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SBM: Kogelnik, Rituximab and CFS: Jumping the gun

Discussion in 'General ME/CFS News' started by Firestormm, Jan 13, 2013.

  1. alex3619

    alex3619 Senior Member

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    HI Gemini, to my understanding a large range of pathogens infect B cells. This paper specifically talks about CV B3 infecting B cells, and shows that this might somehow be antibody mediated. Perhaps viral particles bound to antibody are absorbed by the cells? So far as I am aware, most of the pathogens associated with ME are capable of infecting B cells. This includes, I think, most picorna viruses, and Coxsackie viruses are in that family. What we did not know is how CV B3 infected B cells as they should be immune to the regular means of infection (it requires certain cell receptors). This is why they are looking at mechanisms, to try to explain how this virus infects B cells - it had to be an alternative mechanism.

    I have only read the abstract so there is no way of telling what additional information might be in the full paper that might enhance our understanding.

    There was a paper last year (that I keep forgetting the name of) that talked about pathogen life cycles in ME. Most of them travel in B cells and infect inflammed tissue they are passing through, especially gut mucosa. That seems to be the common pattern. Additional factors occur with Coxsackie as it tends to infect muscle, and herpes viruses which tend to hide (often latent) in nerves. Coxsackie B3 is suspected of being a leading cause of heart failure, and there are no effective antiviral therapies for it.

    With most of these pathogens killing off the B cells will not deal with the virus in other tissues. However, it will slow the spread of virus by preventing at least some new infection, and it might induce changes in the immune system to Th1 (T cell, NK cell, macrophage etc.) which will enhance killing of virus in infected cells. We need that Phase 3 clinical trial and more lab research on this.

    Something else might happen though, with Rituximab as an agent against these types of pathogens. While it will not remove pathogens from gut, muscle or nerve, if the B cells are signalling their infection and this induces the changes in ME or CFS, then removing the B cells will remove the signal. In effect it will cause remission of ME or CFS if enough B cells carrying the infection are removed. However, under this interpretation it would not be a cure. The latent pathogens will persist, and can potentially reinfect the B cells.

    Bye, Alex
     
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  2. In Vitro Infidelium

    In Vitro Infidelium Guest

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    And persistence of latent pathogens brings with it the potential for treatment resistence, with at least a selection pressure in favour of mutations that support occult behaviour (ready latency,difficult to find dormancy, productive reactivation). Other less obvious selection pressures may also be engendered by B cell depletion, and/or treatment resistance and/or increased virulence could be selected for coincident with mutations that suport occult behaviour. These are all issues that need to be explored experimentally in M.E/CFS. While the RA experience has been quoted as benign, it is not necessarily as problem free as some people seem to believe: http://bloodjournal.hematologylibrary.org/content/102/5/1930.full . If the model of M.E/CFS is that a persistent, occulted pathogen is the cause or contributor to the condition, then B cell depletion as a long term intervention should be considered as having potentially serious consequences.

    IVI
     
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  3. Roy S

    Roy S former DC ME/CFS lobbyist

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    curiouser and curiouser -- The author of the blog, Harriet Hall, at the top of this blog linked to her previous blog from February 2010 -- Chronic Fatigue Syndrome and Retroviruses- Jumping the Gun (apparently we have a REALLY bad habit of jumping the gun!)
    http://www.sciencebasedmedicine.org...ue-syndrome-and-retroviruses-jumping-the-gun/
    In the comments section Dr. Wallace Sampson, who is another blogger on sciencebasedmedicineorg is discussed. Although I missed these at the time there are are some good comments by patients criticizing him for what looks to me like 'More Skeptical Than Thou' prejudice. Harriet Hall doggedly defends him. Interestingly, it looks like that was his last blog there. http://www.sciencebasedmedicine.org/index.php/cfs-viral-vs-somatization/vs-somatization//?p=2096
     
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  4. alex3619

    alex3619 Senior Member

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    @IVI, the issue with latent enterovirus at least should not lead to this kind of selection pressure the same way as it does in typical lytic virus infection, or at least lead to less, due to the nature of the two alternate lifecycles. That may or may not be the case for herpes viruses, I suspect their latency is different from enteroviruses though I have yet to investigate this in detail. I do agree we need phase 3 clinical trials and further studies, because these treatments may not become available widely until after there is strong evidence of efficacy and safety for ME or CFS. Issues with pathogen adaptation are mostly restricted to active viremia. Rituximab is not, so far as I am aware, used on patients who are actively viremic.

