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Rituximab Discussion

Discussion in 'Rituximab: News and Research' started by Bob, Jun 17, 2012.

  1. Bob

    Bob

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    Hi Daffodil,

    Do you mind me asking if you experienced any improvement in health whilst taking AZT, when your NK cell function increased?


    Daffodil, one thing to point out, that you might not have considered, is that these complex pharmaceuticals often work via multiple unpredictable mechanisms that they don't fully understand. So they can affect our biology in multiple ways.

    For example, look at Rituximab... The improvements initially seen in CFS/ME patients were an unexpected side-effect when treating cancer. And we don't yet know why it treats CFS/ME... It might be because it helps to modulate a dysfunctional immune system, or it might be because it modulates the replication of a virus, etc.

    MAOIs (antidepressants) were discovered for depression the same way... They were treating some other unrelated disease and discovered that the patients' moods improved.

    So it is possible that AZT might be working on your immune system in some unexpected way, so that it increases NK cell function... It might purely be modulating your immune system rather than modulating viruses.

    I just thought I'd mention that in case helpful. But I'm open to all possibilities.

    Totally agree!
    merylg likes this.
  2. currer

    currer Senior Member

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    I am interested in the rituximab research, and I met both Drs Fluge and Mella at the conference, and very committed and pleasant people they are!
    BUT...I am afraid that rituximab will prove to be a repitition of ampligen for us...a very expensive drug, given by infusion, only available to the few who can afford it...there will be no incentive to governments to treat us with this, it would not be cost effective for them, in fact it would be disasterously expensive. Ampligen has never been licensed for ME despite ample evidence it works. They will suppress the rituximab research, keep ME "psychological" until/if a cheap cure comes along, they will not admit that such large numbers of people need expensive treatments and qualify for health insurance/social welfare payments.

    I think the true value of the ritux research is the light it may throw on the pathogenesis of this disease. There may be a safer drug which already exists and which is cheaper, that we can use. I think ritux would be too dangerous

    Drs Fluge and Mella did say that they cannot proceed with their larger study of rituximab in more patients because they cannot yet get funding and the reason is the cost of the rituximab for the trial!
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  3. currer

    currer Senior Member

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    Yep I think the Snyderman results deserve attention and clarification of why his biomarkers responded as they did.

    Fluge and Mella, are both very committed to this ME research, it is not their speciality as they are oncologists, but they are very comcerned about the amount of ill-health and disability they have unearthed hidden in this disorder and are very motivated to help us and very enthusiastic about their rituximab findings. The discovery that they can induce recovery even in those with intractible long term disease with rituximab has made them enthusiastic for the therapeutic potential of this drug. They cannot yet find any autoantibodies in ME patients.
    They have to do the ME / rituximab research whilst running a busy oncology department, so the rituximab research is not part of their formal medical responsibilities. They are not specialists in ME.
    Sorry, I realise this is off-topic for this thread. I will get a DVD from IiME and write up the Ritux presentation later, on the correct thread. There were no stunning announcements at this year's conference, but many reports of research in progress.
    My opinion is that the best hope for us with regard to rituximab is that it will lead to the discovery of another treatment that will be cheap and easy to deliver. I think rituximab will always be to dangerous for long-term use, unfortunately, but that does not mean that there are not other drugs which already exist which could be used in our disorder. The research that could lead to a treatment has never been done.
    merylg, jeffrez, justy and 2 others like this.
  4. Bob

    Bob

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    The good news is that Rituximab comes to the end of its patent in about a years time, if I remember correctly, so there should be cheaper generic versions available.
    merylg likes this.
  5. Esther12

    Esther12 Senior Member

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    Which is one of the reasons why research has been so slow in this area - it's not worth the pharma company investing when they'll not be able to profit from it.

    I think that my cynicism about CFS research generally has left me feeling deeply sceptical about Rituximab for no particularly good reason (although... not a statistically significant benefit at the protocol's primary end point, use of subjective questionnaire scores... if it wasn't double-blind the study wouldn't be that compelling imo, and the recent XMRV drama has shown us how difficult it is to know exactly what happened in a lab based only on the papers published).
  6. FancyMyBlood

    FancyMyBlood Senior Member

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    I disagree with this statement. If you look at their patent application for rituximab (you can find it at Google Patents) they reference many studies and even poster abstracts I've never seen before. While they're not 'specialists' like Cheney, Peterson, DML etc. who've been seeing patients for decades they're very well informed about this illness. Regarding the failure to find autoantibodies, that's unfortunate but no more than that. There are many (supected) autoimmune diseases with no known autoantibodies, but with treatment options. Like prof. Edwards said in his PlosOne response the disease is likely heterogeneous and new autoantibodies are being found all the time.

