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Can Rituximab work in patients with no known autoimmunity?

Discussion in 'Rituximab: News and Research' started by Wonkmonk, Feb 8, 2018.

  1. Wonkmonk

    Wonkmonk Senior Member

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    Hello everyone,

    we are having an interesting discussion in another thread about the question if it makes sense to try Rituximab even if you don't have any known autoantibodies.

    Rituximab is known to help for autoimmune diseases like rheumatoid arthritis and lupus erythematosus, and there is anecdotal evidence in this forum of people with autoimmunity problems who benefitted substantially from it (most prominently Gingergrrl).

    BUT: As far as I know, the Norwegian trials have never established a link between existing autoimmune disease and response to Rituximab.

    In their very first trial, one of the three major responders had no known autoimmune disease:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/

    It may well be that all patients who responded had autoimmune disease of an unknown and undiscovered kind.

    Or Rituximab might work for other reasons in patients without autoimmunity. Maybe the problem isn't autoantibodies, but overproduction of "normal" antibodies that cause harm to the body. Such antibodies are known to exist, e.g., the anti-streptolysin antibody is against streptococcal bacteria (so not an autoantibody), but it also attacks body tissues that have a similar protein.

    Prof. Edwards once surmised that Rituximab might work by stopping overproduction of one or several low-affinity/broad spectrum antibody that aren't actually autoantibodies.

    And there has always been the hypothesis that Rituximab works in some patients simply by killing Epstein Barr Virus, whose main reservoir are the B-cells.

    In any of these cases, patients whose autoimmune panel is negative would have a chance to be responders and, again, the Norwegian researchers have not established a link between autoimmunity and response to Rituximab although this is their main hypothesis of how Rituximab works (so it's probably not because they haven't looked into this).

    I am very curious to hear your opinions!
     
  2. Cheesus

    Cheesus Senior Member

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    The problem here is that Rituximab does not work in patients with CFS/ME. I know there are some anecdotes to suggest it does, but the evidence from a large well designed trial suggests otherwise. Using anecdotes to inform treatment when there is good evidence to contradict those anecdotes is wasteful and hazardous.
     
  3. andyguitar

    andyguitar Senior Member

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    I'd have to agree with @Cheesus here. The Rituximab trial showed it did not work. Time to forget about it and move on.
     
    mrquasar likes this.
  4. Wonkmonk

    Wonkmonk Senior Member

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    I beg to disagree. The last failure in Norway (as far as we know) only suggests it isn't statistically proven to be more effective than placebo in a large, diverse population of CFS patients. On the other hand, there is evidence from prior studies and from medical practice that Rituximab can help in a subset of patients.

    That subset can't be defined at this point in time, and it is probably not "only those with known autoimmune problems."

    It also seems that the research community hasn't given up on it. This here is an informative read:

    http://simmaronresearch.com/2017/11/norwegian-rituximab-chronic-fatigue-syndrome-mecfs-trial-fails/
     
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  5. PinkPanda

    PinkPanda Senior Member

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    We had a discussion on the issue in this thread
    https://forums.phoenixrising.me/index.php?threads/ivig-treatment.56545/page-2#post-940846
    this and the following posts are about that there is a group of people who show signs of autoimmunity and fatigue, but do not fit the criteria of an autoimmune disease.
    These people might receive a CFS diagnosis.

    If this creates a subset of people with CFS and autoimmunity, they might respond to rituximab.
    I think that there might have to be a certain connection between CFS and autoimmunity for rituximab to work and this is not the issue in everyone with ME/CFS.
    We don't know the main connection yet, is it the antibodies to acetyl-choline/ adrenergic receptors that 20-30% have, or comorbity of other immune diseases, high ANA..? Maybe also some other autoimmune factor..

    I agree that trials are limited. Although the rituximab trial definitely concludes that rituximab is not a magic bullet for everyone, this does not rule out every possible positive effect of rituximab for a subgroup.