    Let me give you the name of a drug that is very dangerous yet widely prescribed off label: paracetamol. Here is another: aspirin. Both can kill or cripple. Some doctors do not prescribe aspirin for pain or fever due to its dangerous side effects. Off label use of drugs is standard - nearly every drug, every treatment, and indeed every test, used for CFS and ME that are actually useful are not considered standard. Short of giving up doctors and patients have no choice if they are restricted to "evidence-based" treatments, and I include both CBT and GET in that. Both are not proved effective and the evidence strongly suggests they are ineffective in improving functional capacity.

    As far as I am concerned off-label drugs should continue to be used until we have better science. There is no acceptable alternative. The only alternative really is to crawl into a hole and hibernate. Any source willing to fund better science will be welcome.
     
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  5. user9876

    user9876 Senior Member

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    If I understand the phrase actively viremic correctly then Rituxmab is used for transplant patients whose EBV levels rise to avoid post transplant lymphoma. Its used because it takes out the bcells carrying the virus.
     
  6. alex3619

    alex3619 Senior Member

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    Rituximab in that case though is used to prevent lymphoma. The reason drugs like this are not used in active infections is due to a risk of pathogens running out of control in the immune weakened patient, which sometimes leads to deaths. The discussions I have read have stated that its not used in patients with active infections. It might be though that B cell carried infections are considered an exception, because Rituximab will lower the viral load. This brings me back to the point though that most pathogens implicated in ME seem to be carried by B cells. Does anyone know of any review papers discussing these issues?
     
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  7. Gemini

    Gemini Senior Member

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    Alex,

    Thank you for the great review of latent infections!

    Here's a paper re: HHV-6 infection of B-cells:
    http://www.ncbi.nlm.nih.gov/pubmed/10555198

    Given B-cells are "antibody" factories, what are your thoughts about how their function is
    disrupted by multiple intracellular infections, ie. EBV, HHV-6, Coxsackie. etc?
     
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  8. alex3619

    alex3619 Senior Member

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    Hi Gemini, its become apparent (but needs more study) that we lack sufficient mature B cells. Ours seem to be immature, though I would like more replication of the evidence. This implies that they are dying and being replaced, which alone is one reason why we might get lymphoma - if the replication process is always over-active the risk of it going out of control is higher, I think.

    A second problem often noted by patients is that they fail to seroconvert, or lose it at some point. Stimulated B cells (that produce specific antipathogen antibodies) replicate and produce more antibodies to a pathogen. Some of these, I think perhaps in germinal centers in lymph nodes, become memory B cells. These are typically maintained for many years, even a lifetime. When they see a target epitope (the bit of a pathogen that they respond to, though in autoimmunity that epitope can be in our own body) they replicate more B cells to make antibodies. This speeds up the process of fighting the infection and is the basis of "immunity" to pathogens we have had before, and the reason for using vaccination. The process of making these cells to an epitope/pathogen is, I think (I have not looked up the technical definition) called seroconversion.

    If those memory B cells die, then we lose the adaptive response and no longer rapidly make more B cells to fight off infection with antibodies. We lose seroconversion, which means we lose the adaptive antibody immune response.

    There are only so many reasons that we know of why B cells die. A big one is pathogen attack. We seem to frequently have infections that attack B cells, sometimes multiple infections. Something is killing off our B cells so far as I can see. This might not be pathogens, but they would be my leading candidate. If our B cells are dying, then if we are to maintain a better immune system we must be making them rapidly.

    The problem is these are probably naive B cells. Rapid production of these increases risk of developing autoimmunity, if such replication is not due to expansion of mature cell population but creation of new cells. This is because they have randomized immune genes that reshuffle in development of the cell. This is what gives us a massive variety in potential antibodies. Its also a factor in inducing autoimmunity as B cells that make antibodies that target the body are supposed to be eliminated, but that process sometimes fails.

    This is in part why B cell infections (and EBV is a bad one for that) can lead to lymphoma or autoimmunity.

    Viruses like EBV following a normal life cycle will destroy the B cell to be released (lysis). Alternatively latent infections can disrupt the energy and metabolic pathways of B cells, leading to reduced activity and premature death as the normal maintenance of the cell is compromised.

