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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. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I'd be interested in discussing this in one of the leaky gut threads, alex3619, rather than take this thread too off-topic - or have we already discussed it there? I mean why different autoimmune conditions might have different/different diversities (for want of a better word) of autoantibodies. I have theorised about this but am keen to know if anyone has anything more solid.
     
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  2. lansbergen

    lansbergen Senior Member

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    Could it not be possible the immunesystem is attempting to eliminate the pathogen by trial and error?
     
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  3. Jonathan Edwards

    Jonathan Edwards Board Member

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    Thanks. Yes, I am aware that populations of ME/CFS patients have been found to have various differences from controls in their immunological test results. The difficulty is in knowing what to make of these results. They are not always consistent from group to group. That may just mean that different physicians tend to collect different types of patient but it is good to see consistency or at least know why it is not there.

    NK dysfunction may be too strong a term. Our understanding of NK cell function has developed enormously in the last ten to fifteen years and it is very complicated. It is so complicated that it is quite difficult to know how one should interpret the 'function tests' in terms of NK efficacy. Different results might just indicate that different people's NK cells work slightly differently, using different receptors and co-receptors, for instance. We certainly know that these differ between people. These differences in NK and T cell function tests may well be indicating something important but I think it would be rash to assume that it has anything to do with being susceptible to viral infection. My understanding is that there is no reliable evidence that any specific viruses are causally involved in ME/CFS. I know the idea is popular but I think there may be more subtle explanations that in the long run make more sense. The immune system may be behaving as if it 'thinks' it is fighting viruses but it may be fighting itself or just in overdrive.

    Another point that keeps coming up is that we are almost certainly dealing with several causal mechanisms all giving similar symptoms. This was the case for rheumatoid arthritis until we separated them out. So NK cell differences may be central to one group of people's illnesses and B cells to another group. If this is the case then altered NK cell function tests might tell us which patients NOT to give rituximab, but even that would be too hasty. Maybe misbehaving B cells are confusing the NK cells in some cases and confusing other cells in other cases. So I think it would be unwise to pin too much on NK cell assays when selecting cases for treatment.

    I am not personally aware of evidence from systematic scientific studies of increased herpesvirus infection in ME/CFS patients. The one we are all infected with is, of course, EBV. EBV lives in B cells and so rituximab actually gets rid of EBV infected cells. Apart from that I suspect that testing would not get us very far to be honest.

    What makes sense to me in the context of using rituximab is to look at B cell life history and function in detail. There are not that many leads but there are a few.

    I have picked up that there are members on this list who know quite a lot about autoimmunity and about rituximab. However, things sometimes get joined up not quite the right way! The explanation for autoimmunity that made us try rituximab, and which looks as if it roughly right, since rituximab does what it predicts, is quite subtle, but not too difficult to follow. It depends on a vicious cycle and it does not depend much on infections, at least as triggers. This raises interesting questiosn for ME where infections do seem to be triggers at least for some people. I would be very happy to try to explain some of this in more detail as time goes by but not just now! Opportunities will arise no doubt.
     
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  4. lansbergen

    lansbergen Senior Member

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    Or fighting a slow infection where there is no test for yet.
     
  5. alex3619

    alex3619 Senior Member

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    Interesting idea. I am not sure it is possible, but then I am not sure its not. I suspect that the maturation of B cells is defective, just as there is evidence that maturation of NK cells is defective. This is only an hypothesis though, nobody knows, and quite a few theories have been put forward. We need more research, better research, and research into specific issues that have been proposed might contribute to symptoms or cause ME.

    There are many hypotheses that seem to fit just now, from autoimmune to autoinflammatory, B cells and tissue infections (and not just viral), oxidative and nitrosative stress and so on. I still suspect enteroviruses are damaging B cell maturation, but this requires confirmation and further investigation. Not all my resources are back up yet, I have only just rebuilt my computer system, it took most of a day, and not all my backed up files are restored yet. There was a paper a few years ago demonstrating that most pathogens implicated in ME (CFS in that paper?) infect both B cells and the gut. In other words, the common factor is their lifecycle.

    If B cells are not maturing properly, then killing them off with Rituximab allows them a reboot ... but they might come back defective. So reboot again ... in this model mulitiple doses of Rituximab might cure most people, but if that were the case I would have thought we might have already heard about it. Another issue is that coinfections might have to be treated while rebooting the immune system, which is Kogelniks angle. They don't have to be eliminated, just prevented from reinfecting the new maturing B cells.

    One thing I would want to see is replication of Maes result that we have multiple autoantibodies to multiple targets. Its like we have a generalized autoimmune disease. In his model though this is due to oxidative and nitrosative stress creating altered proteins, which then trigger an autoimmune state. This may or may not be right, but its certainly interesting.
     