    I'm quoting from the article you posted

     
    Last edited: Feb 8, 2018
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  6. Wonkmonk

    Wonkmonk Senior Member

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    In the 2011 study, only 20% of those who received Rituximab had a known autoimmune disease and only 33% had a known autoimmune disease in a first-degree relative:

    https://doi.org/10.1371/journal.pone.0026358.t001

    "The high rate of CFS in women compared to men is a suggestion of an underlying autoimmune process. On-going autoimmune phenomena in CFS have been discussed perhaps triggered by infections through molecular mimicry, through structural similarity between a pathogen component and self-structures. Several autoantibodies have been reported in CFS, but their pathogenic roles have not been established. In the present study, 23% of the patients had a previous known autoimmune disease, and 40% had first-degree relatives with an autoimmune disease. However, there were low frequencies of positive known common autoantibodies, none had elevated anti-nuclear antibodies, and two had elevated anti-thyroid peroxidase antibodies."
     
    Last edited: Feb 8, 2018
  7. Wonkmonk

    Wonkmonk Senior Member

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  8. Wonkmonk

    Wonkmonk Senior Member

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    Also buried in the 2015 study and quite interesting:

    "One patient had a distinct allergic reaction including an urticarial exanthema at the end of the 3-months rituximab infusion. She then had a major transient clinical response between 3 and 6 months follow-up. Due to a ME/CFS symptom relapse she was subsequently treated with the humanized monoclonal anti-CD20 antibody ofatumumab from 8 months follow-up, with no allergic reaction and again with a clear clinical response starting three months later (from 11 months follow-up)."
     
  9. Gingergrrl

    Gingergrrl Senior Member

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    My best guess (which could mean nothing in the end) is that there is a sub-group of us with autoimmunity, to which I belong. IMO, we are either a unique sub-group of CFS, or were misdiagnosed and never had CFS. My case started out viral with Mono/EBV but then shifted into autoimmunity. My two doctors are prescribing the Rituximab specifically for autoimmunity and not for ME/CFS (in my case).

    Because of my positive ANA, 11 autoantibodies, and my extremely positive results to high dose IVIG prior to Rituximab, I assessed that it was worth the risk in my case and it absolutely 100% has been. But if I had no proven autoimmunity and just a "CFS" diagnosis, I would not have done it.
     
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  10. Wonkmonk

    Wonkmonk Senior Member

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    Here is what seems to be the latest from Norway (subtitles available).

    Dr. Mella says despite the latest negative study he still believes a subgroup of CFS patients benefits from Rituximab (24:10).



    The cyclophosphamide trial (discussed right next) appears to have been encouraging, although side effects seem to be an issue.
     
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  11. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    You have a phase 3 showing it doesnt work, as well as anecdotal reports from those taking it privately. I mean, it might be 5-15 perc who get some response, and some very few few with lasting effect - but then one really seems to be clutching at straws, and the hypothesis is now not supported by current evidence..
     
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  12. Wonkmonk

    Wonkmonk Senior Member

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    I agree it's clutching at straws, but sometimes a straw is better than nothing.
     
  13. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    If it was not so expensive i would agree, i still think its reasonable to try in vacuum
     
  14. Wonkmonk

    Wonkmonk Senior Member

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    Perhaps in the end we'll end up with Cyclophosphamide which is much less expensive, but also much less tolerated. Dr Mella suggests results were "very good".
     
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  15. Wonkmonk

    Wonkmonk Senior Member

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    The following just entered my mind:

    Assume you are treating patients with similar symptoms, but these patients actually have 10 different diseases - distributed about equally - that just happen to share some nonspecific symptoms (e.g., fatigue, joint pain). Further assume over a 1-2 year period, disease in 10% of these patients resolves spontaneously or the patients were misdiagnosed and actually have other conditions that resolve spontaneously.

    Then you make a study with a medication that actually cures one of the 10 diseases. You give it to 100 patients and 100 patients get a placebo. You will find that in each group 10 patients are healthy again at the end of the trial and infer that the medication is useless because it's no more effective than placebo, although you actually found a cure for 10% of the patients.

    This may or may not be the case with Rituximab. All I want to say is: If you have a patient population of which you don't know if they are all correctly diagnosed and you don't know if they all have the same disease, ruling out treatment options on the basis of placebo-controlled trials might give you false negative results.
     
