From the patient’s perspective, it is often difficult to take something and notice an immediate improvement – or one a few hours later – and not start coming up with mechanistic theories (even though very often a whole host of factors, both within the substance itself and in the circumstances, which are beyond our control, are at play), often just to be dispel that there isn’t some uncontrollable magic at work. I note that Ryan does not mention any improvement in fatigue, but only the disappearance of pain.
A doctor who sells the product without having carried out serious research into the matter, on the other hand, is being dishonest.
A doctor who sells the product without having carried out serious research into the matter, on the other hand, is being dishonest.
ryanc97
Senior Member (Voting Rights)
Well that’s the point of a forum, to have differing perspectives and debate. I think I just laid out my argument, so there is the stance. And I don’t mean any personal offense at all, this is my view which I try to be as objective as possible.
Furthermore. I think the facts are this. ME right now is still unsolved. The knowledge base of current biology cannot figure it out.
Thus, there must be a paradigm shift needed. Because the current stuff isn’t cutting it.
The paradigm, imo, is being unraveled by a trail of clues which I listed previously.
@Jonathan
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ryanc97
Senior Member (Voting Rights)
I think nothing wrong with sharing anecdotes.
Also we don’t know if this doctor writes letters to patients insurance to get them covered. If he does, then it’s hard to say that he’s doing it purely for profit.
If he waits for a clinical trial then there is basically patients who want to get it and it may help them who can’t get it
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Dude
Senior Member (Voting Rights)
Autoantibody Detection Studies:
ME/CFS
Tanaka S et al. Int J Mol Med. 2003
Yamamoto S et al. PLoS One. 2012
Loebel M et al. Brain Behav Immun. 2016
Fujii H et al. J Neuroimaging. 2020
Jensen MA et al. Biochemistry. 2024
Long COVID
Rojas M, et al. J Transl Med 2022
Woodruff MC, et al. Nat Commun. 2023
Jernbom AF, et al. Nat Commun. 2024
Enough to pursue it.
Jonathan Edwards
Senior Member (Voting Rights)
Doesn't it worry you a bit that someone who devoted their career to developing B cell depletion for autoantibody-mediated disease sees all these studies as unconvincing and in many cases negative evidence? You can always find a dozen studies hoping to prove a popular theory. And there are twice as many studies that failed to replicate these findings.
The antibody paradigm shift occurred fifteen years ago. Then it lost momentum. So yes, we need something new, not something on its last legs. We have a different paradigm shift now, based on good data - that point to neural pathways and away from autoimmunity (no DR linkage).
Dude
Senior Member (Voting Rights)
It’s undisputed that you have an enormous amount of knowledge and experience in this field, and that’s exactly why I take your perspective seriously. But I would put it this way:
Imagine I have a problem with my car engine. One highly experienced mechanic examines it and says, “There’s nothing wrong with the engine.” But then another highly respected mechanic, in this case Professor Carmen Scheibenbogen, examines it and says, “Actually, I think the problem is right here,” and provides scientific arguments and research to support that view.
As a layperson, who am I supposed to simply believe?
That’s why I find it difficult when one expert’s perspective, even from someone with enormous experience, is treated as if it settles the question. Science is supposed to work by testing competing hypotheses against the evidence and being willing to change its understanding when new evidence emerges.
I’m very aware of the problem that once we become convinced of a particular hypothesis, we can start interpreting new evidence through that lens. That applies to all of us. But I think one of the greatest strengths a scientist can have is the willingness to question their own assumptions and remain genuinely open minded.
Being open minded doesn’t mean believing every hypothesis is correct. It means being willing to change your mind when the evidence eventually points in another direction. To me, that willingness to question even your own position is one of the qualities that truly distinguishes great scientists.
I mean, we know from a document that even Fluge and Mella supported the autoantibody hypothesis at some point. And daratumumab also seems to be showing some signs of working.
Jonathan Edwards
Senior Member (Voting Rights)
But we don't believe anyone in science. We evaluate the evidence for ourselves. If you not in a position to do that you shouldn't be holding any opinion at all on this, surely?
And who is suggesting that one expert's opinion settles the question? I have simply argued from evidence. I have not expected other members to take that as gospel. But I think you will find that the majority of members who have examined the evidence agree with me - on the basis of their own rational analysis. You seem to be attacking your own position attributed to someone else. You are the one with the belief in a theory. I can see about ten theories with some merit, but not one based on the current evidence on autoantibodies.
