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

I watched a introductory video of one of the senior authors, Camilla I. Svensson, where she mentioned that her research interest the fibromyalgia pain field and "what if there was a factor in the blood contributing to this disease?".

 

If replicated and built upon, this could be a big deal, but this is not guaranteed.

It is interesting that they claim the IgG sensitised nerves but did not cause systemic inflammation or cytokine differences.

They also found no effect in the spinal cord, suggesting it is a peripheral phenomena (or in the dorsal root ganglia I guess)!

This suggests direct interactions with proteins, but they didn't find any specific common targets, which casts some doubt on the findings. They claim the IgG was most sensitive to microtubules which I'm not quite sure why B-cells would be sensitised to them. Nor do the authors (or I) propose a specific mechanism on how this could sensitise nerves, though structural components like this can be involved in the pressure sensing mechanisms.

An aside, there was an old study:
"Autoantibody to microtubules in infectious mononucleosis"
https://pubmed.ncbi.nlm.nih.gov/4466601/

 

I wonder if the Biobank could be utilised here. I hope we don’t have to wait a decade for replication (or lack thereof).

 

I noticed that it looks like this paper was put up as a pre-print in July 2019:

https://www.biorxiv.org/content/10.1101/713495v1

so, they must have made changes. In skimming the preprint, I did not notice the small fiber density data in the preprint…

 

I don't think this will prove reproducible.

There are a whole lot of things in the man script that make me sceptical I am afraid.

The key problems that it is vanishingly unlikely that all 8 of a sample of 'fibromyalgia' patients would have autoantibodies that do the same thing. The diagnostic uncertainty for fibromyalgia is huge.

A second concern is that if pain in fibromyalgia had some specific mechanism as they suggest like sensitisation of nerve endings then the story told by people with fibromyalgia ought to be characteristic in some way. one would expect it to be like a neuropathic pain from a peripheral neuropathy -probably worse in feet and hands. The literature does not describe this.

I guess the impression that I get that worries me is that all these results are the sort of results that someone who is not that expert in autoimmune disease might expect to find but that someone more familiar would consider rather discordant with the clinical picture. The suggested therapies are also impractical and old fashioned (like adsorption and plasmapheresis) and more linked to private fringe clinics than to mainstream medicine.

I may be wrong but my guess is that it won't be repeatable. I cannot see any experiment like this being sensible in ME.

 

From my brief skim, the study seems to be to have been well-conducted, although there is no clinical detail; nothing as to how the patients were selected & diagnosed, so who knows whether these patients meet any diagnostic criteria or whether they are indeed representative of fibromyalgia patients. As usual, I have more questions than answers...

Generally - and I hope Prof Edwards will correct me if I'm wrong - not only the presentation but also the epidemiology of fibromyalgia don't seem to me to sit well with autoimmunity. Although there is female predominance, autoimmune diseases tend to exhibit familial clustering of cases; there are positive twin-study associations, and there is an increased prevalence of other autoimmune diseases in family members of affected patients. Additionally, as far as I know there is no association with HLA antigens (encoded by genes within the major histocompatibility complex) in fibromyalgia, which one might also expect to find if it were autoimmune. Also, more obviously, clinically fibromyalgia also never progressively worsens; there are no fibromyalgia cases that, left untreated, result in end-organ damage (think of how e.g. untreated SLE might eventually result in lupus nephritis); the pain in FM is diffuse & migratory, & the presentation doesn't seem at all consistent with the peripheral process described. Also, would there not be evidence of progression to a sensory ganglionpathy if there were immune-mediated damage to the sensory neurons in the DRG, and would we not have seen studies showing associated histological hallmarks in the DRG at post-mortem in FM patients by now?

What is being diagnosed as "fibromyalgia" may in fact be multiple different conditions & suspect there's a high level of heterogeneity. Fascinating, though, & very interested to see if this replicates.

 

Yes I realise these points but that is not really what bothered me.

Peptide arrays are a bad way to look anyway so that is another minus Brownie point. Don't even bother.
They are trying to persuade us that all8 people had autoantibodies that had the same sort of effect on nerves - hence all the different results that superficially look consistent with that.

I just don't think it is plausible, given how much uncertainty there is about who if anyone you put in this diagnostic category that they would have hit on 8 people all with this magic effect on nerves.

 

Although the JCI’s article layout is unhelpful in that it describes the results before the methods of the study, the authors present their patient cohort as such (bolding mine):

Patient samples. Serum samples for individual testing were derived from UK patients managed for their fibromyalgia at a department of pain medicine, or from age- and sex-matched HCs between April 2017 and November 2018. Pooled samples were obtained from Swedish patients between September 2015 and December 2016 or HCs responding to a study advert between March 2016 and March 2017. All patients had been examined by a consultant rheumatologist, and UK patients had additionally been examined by a consultant in pain medicine.

We purified serum IgG from 44 FMS patients and 39 HC subjects. All patients fulfilled both 1990 and 2011 ACR diagnostic criteria for fibromyalgia (61, 62). Most patients (42 of 44) and all of the pooled-sample donors were unaffected by other sensory, autoimmune, or rheumatological conditions. Most patient donors (43 of 44) were women.​

Unless conditions with a (possible) autoimmune etiology such as small fiber neuropathy and Sjögren’s syndrome were missed when the patients were screened, and despite the uncertainty in the diagnostic of fibromyalgia, it seems that the cohort was decently well characterized.

