International ME/CFS Conference 2025 Berlin May 12-13

arnoble said:
Given LLPCs express CD38 but not CD20, and given LLPCs are largely responsible for sustained antibody production, a non-scientist like me is curious to know why the RituxME study did not try something like Daratumumab instead?
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The history of this is quite complicated. The original motivation for using rituximab in rheumatoid and lupus by us was to try to remove B cell clones implicated in long term perpetuation of an autoantibody response. (This involves a complex feedback loop between different B cell clones.) That would imply a reduction in inflammatory effector antibodies too but the prime objective was to delete clones long term.

By 2005 it was clear that removing sufficient clones to allow persistent autoantibody production to collapse was not proving possible in most autoimmune diseases, including RA and lupus, although a good proportion of ITP cases went in to long term remission. Nevertheless, it became apparent that rituximab was useful because it removed short lived plasma cells, indirectly, by removing an ongoing source of new CD20+ B cells and plasma blasts. Because the inflammatory effector antibodies were almost entirely produced by short lived plasma cells it proved possible to block inflammation more or less continuously. It seemed that at least for some autoimmune diseases sustained effector autoantibody production is not from long lived plasma cells.

Fluge and Mella picked up on the beneficial effects of rtx on these autoimmune diseases and tried it in ME/CFS. At the beginning they were not that aware of the pharmacodynamics we had studied ten years before. (So they chose an endpoint at 3 rather than 6 months.) With no benefit in phase 3 they took the logical step of thinking that in ME/CFS effector antibodies might be coming from LLPC, as they seem to in scleroderma, for instance.

The argument against killing plasma cells has always been that neither would there be any specificity for auto reactive clones, nor would there be a chance of breaking a B cell cycle. To reduce effector antibody you would have to produce continued hypogammaglobulinaemia long term - which is not an attractive option. So my thought is that using a drug like Dara might prove the point that antibodies are effector signals in ME/CFS but it would be hard to justify it as a routine treatment. Unless of course the pharmacodynamics turned out unexpected, as they had done (in another way) before.
 
Jonathan Edwards said:
The history of this is quite complicated.
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That's REALLY helpful - and very clear - thank you so much.

Watching , in response to Yehuda Shoenfeld at 34:36 "... should we not learn from Charite researchers who looked at long-lasting plasma cells and made no breakthrough to help fight SLE ..." Fluge cites a review article pulling together 80 pts given Dara for a range of autoimmune diseases, with an 83% pooled response rate. Can someone please point me to that article?
 
arnoble said:
in response to Yehuda Shoenfeld at 34:36 "... should we not learn from Charite researchers who looked at long-lasting plasma cells and made no breakthrough to help fight SLE ..." Fluge cites a review article pulling together 80 pts given Dara for a range of autoimmune diseases, with an 83% pooled response rate. Can someone please point me to that article?
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Haha!

Firstly, I doubt anyone will learn much from Yehuda Schoenfeld in this field. And maybe not from any of the lupologists much since for twenty years they understood so little about what ritux would do they could not even design a trial to demonstrate its effect. Venkat Reddy and co finally got that right. You won't do much to lupus by clearing long lived plasma cells because the effector autoantibodies are mostly in the short lived set - which is why ritux works but you won't show that unless you know what time points and dosing schedules to use. The hot air around this is generated by a T cell lobby as strong as the BPS people in ME/CFS.

Oystein knows a darn sight more about this than Yehuda.

But no, I have no idea what article he is referring to. Dara hits both long and short lived plasma cells. Showing the effect depends on how you time your outcome assessments. Someone was talking through their headgear.
 
forestglip said:
Well now I'm curious. Why are there people who care whether it's T cells or B cells? Just because that's the ones they've been working on thus far?
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Well, if you want to know the history of autoimmunity research since I demonstrated MHC Class II in synonym in 1979, sit back for a hour or two and listen....

But to be brief. The T cell boys led by Avrion Mitchison and Marc Feldman in the UK and I forget quite who in the US thought they were in charge and could pull in all the grant money until we finally showed that B cell actually mattered in 1999 - twenty years of just the sort of evidence-free hype we have had from the Wessely school.

At least I can enjoy seeing B cell therapies gradually take over the entire field twenty five years on but God did it take them a long time to give in. When I retired in 2010 the T cell people were still rowing against the tide as hard as they could - even in lupus, the antibody disease to end all antibody diseases.

I did the MHC II work in George Janossy's lab at the suggestion of my older brother who was a basic scientist and knew someone in that lab who was good - Alero Thomas. Janossy got wind of what we were doing and completely misrepresented the data, wrote a review in the Lancet and got any number of grants on T cells even though we have MHC II to support antibody production by B cells. At the time I was interested in macrophages but fifteen years later I realised what my slides had really meant so I got interested in lymphocytes and antibodies after all.
 
