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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. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    What about methotrexate? a quick google with methotrexate and B cells brought up several studies. one was about low dose methotrexate lowering B cells in lupus.

    I recall that in one of the Norweigan studies that some were also on methotrexate with ritux or was it they were non responders to ritux but the addition of methotrexate then turned them into responders???

    Methotrexate seems to be a common drug used in auto immune illnesses, maybe useful for a sub set of ME patients??

    cheers!!!
    alex3619 and Sasha like this.
  2. Marco

    Marco Old blackguard

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    I wonder what Jonathan Edwards might think of a possible link between ME/CFS and autoimmune type I diabetes given that many of us report (subjective?) issues with blood sugar regulation and peripheral neuropathies?

    This recent abstract caught my eye :

    Chronic fatigue in type 1 diabetes: highly prevalent but not explained by hyperglycaemia or glucose variability.

    http://care.diabetesjournals.org/content/early/2013/08/13/dc13-0515.abstract

    This is a fairly unremarkable study that looked at 'chronic fatigue' in type I diabetes subjects and compared fatigue to markers of disease severity. The researchers concluded that reported fatigue (and its relation to age, depression, pain, sleeping problems, low self-efficacy concerning fatigue and physical inactivity) was unrelated to measures of disease severity such as hyperglycaemia or glucose variability and was most likely mediated by psychological factors and therefore amenable to treatments such as CBT.

    Note this study has been picked up and misinterpreted as relating to chronic fatigue syndrome. It does not - it just refers to (physical and mental fatigue) in type I diabetes.

    But were they right to suggest that the disease process in type I diabetes was not directly associated with the disease process?

    GAD65 – the rate limiting enzyme that converts glutamate to GABA is a major autoantigen in type I diabetes with both GABA and insulin secreted by pancreatic beta cells which when damaged (depleted) result in both lowered GABA and insulin production.

    Antibodies to GAD65 are also associated with stiff person syndrome – an autoimmune disease already discussed here that may have parallels with some subsets of ME/CFS (not least the sensitivity to sensory stressors and frequent 'co-morbid' anxiety and depression - the latter also common - twice the population rate - in diabetes). Its striking how often autoimmune diseases such as SPS, diabetes and thyroiditis appear 'co-morbidly'.

    Actually cognitive deficits in autoimmune mediated type I diabetes are correlated with GAD antibodies and GAD antibody positive (GADA) type I diabetes patients have worse cognitive deficits than type II diabetes controls despite the latter group showing more physiological risk factors for dementia like cognitive decline.

    http://www.biomedcentral.com/1471-2377/13/76

    The cognitive deficits described in the discussion should sound familiar :


    Although found only in two patients, this finding is intriguing :
    .... given the recent findings of eye movement dysfunction in ME/CFS patients discussed in this thread :

    http://forums.phoenixrising.me/inde...ing-eye-movement-dysfunction-in-me-cfs.24844/

    Furthermore an imbalance between glutamate and GABA I in the prefrontal cortex of type I diabetes patients has previously been linked to cognitive deficits and mild depression.

    http://www.ncbi.nlm.nih.gov/pubmed/19652127

    At least one ME/CFS doctor has anecdotally reported high levels of diabetes in ME/CFS patients and the CDC have previously linked ME/CFS with metabolic syndrome.

    http://www.ncbi.nlm.nih.gov/pubmed/20102774

    Several recent studies have also reported high levels of clinically validated peripheral neuropathy in fibromyalgia patients with low GABA levels also found.

    Could ME/CFS be related to autoimmune mediated diabetes with GABA levels perhaps taking a bigger hit and could treatments targeting GABA help with both cognitive dysfunction and possibly even reverse autoimmune mediated diabetes?

    http://www.ncbi.nlm.nih.gov/pubmed/21709230
    rosie26 and OverTheHills like this.
  3. voner

    voner Senior Member

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    Prof. Edwards,

    any comments on the use of Rituximab in Treatment of Sjögren's? Any helpful hints in that when applying it to ME? There is some Symptomatic overlap between the two diseases....
    Marco likes this.
  4. Sasha

    Sasha Fine, thank you

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    In this paper by Montoya et al. on Valcyte for people with ME who have high HHV-6 and EBV antibody titres, they discuss the results in the context of the Fluge & Mella work on p. 8:

    http://onlinelibrary.wiley.com/doi/10.1002/jmv.23713/abstract

    They say, 'Monocytopenia in this [Montoya's] study and depletion of B cells in theirs [Fluge & Mella's], would suggest that excesses or abnormalities in antigen presentation might be a key underlying mechanism in CFS.'

