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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. Snow Leopard

    Snow Leopard Senior Member

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    Quite a large subset of ME/CFS patients have Hashimoto's thyroiditis, or likely to have some sort of autoimmune hypothyroidism and maybe this is a distinct subset that will respond to Rituximab. On the other hand, thyroiditis doesn't fully explain the fatigue, since it doesn't explain the rest of the cases where the thyroid appears to be functioning okay.

    That is the funny thing about the exclusions from the various ME or CFS criteria. Certain other conditions exclude you from a diagnosis, but in few cases (unless it is a mitochondrial disease or something) does it actually explain the fatigue, since the mechanisms of fatigue are still poorly understood.
  2. Bob

    Bob

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    I'm not certain that it's a large subset. I thought it was quite a small subset, but slightly larger than the general population. Do you happen to have any stats? (I can't find any, but I have come across them before.)

    I wasn't suggesting that thyroiditis is in any way a causative factor for ME, or that it causes ME symptoms. The two conditions are completely separate diseases, although there can be similarities in symptoms with ME and hypothyroidism. I just meant that a subset of ME patients have co-morbid ME and a thyroid disorder. Over the years, I've had normal thyroid levels, hypothyroidism, and hyperthyroid symptoms, and the ME has been a constant throughout. When I've had hyperthyroid symptoms, the increased rate of metabolism antagonises the ME symptoms, just as increased exertion does, and I am over-stimulated and exhausted at the same time, which results in lots of muscle cramps.

    Only untreated thyroid disorders are exclusionary criteria for ME/CFS.
    aimossy likes this.
  3. Marco

    Marco Old blackguard

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    Many thanks again. Its good to see these ideas tested to destruction:)

    Just a few suggestions. Why the delay in response? (did Fluge and Mella measure cytokines - I'd a feeling all the outcome measures were based on self report?). Several researchers are working on neurological models of ME/CFS which include variants of a 'neuroinflammatory vicious circle' (which other researchers propose underlies mental fatigue - bearing in mind that PEM just as often follows mental rather than physical exertion). TNF-a attenuates the clearance of extracellular glutamate by astrocytes and once this 'vicious cycle' is established activated microglia pump out TNF-a themselves negating the need for ongoing peripheral inflammation. Over time, either through 'kindling' or neuroplasticity, structural changes may result in the brain being hyper sensitive to even trivial sensory input (light and sound etc sensitivity?). Assuming the above (big assumption), even when the trigger is shut off (TNF-a by Ritux treatment) it would take some time for the 'aberrant neural network' to be extinguished, again through neuroplasticity.

    OK - pretty contrived I admit.

    CRP does appear to be raised in ME/CFS patients - maybe not to the levels seen in RA. Perhaps because RA patients' pain is related to actual tissue inflammation whereas there's no apparent similar tissue damage in ME/CFS?

    Why do ME/CFS patients feel worse? Julia Newton's work on primary biliary cirrhosis as a quasi model of fatigue in ME/CFS is interesting. The same cytokines appear to contribute to fatigue in PBC and recent research has linked 'sickness behaviour' (fatigue, malaise, mood) in PBC to polymorphisms in a TNF-a regulating gene. A 2006 paper found increases in a similar TNF-a promoting gene polymorphism in ME/CFS patients which prompted them to comment : “We hypothesize that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults of unknown nature.”

    Then there's the findings of attenuated heat shock protein production in response to exercise that would normally counter exercise induced pro-inflammatory cytokines. Exercise for ME/CFS patients could be pro rather than anti-inflammatory as per normal healthy controls.

    Lots of possibilities - but highly speculative and more than a little off-topic.

    I do believe though that Fluge and Mella are trying out etanercept with some of those patients who didn't respond to Rituximab (hopefully for a similarly extended period) so the TNF-a angle may be tested sooner rather than later.
    aimossy, froufox and MeSci like this.
  4. Jonathan Edwards

    Jonathan Edwards Board Member

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    Except that on counter-argument 2 you seem to have defended the TNF idea very plausibly! Maybe where the TNF is released and active is crucial. My understanding was that TNF does not normally cross the blood brain barrier but acts on hypothalamic blood vessels to generate local prostanoids, which signal to the brain. This could be wrong but it is quoted in believable sources. But since there are microglia in the brain it seems reasonable that TNF could also act within brain tissue. In which case there is no need for CRP to go up because it the brain is miles away from the liver.