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  6. Esther12

    Esther12 Senior Member

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    I was a bit surprised you were so blunt about a complicated and uncertain area, but I didn't think that there was anything in there that you needed to take down (I have been told that I can be rather rude though, and personally prefer having people argue bluntly with me so that I can then respond to them... I may not be the best judge of etiquette). Just my opinion, in case you were polling!

    Personally, I was pleased to see Jonathan Edwards seeming to take a cautious and critical approach (this might be a patronising thing for a patient to say about a researcher). In the past, I've seen some people new to ME/CFS come in and start using small and unreplicated studies to support their own assumptions and theories, and this doesn't seem to go well (actually - this seems to be the modus operandi of a lot of people who've been working with ME/CFS for a long time too - and then it's even worse!). One reason why I'm a bit concerned about doing a small trial, is that it makes patient selection more important, and I'm not that confident in any ME/CFS expert's ability to select patients likely to benefit, or even likely to fairly represent the ME/CFS patients seen by others. Being aware of how little we know for sure is a pretty good starting place imo, and much better than trusting the, perhaps unfounded, claims of others.
     
  7. SOC

    SOC Senior Member

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    Thanks, Esther12. I decided to take down my response on the theory that this is primarily a UK issue and I shouldn't do anything, even if it's acceptable, that rocks the UK boat.
     
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  8. Bob

    Bob

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    I would encourage you to present any info or evidence that you think is relevant.
     
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  9. SOC

    SOC Senior Member

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    Thanks, Bob. :) UK members know as much about immune and secondary infection evidence as I do. They also know a lot more about the political situation with ME/CFS in the UK. So, I'll leave it to the UK contingent to bring up the issues if they think they're relevant.
     
  10. ukxmrv

    ukxmrv Senior Member

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    Thank you for the warning and the explanation.

    No reason to feel that there will not be patients who do need a warning. In around 2005 I started taking Humira (for a non-ME related matter) and although I responded well to it, the result could have been catastrophic. There had been no trials in people with ME and CFS and I personally knew of no other patient with my condition taking that drug.

    The doctor I was under at the time did have other ME and CFS patients and did have an understanding of the disease though. I had a test for TB and TNF-a before taking Humira and I was able to be under the care of a doctor with a knowledge of pathogen reactivation.

    I'm one of the patients who does respond well to drugs that target the immune system or target viruses and when I have a choice I've gone for those options because of my good past experiences.
     
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  11. Mark

    Mark Acting CEO

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    I read something the other week which seemed to me to offer a most interesting possible explanation of the variation in findings regarding immune markers.

    This article by Scott F. Dowell of the CDC, from 2001 (posted here by Hip, my response is just after that post) looks at seasonal variations in epidemics of various infectious diseases. It says that for several types of infectious disease, the epidemics occur at a very specific time of year, independent of climatic conditions. Notably, the time of year is the opposite in opposite hemispheres. The article concludes that all the evidence suggests that the latitude and time of year are crucial to outbreaks of these particular infectious diseases, and the only reasonable explanation for this seems to be some kind of seasonal variation in host physiology, with the evidence suggesting that this is regulated by the incidence of light.

    Of particular relevance here:

    Such seasonal variation could perhaps explain the discrepancies between the various comparisons of immunological markers between ME/CFS patients and controls. I'm aware that some studies find elevated levels of certain markers in ME/CFS patients yet others find lower levels of the same markers. Perhaps it's now necessary to ask at which time of year the samples were taken? Perhaps it's important to be sure the patients and controls were sampled at the same time?

    Many patients here have remarked on notable seasonal variations in their illness, which are often consistent over several years, with a particular time of year being significant for worsening of their condition. But the 'bad' time(s) of year seem to be different for different patients. We've tended to assume that this may be related to seasonal environmental triggers like mold and pollen. But perhaps there are seasonal physiological cycles and/or seasonal susceptibility to specific virus types involved?

    I'm quite excited about these ideas because they do seem to me to offer a potential explanation for several questions which have puzzled me in recent years. If this line of thinking is correct, it might be that a study that found elevated IL-6 in ME/CFS patients and another that found lowered IL-6 could both be right - but they apply at different times of year. These ideas also seem to me to fit in with other observations like impaired sleep regulation and "sleep reversal" in ME/CFS patients...though I can't quite put my finger on why yet...

    Anyway, the bottom line is that the precise time of year of sampling and of illness fluctuations may turn out to be crucial, and my guess is that this potentially very significant data has rarely been surfaced in studies to date.


    I'm not sure whether this is what you're referring to, but I attempted to summarise Dr Bansal's presentation at this year's Invest in ME conference here (towards the end of the section on Dr Bansal, about a third of the way through a very long article):
    http://phoenixrising.me/archives/17049

    The part of my article that seems relevant is the proposed explanation of a vicious cycle involving B cell production - specifically, defective B-cell gating which causes the production of low avidity B cells, which in turn may then mount autoimmune attacks on the very cells which caused the defects in B-cell gating.