 

We are at cross-purpose. My point about the implausibility of 8 all showing the same effects (on mice) being attributed to autoantibodies is independent of any actual measuring of autoantibody activity in pooled sera. The pooling of sera is another thing that a competent immunologist just would not do in this situation. What gives you the sort of data detail that distinguishes real results from non-specific comes from looking at the spread of findings in individuals. Spurious results with autoantibody tests are so common that pooling takes away any chance of sorting out what's what.

I am afraid not. In my experience rheumatologists and consultants in pain medicine interested in 'fibromyalgia' by and large don't have much grasp how to categorise patients for research and application of these criteria is about as elastics a Chalder fatigue score or a GRADE scale.

If I was asked if a patient fitted some criteria for FM would have to say I really had no idea - which is why I never made the diagnosis.

And yes, that was another worry for me, but there are so many I didn't put them all down! If it is really credible that 30% of people with RA have fm and 25 of the population have FM and it is due to autoantibodies why has nobody responded to rituximab - and why do they talk of old fashioned techniques for antibody depletion rather than rituximab?

 

I've only scanned the paper for a few minutes and my understanding is very basic.

You may recall the recent discussion on a new technique ("REAP") to test for autoantibodies*; here's an extract:
"Similarly, technologies that rely on the use of peptide fragments are not able to detect autoantibodies that recognize “conformational” protein epitopes (i.e., three dimensional epitopes present when a protein is folded into its native state). This limitation may significantly hamper autoantibody detection, since as many as 90% of antibodies recognize conformational epitopes as opposed to linear peptides24."**
The technique used in this publication relied on linear peptides "peptides in the array are linear". So the assay doesn't seem to be ideal.

The REAP method was tested on some known autoimmune diseases and the results seem encouraging i.e. known autoantibodies were identified plus some possible new ones. I assume that the problem with this method is that you have binding to the linear peptide array but you don't know what antibodies/autoantibodies this correlates to.

Aaron Ring (author REAP publication) was looking for ME/CFS samples to test them for autoantibodies. Maybe one way forward for this research is to use REAP to look for autoantibodies in fibromyalgia.

*https://www.s4me.info/threads/reap-...-the-human-exoproteome-2021-wang-et-al.20747/

**https://www.biorxiv.org/content/10.1101/2021.02.11.430703v1

 

I am sorry but this is a nonsensical statement, it implies that there are per definition no distinct pathological conditions with a similar/same observable pattern of dysfunction in patients with similar/same symptoms. To find this pattern in 8 patients might be unlikely, but maybe still true.

 

I understand your problem @Trish . I am not dismissing the research but expressing my opinion that it is very unlikely to hold up. It is difficult to give precise reasons but there are at least half a dozen things in this study that tome indicate that the authors do not really grasp the immunology they are trying to work with. Some of them I have alluded to.

The thing that seems most implausible to me is that they selected 8 people they thought had FM and 6 controls and all the 8 FM cases did predicted things to various aspects of mouse physiology and none of the controls. You are very lucky ever to get such a clear cut result. But it is particularly surprising in a condition where agreement on who actually has the condition varies so much that some physicians make the diagnosis 100 times more often than others. Surely even the specialists in FM would find it hard to select a group, all 8 of whom had just the right amount of a predicted abnormality to show up on an assay when no controls did?

It would be if that is really how things were. Remember that in this field 90% of findings turnout to be unrepeatable. And we are dealing with assays, at least some of which have quite subjective, or bias-able, endpoints.

I don't like to be too critical but in terms of my own expertise there are lots of aspects that look a bit too good to be true. The neurological aspects I have less direct expertise in but have had doubts about these sorts of assays for some time and Angela Vincent, who is probably the world authority on neurological autoantibodies is even more sceptical than I. This is an area where you can get the results you want to get any time you like because of all the spurious effects that immunological interactions throw up.

I hope I am wrong but it is precisely because it all looks to fit together so nicely (when it doesn't) that I am concerned.

 

How to define fibromyalgia is definitely more complex due to the fact that there is no longer a medical specialty looking after fibromyalgia patients. Nowadays, these patients are treated as ‘chronic pain’ patients, and are sent to BPS for self-management which includes discussions about catastrophization, symptom focusing, central sensitization and drug-seeking behavior, just to name a few.

My question in regard to this paper is… what would be the next step in research, if any?

Lastly, i assume that the poor mice who received the sick plasma, they were too lazy to exercise, right?

 

Rather than playing with mice I would concentrate on establishing the validity of the claim to autoantibodies being present. I would ask Angela Vincent to get her colleagues to repeat the immunochemical/cytological studies and see if they hold up.

I have not had time to look at the paper in full but it sounds as if they did not find any one consistent auto antigen. That is also worrying. In autoimmune disease it is usually clear that one particular target is involved. it may not be a specific protein and certainly not a peptide but cytochemical or fractionation studies show consistent binding to a particular organelle. but it has to be done with individual sera.