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Jonathan Edwards said:
Well, if you want to know the history of autoimmunity research since I demonstrated MHC Class II in synonym in 1979, sit back for a hour or two and listen....

But to be brief. The T cell boys led by Avrion Aitchison and Marc Feldman in the UK and I forget quite who in the US thought they were in charge and could pull in all the grant money until we finally showed that B cell actually mattered in 1999 - twenty years of just the sort of evidence-free hype we have had from the Wessely school.

At least I can enjoy seeing B cell therapies gradually take over the entire field twenty five years on but God did it take them a long time to give in. When I retired in 2010 the T cell people were still rowing against the tide as hard as they could - even in lupus, the antibody disease to end all antibody diseases.

I did the MHC II work in George Janossy's lab at the suggestion of my older brother who was a basic scientist and knew someone in that lab who was good - Alero Thomas. Janossy got wind of what we were doing and completely misrepresented the data, wrote a review in the Lancet and got any number of grants on T cells even though we have MHC II to support antibody production by B cells. At the time I was interested in macrophages but fifteen years later I realised what my slides had really meant so I got interested in lymphocytes and antibodies after all.
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Very interesting, thanks. Sounds like it could make for a good movie.
 
Arfmeister said:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10729190/?utm_source=chatgpt.com

https://www.researchgate.net/public...b_for_autoimmune_diseases_a_systematic_review
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Very very helpful - thanks so much. Although the review is encouraging I am very conscious of:
Jonathan Edwards said:
So my thought is that using a drug like Dara might prove the point that antibodies are effector signals in ME/CFS but it would be hard to justify it as a routine treatment.
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Jonathan Edwards said:
If there was no difference from controls in blinded studies then I don't think anyone can claim efficacy in individuals. The blinded phase II study did not convincingly show benefit. There was a statistical difference at a six month endpoint that was not the primary outcome measure. But looking at the pharmacodynamics I think that could easily have been a chance finding. I have not heard claims from Fluge and Mella that it definitely works in individuals. If they are making such claims I don't think I can agree.
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In the YouTube presentation above listen starting at 5:30
 
Jonathan Edwards said:
And of course the ones who don't respond seem to already have low NK cells - so why didn't they do even better? And if CD38 has a big impact on NK cells how does it manage to mediate ADCC against plasma cells? For these monoclonals the killing mechanisms are multiple but I think you end up arguing some fairly contradictory proposals.
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Pulling this quote from another thread to avoid going off topic there. @Jonathan Edwards would you generally expect to see a higher level of NKs in response to autoantibodies, regardless of the specific autoantibody? I know it’s been observed in SLE but not sure how generalizable that is.

In which case, there might actually be two distinct subsets of pwME, some of whom have disease that is driven by autoantibodies, some of whom do not, and the ones whose disease is driven by autoantibodies are the high NK cell “responders”
 
Jonathan Edwards said:
Not that I know of. Not sure what you are referring to in lupus? But leucocytes in lupus are all over the place for rather unique reasons I think.
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This is the study I’m thinking of:
https://pubmed.ncbi.nlm.nih.gov/39427243/
though I’m not well read on lupus so obviously this might not be a consistent finding.

Just a thread I was running down to potentially explain the NK discrepancy in the Dara trial and how it might fit into some other strings I’m pulling together.

To avoid being totally cryptic, I’m looking into the possibility of a positive feedback loop that is not dependent on autoantibodies, but may generally make them more likely to occur under certain circumstances (where they can then continue to drive disease somewhat independently from physical and mental exertion). The idea just comes from some genetic predispositions associated with SLE.

In which case this NK cell finding would simply be a marker of whether autoantibodies have been generated or not.
 
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jnmaciuch said:
This is the study I’m thinking of:
https://pubmed.ncbi.nlm.nih.gov/39427243/
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That looks like an isolated observation from a group nobody has heard of. It could mean just about anything I think.

NK cells express CD16 (FcRIIIa) and are likely to be tickled up by small immune complex disease but that is pretty specific to lupus and rheumatoid (where in severe cases you get splenomegaly and CD16+ lymphocyte expansion - so called large granular lymphocytosis). But it is a very idiosyncratic finding - only a minority of cases.
 
Jonathan Edwards said:
That looks like an isolated observation from a group nobody has heard of. It could mean just about anything I think.
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Fair enough, thanks for your insight.

The NK thing has been niggling at me, I’ve been trying to find a way to make sense of it. If they were somehow an indirect marker of autoantibody presence in the first place, it would make sense why they would correlate with responders.
 
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