Which is what I am doing all the time, isn't it? Questioning not only others' assumptions but my own. I have shifted my position on what I think is most plausible many times here over 10 years.
That sounds awfully like clutching at straws.
Dude
Senior Member (Voting Rights)
I mainly form my opinions based on the studies, but ultimately I also have to rely on the experts who have the expertise to interpret them. The problem I have with your position, as Margaret Williams also pointed out in her response, is that you seem to categorically dismiss some of the more recent findings and continue to base your conclusions primarily on your existing hypothesis. Of course, I understand that this is easier to do when there is still no clearly established mechanism.
The reason the majority of members seem to agree with you may simply be that there are very few experts presenting a competing interpretation. In a sense, you are one of the few experts in this particular debate, which makes your level of confidence in presenting your hypothesis all the more striking to me.
Please don't misunderstand me: I actually think it is a good thing that you have developed your own ideas, especially given your expertise. But I find it difficult to accept the categorical dismissal of autoantibodies when there are multiple studies reporting findings that point in the opposite direction. At the very least, I think the evidence warrants keeping the hypothesis open rather than ruling it out.
There is a quote that I think fits this discussion well, and with that I would like to leave the discussion:
“An open mind can learn; a mind fixed on a single perspective can only defend what it already believes.”
Jonathan Edwards
Senior Member (Voting Rights)
I only dismiss claims based on grossly unreliable evidence. I forget who Margaret williams really is but she has o understanding of the difference between reliable evidence and some of the claims being made.
And no way do I base my opinion on existing hypotheses. I am constantly considering new ideas - about eccentric medium spiny neurons or dopamine pathways, or interactions between neurodevelopmental dispositional factors and viral exposure, or lysophosphotidylcholine or whatever. And even my longer standing interest are new in comparison to the dinosaur theories most researchers still seem to want to stick to.
Can you give an example of anything I dismiss that has a sound evidence base?
This is nonsense. Members make up their own minds. They are constantly pointing out where i am wrong, for which I am truly grateful. People like jnmaciuch, Utsikt, forestglip, chillier, snow leopard, SNTG or ME/CFS Science blog would not dream of taking my word for anything. As soon as I make a weakly justified statement they are on to me like a pack of dogs. Most people like the forum precisely because nobody has authority.
I am not sure what you are getting at there. Everything I know about ME/CFS comes from the members here. I rarely look up a paper myself. The forum is the expert, not me. I have background knowledge of some of the immunology and neuroscience and the pitfalls of theorising about clinical syndromes but I mostly throw that in to temper what I see as understandable but often too eager enthusiasm for old ideas that have been recycled as something new.
Which hypothesis are you referring to, that I present with confidence. I have no idea what is supposed to be 'my hypothesis'. Certainly, not the one in the Qeios paper. I just don't think you have got a realistic perspective on what is going on here.
Since when did I 'categorically dismiss' autoantibodies? All I have ever done is point out the serious deficiencies in the evidence. Like Carmen Scheibenbogen not even putting up a slide of anti=GPCR antibodies in ME/CFS, I guess because the difference from normals is so underwhelming. There are always multiple studies supporting a popular idea in this game. Most scientists spend their lives trying to prove what everyone in the in crowd likes to believe. The number of studies is irrelevant. If there is a serious weakness in one piece of evidence then the whole idea has to be put on hold until someone has explained why.
Precisely. That seems to be a rather neat summary of the difference between me and you!!
Dude
Senior Member (Voting Rights)
That is a fair clarification. I may have phrased my criticism too strongly by saying that you “categorically dismiss” autoantibodies. I understand that you are not ruling them out in principle, but that you consider the current evidence too unreliable to support the hypothesis.
I think the real disagreement is more about what counts as sufficient evidence.
You seem to put a lot of weight on weaknesses in individual pieces of evidence. I understand that position. But if several independent studies find abnormalities involving autoantibodies, B cells, IgG or related immune mechanisms, I don't think methodological weaknesses or imperfect replication necessarily mean that the whole hypothesis should be dismissed. That is the impression I get when you discuss autoantibodies.
It could also mean that the original hypothesis was too simplistic, that only a subgroup of patients is affected, or that we simply haven't identified the relevant antibodies or mechanism yet.
So I think the real disagreement is not whether we should follow the evidence. We clearly both agree on that. It is more about how much weight we give to the different pieces of evidence and how much uncertainty we should accept before moving away from a hypothesis.
And to be clear, I don't think the current evidence justifies saying that autoantibodies are definitely the cause of ME/CFS. I simply think the evidence is still interesting enough that this line of research deserves to be investigated further.