    There might be more in there that's relevant - the discussion section was over my head.
  5. Jonathan Edwards

    Jonathan Edwards Board Member

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    Anti-T cell drugs had been tried and they did not work. A lot of other drugs that have effects on the immune system do work but we do not really know why. Cyclophosphamide probably works by poisoning B cells but is too toxic for use in most conditions. Anti-TNF and Anti-IL6 receptor probably work more on the downstream inflammation than on B cells although IL6 is important for B cells.

    In more general terms I don't think it is helpful to think of drugs 'acting on the immune system' really. Things are too complicated for that to be helpful. We need to consider detailed pathways.

    Methotrexate poisons all cells but particularly lymphocytes at high dosage. However, it may do quite different things at the dose used for RA. Rituximab is licensed to be used alongside methotrexate but there is no good justification for this. Using methotrexate in ME/CFS might work for some but if it works on effector pathways that do not apply to ME/CFS then it will be no use. It makes people sick very often so I am not enthusiastic about trying it. I think it is more useful to try drugs for which we know the mechanism precisely, like rituximab.
  6. Jonathan Edwards

    Jonathan Edwards Board Member

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    Rituximab has been used in Sjogren's but I am not sure which features really respond well or whether there has been a good controlled study.
  7. Jonathan Edwards

    Jonathan Edwards Board Member

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    That sounds like the usual misunderstanding of how rituximab works to be honest. Certain people wanted to believe it affected antigen presentation but it makes no sense either theoretically or in terms of the results. There are still a lot of people talking mumbo jumbo (to my mind) about T cell roles that have never been substantiated - and things like Th1: Th2 balance which I think is largely a figment of the imagination!
    aimossy, Firestormm and Sasha like this.
  8. Jonathan Edwards

    Jonathan Edwards Board Member

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    This is interesting and brings me back to the previous discussion of thyroid disease. I think it very likely that people with an autoimmune disease like Type 1 diabetes will feel ill because of various effects of the autoimmune process that have nothing to do with the traditional 'target organ dysfunction'. I am quite sure that people with thyroid autoimmunity feel ill for reasons independent of their thyroxine level. I would think it very likely that the same applies to Type 1 diabetes and I see no reason why it should not involve GABA. Doctors are all too ready to ignore anything except what they think they are looking for - a blood sugar level in this case.

    So it would not be surprising if there were people who had similar autoimmune processes and entirely normal thyroxine and sugar levels all the time but felt dreadful and were therefore said to have ME/CFS!
    voner and Marco like this.
  9. Jonathan Edwards

    Jonathan Edwards Board Member

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    The eye movement study looks like something very well worth repeating. It sounds like just the sort of thing that might produce an objective biomarker of neurological dysfunction. Hot off the press by the looks of things.
    Firestormm, rosie26 and Legendrew like this.
  10. user9876

    user9876 Senior Member

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    When you say people feel ill due to the effects of the autoimmune process do you mean that the antibodies that target the specific organ also have other effects in which case are there subtle differences in the antibodies (or receptors?) that lead them to cause these effects in some people and not others. Or is it that several different bad antibodies may exist concurrently and hence have multiple effects (perhaps due to filtering failures at some point in time letting a number of different random patterns through)?

    I was also wondering about those people that Rituximab doesn't help with. In RA does that mean that there is a different mechanism hence requiring different drugs?
    Valentijn likes this.
  11. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, when we say that someone has antibodies to thyroid peroxidase, for instance, it means that their immune system is trying to make antibodies that fit, like a key to a lock, either thyroid peroxidase itself or something very like it. I suspect it is thyroid peroxidase itself. The immune system does this by randomly generating antibodies of billions of different shapes and manufacturing in bulk any that fit. I have just come back from Tesco where I was looking for a phone charger. As you can imagine the rack looked a bit like an immune system, with about fifty different chargers, each with slightly different adaptors on the end. The charger that fits my Nokia phone may fit Vodafone but not an iPhone or Blackberry. If antibodies can be any shape they can fit their targets in all sorts of directions and ways and also maybe fit other proteins some of the time. Whether differences in symptoms relate to the angle the antibody binds to peroxidase or a tendency to bind to other things as well nobody knows. And each person with these antibodies will have not one type but maybe an assortment of a hundred types. There are quite a lot of people walking about with anti-peroxidase antibodies who are perfectly well, so sometimes none of these antibodies causes any trouble.

