Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

An IgG degrader called efgartigimod (vvygart) was trialed in long covid a couple of years back. It was trialled for POTS, and the primary outcome was a questionaire called COMPASS or something similar.

Many people in the trial reported significant improvement in PEM and POTS/OI, including improved readings on tilt table tests. The drug company ignored all of this, and because it wasnt picked up on their questionnaire, declared the trial failed.

The patients say the questionnaire was a terrible measure of improvement, and last I heard were campaigning for the release of the raw data. I don't think the study tracked PEM at all.

As we have discussed elsewhere in regard to other drugs we can't say for sure why these people improved but a mechanism like you propose here could probably explain it.
Just to add to this, I did a bit of research the other day to refresh my memory. The questionaire was the COMPASS-31.

And there were participants on reddit and in a private lc group im a member of saying they went from having heart rates shoot up from 60ish to 160 on tilt tests to not being symptomatic during a tilt, and not meeting pots criterea anymore. The tilts were part of the trial so i have no idea why this was ignored. Improved PEM was also reported as I said.
 
I then trialed Rinvoq for a month with absolutely no changes to anything.
I was always somewhat skeptical of the idea that a JAK inhibitor would show improvement immediately—Saphnelo for lupus has a reputation for taking months to show an effect, for example.

Which, to clarify, is not me saying that the disease is definitely driven by interferons and if you have stayed on the drug longer it would have worked for you—just that the idea of “take a JAK inhibitor for a few weeks to break the cycle” always seemed contrary to what is known about targeting interferon signaling even if interferon was proven to be the culprit.

Also another point on their theory is they mentioned ammonia is a product of the re-wired TCA cycle in shunting cells, and ammonia is toxic to brain. If that was the case surely CFS would cause permanent brain damage but we have seen in recovery cases that is not the case.
As with all things it is concentration dependent, a certain amount of ammonia is produced and cleared out all the time without toxicity. But regardless I do share skepticism about ammonia mediating symptoms

I just feel like now there is no basis for the theory since it came purely from conjecture and we have other theories that are observation first.
again, any “observation first” theory I’m aware of has issues actually explaining the features of the disease, and those observations are questionable themselves. I’m with you that the particular theory we’re discussing has issues, but I’m not sure I’d agree that we have other theories on much better footing.
 
again, any “observation first” theory I’m aware of has issues actually explaining the features of the disease, and those observations are questionable themselves. I’m with you that the particular theory we’re discussing has issues, but I’m not sure I’d agree that we have other theories on much better footing.
That’s a really good point. We need both a mechanistic theory, the hypothesis and the observations, the evidence. I suppose in some ways it may not matter which comes first but as you said before, it’s usually the hypothesis which leads to the experiments to find the evidence to back it up. That said there are cases when prior observations can be cast in a new light when the right hypothesis comes about. And many a hypothesis which is at least based upon prior observations. A bit chicken and egg perhaps?
 
That’s a really good point. We need both a mechanistic theory, the hypothesis and the observations, the evidence. I suppose in some ways it may not matter which comes first but as you said before, it’s usually the hypothesis which leads to the experiments to find the evidence to back it up. That said there are cases when prior observations can be cast in a new light when the right hypothesis comes about. And many a hypothesis which is at least based upon prior observations. A bit chicken and egg perhaps?
Yup I agree. A viable theory will be able to make sense of a critical mass of important features about the illness (i.e. explaining the symptoms or why PEM occurs after activity, etc.)—a great one will be able to tie together some portion of prior findings as well. It’s just likely that those relevant prior biological findings will be several degrees removed from the disease mechanism itself and unspecific enough that they needed a viable mechanistic theory to connect them all together in the first place.
 
The idea that JAK STAT inhibitors could be beneficial for ME/LC is not exclusive to Ron Davis' group, or a pharma conspiracy. Iirc JE et al. even suggested them as one of the possible treatments in their hypothesis paper.

Whether they work or not, we'll have to wait and see.
 
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