Utsikt
Senior Member (Voting Rights)
My impression is that it’s negative, not unreliable.
Science is about doing your best to disprove yourself, not trying to find things that might be in line with you hypothesis. It’s fairly easy to build up stories that «make sense», but that have no connection to reality.
A question I frequently use when I try to poke holes in ideas is to ask «what would we expect to see if this was true?»
Try to look for the things that are not there.
Concentric_Spiral
Senior Member (Voting Rights)
Shouldn't evidence precede hypothesis?
fst
Senior Member (Voting Rights)
I think realistically, it's a cycle and you can start it either way. The important part is making the hypothesis falsifiable.
Dude
Senior Member (Voting Rights)
Not necessarily. The process is often: observation /anomalie -> hypothesis -> predictions->testing -> evidence -> confirmation or refutation
What I think you mean, however, is that a hypothesis should not be treated as established before there is sufficient evidence to support it.
Concentric_Spiral
Senior Member (Voting Rights)
But if there isn't a good observation of an anomaly in the first place - e.g., no slide showing a sufficient deviation from normal - then why would one put effort into generating a hypothesis to explain it? Something I've gleaned in passing on the forum is that many of the commonly cited anomalies among pwME don't appear to actually exist - e.g., abnormal cortisol, mitochondrial dysfunction, inflammation, etc. That's one of the biggest takeaway for me as a layperson.
Given how complicated this problem is, and the limited resources available to try to solve it, it seems reasonable to insist on a very strong signal of a deviation from normal to be the starting point for inquiry.
fst
Senior Member (Voting Rights)
And I think the antibody hypothesis has already been through a few iterations and instead of getting better, it seems to just get more convoluted and unlikely in my lay opinion.
Just thinking about what we need to make it work.
Why does Rituximab does not help at all?
Maybe it's LLPCs, but why should it be exclusively them in the first place?
Maybe the damage is already done.
How can we reconcile that with the wild fluctuations some people have?
Maybe the antibodies don't determine your severity. Or maybe there's multiple diseases, only one of which is AB mediated.
Then let's filter them out via immunoadsorption (IA). But that doesn't work either. Why?
Why does DecodeME not show genes related to this?
I am sure there are ways to reconcile all these points, but at this point it just raises a lot of questions for me.
I am glad, though, that we'll get some proper trials for it.
Dude
Senior Member (Voting Rights)
I can tell you an anecdote about this. I know people hate anecdotes, but my best friend has high levels of autoantibodies. He travelled here from Austria to Kempten because there is a dialysis centre that offers immunoadsorption. He is mildly to moderately affected and still works about 8 hours a week. He paid €15,000 for five sessions using the Miltenyi filter.
After the treatment, he improved so much that he was able to go bouldering again. However, the effect disappeared after about two months.
Something very similar happened in the 2018 study. Scheibenbogen and colleagues investigated immunoadsorption in 10 selected ME/CFS patients with elevated β2-adrenergic autoantibodies. Seven reported rapid clinical improvement, with the effect lasting 6–12 months or longer in some patients.
Why am I mentioning this? The current PIONEER trial with inebilizumab (CD19 B-cell depletion) appears to go one step further. According to the study design presented in 2026, it selects patients with an infectious trigger, demonstrable autoantibodies, and a previous clinical response to immunoadsorption.
The idea seems to be to enrich the trial for a subgroup in which B-cell depletion is more likely to work l, rather than testing it indiscriminately in the entire ME/CFS population.
fst
Senior Member (Voting Rights)
Yes, but the n=20 study looked much less impressive with most people only having a minor (10 points SF-36) or no response, even though they all had elevated GPRC antibodies.
Then IA-PACS-CFS also failed on the primary endpoint. We'll have to see how many people with elevated GPRC AAB were in there, as they did not require those in the first place. I think it should be large enough to pick up a responder subgroup, but we'll have to see (also if any of the secondary endpoints maybe showed success).
On a side note, I think it was quite good to not require those AAB for IA-PACS-CFS, because with such a design we could have learned if GPRC AAB actually play a role.
Something we will not learn from trials that look only at patients with elevated GPRC AAB.
Although I think there is good evidence already that GPRC AAB are not the cause.
And, to be fair, Carmen Scheibenbogen's current position appears to be that they roughly select a potential auto-immune subset, not cause the disease.
But yeah, in summary, it's good those trials are done, and we'll just have to wait and see.
I just hope that this generation of trials will settle the question.
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