    I like the idea of neuroplasticity allowing the reinforcement of a hypersensitivity cycle within the brain. In my primitive attempts so far to find what elements a disease model would need, on purely logical grounds, I had come to think we need something like that too. The astrocyte/microglia story sounds a good option. I clearly have a lot of reading to do but I quite like trying to work things out from first principles first because when you find that someone else has already come to the same conclusion and found a pathway that would do, you feel you are not just being led along by some crackpot enthusiast (either her or yourself).

    Such a neural loop based on reinforcement could certainly take months to unwind. However, I think counter-argument 1 still holds force. I think it fairly certain that rituximab really does not do anything to anything in the body except remove B cells. So we need a link between B cells and unwinding the neural loop. Immediately after removal of B cells there is pretty little effect and that makes sense if the B cells are just learning cadets. There is a story that B cells are important in presenting antigen to T cells but I find it hard to see how this could explain anything we have seen with rituximab so far. (A lot of immunologists still want T cells to explain everything but it will die down in time.) The effect of rituximab on antibodies takes months, so that would explain the slow improvement. But that does not at all exclude the neural loop taking time to unwind too - it would be hard to tease the two time courses out. I still think we need to suggest that in Fluge and Mella's improving cases any neural loop is still dependent on continued presence of antibodies. Maybe those that did not improve had neural loops that had become resistant. Or maybe more optimistically the antibody fall off was just too slow - we know in some autoimmune diseases the autoantibodies hang around for much longer (they seem to have all gone to bone marrow maybe) and poor responses can perhaps be explained because the antibody levels sit there without budging. We need another sort of drug to deal with that.

    Yes, I want to look at those slight CRP rises. I think this makes sense. And the Newton approach looks to fit in too. Where I like to disagree is with the need to bring in environment. So many people are stuck with this idea that it is all genes and environment and it isn't. The internal stochastic factor of random immunoglobulin gene rearrangement and mutation ought to be central to any B cell dysregulative process - i.e. any process that responds to rituximab.

    And not off topic I would say. I have, perhaps rather cheekily, assumed that this thread could be the place where I can discuss anything with ME people that seems to relate to the rationale for rituximab and this is all good stuff. Jo Cambridge and I worked out that rituximab ought to work for RA by having exactly this sort of chat.

    My understanding was that etanercept had already been tried, with mixed results. But that might mean that the response rate was a bit low and financial interests pulled out. If we could identify a responsive subset then it might turn out to work very well for them. Maybe some people have a neural loop that is not set off by antibodies so would respond to anti-TNF but not rituximab?
    Gemini, Svenja, froufox and 5 others like this.
  5. Jonathan Edwards

    Jonathan Edwards Board Member

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    Bob, I am very interested in this, for reasons I would like to explain later. Can I ask you at this point whether you had anti-thyroid antibodies, or still have and what sort, if you were told? (It would be anti-thyroglobuin or anti-peroxidase usually.) This is directly relevant to a rituximab trial design.
    aimossy and Firestormm like this.
  6. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I developed an apparent goitre a year or so ago, and my GP agreed that it looked like one. My thyroid tests came back normal (of course!:rolleyes: ) but there is some question as to whether NHS tests are the correct ones, or whether they are using the most-appropriate reference ranges. I also had an ultrasound scan which apparently found my thyroid to be normal, but my submandibular glands were enlarged.

    I still have the apparent goitre.
    aimossy and Bob like this.
  7. bertiedog

    bertiedog Senior Member

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    I am not Bob but I had raised levels of anti thyroglobulin antibodies in 2002 but these were only found because I was tested privately. It is my understanding the NHS does not test for this type of antibody but I might be wrong about this. They certainly missed my case though because I had the symptoms for many years but kept being told my results were normal.

    There is another reason for this in my case because I probably had a mild Sheehan's syndrome where many of my hormones weren't functioning properly. I often wonder if the extreme blood loss immediately after childbirth in 1975 set me up to develop ME/CFS in 1979 after 2 weeks of flu.

    Treating the Hashimotos has helped me a lot (2 1/4 grains of dessicted thyroid plus 0.25 mcg thyroxine) as well as 6mg Prednisolone daily but it hasn't helped me exercise anymore than a maximum of 30 minutes at a time nor has it helped the extreme migraines I get very frequently. One interesting thing I note is sometimes when I am running out of the steroid and due for a dose I will start to get a lot of pain in my body something that goes away with my next dose of steroid. Apart from the migraines in general I don't feel pain and can feel quite well until I try and do physical stuff.

    I do hope you can get to the bottom of what is going on in this illness.