    So we are not surprised that there is quite a bit of variation in symptoms with autoantibodies. It is perhaps surprising that these illnesses are often quite standard in their symptoms, but maybe there are only a very few bad ways to bind to the target protein.

    We do not know why some people who have the usual sort of RA antibodies do not get better on rituximab. One obvious possibility is that their antibodies are being made by longer lived plasma cells and the rituximab is just not getting a chance to affect antibody levels. Some people also have too much joint damage. Others might have variations in proteins that protect B cells against killing. I strongly suspect that rituximab really needs to be given together with something else that boosts its effects on B cells hidden away in what are called follicle centres but so far there does not seem to be anything safe and obvious to try combining it with.
  12. Marco

    Marco Old blackguard

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    As I raised autoimmune type I diabetes, I hope you don't mind me answering this very specific part of your question to Prof Edwards.

    As I understand it, one of (or perhaps the) major targets of autoimmunity in autoimmune mediated diabetes is GAD65 - an isoform of the enzyme which converts glutamate to GABA. GAD is concentrated in the nervous system and in beta cells in the pancreas where they appear to play a role in signalling mechanisms controlling the production of insulin. Antibodies to GAD65 not only interfere with the production of GABA (big time in stiff person syndrome) but also in the production of insulin leading to the cardinal symptoms of diabetes.

    Fatigue, depression and cognitive dysfunction in diabetes tends to have been put down to variations in blood sugar levels (not surprisingly as this is the key pathology in diabetes) but recent research suggests that attenuated GABA production may be responsible for these symptoms independently of blood sugar issues.

    Hence antibodies to one enzyme may result in different symptoms via different physiological pathways.

    Here's a case study detailing type I diabetes and neurological symptoms in a child with anti-GAD antibodies :

    http://pediatrics.aappublications.org/content/109/3/e50.full.pdf
  13. Jonathan Edwards

    Jonathan Edwards Board Member

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    That makes a lot of sense to me too. It probably answers the question better than I did too! Somebody said nature is subtle but not vindictive. It may sometimes seem a bit vindictive, I know very well, but maybe not in the way meant. These mechanisms are subtle but once you get the hang of them they make sense I think. Nature does not deliberately mislead scientists, they mostly do that to themselves.
  14. Legendrew

    Legendrew Content team

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    That makes a lot of sense once you think about it. I remember when I was doing my A-levels my teacher would often stress that the human genome only seems long when you think about it in terms of individual base pairs but once you convert these sequences into the potential for individual proteins there's not the potential for that many proteins to be produced, meaning many are reused with very slight post-transciptional and translational modifications. It's easy to see then that a lot of the symptoms in these autoimmune diseases could come from the autoantibodies binding and disrupting these isoforms, whose functions and locations are often very different to the protein form which is initially being targeted by the immune system.
  15. lansbergen

    lansbergen Senior Member

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    Did the patients get worse?

    I ask because I try to improve T cell functions and that works for me.
  16. Jonathan Edwards

    Jonathan Edwards Board Member

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    Not as far as I know.
  17. Legendrew

    Legendrew Content team

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    Quite interesting to see migraines once again in the news today showing white matter abnormalities and mini stroke-like lesions much more frequently than the general population. I think I mentioned a few pages back that up to 80% of ME suffers have migraines frequently. I wonder whether the disease process of ME could aid in the development of these lesions.
  18. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Do you have a link to evidence of this? I don't think I've ever had a migraine.
  19. Legendrew

    Legendrew Content team

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  20. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Thanks.

    I'm a bit confused by this paper, but it may be my ME brain and not having time to peruse the paper thoroughly.

    From the full text here:

    it initially says
    But further down it says

    then

    :confused:

    How can 61% have migraine and tension headache if only 39% have migraine? Or are they adding the two groups together?

    Then further on it cites 84% again.

    But we are perhaps straying too much from the subject of this thread! It may be worth doing a poll on the incidence of migraine.

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