    Now, it's very important that Mella and Fluge get the funds to start their phase III clinical trial. If these results are also positive, big pharma will probably jump in and fund more research to find out if new, still patented autoimmune drugs also have positive effects. Hopefully they're already planning this after the findings of the PlosOne paper.

    One thing I don't understand is why these studies have to be this expensive. Obviously it's because of the costs of rituximab, but why wouldn't Roche give it for free or at cost price? Their patent expires anyway and positive results may be interesting to them to find out wether another, patented monoclonal antibody (R7159/GA101) has the same/better effects.
    merylg likes this.
  7. Bob

    Bob

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    Maybe they would have given the drugs for free if their patent wasn't about to run out...
    And maybe they are squeezing every last dollar out of it while they can.
    But it will be cheaper as soon as the patent runs out.

    But I understand the point you are making... They could potentially create a similar new drug, with a new patient, but maybe they haven't got plans for that, or haven't got around to it yet.
  8. currer

    currer Senior Member

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    Hi Esther,
    Your scepticism is unwarranted where rituximab is concerned. The results are really dramatic, in those that respond - which are about two thirds of patients. The two patients from the first study who "recovered" after the initial infusion are still working and apparently in good health - after only one infusion. Others follow a different pattern of delayed recovery about two months after the first infusion. Fluge and Mella are trialling giving the infusions closer together so that the pattern of recovery then relapse can be overcome, and that seems to work. Responders seem to generally relapse back to illness once the effect of the infusion wears off and the B cells increase in number again. Giving ritux infusions closer together could prevent the B cell increase and relapse. The two patients who recovered completely after the initial infusion are atypical.
    What happens is that the B cells are reduced to virtually nothing soon after the rituximab, but there is a delay of a couple of months, sometimes even longer, before the patient responds.

    This is what requires investigation. Fluge and Mella think the true therapeutic effect is not because of the effect on the B cells but on another as yet unknown immune cell/immune mechanism which is responding in a way that is secondary to the B cell depletion - that is why it lags after the initial drop in B cells. They have no idea what this mechanism is as yet, and given the complexity of the immune system it could be a long time before anyone figures it out.

    However it is noticable that ALL the ME symptoms improve once this immune mechanism / immune cell is affected by the rituximab - so the Norwegians think they have found the underlying biomedical abnormality that perpetuates this disease.

    So "autoimmune" just poses another set of unanswered questions - but they could lead to treatments and there are a number of studies being planned to investigate all this.

    Yes, the IiME conference is tiring for patients, and you have to sort through a lot of unneeded information - I was basically just listening for anything remarkable at the conference- that was all I had the energy for this time.
    There will be a lot of research interest now on immunity and ME and we will see papers coming out, but they are all work in progress - there is nothing dramatic as yet.

    The important thing about the IiME conferences is that they act to draw all the researchers together and allow them to share ideas and educate other professionals who are just starting to develop an interest. They have a wide spread of research interests - not all the talks are ones I would agree with or be interested in - but the important thing is that the professionals are talking to each other during this event.
    rosie26, JAH, SOC and 4 others like this.
  9. currer

    currer Senior Member

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    Hi Daffodil,
    You dont need to get despondent - for those who are seriously ill the risk/benefit ratio would be worthwhile for rituximab.
    I was thinking of those who are moderately ill.
    It is quite noticable when you talk to the Norwegiamn doctors that they are completely behind their discovery and feel it is worth continuing their research on ritux despite the problems with this type of drug. They do not feel the side effects have been severe enough in their trial patients to halt the use of rituximab in ME though they do say that the drug is only used for research atm. not to be used on real patients as a treatment yet!
    merylg likes this.
  10. alex3619

    alex3619 Senior Member

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    In reply to currer, post 125, the Rituximab results are so dramatic that I think, as working hypothesis, it would be fair to say that ME is a B cell mediated disorder. That doesn't mean that B cells are the cause, as you reported, but it does mean that they are essential to the pathophysiology. My guess is that if Rituximab can be shown to work in the Phase 3 clinical trials then other and better drugs will be found using this research as a base.

