Long-lived plasma cell (LLPC) theory - Similarities between CFS and Lupus?

ryanc97 said:
This argument only works if you found two opposing studies showing low NK cells and high NK cells both correlated with success in Daratumumab treatments.
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Fair enough, but was it not you who suggested that RTX works in some cases along the same lines of Daratumumab? Then your counterexample has already been provided. You can't have your cake and eat it too.

In any case nobody has yet found a study for Daratumumab where someone did a NK cell measurement that is comparable to the one by Fluge and Mella. The studies all seem to suggest that functional state plays a role, rather than total numbers.
 
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EndME said:
Fair enough, but was it not you who suggested that RTX works in some cases along the same lines of Daratumumab? Then your counterexample has already been provided. You can't have your cake and eat it too.

In any case nobody has yet found a study for Daratumumab where someone did a NK cell measurement that is comparable to the one by Fluge and Mella. The studies all suggest that functional state plays a role not total numbers.
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In this case it would seem that the data are saying Ritux success is negatively correlated to NK cell count but Dara success is positively correlated to NK cell count.

So B cell depletion is thus negatively correlated to NK cell count (for some reason) and Dara success is positively correlated.

So I'm wrong to suggest that RTX works along the same lines of Dara because data shows otherwise. In theory it should, but the data shows it the opposite, so the theory is wrong, and they are not similar.

So in this case cross-comparing across drugs would not be the way to go. You have to fix the same drug to make the comparison.
 
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ryanc97 said:
In this case it would seem that the data are saying Ritux success is negatively correlated to NK cell count but Dara success is positively correlated to NK cell count.

So B cell depletion is thus negatively correlated to NK cell count (for some reason) and Dara success is positively correlated.
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To be honest, I don't think it really says that at all because you cannot just read the NK assays like that (you will find enough Rituximab studies with the opposite results anyways especially when things are disease specific). You have to understand the assay in the given context and I'm not sure whether someone that has enough expertise has done that. It seems completely different assays one in blood and one bone marrow are still being compared here in the context of Dara success. I doubt any researcher will take that serious. Blindly talking about NK cell count appears to be meaningless in the first place. I think it would be good to get somebody with actual knowledge to look at these things.
 
EndME said:
To be honest, I don't think it really says that at all because you cannot just read the NK assays like that (you will find enough Rituximab studies with the opposite results anyways). You have to understand the assay in the given context and I'm not sure whether someone that has enough expertise has done that. It seems completely different assays one in blood and one bone marrow are still being compared here in the context of Dara success. I doubt any researcher will take that serious. Blindly talking about NK cell count appears to be meaningless in the first place. I think it would be good to get somebody with actual knowledge to look at these things.
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Alright, so you are saying that I don't have enough biological knowledge therefore my argument is wrong. Fair enough.

And now you are saying that it's not sampling bias like you said previously but because blood and bone marrow NK cells are two completely different things.

The question then to ask is to what extent do we have data that shows blood and bone marrow NK cell counts are correlated?
 
ryanc97 said:
Alright, so you are saying that I don't have enough biological knowledge therefore my argument is wrong. Fair enough.
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I'm saying that one would be comparing apples to oranges if the measurements in the MM study are entirely different to the ones in the Fluge and Mella study and I don't think anybody has provided evidence for them being comparable in the given context.
 
So nothing to with sampling bias? If that is apples to oranges, isn't using Rituximab + B cells + Nk cell counts apples to oranges too?

I don't think its a stretch to say blood and and bone marrow NK cell counts might be correlated because NK cells come from the bone marrow then move out to the blood.

I also don't think it's a stretch to say count and function might be correlated. However I have no idea on this.

I've asked ChatGPT on the correlation between counts (in diff places) + function but I don't know.
 
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ryanc97 said:
So nothing to with sampling bias?
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It can be depending on your measures/spaces ;). But the point would more so be that there's probably no sample in the first place if you restrict yourself to those that are meaningfully comparable, which is anyways what you want to be doing in the first place.
ryanc97 said:
If that is apples to oranges, isn't using Rituximab + B cells + Nk cell counts apples to oranges too?
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That's why the argument was made in the first place (and why I already said you will find results stating something else as well). The context has to be understood otherwise Google (or whatever else) will give you all sorts of results that actually have no relevance.

ryanc97 said:
I don't think its a stretch to say blood and and bone marrow NK cell counts might be correlated because NK cells come from the bone marrow then move out to the blood.

I also don't think it's a stretch to say count and function might be correlated. However I have no idea on this.

I've asked ChatGPT on the correlation between counts (in diff places) + function but I don't know.
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I think it's already been discussed on S4ME why such comparisons fail (respectively you can't assume a correlation). And of course we've seen that others seemingly can't replicate the findings by Marshall-Gradisnik.
 
If the conclusion is 'all correlations can't be assumed' and you can't draw any conclusions then fair. I've drawn my conclusions and am on a plan of action based off it. Because that's the only thing that can be done. I don't have the patience to wait for the perfect study to come out.
 
I doubt bortezomib will give us a clear answer. I explored it years ago as an adjunct to rituximab to get better antibody depletion and my haematology colleagues were not confident it would do much on its own. You would need a full controlled phase 2-3 trial and that may not be justified. It is one way to approach things but I would be tempted to look at other approaches.
 
