A recent publication by Goebel et al. with research carried out at King’s College London has challenged the widely held opinion that fibromyalgia may in fact be a condition of the immune system and not the brain.
This study has brought much excitement and promise to the ME/CFS community and those with long Covid and may help to lead the way for new treatments.
The authors hypothesised that fibromyalgia (FM) may have an autoimmune basis due to previously reported altered levels of cytokines suggesting immune processes are dysregulated in FM. As well as this FM is higher among those with autoimmune rheumatological conditions caused by autoantibodies.
What was investigated?
The aim of the research was to determine whether administrating immunoglobulin G (IgG) (a type of antibody) from FM patients to mice transferred characteristic FM symptoms.
The study was divided into four separate parts:
- Assessing whether IgG from FM patients drove pain-like behaviour in mice by transferring IgG from single individuals into mice as well as pooled IgG from several individuals.
- Investigating whether primary sensory afferents were sensitised following transfer of FM or healthy controls IgG into mice.
- Examining whether FM IgG localisation following transfer and cell-type binding in vivo (experimental work performed outside of a living organism such as in a test tube).
- Assessing whether IgG-induced changes in the skin.
How was Fibromyalgia studied?
FM patients were age-matched with healthy individual's from the UK and Sweden., serum was collected and IgG purified.
Purified IgG was collected from 44 people with fibromyalgia and 39 healthy matched controls. A sample selection of IgG was injected into a different mouse as well as studying the effect of pooled IgG.
The image below has been taken from the paper showing the different aspects studied, where HC is healthy controls, FMS is fibromyalgia, DRG is dorsal root ganglia and SCG is satellite glial cells.
Image taken from the paper
What is fibromyalgia and how does it differ from ME/CFS?
Fibromyalgia (FM) is characterised by widespread pain and tenderness in the muscles, where the pain is felt on both sides of the body, above and below the waist, in the neck, back and pelvic area.
FM causes fatigue, sleep disturbances and emotional distress. Many of the symptoms overlap with those in ME/CFS, similarly there is no diagnostic test. Typically, ME/CFS is diagnosed by a neurologist and FM by a rheumatologist.
Unlike ME/CFS, finding “tender spots” in characteristic sites on physical examination is very important to making a diagnosis. Diagnostic guidelines produced by the American College of Rheumatology have identified 18 specific sites around the body (nine on each side) where tenderness is likely to be found. FM is likely where 11 or more tender spots are found.
ME/CFS is more likely to have an infection trigger compared to a trauma trigger in FM, exercise intolerance is higher in ME/CFS compared to FM, substance P (a neurotransmitter responsible for the transmission of pain) is normal in ME/CFS and increased in FM, whereas RNasel (a cellular antiviral enzyme) is increased in ME/CFS and normal in FM (A comparison of ME/CFS and FM can be found here). Reviews of the literature have found that the underlying pathophysiology in CFS may differ from that of FM (Abbi and Natelson, 2013).
The ME Association has a leaflet on Fibromyalgia with more information which can be found here.
Why mice?
Mice are commonly used to study human biology due to their genetic and physiological similarities. Using mice as model organisms in studies has several advantages: their genome being 99% similar to the human genome. They also provide a cost-effective model due to their small size facilitating large scale/high throughput studies (Vandamme, 2014). The key facts in why mice are used in research can be found here.
However, mice and humans have adapted to their environments differently making mice less reliable as models of human disease. The networks linking genes to disease are likely to differ between the two species. Using mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans (Perlman, 2016).
What are the main findings of this study?
The key finding of this paper found that the transfer of IgG from FM patients to mice resulted in mice displaying several key FM symptoms. The mice displayed increased sensitivity to noxious mechanical and cold stimulation, lower pain threshold in pressure and reduced paw grip strength.
“Transfer of hypersensitivities from patients to mice was reproducible across all tested FMS subjects, strongly suggesting that antibody-dependent processes typically underpin the characteristic tenderness and thermal hypersensitivities experienced by patients.”
Importantly, when IgG was transferred from healthy controls to mice, there was no effect. Similarly, IgG depleted serum from Fm patients had no effect. This shows that the findings were due to the IgG being injected and that FM is an antibody dependent illness.
“IgG-depleted serum preparations were without any influence on mechanical or cold nociception, confirming that IgG is the principal pronociceptive, pathological serum component in FMS patients.”
All effects on the mice were reversible and FM symptoms reversed after 2-3 weeks of IgG from FM patients stopping being administered. The effects were also shown to be dose dependent.
Other key findings from this paper:
- All effects on the mice were reversible and FM symptoms reversed after 2-3 weeks of IgG from FM patients stopping being administered.
- The effects were also shown to be dose dependent.
- The study successfully used British and Swedish patients and showed the same effect for each.
- The mechanical and cold hypersensitivities were shown in female and male mice therefore the findings are unlikely to be due to increase female sensitivity to FM IgG.
- A small effect was seen on the activity of mice at night.
