Passive transfer of fibromyalgia symptoms from patients to mice, 2021, Goebel et al

The author in research recommendations 'Anecdotal evidence from patients with co-morbid FMS treated for their rheumatological condition with biologics including anti-cytokine agents, or B-cell therapies suggest that FMS condition may not readily respond to these therapies; independently, the situation in axial spondylarthritis may be more complex, as in this condition fulfilling FMS criteria may not necessarily mean that FMS is truly present, and the symptom severity score may be a better measure [35]. More systematic understanding of these issues is required to avoid potentially futile trial efforts. ' so he knew that rituximab didn't work probably why he mentions' old fashioned' methods like apheresis.

One thought I had, does this mean fibromyalgia can be detected in autopsies?

And why has nobody replicated this yet? It seems easy to me and not time consuming as a layman, the cell culture test that is

https://www.biorxiv.org/content/10.1101/2022.06.29.498149v1 this one says neutrophils are the cause. Either they're all wrong or this is an establishment of multiple mechanisms?

Also if antibodies bind to nerves, does that mean they stop flowing around the body?
 
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I'm confused. This paper is not in preprint. It was published in June 2021. It's now 2023. The author suggests procedures that lower Antibody circulation may be good treatment. I was initially doubtful, because there was nothing, nada about any anecdotes, nobody with fibromyalgia has tried immunoadsorption or plasmapheresis, but then I realised plasma donation is the same as plasmapheresis. Transfer of human antibodies is not the first time to be shown here, it was recognised AFAIK 10 years ago in other illnesses, giving mice the Antibodies of sick people made the mice sick with the same symptoms! The author is trying to set up a trial to test immunoadsorption. Autoantibody pain that doesn't cause inflammation is NOT a new phenomenon. This paper is not the first to demonstrate it. I can't remember all that I've read but I feel strongly that one cause of fibromyalgia must be due to these antibodies. But there will be many I'm sure.
 
I don't want to preach because I am not an expert, but I please ask you to go read through the history so you can make a judgement yourself, the author Andreas Goebel started publishing about non inflammatory autoantibodies causing pain in 2016. He has now shown this phenomenon through passive transfer is 5 conditions, CRPS, FMS, Long covid, Rheumatoid Athritis, and chronic post-traumatic limb pain. These types of autoantibodies are even in cancer apparently. I don't have enough effort to dig deeper. I do note the sample size is tiny, but it's an objective finding I believe. The SFN neuropathy is linked here, injection into mice led to reduction in IENF density, interestingly another paper also found this. One hypothesis is that all fibromyalgia patients have SFN, but that is not detectable. SFN seems difficult to diagnose as well, not one test is enough. And the symptoms of SFN and fibro are difficult to distinguish. It all seems linked. But IENF density reduction is non specific, as its found in other illnesses too
 
1. It is not pre print! It is published and peer reviewed! You're looking at the old paper lol. Unless you're talking about the neutrophils.
2. The donation of plasma imo seems likely it would always make you feel worse off, that's the most common side effect it'd be Wierd if somebody felt BETTER, right?? It's basically immunosuppressive. Why would a placebo happen instead of nocebo?
3. Yes, is not inflammatory and does not respond to immunosuppressants, but it responds to LDN for whatever reason. And now we have an anecdote of it responding to the physical removal of immune components? Idk how to describe it. Even if fibromyalgia isn't autoimmune, it 'likely involves inflammatory processes' - Jared Younger. Also note this, the Antibodies are not inflammatory they don't trigger any inflammatory response, or not much I think .
4.Let's just drop the fibromyalgia term for a second, let's called it unexplained chronic widespread pain. The connotations are different yea. What I wanna really ram home is not that guys this is it!!! But rather guys, this might be something!!!! A coincidence is worth looking into, it seems lots of drugs end and discoveries are circuitous. It's how bc007 got its start, and I think LDN had the same start. An accidentally discovery, that looked like coincidence.
 
Mister Person said:
I was initially doubtful, because there was nothing, nada about any anecdotes, nobody with fibromyalgia has tried immunoadsorption or plasmapheresis, but then I realised plasma donation is the same as plasmapheresis.
Click to expand...