  16. Gingergrrl

    Gingergrrl Senior Member

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    I am in the minority but I agree with you @Wonkmonk. I believe there are at least ten different sub-groups, or misdiagnosed groups, who are being represented in most of these studies. I do not believe that all of the people in these studies (whether the PACE trial or the Rituximab trial) all have the exact same illness.

    I totally agree with you but you explained it better than I ever could have.
     
    MEMum likes this.
  17. Wonkmonk

    Wonkmonk Senior Member

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    Thanks for the kind words, @Gingergrrl.

    It is also important to note Fluge/Mella don't say it doesn't work. They say it might very well work in a subset of patients and they haven't figured out yet how these patients can be identified and how large that subset is, though it seems to be a rather small one. That leaves patients in a bad situation because the only chance to find out if they are in that subset (if it exists) is to try Rituximab.

    But again I want to stress like Fluge/Mella I also wouldn't recommend anyone using Rituximab for CFS. In American football, I think one would call it a Hail Mary pass. Judging by the data and experiences we know of, one probably has to conclude that a successful treatment is rather unlikely (although not imposssible). Given that there are risks involved and the costs are high, it needs careful deliberation before such a step should be taken.
     
  18. Wonkmonk

    Wonkmonk Senior Member

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    I just realized I made an error in the above calculation. In the Rituximab Group, the 90 who aren't cured by the medication of course also have a 10% spontaneous recovery rate, so it is 19 cured vs. only 10 cured in the placebo group.

    But I also made another error, that is it's likely the medication (e.g. RTX) doesn't cure 100% of the people, but maybe just has a 50% chance of curing people and then there is another unknown, i.e. you don't know if you have a 10/10 split in the placebo vs. verum group of those who respond to the medication (you can't identify the responders), so you might very well sort 15 responders in the placebo group and just 5 in the group who actually get the medication.

    In that case (50% Response rate and a 5/15 split between placebo and verum), you get 12 responders in the verum group and 10 in the placebo group and you'd probably conclude that the medication didn't help much. Plus: These are all probabilities, perhaps in the verum group only 8 instead of 10 people recovered spontaneously and in the placebo group 12 instead of 10.

    So what I want to say is despite my maths error above, in a situation in which you have only a small fraction of people who have the disease to which the medication is effective and only a fraction of those are responders and you have possible spontaneous recovery, then there are a lot of scenarios in which you don't find results where there actually could have been results.

    If you do several studies with this or a similar design, you are probably going to find what Fluge/Mella found: Some studies will be positive and some will be negative.
     
  19. Desertstorm

    Desertstorm

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    In my case, given all sorts of symptoms from organ inflammation to rashes to FM and CFS all started about the same time and have all advanced in severity as I age it's hard to get my mind around having a bunch of these issue independently of the others. In the GULF WAR ILLNESS world which parallels the ME/CFS world all are lumped into the unexplained muti illness category.

    Now to be clear this simply facilitated disability claims for affected vets by recognizing that medically we have no clue but yet we have 100k sick vets in the US alone. This has led to quite a bit of unremarkable medical research by the VA and others, but the only solid evidence they came up with is just how widespread GWI is within the population of vets who fought in the PGW.

    My approach has been to address/target symptoms individually. For instance anything caused by autoimmune/inflammation such as rashes, vasculitis and organ function (pulmonary and renal to the greater extent) have been controlled by high dose steroids. Myalgias and joint pain I either deal with or use medical cannabis at night. The fatigue only through monitoring my activity levels and learning the warning signs of an impending crash.

    If rituxan can replace the steroids effectively I would be miles ahead and certainly will prolong my useful life span. Long term systemic steroids do work but at a great price. Bones, old skin, hematomas....

    Still trying to make up my mind to try it or not. Leaning toward yet another shot in the dark...might kill me but it won't taste as bad some of the green goo "cures"!
     
    Gingergrrl likes this.
  20. Desertstorm

    Desertstorm

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    I am having 5 hour long rituxan infusion this week and the second in two weeks. Next infususions scheduled for September. The idea is to beat down he B cell population and reduce the effects of the autoimmune/inflamatory battle that rages within while getting off of steroids finally.
    Given nobody really has a clue about the overall condition I continue to attack this one symptom at a time. Will report back.
     

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