    In case it helps save you time going into the detail later, here's the part of my article that I'm thinking of...



     
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  12. Sasha

    Sasha Fine, thank you

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    I thought that Dr Nancy Klimas had said that the reason for the inconsistent NK cell findings in ME research had been due to small studies (?) and tests that weren't as advanced as they are now (?) and that now, more consistent findings are appearing as long as the studies are large and use the more advanced tests. I'm talking in very general terms here because, basically, I don't know what I'm talking about! I'm no biochemist, that's for sure.
     
  13. ukxmrv

    ukxmrv Senior Member

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    I have exactly the same concern SOC but things are/were no better in Norway before the trial of Rituximab there. It's a Europe wide problem with many patients without testing for known bugs or treatment plus lack of basic immune system testing.

    If Dr Klimas thought that a drug like Rituximab was going to be beneficial for her CFS patients then why wasn't she using it already? As far as I am aware she's not using it now. So her input may not be as beneficial or insightful as we would hope it would be. Same for Dr Peterson. Enormous respect to them both. Dr Kogelnick, on the other hand has had actual experiences of real patients using the drug so I would hope that he is consulted before any trial.

    I'd hate to think that a barrier would be put in the way of a UK trial in this way when we don't even know as yet if any of our tests for immune system markers is relevant to the trial and that goes for other pathogens. I'd like to think that we could learn that along the way but there is a chance that none of our current thinking is going to be useful here.
     
  14. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    lansbergen said:


    Abnormalities in the innate immune system have been found in ME/CFS as well as in the adaptive immune system. It is the latter that involves antibodies to specific antigens. The former is non-specific and includes a cascade of chemicals called complement. I did a search of the ME Research UK database for 'complement' and found several papers relating to observations of complement abnormalities in ME/CFS. I am pretty sure that some of them have been discussed on PR. Here are a few:

    from 'Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta'

    here:

    http://www.ncbi.nlm.nih.gov/pubmed/20433584

    "Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS...Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1beta, complement C4a split product or elastase activity."

    Also see earlier study 'Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome' here:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/

    and 'Complement activation in a model of chronic fatigue syndrome' here:

    http://www.ncbi.nlm.nih.gov/pubmed/12897748
    which says "Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group"

    This one 'Frequency of deviant immunological test values in chronic fatigue syndrome patients' here:

    http://cvi.asm.org/content/2/2/238.full.pdf

    found that "Of 11 immunological tests done on chronic fatigue syndrome patients and on fatigued controls, 3 tests (protein A binding, Raji cell, or C3 or C4 [deviant values
    in either complement component were counted as positive]) with deviant results discriminated best among the groups."

    But this study cites reduced complement levels in CFS after parvovirus infection: 'Chronic fatigue syndrome after human parvovirus B19 infection without persistent viremia'

    http://www.ncbi.nlm.nih.gov/pubmed/18277075

    as does at least one earlier one, for CFS generally.

    A quick internet search for 'innate autoimmune' found several papers immediately, and a very quick look at a couple revealed info about interactions between the two main branches of the immune system. Perhaps, at least for some of us, the dominant immune abnormalities may be of the innate immune system, which could perhaps explain the lower specificity observed.
     
  15. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    That is certainly interesting. Re conflicting findings, Brenu et al refer to variations in cytokine release "causing either a shift towards a predominant Th1 or Th2 immune response in CFS/ME" here:

    http://www.translational-medicine.com/content/10/1/88

    What a slippery bunch we are. No wonder the medics despair of us (and vice versa)! :alien:
     
  16. lilpink

    lilpink

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    From a very simplistic point of view I wonder if Jonathan Edwards is able to make any comment on how patients might be chosen as good Rituxan responders (or otherwise) in terms of prior life events? I'm thinking particularly about my own situation in pregnancy where I derived great benefit from the middle of the 2nd trimester onward in both pregnancies, a remission which prevailed for about 18 months after parturition of my second child (the two pregnancies were VERY close together (!!)...not of our own design needless to say). I have tried to replicate this situation by tinkering with the female (and male) sex hormones to no avail at all, and so must ponder that the immune suppression of pregnancy might have given me those months of respite in an illness which now spans 43 years. Does anecdotal 'evidence' such as this augur well for Rituxan or is it irrelevant I wonder?
     