Jonathan Edwards said:
I doubt bortezomib will give us a clear answer. I explored it years ago as an adjunct to rituximab to get better antibody depletion and my haematology colleagues were not confident it would do much on its own. You would need a full controlled phase 2-3 trial and that may not be justified. It is one way to approach things but I would be tempted to look at other approaches.
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Why not Teclistamab? I know papers say LLPCs resist Bort. Teclistamab looks pretty powerful and does not use CD38 at all.

But since nobody is willing to do those trials, it is going to come from patients like me :)
 
I know discussions about how antibodies don't make sense have happened a million times probably but it's mostly been hard for me to understand. Can someone say why what seems to be simplest way to look at the results we see is not the most likely: that the mechanism of action of dara is due to reducing antibody.

This matches with the known role of NK cells in antibody-dependent cytotoxicity, so the correlation makes sense.

And even though none of the other B cell depleting therapy trials have ultimately been very convincing, they still somehow led to the use of dara. If dara turns out to actually be effective, I'm probably going to go ahead and assume the phase 3 trial of rituximab just did not have enough power to detect an effect. Why would the Norwegians be so convinced of the potential of B cell depleting therapies and then actually find one that works if the two they originally looked at were just placebo? So I think the response would be related to something that two or three of these meds (cyclo, ritux, and dara) have in common. Do they have other convincing mechanisms in common apart from depleting antibody?

And doesn't antibody provide a good explanation for the 'memory' in ME/CFS? I don't know how the timelines of PEM or sudden recovery would fit in, but antibodies can suddenly appear and stick around for a very long time, so sudden and protracted disease related to immunological events makes sense. The improvement from dara also lasted for months after the intervention, which lines up with antibody depletion therapies in other diseases.
 
forestglip said:
Can someone say why what seems to be simplest way to look at the results we see is not the most likely: that the mechanism of action of dara is due to reducing antibody.
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But blocking CD38 is an even simpler explanation.

We have not a jot of evidence for antibodies being involved in ME/CFS, although we can speculate they might be. Circumstantial evidence points much more to a process triggered by T cell responses and CD38 is intimately involved in activation of cells involved in such interactions.

The number of NK cells in blood isn't necessarily any indication of the ability of NK cells to kill targets. Blood cell numbers are rarely of any great relevance in immunologic disease.

There are any number of examples of treatments that work for reasons that have nothing to do with why they were tried!! Gold, chloroquine and phenylbutazone for RA, for instance.

The phase 3 ritux trial had enough power to detect any meaningful usefulness. The result was a complete negative.

forestglip said:
Why would the Norwegians be so convinced of the potential of B cell depleting therapies and then actually find one that works if the two they originally looked at were just placebo?
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Cyclo might work very well by affecting T cell activation. Cyclo has very potent effects on T cells. The original observation of a lymphoma patient getting better was a case of B cell malignancy but the chemotherapy almost certainly targeted T cells too. I am not sure why the Norwegians should be convinced that B cells are the target or whether in fact they are. They may just be doing the sensible thing of exhaustively testing their original hypothesis before moving on to something else.
forestglip said:
(cyclo, ritux, and dara) have in common.
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We can discount ritux because none of the studies were actually positive for it. Even phase 2 failed strictly speaking - i.e. on the primary outcome measure. Cyclo and dara will both knock all lymphoid cells and other white cells too - pretty much any immune cell you like in fact, so there is nothing to suggest any specificity here. NK cells have a lot of CD38 but the relative level of expression on a cell type is not necessarily that relevant as long as it functions there.
 
forestglip said:
If dara turns out to actually be effective, I'm probably going to go ahead and assume the phase 3 trial of rituximab just did not have enough power to detect an effect. Why would the Norwegians be so convinced of the potential of B cell depleting therapies and then actually find one that works if the two they originally looked at were just placebo? So I think the response would be related to something that two or three of these meds (cyclo, ritux, and dara) have in common. Do they have other convincing mechanisms in common apart from depleting antibody?
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Maybe, but it's equally possible that they had to venture somewhere else precisely because other approaches failed. That's essentially how things often work. Also note that the sample size for the Rituximab study was almost 3x the sample size of the planned Daratumumab study (and there's additional data from the other failed studies making the total sample size even larger), so a straightforward power argument can anyways not work (one will have to invoke much higher efficacy, patient selection, outcome measures, different mechanism or something else).

forestglip said:
And doesn't antibody provide a good explanation for the 'memory' in ME/CFS? I don't know how the timelines of PEM or sudden recovery would fit in, but antibodies can suddenly appear and stick around for a very long time, so sudden and protracted disease related to immunological events makes sense. The improvement from dara also lasted for months after the intervention, which lines up with antibody depletion therapies in other diseases.
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The point was made that improvements seen in the RTX trial seemed to have largely been permanent. That would not fit the same memory description of many cases of other autoimmune diseases, where people typically require continued Rituximab.
 
Jonathan Edwards said:
We have not a jot of evidence for antibodies being involved in ME/CFS, although we can speculate they might be. Circumstantial evidence points much more to a process triggered by T cell responses and CD38 is intimately involved in activation of cells involved in such interactions.
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How much probability could it be that the antibodies that are causing harm are not detectable with current technology? Sounds crazy but you know.

For example, back in the day before people discovered the presence of the Lupus antibodies. That kind of stuff. Could it be the same for ME?
 
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