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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. rosie26

    rosie26 Senior Member

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    Interesting lansbergen, I guess it's also possible "if"' the cause is viral I could have caught it earlier on in the piece. But I think Prof. Edwards isn't inclined to think the cause is viral, if I remember rightly. So guess we are still waiting. Hope we get to the bottom of all this !

    Big thanks to you, Prof. Edwards for joining us here, so appreciated.
     
  2. garcia

    garcia Aristocrat Extraordinaire

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    If you read my post I was responding to Prof. Edwards hypothesis that: the immune system is behaving as though there is a serious infection, but there is no serious infection involved. As an hypothesis it is certainly plausible, but needs to be tested first. Part of being tested is to make sure it fits the observations we have about ME (in science observation is king).
    If indeed there were no serious infection involved in ME, but the body is behaving as though there is a serious infection, then one would expect corticosteroids such as hydrocortisone to have a positive effect, since one of their primary purposes is to suppress the immune system:

    http://en.wikipedia.org/wiki/Hydrocortisone

    However most patients have a negative effect from hydrocortisone and other corticosteroids, many (like me) a profoundly negative effect. I was wondering what Prof. Edwards thought of this (hence the @ Jonathan Edwards in my post).

    I too am very glad Prof. Edwards has chosen to learn about ME, and is forming hypotheses (which is the job of every good scientist). Part of our job as patients is to help people like Prof. Edwards test their hypotheses with our facts/observations (indeed I believe Prof. Edwards alluded to this in one of his posts).
     
    Bob likes this.
  3. Sasha

    Sasha Fine, thank you

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    garcia - is there any study evidence of that? (I'm not contradicting you, I'm just curious to know if there's a paper on it!).
     
    Valentijn likes this.
  4. user9876

    user9876 Senior Member

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    Corticosteroids can have huge side effects so they could suppress the immune system whilst also causing all kinds of other problems. A friend who was given prednisolone for GVHD lost a lot of muscle strength as a side effect. They can also cause sleeping problems.
     
    Sasha likes this.
  5. user9876

    user9876 Senior Member

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    Where there is a remission after five years is this actually a relapse of is it a new occurance of the disease with the same random process that initially made the bad antibodies happening again as opposed to some form of latent memory?
     
    Bob likes this.
  6. Jonathan Edwards

    Jonathan Edwards Board Member

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    In relation to my cryptic comments a page or two back, I will say one or two more things about why I think chasing individual viruses may be unfruitful (as others have commented too). There are lots of ifs and buts and different angles to put on this but here goes. My impression is that many of the symptoms of ME are in a sense apparent sensitivities to, or intolerances of, stimuli: including exertion, foodstuffs, light, noise, chemicals etc. Some of these stimuli, like light, impinge so directly on the nervous system that it seems it must be the nervous system itself that is hypersensitive. That suggests that some circulating factor, or maybe a factor like TNF within the brain is making trivial things seem intolerable. An example would be when one feels intense nausea looking at rich delicious food when one has an acute viral illness. It is not that one has become sensitive to that food especially but that one’s brain has become sensitive to almost everything. My suspicion is that the sense of constantly being afflicted by viruses may be part of the same thing. I agree that it is not going to be as simple as that but I think it is worth considering.

    The next point is that if infections with particular viruses were to be blamed one would expect to have occasional reports where the presence of that virus became very obvious – if for instance the person with ME was given certain types of immunosuppressive therapy. I appreciate that epidemics of ME do seem to occur but if it was all due to one virus the epidemic pattern ought to be much more general. Again, you can argue against this, but I am trying to redress a balance. There seems to be an assumption that we need a specific environmental trigger, but, as I have been saying, epidemiological theory does not in fact require this if we factor in the dynamics of the immune response.

    What we might be left with is that the dominant sense that ME is like constantly suffering from viral symptoms might point us in the direction of thinking that it is a dysregulation of mediators specifically associated with virus infection. As an example, there is a hint that the molecule TRIM21 might be involved in the handling of viruses within cells by the immune system and there is a link between TRIM21 and Sjogren’s syndrome.

    This links back to the debate about mediators like TNF and cortisol. Cortisol suppresses certain effector systems in the immune response, including TNF, at least in the bloodstream, but not others. Cortisol, as far as I am aware, has no effect on circulating antibody levels, presumably because it does not affect plasma cells much. So although cortisol makes RA better by suppressing inflammatory mediators, it may be of little use where antibodies are causing trouble without causing inflammation. A clear example would be the exophthalmos (eye protrusion) associated with anti-thyroid peroxidase antibodies. The absence of any benefit from cortisol in ME would tend to suggest that the symptoms are not due to standard inflammatory pathways. This might be because inflammation is within the central nervous system but even then one would expect cortisol to have some benefit.
     
