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Fluge/Mella 2009 paper--why the rapid response to rituximab?

Discussion in 'Rituximab: News and Research' started by jaybee00, Apr 30, 2017.

  1. jaybee00

    jaybee00

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    Hello,

    Any ideas why 2 of the patients had a rapid response to rituximab at six weeks in the 2009 Fluge/Melle paper, but this type of rapid response wasn't seen in the subsequent studies?

    https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-9-28

    Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series


    Thanks.
     
  2. A.B.

    A.B. Senior Member

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    Did you check that no patients showed a response at six weeks in later studies?

    The B cells disappear quickly with treatment, but the antibodies take longer to go away. If I remember right the later studies showed considerable variation in response times which suggests that the antibodies in this group of patients can be short or long lived.

    I wonder if that implies that there are multiple immunological paths to the same illness, or if it means that there are at least two autoimmune forms of ME/CFS?

    So the observations in this study may be simply due to chance. Rapid responses are more noticable as well and therefore more likely to end up in early reports like these.
     
    Last edited: Apr 30, 2017
  3. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Some of the pilot patients were on other immunosuppressives as well since some were cancer patients.
     
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  4. Jesse2233

    Jesse2233 Senior Member

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    @Marky90 are you referring to Methotrexate? If so might that plus RTX be a more reliable cocktail?
     
  5. Forbin

    Forbin Senior Member

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    My understanding is that Fluge and Mella's hypothesis is that there is something, call it "x," that starts to clear from the body following B-cell depletion. The positive response kicks in when when the concentration of "x" falls below a certain level. The speed of response and its duration are thus thought to be linked to the original concentration of "x" in the system and this is thought to vary between individuals.

    It's not entirely obvious from Fluge and Mella's diagrams below, but the concentration "x" starts out lowest in the "long response" diagram. Its initial value is higher in the "short and late response" diagram, and "x" is most elevated at the start of the "no response" chart.

    Because the B-cells will start to repopulate after they are depleted [red line], causing "x" to increase again, the sooner that "x" drops below the "CFS response threshold" [the gold line], the longer the response will be. The final chart [lower right] suggests that, if the response is long enough, "x" may continue to remain below the threshold where symptoms start to occur.

    This is the hypothesis. To directly confirm it, I'd assume that you would need to know what "x" is and also be able to measure it.

    Early responders would suggest that "x" is initially fairly low in them.

    I don't know if there is thought to be a correlation between the level of "x" and the severity of symptoms. Were that true, you would expect to see milder cases respond more quickly than severe ones. Although I think very severe cases have been less responsive, I'm not sure if a correlation between severity and response time holds true across the spectrum.

    Fluge Mella X-Factor.jpg
     
    Last edited: May 1, 2017
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  6. Gingergrrl

    Gingergrrl Senior Member

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    I am wondering what other treatments the "rapid responders" may have had prior to RTX? I have read so much stuff on RTX that it is hard to keep it all straight but am wondering if any of them had a treatment like IVIG, plasmapheresis, or other immunosuppressants (as mentioned by @Marky90), prior to RTX so they had their first dose of RTX already with lower autoantibodies from day one?

    I think factor "x" that @Forbin is referring to are the autoantibodies (but which ones and at what amounts must vary from person to person)? The main thing I remember from the Fluge & Mella paper (the one from 2015 with about 12 authors including Dr. Sheibenbogen and Dr. Heidecke of Cell Trend labs) is that the responders were positive for beta adrenergic and anti-muscarinic-cholinergic autoantibodies, for anti TPO (thyroid) antibodies, and also had a positive ANA titer. I was struck by this b/c it is an exact match with my own case.

    So I would guess if someone had IVIG, or another treatment that reduced autoantibodies prior to even starting RTX, that they might have a faster response time (but this is just speculation on my part). Am curious what @Jonathan Edwards thinks of this (and hoping he does not say it is "immuno-babble" :D LOL.
     