I don't actually think there is any significant similarity. Donation of a pint of blood, including plasma, (maybe even a litre) will not produce any noticeable change in antibody levels immediately, just a change in volume. Even when plasma volume is restored after a period of hours the Ig level is unlikely to be reduced by more than 10%, which is unlikely to be relevant.

For the first hour, certainly, there is going to be no real change in antibody levels.
 
While plasma can be obtained from whole blood donation, I think most plasma donation is by apheresis. The cells are separated off and returned in citrated saline. This would presumably be more-or-less volume equivalent to the plasma taken.

From the NZ Blood Service page —

How is it different from giving blood?
Giving plasma is an automated process that involves drawing blood and separating the red blood cells and platelets from the plasma. The red blood cells and platelets are returned to the donor’s body, while the plasma is collected in a sterile, single-use bag for processing. Using this process (known as apheresis), 2-3 times more plasma can be collected compared to a blood donation, and plasma donations can be made more frequently.
Click to expand...

What does “apheresis” mean?
Apheresis (pronounced ay-fur-ee-sis) is the name for the process used to collect a single blood component, e.g. plasma, and comes from the Greek word meaning “to take away” or “to separate”.
Click to expand...

How frequently can I donate?
You can donate plasma every two to three weeks. This is because the red blood cells and platelets are being returned to the body during the apheresis process.
Click to expand...


See the patient info video
 
shak8 said:
I have recently done a review of FM research after a desultory visit (again) with my primary care MD who thinks he knows FM. I am going to forbid him from talking about it, or else change MDs.

Low dose naltrexone for FM patients makes about 10-15% who try it feel better. I would also point out that trying a supplement or LDN can invoke a placebo response that would fade after a period of time (not sure how long, maybe six weeks). But still some do benefit and swear by it.

It's not what is considered effective. Same for pregabalin with duloxetine and the About 10-15% get about 30% improvement (effectiveness in FM is defined as a 60% reduction in pain in a majority of patients).

Younger is doing a study in Spain (Catalonia) where LDN is will be evaluated in a much large cohort of patients. It is a medical economics study because it is a cheap drug, and not because it is effective in a majority of FM patients.
Click to expand...

Can you give me a source of the 10-15% for low dose naltrexone? From the younger studies, the number is 70%~ that have a(not necessarily effective) response. I see what you're saying now though, but I've yet to dig into the numbers. Do you know where I can find them

'The percentages of participants who exhibited at least a
30% reduction in pain levels was very similar between
the two studies, with a 57% pain response rate in the
current study and a 60% response rate in the previous
study'
How do I find the raw data? This is what I've found
 
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Keela Too said:
As I understand it, the removal of blood is not going to change the concentration of what remains.

The blood volume will be reduced of course, but it’s the concentration of the blood components that’s important.
Click to expand...

Keela this is plasma donation though, not blood donation.
 
Regarding the staining of cells by Antibody not having a pattern and just being brighter, I have no clue if I'm being an idiot asking dumb questions bc I'm a layman, or if this is relevant. And I quote
'Additionally, new insights and the term ‘autoimmune pain’ have emerged through discovery of specific IgGs targeting the extracellular domains of antigens at nodal and synaptic structures, causing pain directly without inflammation by enhancing neuronal excitability. ' extracellular domains of antigens? Nodal synaptic structures? Pretty sure I'm being ignorant here but wanted to check.
Also you say it's brighter, and that specific staining isn't like that. Could it be similar to how 20% of healthy people have ANA positive? But few of them have strong positives/titres. Thus brighter could be explained?

http://dx.doi.org/10.1136/jnnp-2018-318556

Additionally, Andreas Goebel the author of the Antibody study showed the same process is occurring in rheumatoid arthritis, but in a different manner.
https://doi.org/10.1016/j.autrev.2021.103015
And another link I can't help but wonder, if this is why fibromyalgia patients do not respond to immunosuppressants, is that RA patients with fibromyalgia are less likely to respond to DMARDs. I haven't got access to the last paper, unable to read it
https://doi.org/10.1007/s00296-019-04506-2
 
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shak8 said:
\

I always start with Pubmed and enter search terms. I am not at the moment going to re-do my FM research reviews (didn't print them out). I stand by my figures. The figures I quoted may have come from respected FM specialist researchers like Mease, Clauw, etc.