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  7. Jonathan Edwards

    Jonathan Edwards Board Member

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    I think to begin with it would help to have a biomarker of any sort and it might be one that is not readily usable in routine clinical practice and it might be a blood sample! Once that has been pinned down by good statistical significance in a scientific study the attitude to ME will change. Finding a practical biomarker for clinical use may then take longer but at least there will be motivation to develop the technology if it is known that there is a particular pathway to focus on. I am not sure why blood tests are not your favourite. In practice they tend to be the most practical way of getting information. On the other hand some sort of exercise stress test might give an answer - but maybe I would prefer the blood test if I had ME!
     
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  8. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes memory B cells have CD20. Not sure why this comes up. Even memory B cells are in a sense cells undergoing education, to the extent that they do not make much antibody until they go through another round of checking their skills against antigen. As to whether long term antibody responses are determined by memory B cells or plasma cells, this is still something nobody is quite clear about. It may be a bit of both. One other point is that rituximab may not kill certain populations of memory cells if they live in protected zones in lymph node and spleen. So although all B cells have CD20 (not plasma cells) we do not assume they are all killed.
     
  9. Jonathan Edwards

    Jonathan Edwards Board Member

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    I agree that the events around the onset phase of acute onset ME may be hard to tease out. A condition that looks a bit like ME is Reiter's syndrome, which can have similar severe fatigue and is associated with an initial intracellular bacterial infection. Viral infections are intracellular too but they do not ever seem to trigger Reiter's syndrome, which is interesting. Maybe the mediators are different so you get ME instead. In Reiter's syndrome it is not clear that there are any autoantibodies. It seems more likely that there is an overactivity of T cells that can last for a year or two or sometimes for many years. I find it hard to understand what keeps that going and sometimes wonder if a B cell loop is helping the T cells keep going. I don't think anyone has a good model for this.

    I am not sure that we recognise 'active' or 'quiescent' immune systems so much. The number of mutations in antibody genes may be about the same every day. What may be different is whether or not the results are being grown up by plasma cells for immediate use. But I think there may be times when more secondary mutations occur during infections and these could form loops. It's a good question. A lot of these questions are very much on the edge of what anyone really has a handle on I think.
     
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  10. Sasha

    Sasha Fine, thank you

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    I've got serious concerns about the 'testing to destruction' that could be involved in the exercise stress test. I understand the current need for it for research purposes and admire those patients willing to undergo it for the sake of the rest of us but I'd hate to see it established as a diagnostic test. I don't know of any other disease where patients risk serious harm from a diagnostic test.
     
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  11. garcia

    garcia Aristocrat Extraordinaire

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    Many thanks for the reply Prof. Edwards.
    I'm not talking about absence of benefit so much as outright worsening. Some of us do in fact get some symptomatic relief from hydrocortisone in the short term, especially with regards to inflammation. The issue is that corticosteroids can cause us immense long term relapse. I'm not talking about huge doses either, I'm talking about anything from a physiological replacement dose (say 20mg hydrocortisone), down to 1mg or lower. Immune suppression seems to be one of the worst things to do in ME. Obviously this doesn't prove infectious aetiology, but at least strongly suggests it, to my mind at least.

    This is what I'm saying happens. By giving immunosuppresive therapy such as corticosteroids, ME patients are generally made much worse.

    If there is an infectious cause for ME (or at least a subset of patients) then it is not likely to be an existing known virus.

    P.S. in case it isn't clear, I am still open to the possibility of a non-infectious aetiology for ME, though I personally think it less likely than an infectious aetiology. But immune suppression does seem to be an overt part of this disease. Acquiring infections not only seems to trigger the disease in most, but also seems to cause permanent worsening in those who already have the illness.
     
  12. Gemini

    Gemini Senior Member

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    Professor you bring to mind my favorite 2012 paper involving infectious triggers in general perhaps you are familiar with it as it caused quite a stir in the press? Researchers monitoring the immune system's interaction with the environment in a 54-yr old man over a 14 month period unexpectedly on Day 289 caught a respiratory syncytial viral infection (RSV) apparently trigger Type 2 diabetes to which he was genetically predisposed. They had been tracking 40,000 variables (with the help of a computer!) including his [Michael Snyder's] autoantibodies : "Snyder also exhibited increased levels of autoantibodies, or antibodies that reacted with his own proteins, after viral infection. Although autoantibody production can be a normal, temporary reaction to illness, the researchers were interested to note that one in particular targeted an insulin receptor binding protein." The researchers concluded: "We speculate that perhaps RSV triggered aberrant glucose metabolism through activation of a viral inflammation response in conjunction with a predisposition toward T2D."

    A confounding mystery in this story to me is that Snyder experienced a second viral illness during the experiment a human rhinovirus (HRV) on Day 0 which did not trigger his autoimmune disease. Would you suppose the generation of his insulin receptor binding protein autoantibody was random, or is it possible that some unique characteristic of RSV but not HRV played a role? Bringing it back to ME, I wonder if some "unique" characteristic of the enteroviruses and other viruses/vaccines mentioned over the years as triggers might provoke an overly strong immune response leading the interferon pathway to protectively switch to immune supression mode setting off a cascade of immune and neurological symptoms?

    http://www.sciencedaily.com/releases/2012/03/120315123020.htm

    http://www.ncbi.nlm.nih.gov/pubmed/22424236 Open Access
     
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  13. lansbergen

    lansbergen Senior Member

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    There was a dispute on the forum a while ago. Now it is clear it has not to be discussed again.
     