    So this leads to several conclusions, all of which need more evidence and hence research in my opinion:

    1. We are losing our memory B cells which means we slowly lose adaptation to prior infections and vaccinations. (This is why I don't get the flu vaccine, we have equal or higher risk to vaccines as others, but their benefit is much less. The risk/benefit ratio is different. Flu vaccines rely on regular vaccination with different strains to build up immunity over time. In us that immunity may only be to current strains in the current vaccine.)
    2. High replication rates of B cells mean we are at more risk of lymphoma and autoimmunity.
    3. Existing infected B cells may be sluggish, slow to respond to a pathogen and with a weakened response.

    The paper cited earlier http://www.ncbi.nlm.nih.gov/pubmed/10555198 shows that herpes virus infections might induce a Th2 shift, which means a reliance on B cells for immunity. If our immune systems are being railroaded into relying on B cells, and our B cells are ineffective, then we have compromized immunity. For those T cells and NK cells that are still working/activated this would be forcing them to work overtime, perhaps leading to other issues.

    In anticipation of some comments that usually arise on these issues, let me say that the immune system has many parts that operate together. Some of those bits are not working properly in us, which means the other bits need to work overtime or we wind up with an AIDS like syndrome. Those other bits are probably exhausted. If they start to fail then latent infections can resurface. They recover and we improve. Its a cycle.

    Bye, Alex
     
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  9. Firestormm

    Firestormm Guest

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    Rituximab and Sjorgen's Syndrome

    January 17, 2013

    Also, taken from the MEA Facebook page:

    This blog back in March last year (2011) was talking about the success observed in taking Rituximab (in trial) for MS but how further research was dogged by patent concerns, lack of investment, and patient deaths:

    Of course I don't know what the situation is now (nearly two years later) but I hadn't realised Rituximab was being trialled in MS and other conditions or that it had been shown to be at least initially quite effective. Still. Interesting reading I thought and seemed appropriate on this thread. I wonder if Dr Hall knows?
     
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  10. Firestormm

    Firestormm Guest

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    Oh. Here's another one:Rituximab Possible Treatment Option for Patients with Primary Biliary Cirrhosis: February 2, 2012:

    I suppose one should say that in PBC they had the hypothesis in place i.e. "previous work implicating B cells to the development of this disease".

    In ME this was a 'stumbled upon' treatment - cart before the horse so to speak. Still, what will be will be.
     
  11. Firestormm

    Firestormm Guest

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    Or, maybe the Rituximab was stumbled upon, but there has been research that extrapolates the possibility that ME (or in subsets) did demonstrate problems with B-cells.

    I haven't got or read the full paper and am unsure of the publication date:

    I think there will need to be more papers that try, like this one, to explain why Rituximab might be so seemingly effective; as well as papers that demonstrate exactly how it is effective and explain why in some other patients it is not.
     
  12. ukxmrv

    ukxmrv Senior Member

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    Dr Bansal was talking to patients about doing research into B cells memory in early 2010. It could have been earlier but that was when my contact spoke to him about research project he had planned.

    Think it was something about EBV that was leading him to that direction.
     
  13. Whit

    Whit Senior Member

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    I haven't read this whole thread, but I know Dr K well, and I also know more about the current studies than some.

    The writer of this article is very misinformed as far as I know. She's making some bold, sensational statements based on very little understanding or knowledge. Accusing Dr K of taking advantage of patients because she talked to ONE of his patients? That is so unethical and so irresponsible. And meanwhile, she's griping about a lack of larger sample sizes or better studies. Maybe she should take her own advice. Is one patient a good sample size for evaluating Dr K's practice as a whole? Give me a break.

    She also seems to know very little about Rituxan. Risk of death? Are you serious? She's just trying to be sensational.

    Third, I would like to point out that Dr K is in close contact with the Norwegian researchers, and knows more about the current state of the new studies than this writer, who is basing her accusations on the old, preliminary studies. Suggesting that Dr K isn't following the Norwegian's protocol is a bit ridiculous.

    I do think we should be careful trying new drugs, but this article to me reeks of ignorance and sensationalism which are not a good combination.

    Dr K does want to try new things, but it's for the benefit of CFS.
     
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  14. alex3619

    alex3619 Senior Member

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  15. CallieAndToby

    CallieAndToby Senior Member

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    Extremely well written blog.
     
  16. barbc56

    barbc56 Senior Member

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    Therein lies the problem. We don't know what low B Cells mean. Are any changes in B cells a cause or effect of me/cfs? How are these changes compared to a healthy population. Again we don't know.

