I agree as a severe person who during bad months does 800 — 1500 steps a day, but when am in a good month (recently due to Botox for migraine helping me) can do 2000 to 3000 just around a two bedroom apartment and patio. You can increase steps a lot around the house without leaving when you feel a bit better just doing chores / organizing.
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Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al
ME/CFS Science Blog
Senior Member (Voting Rights)
Do I understand their view correctly that Rituximab might work if applied long enough so that new plasma cells cannot be formed. If it is applied too briefly like in the phase III trial, the B-cells are targeted but the long-lived plasma cells might still be producing antibodies?
Jonathan Edwards
Senior Member (Voting Rights)
Roughly yes, I think. But plasma cells can last for years and IgG levels stay normal without any replacement in the context of rituximab.
Yes, like the NK finding this is very intriguing - a subset with 4x higher IgG4 respond.
If I work at home I probably only do 1000 or 1500 steps per day. I was thinking in terms of smaller improvements and where energy gets spent.
I believe that the reason the non-responders in the study weren't reacting wasn't because their NK cell counts were low, which would have prevented the ADCC from functioning as intended. It didn't work because they developed a distinct subtype of the illness that included low NK cell counts and maybe low IgG4 that isn't strongly B cell mediated like in the responders group. Maybe the BCG vaccine can improve their condition like it helps others who have low NK counts.
I think one should be careful about not overinterpreting some of the findings (such as the low NK count correlation). From what I can tell none of these things were part of the prespecified outcome measures or protocols so multiplicities/retrospective analysis might be a problem. From what I recall there was a similar retrospective analysis for the Rixtuximab trials (improvement being correlated to certain GPCR-aabs) that never led anywhere.
jnmaciuch
Senior Member (Voting Rights)
I agree, if you measure enough things you can nearly always find something that significantly correlates with your non-responders/responders condition.
And those correlations may not even be false positives, but as @zar nola is getting at, there’s no reason to believe they are causative for responsiveness rather than just being an indirect indicator of different underlying biology in the cohort that happened to be measured in the trial.
Utsikt
Senior Member (Voting Rights)
There’s no mention of the four added patients on that page (it was last edited in 2023). The planned dosing schedule was 4 injections with 2 weeks in between.
I believe that they are referring to 4 new patients not reported on here. If they amended the protocol it should be somewhere on their website.
Attachments
Utsikt
Senior Member (Voting Rights)
I’ve looked for that previously, but unfortunately I wasn’t able to find anything. Maybe someone else knows more?
Cort Johnson article. In the comments there is one MECFS patient on Dara for MM, with no beneficial effects on MECFS symptoms.
ETA Cort highlights IgG4 because he has high IgG4.
Has the Right B-cell Depleting Drug Been Found for ME/CFS? Daratumumab Shines in Pilot Study - Health Rising
A B-cell depleter called daratumumab does well in an early trial in ME/CFS. A larger trial is underway.
www.healthrising.org
ETA Cort highlights IgG4 because he has high IgG4.
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It makes sense that it’s IgG4 mediated. But IgG4 is more likely to be produced in SLPC. And here daratumumab helped, which is killing LLPC.
So it’s little weird
Jonathan Edwards
Senior Member (Voting Rights)
Do we have information for IgG4 coming from SLPC?
Daratumumab will kil both SLC and LLPC. Rituximab should work if the source is SLPC in theory.
But I am not sure why IgG4 would make sense for ME/CFS? What do we think it would be blocking? My suspicion is that if antibodies are involved in ME/CFS it is through some active signalling effect through Fc.
"Furthermore, IgG4 production by antibody-secreting cells can be markedly shorter lived than for other IgG subclasses, requiring continuous input from newly differentiating B cells. Indeed, rituximab (anti-CD20) therapy for B cell depletion has been shown to be particularly beneficial in autoimmune diseases characterized by pathogenic IgG4 (auto)antibodies" The unique properties of IgG4 and its roles in health and disease.
And when rituximab was used in ME, it didn't help, even though SLPC was affected by the drug. And as you said, "Rituximab should work if the source is SLPC in theory." In reality it didn't work. Maybe the target wasn't correct, or they didn't use the drug in the optimal way in the study.
I think IgG4 makes sense because it's a blocking antibody and it's known to be noninflammatory and does not activate complement or ADCC, and there are no signs of inflammation or autoimmune tissue damage in ME. It can bind to some of the many proteins that we don't recognize yet as a target. for example, like in MuSK myastenia gravis.
The other question is why the disease hasn’t come back after stopping datratumumab if dara isn’t touching B cells?
Why new autoreactive plasma cells weren’t made
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Jonathan Edwards
Senior Member (Voting Rights)
Yes, you could argue like that if you think it is autoantibody. And then the question comes up why the autoantibody doesn't come backif you stop Dara.
But the antibodies involved would not need to be autoantibodies. They might be antibodies to pathogens seen in the past or continually present in a latent state. It might then be that if you knock out all the IgG4 plasma cells for these antibodies that you don't immediately produce more IgG4, because you are no longer in that phase of a response. If some of the IgG4 was from LLPC, which it might be, that would be even more likely.
hotblack
Senior Member (Voting Rights)
Terminology I had to look up which may be useful for others
SLPC - Short-lived plasma cells
LLPC - Long-lived plasma cells
SLPC - Short-lived plasma cells
LLPC - Long-lived plasma cells
Ok, but autoantibodies for some proteins could block some important physiological functions, while antibodies for pathogens aren't known to cause any type of symptoms like that.
Jonathan Edwards
Senior Member (Voting Rights)
That is perhaps the argument from first base but I think there are problems with it. The fluctuation of symptoms typified by PEM doesn't seem to fit with a direct antibody effect - since antibody levels are likely to be constant over many days at least. It seems that there is some other signalling event that can be switched on and go off. Maybe an antibody blocking something might prime cells to signal but I am not sure what it would be. Moreover, people have looked quite hard for autoantibodies (including just screening people for differential diagnosis) and not found anything that would fit.
I agree that antibodies to pathogens aren't usually associated with symptoms in the textbooks. But in fact antibody responses to foreign antigens may be responsible for all sorts of things like rashes, synovitis in rheumatic fever, nephritis after streptococci, maybe the fatal hypersensitivity syndrome of second strain Dengue exposure?
We are looking for something that does not fit any very obvious rules. And in fact most chronic immunological diseases do not fit any consistent rules in one way or another - probably because they are all aberrations of rules. I agree that the question is open but to me blaming an autoantibody is the stock easy solution.