    Pam
    Bob likes this.
  8. MsJustice

    MsJustice

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    Has anyone heard of anyone with ME and RA responding to Rituximab? I know it's not a first line treatment option and this would be purely anecdotal but I was interested in reading about people's experience of Ampligen aside from the clinical data.
    Sasha likes this.
  9. Sasha

    Sasha Fine, thank you

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    I've been wondering that - it's a really good question.
  10. Bob

    Bob

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    I'm afraid that I've just had bog-standard NHS GP thyroid tests, and it was never confirmed that I had auto-immune hypothyroidism, but just that I had hypothyroidism. (I should have mentioned that I assumed it was an auto-immune issue, as no other explanation was given, and the thyroid levels fluctuated and then returned to normal, which appeared to fit the pattern of autoimmunity.)
    So they may not have tested for anti-bodies, but I'll get a copy of my test results, and I'll let you know.

    Perhaps there are other UK people on here who have paid privately and had more extensive thyroid tests.
    aimossy and Firestormm like this.
  11. Marco

    Marco Old blackguard

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    Might this mechanism avoid any issues of TNF-a crossing the BBB? :


    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188868/#!po=5.35714

    One other (of the few) consistent findings in ME/CFS is dysregulation of the autonomic nervous system with reduced parasympathetic function. Might this impact on the effectiveness of the 'vagal cholinergic antiinflammatory pathway'?

    You're likely to encounter quite a few of those - if you haven't already:)
    MeSci likes this.
  12. Gemini

    Gemini Senior Member

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    Professor thank you so much for this helpful information. I'm quite curious myself about a possible role of interferon in ME. As a longtimer I remember over two decades ago it was a prime suspect with quite a number of papers still in the archives I believe suggesting interferon as the cause of most ME symptoms. I'm even more curious now after reading a 2012 paper from researchers in Amsterdam describing an interferon [gene expression] signature used to predict non-responders to rituximab in RA. Are you by any chance familiar with their work and interferon signature and might something like that be helpful in trying to sort out which ME patients may respond to rituximab?
    rosie26 and ukxmrv like this.
  13. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    There's some fascinating info there - thanks, Marco
  14. Firestormm

    Firestormm Guest

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  15. Jonathan Edwards

    Jonathan Edwards Board Member

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    OK, so since I am no longer registered as a medical practitioner and should not be handing out personal advice anyway I will explain my general interest in the thyroid and ME.

    Doctors love to have simple explanations. It probably dates back to the days, not so long before I was a student, when eminent hospital physicians could bullshit to the students whatever they could remember because none of the treatment actually worked - except maybe aspirin and digitalis - so it did not matter. So medical education is still full of simple stories that are nonsense. For instance, every doctor learns that your feet swell up in heart failure and kidney disease because of an imbalance in hydrostatic and osmotic forces in the venules according to Starling's Law. Trouble is it can't be true. If the difference in pressure in heart failure mattered all tall people would have swollen feet. And people with kidney disease get swollen feet before the osmotic pressure changes.

    So the story for autoimmune hypothyroidism is that you make autoantibodies to thyroid proteins, these interfere with thyroxine production and you feel lousy because you are hypothyroid (low thyroxine). But hang on a minute, for some odd reason it is well known that it takes many weeks for a lot of people to get better on replacement thyroxine and some never seem to feel much better (they are regarded as being a bit unhelpful by the doctor). Thyroxine acts within hours. Maybe some of its actions would require clearing away accumulations of 'myxoedema' over weeks but most patients d not have much myxoedema these days. And I have seen at least one case where the patient felt lousy before the thyroxine levels went down. Also the books say that the condition often starts with a flu-like illness - which does not make sense in thyroxine terms at all.

    If you look at the other form of autoimmune thyroiditis it becomes clear that it is seriously oversimplifying to blame thyroxine for all the symptoms. Thyroxine makes people jittery and hot but what about the eyes being pushed forward by swollen fatty tissue in the orbit, or lumps on the shins or fat ends to the fingers? These do not occur if you just give people too much thyroxine; they are something to do with other aspects of what the autoantibodies are doing.

    So about fifteen years ago I came to the conclusion that the 'flu'ish feeling that people with autoimmune hypothyroidism often complain of may well have nothing to do with low thyroxine. After all, if you have active inflammation in your thyroid you might expect to feel a bit crummy. It may be hard to separate the 'flu'ish aspects from the sleepiness due to low thyroxine but if things are complicated then we need to think complicated.