    The science is still not validated enough yet but I have been toying with names: like B-cell-mediated Neuro-Immune Disorder, or BNID. The real name will come when we understand the mechanisms.

    Bye, Alex
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  11. Bob

    Bob

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    Continuing the Rituximab discussion (sorry to everyone who isn't interested... I'll ask for it to be separated into a new thread)

    Wouldn't it make logical sense for there to be a delayed reaction after depletion of B cells, if some antibodies last in the body for a while? I don't know how long antibodies stay in the blood, once created, so I could be barking up the wrong tree here.

    edit: I've just done a brief google search, and it seems that IgG has a half-life of 21 days (which is quite a lot longer than the other types of antibodies.) So maybe that explains the two month delay?

    Currer says that there is a two month delay before symptoms improve, after administration of Rituximab...
    After two months, IgG levels would have decreased to one eighth of their original levels.
    So maybe they need to start exploring if it might be IgG that might be causing ME symptoms.

    IgG makes up approximately 80% of the serum antibodies.

    Another interesting thing is that "the Fc portion of IgG can bind to NK cells for antibody-dependent cytotoxicity or ADCC"...
    So it seems there is an interaction between IgG and NK cells...
    So maybe IgG in ME patients has a harmful effect on NK cells... Or stops NK cells working properely...
    As we know we've got low levels of NK cell activity, according to the recent research from Dr Peterson's organisation.

    So maybe the Rituximab has an indirect effect on NK cell levels, but it is the IgG that is the cause of the problem.

    Anyway, I'm just exploring all of this for the first time... And I think I might be gaining an interest in immunology!!! Who'd have thought it! I didn't think that immunology could be interesting, after our journey with XMRV!


    Does anyone know if there are any other B-cell depleting drugs?
    If there are, it seems like a good idea to test those on ME patients as well.
  12. natasa778

    natasa778 Senior Member

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    Autoimmunity could easily be a secondary phenomenon of B-cell infection (malfunction induced by an invader), but it could STILL be truly pathogenic.

    Does anyone know what type of B cell rituximab targets? Have a look at this:
    http://www.ncbi.nlm.nih.gov/pubmed/15633017.1

    then there are subtypes of B1 cells too... http://www.ncbi.nlm.nih.gov/pubmed/7511005.1

    and what about plasma cells, which are also antibody-producing - these are two types of these (at least) one is short lived and depleted by rituximab, and the other type is long-lived and not affected by rituximab treatment. Apparently. At least not in mice, and not short term. Is it possible that they too are affected by rituximab, but it takes longer for them to die off (would explain delayed reponse?).

    Long-lived plasma cells and their contribution to autoimmunity
    http://www.ncbi.nlm.nih.gov/pubmed/16014527


    Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis
    http://www.ncbi.nlm.nih.gov/pubmed/20176942

    further reading on the above:
    http://www.ncbi.nlm.nih.gov/pubmed/15173206
    merylg likes this.
  13. currer

    currer Senior Member

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    Whatever is going on in the rituximab study it sure aint obvious - because Drs Fluge and Mella were confidently looking to find auto antibodies last year when I was at the previous conference - and they have not found them to date although they are still looking. So I think that rules out any obvious approach to this problem
    http://www.investinme.org/IiME Conference 2012/IIMEC7 Conference 2012 Conference Report.htm
    I spoke to Dr Fluge afterwards and he said that an auto-antibody has not been discovered in the majority of autoimmune diseases.
    Autoimmune sounds like a catch - all category to me. Who knows what is going on in detail? The immune system is fiendishly complex.​
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  14. Bob

    Bob

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    Yes, doesn't everything just get labelled as 'autoimmune' when they don't understand the biological underpinnings, inflammation is involved, and they can't find any external agents at play?

    Even when they do find auto-antibodies, then they still don't really understand the underlying biology that causes the immune dysfunction.
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  15. Bob

    Bob

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    I'm just looking at all of this for the first time...

    From wikipedia:

    Rituximab has been shown to be an effective rheumatoid arthritis treatment...

