drug-new-weapon

    It describes how they are going to test etanercept for Alzheimer's.
    Etanercept is a drug widely used for rheumatoid arthritis, and is also being tested by Fluge and Mella for patients who are not responsive to Rituximab.

    There's a separate forum thread for this, here:
    http://forums.phoenixrising.me/index.php?threads/arthritis-drug-for-alzheimers.26525/
  10. Jill

    Jill

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  11. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Thanks Jill,
    Bob flagged this paper up in September and I ducked out of commenting. Some other relevant comments have been made so I feel a bit more comfortable about doing so now. It is written as if by a rather overenthusiastic student on one of the non-clinical biomedical science courses. Full marks for reading references but not so many marks for critical analysis. Not up for the course medal. The stuff on rituximab is mostly nonsense I am afraid. I am slightly surprised that a senior academic has put his name to it.

    I may sound stuffy at times, but, as you may have noticed, I am about as subversive as you can get in terms of received dogma. The truth is that this is not how science gets done, even if, in this era of publishing as commercial advertising (both for the publishing company and the authors), a lot of people in science have come to think it is. The secret is to look for things that DON'T fit, not for things that fit, to see why ideas do not quite work and move on to ones that do. Similarities are two a penny. Important inconsistencies are not.

    Still, it is worth looking at everything that comes along. Other people's attempts to piece things together can be very useful for making one realise why one idea does not quite work and another does.
    NK17, Svenja, Esther12 and 11 others like this.
  12. Marco

    Marco Old blackguard

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  13. Simon

    Simon

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    Thanks for the critique: I think that philosophy would have saved more than a few dead ends in mecfs research.
    Svenja, aimossy and Esther12 like this.
  14. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I think these results are quite interesting but I think the most useful sentence in the paper may be:
    "Although we find relatively high levels of antibodies to specific HSP60 epitopes in ME, the high frequency of anti-HSP60 antibodies in control samples, and the high conservation and many functions of HSP60, argue against simplistic conclusions regarding its etiological role(s) and possible therapeutic implications."

    Heat shock proteins (HSPs), especially HSP60 have fascinated research workers since about 1985 and antibodies to HSP60 have been looked for in lots of diseases. They have often been found, but this is really the problem, there does not seem to be a lot of specificity about them. The authors come up with sentences like "HSP60 is a central autoantigen." but I am not sure they are entitled to. Antibodies to HSP60 are trendy in labs but for someone like me working with autoimmune disease in the clinic they were never more than a sort of vague non-secific suggestion that kept coming up and dying down - a sort of pervasive low level noise. You cannot really talk of a 'central autoantigen' because for the antigens that correlate closely with clinical disease, each disease has a different autoantigen. If you are looking for an explanation for ME, and specifically ME, then HSP60 seems rather unlikely to help, simply because it does turn up so often.

    There are also technical aspects to the paper that I am not sure help much. Antibodies react with whole proteins and I am not sure what antibody binding to peptides (fragments) tells us. To me what is relevant is whether or not there are antibodies to the whole human protein. Again, the authors bring in the story about cross reactivity between bacterial and human proteins but this story has never had much (?any) evidence for it and the data do not tell us one way or another. There is a touch of the usual looking for what everyone thinks one should find and finding it.

    Nevertheless, if the ME patient had more autoantibodies to human HSP60 than controls that does seem to fit with the more general idea that those patients may have one or more autoimmune diseases (or ME subtypes if you like). What does seem to be true about antibodies to HSP60 is that they are more common in people with autoimmunity of various sorts. The downside is that this could be just another rather vague bit of circumstantial evidence for an idea already supported by some rather better evidence (from response to rituximab). But if, say, three other labs could show that three other unselected ME cohorts had comparable increases in antibodies to HSP60 I think that would be something pretty impressive, as support for an autoimmune basis in general terms. The evidence may be circumstantial but it may be at this stage that just systematically repeating this sort of observation will allow a much higher level of confidence in an autoimmune theory. That is not trivial because once that confidence gets to a certain level trying treatments like rituximab becomes easier to justify not just in formal trials but on a single patient basis.
    NK17, Firestormm, Ninan and 8 others like this.
  15. Marco

    Marco Old blackguard

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    Many thanks. That was very useful. I've just finished (my first) reading of the paper and it does seem (including file S1 - the supplementary material) quite a considered and careful paper whose conclusions (your own concerns excepted) don't go too far beyond the findings.