    So my thought would be that anyone with anti-thyroid antibodies with a normal thyroxine level who feels ill may well feel ill because of the direct effects of the antibodies. In this case the antibodies may not be stopping thyroxine production but they may still be having an effect. If autoantibody production is a cycle that involves interference with B cell regulation then presumably antibodies to thyroid proteins have some sort of knock-on effect on immune regulation - and maybe that is what is causing the symptoms, through upsetting cytokine levels, in a way that does not depend on actual thyroxine levels. This is speculation but it is the sort of speculation that got us somewhere last time.

    The problem now is that all doctors assume that you do not need to know about the antibodies because all that matters is the thyroxine level. The antibodies can be tested for in any standard general hospital immunology service but I suspect most GPs would not bother. This is partly because a small proportion of perfectly healthy people have these autoantibodies - may be in this case the loop does not trouble either the thyroid or the cytokines because the antibodies are binding in a slightly different way (as I said before antibodies can mimic more or less any patterns of function you like). This means that someone with thyroid antibodies does not necessarily need any medical treatment. However, if I had thyroid antibodies I would want my thyroxine levels checked every now and again because we know that the antibodies can change their effects - from down to up or up to down - over time (clonal drift again it would seem). And if I felt fatigued and virusish I would suspect the antibodies might have something to do with it. It is probably safe to say that the symptoms associated with antithyroid antibodies and low or normal thyroxine levels are mostly not very severe, but maybe in a few cases they are very severe and because nobody sees the connection the conclusion is that the person has 'ME' unrelated to the antibodies. Maybe this is an important subset of ME (because it is not in fact hypothyroidism). It might respond well to rituximab if it was but if the antibodies are long lasting bone marrow ones it might not. So there is a lot to think about.

    Interestingly, the only time an endocrinology colleague came to ask me about maybe treating thyroid patients with rituximab it was to try to deal with the thyroxine-unrelated eye problems. Dealing with the thyroxine is easy, but not the other aspects of Grave's disease.
    catly, Sidereal, aimossy and 7 others like this.
  16. MsJustice

    MsJustice

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  17. Firestormm

    Firestormm Guest

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    No problemo. I Googled is all but I agree it would be good to look at symptom resolution from the patient perspective - as we were talking of before. Sometimes it can get lost in the science :)

    There was the video from Norway - did you see it - one of those responders on Ritux in the initial trial. She was filmed kayaking I believe - though am no expert. Could have been a canoe for all I know :)
    MeSci likes this.
  18. froufox

    froufox Senior Member

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    Hi Jonathan, many thanks for engaging with us here :) . Just to add my 2 pennies' worth I and some of my fellow MEers have had private tests done that have revealed high levels of various types of pro-inflammatory cytokines & proteins, in particular things like IL-8, IL-6, sCD14, PGE2, C4A. Conversely, and speaking for myself, Ive always had normal levels of CRP and ESR. So the inflammation does seem to be localised and the activated microglia in the brain theory has always made sense to me .... at least for me the majority of my inflammation seems to be located in my brain causing major brain dysfunction.

    A few of us tried GcMAF which works by boosting the immune system by activating macrophages, and judging by my and some of my friends' responses (although some do seem to tolerate it) which was an exacerbation of this loop/cycle of brain inflammation, we concluded that the overactive macrophages/microglia was probably central to this reaction. Certain natural anti-inflammatories (eg anti- TNF@, cox 2, NFkB) do help to tone down this inflammation somewhat, but not consistently eg luteolin, turmeric, and also in my case, the ARB Losartan, which I wondered was to do with it blocking the activation of ACE on macrophages. I dont know, again all speculation, but I just wanted to add my experience for what its worth. I believe my ME was triggered by a course of Hep B vaccines 20yrs ago....

    Just finally, what about TH17 being involved in the cycle of inflammation? http://www.immunoscienceslab.com/Articles/Role Th17 1.pdf
  19. lansbergen

    lansbergen Senior Member

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    Do you mean this one?

    http://www.ncbi.nlm.nih.gov/pubmed/22540992
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446469/

    Arthritis Res Ther. 2012 Apr 27;14(2):R95. doi: 10.1186/ar3819.
    The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.

    Raterman HG, Vosslamber S, de Ridder S, Nurmohamed MT, Lems WF, Boers M, van de Wiel M, Dijkmans BA, Verweij CL, Voskuyl AE.
    Department of Rheumatology, VU University medical center, de Boelelaan 1117, Amsterdam, 1081HV, the Netherlands. c.verweij@vumc.nl.
  20. MsJustice

    MsJustice

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    No, I haven't seen that video. Is it on youtube?

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