    I have ceased to read all the theories about B cells and will leave that to the credible scientist/doctors such as Mella and Kluge as my scientific understanding of this part of the science is not up to par. This thread is not about that.

    What I don't understand is that posters and I include myself, don't like the cookie cutter approach of PACE/GET/CBT, yet are willing to consider Rituximab as a cookie cutter cure, when it may be a subset of patients who are helped. This is why we need more studies. It's how science works.

    I also find it a bit ironic that some are so against vaccines which do does have credible science behind them as well as groups who should probably stay away from certain types of vaccines and yet are willing to put Rituximab into their system.

    Both the MCI and M and K, as well as a couple of other scientist/institutions are going to be involved in Rituximab studies and this is where I have a problem with Dr. Kolniak.

    Mella and Fluge have asked doctors to not prescribe Rituximab until more is known about it's efficacy and who it helps. Why is Dr. K. not following their advice? They are oncologist. Is Kolniak? The OMI appears to be a credible research lab and IMHO Dr. Kogelnik could take the reputation of the OMI down with him.

    We have seen this before with the WPI.

    We are all desperate. I am desperate but I will not "jump off a cliff" so to speak as a choice for something that is not proven, has the capacity to harm patients. Dr. K. could muddy the waters of legitimate research.

    It also concerns me that the above poster had a friend and the first treatment he wanted to offer was Rituximab. Yes this is hearsay but I find it worrisome if this indeed true.
    Fluge and Mella
    Read the research of Mella and Fluge. While it is a good starting point, we don't have enough information to start taking it as a cure for me/cfs. Results were temporary and we don't know what that means. If there was more information gleamed from their research I would be all for it.

    If people choose to take Rituximab, that is their choice. But my opinion is that it is premature to come to the conclusion the Rituximab may be the answer.

    Barb
     
  17. penny

    penny Senior Member

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    Sorry but your post is just sooo full of assumptions...

    I don't think anyone has said Rituximab is a "cookie cutter cure", whatever that means. Most folks seem interested in it as a possible treatment, and if it is helpful, as a possible elucidation of underlying mechanisms of the illness. No one, except you, has said anything about a one size fits all cure.

    What? For one thing, who says folks who are "so against vaccines" are also "willing to put Rituximab into their system"? This seems like you've totally made up this cohort of vaccine hating, rituximab takers. Not even getting into the variable opinions on what constitutes "credible" and that vaccines are not all alike (in composition, side effects or effectiveness)...

    You don't know what conversations are going on between these folks. The quote that keeps popping into my head when reading this thread is from Mrs. Peacock in the movie Clue: "Oh, where were you in that men's room?"

    We patients are never going to be privy to all the discussions that go on between researchers and doctors. Pretending the only information is that which is published and available to us on the internet, doesn't make it true.

    And that is totally your right to choose. So why do you judge others so harshly who weigh the pros/cons and make a different choice than you? Shouldn't they have just as much of a right to choose as you do?

    If I choose to jump off a cliff without proof, that is MY business, NOT yours. And as has been pointed out, there is not a single treatment which has been proven. Many things I've tried with the most "proof" (ahem, vitamin D) have caused me the most harm. Do I blame anyone else for this? No, because I take responsibility for my choices. I am sick, but I am not helpless. I deserve the right to make choices about my treatment and take responsibilities for the outcome. We all deserve this right.

    And if it comes down to it, to misquote another wildly inappropriate source, "we've got to fight for our right(s)".
     
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  18. ukxmrv

    ukxmrv Senior Member

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    Callie, why did you friend go and see this particular doctor if she wanted help with sleep and POTS?
     
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  19. Purple

    Purple Bundle of purpliness

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    Your post may be more understandable if you had the names of the doctors involved right. And what is "MCI"? Sorry, haven't come across that one before.
     
  20. barbc56

    barbc56 Senior Member

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    We absolutely need to fight for our rights. I am not telling people what to do. It's just my opinion and find it perplexing that people get so upset if someone has a different perspective.

    The cookie cutter approach to treatment analogy is indeed relatvent here. Just like GET we don't know what groups will benefit. I think the same thing can be applied to Rituximab. I do find it disturbing that Dr. Kolniak is prescribing this chemotherapy medication. I would love to see it pan out but we need more data before we know that.

    Mellor and Fluge have indeed said for doctors not to prescribe Rituximab. I'll see if I can find the quote as I did neglect to put that in my post.

    Barb
     

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