  14. voner

    voner Senior Member

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    prof. Edwards,

    Well for us that have been reading medical research papers for years, there have been all sorts of "blood test biomarkers", But the caveat seems to often come along with the question of patient selection subsets, etc. Kind of a chicken and egg. How do you get around that?

    For me, the exercise gene expression studies done by Alan Light, et. al. Certainly shown the most dramatic evidence of illness/Dysfunction. Their test Involved Moderate exercise, Which still could be problematic for some or many.

    Here is one of the papers by Light, etc.

    http://www.ncbi.nlm.nih.gov/pubmed/21615807

    Prof Edwards .... Can you give a couple examples of blood tests that are done in autoimmune diseases? Would you be looking for antibodies?
     
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  15. Sasha

    Sasha Fine, thank you

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    I wonder if one could identify people by the Lights' test and then attempt to use that group to find biomarkers in the blood or other tissue or fluids.
     
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  16. voner

    voner Senior Member

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    I think that is the Eventual intent of Their studies. It's a few years off, it sounds like. I think their Intent is that they will do some more of these gene expression studies In order to weed out a couple subtypes or more. That will allow them to start looking for specific biomarkers.

    One of nice things about the Light studies is that They are not saying The dysfunction is a cause of infection or autoimmunity, etc. They are saying we have these patients that we have carefully verified have the ME/CFS/FMS symptomatic issues and look at the wildly dysfunctional gene expressions they have after exercise.

    It would be interesting to hear what their next step would be as far as looking for biomarkers. I have the opportunity speak to Dr. Bateman at the end of June in Denver, but unfortunately, I didn't even think to ask her that.

    I highly recommend Dr. Batemans video up at the CFIDS site.... even for You, Prof. Edwards, or maybe even especially for you. It will give you a good flavor of the variations in the patients that they're looking at, Dr. Bateman actually shows the gene expression studies of some of the individual patients and describes their symptoms etc.

     
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  17. Marco

    Marco Old blackguard

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    On the basis of my own symptoms (including pre onset of ME) and discussions here with others, I proposed that ME/CFS patients if tested might have an information processing/sensory defensiveness problem and that one artifact of this might be measured as a 'sensory gating deficit'.

    This does appear to be the case (at least as far as a later 'gating-in' measure is concerned - basically the allocation of attention to salient stimuli).

    Event-related potentials in Japanese childhood chronic fatigue syndrome.
    Akemi Tomoda, Kei Miyuno, Nobuki Murayama, Takaka Joudoi, Tomohiko Igasaki. Journal of Pediatric Neurology, January 2007.

    http://iospress.metapress.com/content/w14pg23t125337q8/


    Earlier gating out of repetitive or trivial noxious stimuli hasn't to my knowledge been properly tested in this population.


    As regards a potential model for this central hypersensitivity - Martin Pall's model of multiple chemical sensitivity (and 'related' conditions such as ME/CFS, PTSD and fibromylagia) may be worth revisiting.

    The basic schema is : organic solvents trigger glutamate release leading to ‘long-term potentiation’ of glutamate receptors sparking a ’vicious cycle’ involving glutamate and nitric oxide/pyroxinitrate.

    Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity: central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.
    Martin L Pall

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241647/
     
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  18. Snow Leopard

    Snow Leopard Senior Member

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    I'm not saying it is a good idea to for patients to take it, but Corticosteroids have been shown to have moderate effects in double blinded RCTs. One of the keys from the studies is that dosage was important for both getting an effect and avoiding harms.

    http://www.ncbi.nlm.nih.gov/pubmed/9989716
    http://jcem.endojournals.org/content/86/8/3545.short

    There were a few more, but I don't have time right now to find them.

    That is not quite what was said. The severity of the illness, rather than the severity of the infection was the key predictor. Eg those who were bedbound, suddenly couldn't walk etc. were the ones who were likely to have a CFS like condition at the follow ups, whereas those with more mild fatigue were more likely to claim to be recovered at the follow up.
     
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  19. lansbergen

    lansbergen Senior Member

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    Both only for fatique and both say for some patients.

    Filter out these patients and the bin will become less messy.
     
    garcia likes this.
  20. Forbin

    Forbin Forbin

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    Thanks for the correction. It was indeed incorrect to use the phrase “severity of the infection.”

    The paper says, “The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.”

    During the acute illness, the severity of the symptoms was also strongly correlated with the ex vivo production of the pro-inflammatory cytokines interleukin 1β and interleukin 6.

    However, the severity of the symptoms was not correlated with viral load or antiviral immune responses [though only the EBV cohort was checked for this].

    http://www.bmj.com/content/333/7568/575
     
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