Start with Pubmed.
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Mmm okay if anybody has a source it'd be nice. Because I've never heard this number before, only heard 70%. I remember a quote from Geneva Liptan somewhere on the Internet about 70. I looked through the Younger paper, could not find raw data. Or didn't understand it. Or looked too fast. I don't mean to be abrasive and I get it if you don't want to parse through research again, that's the same thing that's stopping me lol I don't want to a few hours for something trivial, LDN was just an aside. But, I should say when one has a claim, the burden of proof should be with the claimant lol, but it's algood. And I should note too, there are two trials!! Both involving 100 patients and LDN, one is going on in Denmark still recruiting last I saw and another in Mexico(sorry no its Spain) by Younger and Co I believe(nvm its by someone else) . I may be mistaken or misunderstanding though. Honestly I appreciate that anybody is even replying to me lol and entertaining my views/ideas
 
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Mister Person said:
it would reduce IgG then immediately?
Click to expand...
Not as straightforward as we might guess.

I presume IgG levels would reduce over the course of the procedure (90 mins per the above video), however I'm not sure how much IgG would end up being removed. It's not as simple as a 1:1 ratio to the plasma volume removed. I don't have much knowledge but factors include how much of a person's IgG happens to be in the extractable plasma and even how much might passively come back with return of the cellular component.

From Removal kinetics of therapeutic apheresis (2007)

The efficacy of the removal depends on the following factors.
  • - The distribution space of the substance. Red cells are only present intravascularly; 55%, 58%, and 22% of IgG, IgA, and IgM, respectively, is extravascular; bilirubin and ammonia also diffuse in the intracellular space. Obviously, plasma exchange only removes the intravascular portion, unless equilibration between the compartments already occurs during the procedure (see below).
  • - Synthetic and catabolic rates. In a steady state, synthesis and catabolism are balanced. However, when immunoglobulins are acutely removed by plasmapheresis, the catabolic rate decreases, in absolute values, because of the lower plasma concentration. In addition, the fractional catabolic rate of IgG is not constant and is lower at low plasma concentrations. As a result, the recovery rate seems faster than expected. In any case, the effects of plasma exchange are transitory and the recovery rate depends on the catabolic rate and the half-life of the substance. Those values vary widely: e.g., they are 7% and 22 days, respectively, for IgG, and 150% and 0.6 days for FVIII.
  • - The equilibration rate between the compartments (intravascular/extravascular space; intracellular/ extracellular space), that constitute the distribution space of a substance. A fast equilibration means a quick rebound. This may also explain why the removal of some substances is lower than expected: e.g., after an exchange transfusion, where 87% of the red cells were removed, bilirubin was still at 60% of the initial concentration.
Click to expand...

See also:
Safety of Plasmapheresis in Donors with Low IgG Levels: Results of a Prospective, Controlled Multicentre Study (2022)
Effect of therapeutic plasma exchange on immunoglobulins in myasthenia gravis (2016)
 
Mister Person said:
And the symptoms of SFN and fibro are difficult to distinguish.
Click to expand...

I think we need to inject some realism here.
I have never come across a case of fibromyalgia, either in practice or presented as a case, with symptoms of neuropathy (other than maybe coincidental carpal tunnel syndrome or whatever).

They are not similar.

The invocation of neuropathy seems to be based on the symptom of tenderness, but the tender points are local, not generalised as in neuropathy, moreover I think they were shown to be non-discriminatory and removed from the diagnostic criteria.

Looking at PubMed I have seen no real interest in the 2021 Goebel paper other than from Autoimmunity Reviews, which is the opposite of a recommendation. Goebel has subsequently published 'position' papers with the hallmarks of hype (I will not be specific in case I get charged with defamation).

If anybody was taking this seriously then there would be reports of patients with fibromyalgia treated with rituximab. Rituximab usage has fallen during Covid but tens of thousands of people were already treated, at least hundreds of whom should have had fibromyalgia according to the figures banded about. Rituximab might not work for these putative antibodies but I wold expect there to be some discussion of experience.