    They did appear to go to some convoluted lengths though to establish significant differences between the ME group and controls and as, par for the course, most significant differences obtained in the initial cohort tend to disappear when applied to a new cohort.

    I was also struck by their observation that immunoreactivity in healthy blood donors may vary by year or season. I wonder how often this has been a confounding factor.

    Getting back to your quote above, the lack of specificity I find comforting. Despite what some would claim, none of the symptoms of ME/CFS are specific to that diagnosis and the most common symptoms (fatigue, neurocognitive symptoms, sleep disturbances) are quite common in other autoimmune diseases.
  16. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Yes, I tend to agree. But there may be subtleties. In RA there are HSP60 antibodies but I doubt they cause fatigue in RA - I think that comes from the specific antibodies - rheumatoid factor or anti-citrulline - and TNF release. HSP60 antibodies look to be a bit like the 'smoke with a fire' - an epiphenomenon maybe. As another example, in scleroderma you get more or less the same symptoms from one of three quite different autoantibodies. Everyone with scleroderma has an autoantibody but each person only has one of the three options. So, despite some sceptical remarks from some quarters, I am a believer in each autoimmune ME patient having their own specific autoantibodies (maybe twenty options?) as well as anti-HSP60 smoke. The difficulty with twenty different autoantibodies is that none of them might each show up in enough cases for anyone to take notice, so we may learn more from looking for the smoke at the moment. But I could be wrong.
    Legendrew, Ninan, aimossy and 4 others like this.
  17. Marco

    Marco Old blackguard

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    A major problem.

    So what 'smoke' should we be looking for? Cardinal symptoms that are non speciifc?; atypical symptoms that overlap with other disorders, a particular cytokine signature that probably isn't specific?

    What is it that is common about autoimmunity potentially arising from up to twenty autoantibodies that would result in a diagnosis by exclusion of ME/CFS rather than another autoimmune disease or non autoimmune condition that shares similar symptoms?

    I'll stick my neck out and suggest that ME/CFS is not a discrete clinical condition but a particular constellation of symptoms (perhaps of autoimmune origin) that doesn't neatly fit into an alternative diagnosis.
  18. Jill

    Jill

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    Prof , said : "The secret is to look for things that DON'T fit, not for things that fit, to see why ideas do not quite work and move on to ones that do. Similarities are two a penny. Important inconsistencies are not."

    Thinking on this angle, one thing that strikes me about ME is that the severe people also have the strangest reactions to medications. I've always thought this should "tell" us something. For example, recently a friend had all his pain helped by SR voltaren 75mg, BUT he is now so weak he can't walk unaided ( the weakness comes from puffing like a 120 yr old with obstructive heart failure) . He hates the thought of the pain back ( it appears like joint pain, even has some redness), but I suspect thats what will have to happen as he is possibly reacting to the voltaren.
    He may of course, have also now developed some form of arthritis that doesn't show up in RF, ANA , CRP or sed rate. If that is the case he will have to be tried on a different type of med, but the question is , which sort do we punt for? Do folk with arthritis have this sensitivity to meds?
    rosie26 likes this.
  19. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I am not sure it is such a big problem. Non-specificity in relation to 'disease' pigeonholes does not matter if the feature of interest indicates a sort of mechanism to which one can target a rational treatment. Anti-HSP antibodies may not be specific for any pigeonhole but they are pretty good evidence for a disturbance in B cell function. The fact that they do not distinguish ME from other autoimmune diseases is OK if the treatment is the same.

    What would make sense to me would be for the research community to systematically repeat all the studies of this sort to see whether the results really are consistent. If they are confirmed then the long haul of looking for specific antibodies is more clearly justified. Some sort of specificity of the process ought to be there to explain why ME does not include glomerulonephritis, for instance. But even within disease groups where the antibodies are well documented there are lots of fine detail differences between cases that we cannot account for. That is not surprising because for any one antigen target (like thyroid peroxidase or DNA) you can make thousands of slightly different sorts of antibodies.
    rosie26, Bob and aimossy like this.
  20. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Reactions to voltaren are not uncommon in anybody and shortness of breath is one of them. Maybe 30-50% of people with RA find taking voltaren regularly pretty hard going. But people with ME may well have more reactions. If ME involves the activation of some sort of protective response mechanism, like production of a cytokine, then it would not perhaps be surprising if that was aggravated by all sorts of things that in other people caused no more than occasionally feeling slightly nauseous or 'mentally blank' as is very common with drugs like voltaren or, in the old days, indomethacin even more so.
    Gemini, rosie26, Bob and 2 others like this.

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