    ...and there is some evidence for efficacy, but not necessarily safety, in a range of other autoimmune diseases.

    Other autoimmune diseases that have been treated with rituximab include:

    • autoimmune hemolytic anemia,
    • pure red cell aplasia,
    • idiopathic thrombocytopenic purpura (ITP),
    • Evans syndrome,
    • vasculitis (for example Wegener's Granulomatosis),
    • bullous skin disorders,
    • type 1 diabetes mellitus,
    • Sjogren's syndrome, and
    • Devic's disease, and
    • Graves' disease ophthalmopathy.
    ...and rituximab is widely used off-label to treat difficult cases of multiple sclerosis, systemic lupus erythematosus and autoimmune anemias.
    currer likes this.
  16. Bob

    Bob

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    Very interesting blog from the Norwegian journalist - well worth a read:
    http://debortgjemteinternational.wordpress.com/2011/10/30/how-important-is-the-rituximab-study/

    It answers a few of the questions that I had.

    Interesting that Nancy Klimas thinks the improvements from Rituximab could be because latent EBV viruses reside in the B cells.

    It's also interesting how everyone is saying how important it is that the Norwegians do biomarker studies before and after the Rituximab treatments, because this could lead to all sorts of discoveries. Quite a few of the CFS/ME researchers seem to be very excited about Rituximab, esp because the discovery fits in so closely with so much other immunology that's already been carried out by various researchers.

    I think it's helpful for us to remember what Komaroff says:
    "Anthony Komaroff says there are plenty of examples in medical history that a drug has effects the medical community didn’t yet know it had, and therefore it’s important to also look at alternative explanations for possible mechanisms."
    In other words, it's too early to know if B cells play a central part in the disease.

    I found the link in Corts Rituximab resource blog:
    http://phoenixrising.me/treating-cf...hronic-fatigue-syndrome-mecfs-resource-center
    Which I found through his latest article:
    http://phoenixrising.me/archives/11641
  17. lansbergen

    lansbergen Senior Member

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    http://www.copewithcytokines.org/cope.cgi?key=CD20

    CD20 functions as a Ca(2+)-permeable cation channel and is involved in cell activation and growth regulation of B-lymphocytes (Bubien et al, 1993; Tedder et al, 1985; Tedder and Engel, 1994).
    The ligation of CD20 with antibodies causes enhanced CD20 phosphorylation (Tedder and Schlossman, 1988). This coincides with increased expression of CD18, CD58 and MHC class 2 molecules (White et al, 1991; Clark and Shu, 1987), phosphorylation of cellular proteins (Deans et al, 1993), expression of some oncogenes (Smeland et al, 1985; Golat et al, 1992), and induction of B-cell adhesion (Kansas and Tedder, 1991). B-cell cell cycle progression in response to mitogens and mitogen-induced B-cell differentiation and antibody secretion are inhibited (Tedder et al, 1985, 1986; Golay et al, 1985; Golay and Crawford, 1987). In addition, extensive CD20 cross-linking may also influence cell death by apoptosis (Holder et al, 1995; Shan et al, 1998).
  18. Bob

    Bob

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    Komaroff also seems to be open to the idea of the involvement of a pathogen:
    - What are your thoughts on an autoimmune hypothesis in ME/CFS?
    - A number of studies suggest that there are autoantibodies. Autoimmune means that the immune system is confused – that it attacks a tissue that it shouldn’t attack because it is its own self. I think it’s entirely plausible that this attack is mediated because that tissue has within it some foreign infectious agent, and that the attack is perfectly sensible. The immune system is not attacking its own tissue deliberately, it’s attacking its own tissue because it sees something foreign inside that tissue. That’s theoretical, but again there’s some evidence to support it, Komaroff said.
    justy likes this.
  19. ukxmrv

    ukxmrv Senior Member

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    I think that it was the ME Association in the UK that said a Rituximab trial would cost about £200,000 (have a feeling that someone asked them on their facebook page but cannot find it now). They do sound interested in a trial but don't have the money.
  20. alex3619

    alex3619 Senior Member

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    Hi ukxmrv, that amount of cash is a small trial. The Norwegian trial has money but is still short ten million dollars last I read. Phase 3 trials are much more expensive, especially if done properly. Bye, Alex

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