I regularly see Maria Leandro, who with me introduced rituximab to rheumatic disease, and I have heard nothing from her about interesting new evidence in fibromyalgia.
 
Evidently I cannot hold a candle to the excellent (informed) posts above. My eyes glaze over somewhat when I hear "autoimmunity" trotted out as a cause ----. It seems to have been tested for (rituximab). I do wonder if GWAS [DecodeME] may pick up a characteristic "autoimmunity" signature i.e. if it were a common cause of ME/CFS --- bit worried about sub-groups making it difficult to identify cause(s).
 
Jonathan Edwards said:
I think we need to inject some realism here.
I have never come across a case of fibromyalgia, either in practice or presented as a case, with symptoms of neuropathy (other than maybe coincidental carpal tunnel syndrome or whatever).

They are not similar.

The invocation of neuropathy seems to be based on the symptom of tenderness, but the tender points are local, not generalised as in neuropathy, moreover I think they were shown to be non-discriminatory and removed from the diagnostic criteria.

Looking at PubMed I have seen no real interest in the 2021 Goebel paper other than from Autoimmunity Reviews, which is the opposite of a recommendation. Goebel has subsequently published 'position' papers with the hallmarks of hype (I will not be specific in case I get charged with defamation).

If anybody was taking this seriously then there would be reports of patients with fibromyalgia treated with rituximab. Rituximab usage has fallen during Covid but tens of thousands of people were already treated, at least hundreds of whom should have had fibromyalgia according to the figures banded about. Rituximab might not work for these putative antibodies but I wold expect there to be some discussion of experience.

I regularly see Maria Leandro, who with me introduced rituximab to rheumatic disease, and I have heard nothing from her about interesting new evidence in fibromyalgia.
Click to expand...
They're not similar? Okay I was under the impression they were, because if say 50% of fibromyalgia patients have SFN, why were they diagnosed with fibromyalgia? That was my logic.
You're right about realism, but I want to beat this horse and flesh it out. Because that's all that can be done until somebody else replicates this. I do think that there is hype involved, that was my initial impression. Is he reeling us on the hook? It seems like such a convenient explanation doesn't it.

Re 'If anybody is taking it seriously', why would hundreds of fibromyalgia patients have recieved rituximab? Rituximab is a high risk drug right? I find it difficult to even obtain Low dose naltrexone, so this would be difficult for me to understand the inner workings. Are you referring to patients with secondary fibromyalgia being treated with rituximab? Jesus christ, I just realised you said you brought rituximab to rheumatic illnesses. I feel embarrassed now.

From my perspective, a layman's perspective, gosh I must seem so pretentious for arguing back, if nobody is taking it seriously, that doesn't necessarily mean the wisdom of the masses is right, right? Just because science is not recognised, does not mean it is wrong. Just that is not recognised. Wishful thinking but, the area of fibromyalgia seems ripe for revolution.
But why is there such disinterest? Could you explain from your perspective if you were researcher reading this, why wouldn't this be remotely interesting? Could it just be a disinterest in fibromyalgia in general?

My final question would be, what is your take on non inflammatory auto antibodies in general? Just the Goebel paper alone made me skeptical. But Goebel was not the first to publish on passive transfer of IG to mice, nor the idea that non inflammatory auto antibodies can cause pain. Is this whole idea all fringe stuff or what. What about his other papers?
One interesting thing I don't know if it is known:CRPS has the same auto antibodies as long covid/cfs/me:adrb2 and m2 receptor

'in regards to B-cell ablation approaches - no efficacy signal on
concomitant FMS has been reported, to our knowledge from trials con-
ducted in RA or Lupus - similar as with some established antibody-
mediated conditions available B-cell ablation methods may not effec-
tively reduce pertinent pathogenic antibodies which will continue to be
produce by plasma cells or by B-cells residing in privileged environ-
ments' just adding this for context from autoimmunity reviews paper. I have no comment.

Also, https://doi.org/10.3389/fimmu.2018.00835 this paper said B cells may stay in inflamed tissue and they resist treatment, is this somehow linked to your idea that auto antibodies are self perpetuating?
 
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