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  7. Forbin

    Forbin Senior Member

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    @Gingergrrl Yeah, I should have mentioned that antibodies/auto-antibodies would be the primary candidates for "x." I wonder, though, if "x" could be some consequence of antibody activity - like gut inflammation leading to some harmful molecule(s) entering the blood stream via "leaky gut." But that may just be my "immuno-babble" :D.
     
    Last edited: Apr 30, 2017
  8. Jesse2233

    Jesse2233 Senior Member

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    LPSs would be a good candidate for that Forbin
     
  9. TrixieStix

    TrixieStix Senior Member

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    Hasn't Ron Davis recently said that he believes that "x" is likely either a protein or an autoantibody? I think I remember last year he said that it would be less ideal if it's turns out to be an autoantibody because they are hard to find, but I might be remembering wrong....?

    Good thing is you don't have to know what "x" is to find treatments for the disease!
     
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  10. alex3619

    alex3619 Senior Member

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    Ron Davis has a size of the molecule in mind. Antibodies are proteins, we should not forget that. If we knew the approximate size of the molecule, and its not published yet I think, then we might be able to figure out if antibodies are candidates.
     
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  11. Butydoc

    Butydoc President

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    Hi Jabeeoo,

    My understanding is that Retuximab attacks B cells with the CD20 antigen. The plasma cells lack that antigen, so they are not affected. Since antibodies are still being produced, they must be depleted before a clinical response. I suspect there are different time lines in terms of how long a plasma cell survives. This may account for differences in timing of the clinical responses.

    Best,
    Gary
     
  12. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    I would like to add that we might encounter the problem that potential pathological long lived plasma cells are part of some regenerative loop independent of serum b-cells.
     
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  13. Jesse2233

    Jesse2233 Senior Member

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    Do you think regular plasmapheresis could correct that?
     
  14. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    I suspect that would only give transient symptom relief, one would need to disturb the disease process directly AND get the hypophesised pathological cells
     
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  15. Jesse2233

    Jesse2233 Senior Member

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    Right but in light of that symptom management could suffice

    There are other conditions where people get weekly or bi-monthly plasmapheresis and live near normal lives
     
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  16. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Yeah, they are researching plasmapherisis on me/cfs in germany i think. Or it might have been some other country, I dont remember.
     
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  17. Snow Leopard

    Snow Leopard Hibernating

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    Not really. B cell depletion with Rituximab would have the same effect.

    The key is the long lived plasma cells aren't hanging around in circulation.
     
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  18. Murph

    Murph :)

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    One patient responded at 8 weeks in the Phase II trial. Another at 12 weeks. One didn't respond until the 94th week. I guess there is a diversity of results.

    Screen Shot 2017-05-01 at 6.10.08 PM.png

    One explanation for why early trials found early responders might be path determinism.

    If you don't get a response until the 94th week in your pilot patients you would've given up long before any response arrived. We are perhaps just lucky that Fluge and Mella's early patients were swift responders.
     
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  19. Gingergrrl

    Gingergrrl Senior Member

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    Thanks @Forbin and I have no idea if it is the autoantibody itself or a consequence of the auto-antibody but I suspect in my own case, that this is the core of the problem. But my level of immuno-babble knowledge is probably lower than yours :D LOL.

    I don't think it could correct it vs. be a very short-term fix and the auto-antibodies would be back vs. if someone was a candidate for Rituximab and it worked, in theory, they could achieve ongoing remission and the new B-Cells could grow back free of pathogenic auto-antibodies. Of course that is the absolute best case scenario but I think there is a sub-group of people that this could apply to (whether I am in it, I have no idea yet).
     
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  20. alex3619

    alex3619 Senior Member

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    As I understand it the location of plasma cells is part of it. Also with Rituximab stops B cells making antibodies it does not remove circulating antibodies. If the problem is antibodies then anything that lowers the load will help. If the problem is a large protein signalling metabolic shutdown, then plasmapheresis should show good though temporary results ... but we are still waiting on the science.
     

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