  17. Jonathan Edwards

    Jonathan Edwards Board Member

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    Help! I was hoping to post one or two more responses to interesting suggestions and what with being offline for 36 hours I now find it takes all my time to read the next lot of interesting suggestions. I will try to fire off a few responses that seem easy to do quickly. In response to lilpink, remission in pregnancy I think we should take careful note of. It was remission of rheumatoid arthritis in pregnancy that made Hench look for an anti-inflammatory hormone and discover cortisone. It turns out not to be the reason for the effect but it laid the bedrock for research into inflammation. The reason why taking sex hormones does not work seems to be because more complicated cumulative changes occur in pregnancy, maybe in part due to chorionic hormones (i.e. from the baby). One of them is the production of pregnancy associated glycoprotein, but there are many. The situation is further complicated by the fact that some autoimmune diseases get worse in pregnancy (e.g. lupus). But that does not bother us here; what is interesting is that there seems to be a well recognised pattern of change which would fit with an antibody mediated process.

    I think the answer may well be yes, brilliant idea, pregnancy-related remission might be a good marker of B cell related ME, rather than one of the probably several other sorts of ME. It is probably not something we could factor in to a scientific study prospectively but it would definitely be something to take note of and check correlation with response to B cell therapies.
     
  18. Legendrew

    Legendrew Content team

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    The unusual things that strike me as unusual with ME/CFS is that people, over time, often don't get worse as you see in some autoimmune diseases which leads me to thinking that if there is auto-antibodies, then perhaps the target is non-specific as seen in things such as Lupus, or if it is more specific then the organ has the ability to self repair to a certain degree (as I believe some non-myelinated neurones can).

    The other strange thing is that in the Norway trial some patients are reported to have gone into a longer term remission (I'm not going to call it recovery since it's not been long enough to say that yet I don't think). This is also something i've not heard of much in other autoimmune diseases when treated with rituximab.

    Having only had ME/CFS for only a year i'm so glad to see this research is going to be done and welcome the emphasis on the immune system. I'm sure nearly all patients agree that the central problem lies there!
    Andrew (19)
     
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  19. Jonathan Edwards

    Jonathan Edwards Board Member

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    One of the points I would like to raise in a more organised way some time is that the immune system, at least the B cell/ antibody producing part ALWAYS works by trial and error. It makes antibodies at random and if one works it amplifies it. This has huge implications for building a general framework for how these diseases might work. I will try to make sense of that sometime soon.

    So, yes, in that sense I think it is all trial and error. However, in terms of the autoantibodies found in ME, to be honest I would say, no big deal, just a bit more noise in the system. Sometimes when a detailed mechanism for a disease has become clear it is possible to go back and say 'yes, now I see why there is a bit more noise' but at this stage I think these antibodies are not telling us anything very useful. Antibodies that matter stick out like a sore thumb and are consistent. It may be that there are people with antinuclear antibodies and ME who effectively have a 'narrow' form of lupus related illness (i.e. no kidney disease etc.) but I suspect the antibodies that matter, assuming there are some, are ones that we have not yet identified.

    So I guess a general point I might make here, relevant to several suggestions, is that lots of evidence for lots of different immune disturbances in ME does not add up to anything, at least to my mind. It is an 'embarras de richesses' - too many bits of evidence just generate confusion. I appreciate that people want to believe in a hard biomedical basis for the disease. And there is one. But what is needed is one right basis, not a jumble of maybe bases. Or at least, if there are four sorts of ME, four different right bases, not muddled together. 95% of data presented at medical scientific meetings is destined for the waste bin. ME is not alone in this. As I gradually get up to speed on the literature my impression is that what's out there is mostly chaff. The NK data looks as if it is telling us something but I doubt it is quite what has been suggested.

    Part of the problem, I think, is well illustrated by Mark's very good precis of Dr Bansal's work (which I would like to come back to more specifically). A working model for even one type of ME is going to look a bit like the solution to a tricky chess problem of the sort you get on the back page of newspapers. 'Should White's rook take the pawn or the bishop to gain checkmate in six moves?' Our model for rheumatoid disease had fifty one precise steps in it, if I remember rightly. Not just arrows all over the place for every cytokine you can think of. The biomedical model will prove right, but we need to be picky, I think.
     
  20. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, Andrew, those points struck me hard too. ME seems gradually to improve in most cases. Rituximab tends to need to be repeated in most autoimmune disease in order to maintain benefit, unlike the longer term remissions seen in Norway.

    It made me wonder if ME could really be autoimmunity after all. But there are other examples. Immune thrombocytopenia (ITP) often improves in the long term. Even lupus, if it is controlled during the first few years can often stop flaring. Rheumatoid arthritis does settle for some. And 30% of ITP cases get prolonged remission with rituximab. So maybe ME would not be out of line. What I think is encouraging is that the autoimmune diseases that spontaneously settle may tend to be the ones that get long remissions with rituximab - it seems to make sense. If so then B cell related ME might well be one of those. We have to be a bit careful about the Norway remissions because even rheumatoid arthritis can remit for five years with rituximab and then relapse, but that is pretty unusual.
     

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