- IgG was found to sensitise nerves but did not cause systemic inflammation or cytokine differences.
- IgG from FM patients had increased affinity to peripheral glial cells and neurons. There was also an effect on dorsal root ganglia and decrease in the density of nerve fibres in the skin.
- No effect was found on the spinal cord.
- Combination of these findings were suggested by the authors to be driven by peripheral mechanisms.
What are the implications of this research?
“Our results suggest that therapies which reduce the total IgG titer, such as plasmapheresis or immunoadsorption (e.g., with protein A columns), or which specifically reduce autoreactive IgG (using antigen-specific adsorption) may be effective for FMS. Alternatively, symptomatic therapies that interfere with the binding of autoreactive antibodies or prevent their functional consequences may also provide effective treatment approaches.”
However, there are no accounts of people with FM or ME/CFS being ‘helped’ with therapies of removing autoantibodies from blood.
The research methods used in this paper highlights possible future research for autoreactive IgG in the pathophysiology of ME/CFS and long-COVID. It has already been established that sera from COVID-19 patients contain a wide range of functional autoantibodies, which has been proposed to influence the symptoms of patients (Wang et al., 2020).
What are the next steps from the findings in this research?
One of the next important steps to take following the findings from this research is to see of autoantibodies are present in all FM patients' blood.
It is hoped that findings from this study will help to drive further research into the role of autoreactive IgG in the pathophysiology of FM. The authors comment that the next steps would be:
- Investigate the contribution of IgG acting on satellite glial cells and neurons in driving pain-related sensory abnormalities and neuronal hypersensitivities in mice.
- Examine the underlying cellular and molecular mechanisms responsible for FMS IgG–mediated peripheral sensitisation.
- Examine the possibility of the heightened noxious peripheral input produced by FMS IgG generating altered patterns of activity in the central nervous system.
- Investigate whether FM IgG drives sensitivity to other sensory modalities, such as to auditory and olfactory (sense of smell) stimuli.
What are the limitations of the findings in this research?
One of the main concerns over this research is sample size and replication of results. For example, when IgG from individuals was injected into individual mice, only eight FM samples were used.
The authors tried to look from the proposed autoantibodies causing FM by testing against a commercially available microarray of 42,000 peptides. However, no consistent autoantibody was found but then only 4 people with FM were tested. Instead, samples were pooled together within some of the tests, casting doubt on the results with no common target being found. Clearly there is need for more work on identifying the autoantibodies present in people with FM.
There is also concern over the meaning of sera when pooled together, as this doesn’t show the findings and the spread of data across different indvidual's.
The discussion section of the paper ends with a speculation that “autoreactive IgG in the pathophysiology of FM may transform future research”
Experts' comments on the research
Dr Charles Shepherd, Hon Medical Adviser, MEA
I went to a medical meeting a couple of years ago where the background to this interesting approach to research into fibromyalgia was described
The results clearly point to some form of immunological involvement, possibly autoimmune, in fibromyalgia
We already know that people with ME/CFS have evidence of abnormalities in various parts of the immune system response, including in some cases the production of autoantibodies – which instead of being protective are directed against the body’s own tissues
However, this observation is best described as being suggestive of an autoimmune component to ME/CFS – we cannot conclude that ME/CFS is an autoimmune disease from these findings
It would clearly be interesting to repeat this research in people with ME/CFS and I will be discussing this with my colleagues at the ME Biobank – where we have blood samples and anonymised clinical data – in due course
And if it turns out that removing these antibodies in people with fibromyalgia using plasma exchange leads to symptom improvement this could also be relevant to ME/CFS
The one note of caution here is that the research would involve the use of animals and this is something that the MEA has always been very reluctant to do
The MEA has an information leaflet covering all aspects of fibromyalgia and the overlaps with ME/CFS.
Professor Jonathan Edwards
Connective Tissue Medicine at UCL
(Taken from Science for ME forum)
I don't think this will prove reproducible.
There are a whole lot of things in the main 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.
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.
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.
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.
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. 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.
More discussion on this research can be found here.
References
Abbi, B., & Natelson, B. H. (2013). Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome' hypothesis. QJM : monthly journal of the Association of Physicians, 106(1), 3–9. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527744/
Perlman R. L. (2016). Mouse models of human disease: An evolutionary perspective. Evolution, medicine, and public health, 2016(1), 170–176. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875775/
Vandamme T. F. (2014). Use of rodents as models of human diseases. Journal of pharmacy & bioallied sciences, 6(1), 2–9. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895289/
Wang EY, Mao T, Klein J, Dai Y, Huck JD, Liu F, Zheng NS, Zhou T, Israelow B, Wong P, Lucas C, Silva J, Oh JE, Song E, Perotti ES, Fischer S, Campbell M, Fournier JB, Wyllie AL, Vogels CBF, Ott IM, Kalinich CC, Petrone ME, Watkins AE; Yale IMPACT Team, Cruz CD, Farhadian SF, Schulz WL, Grubaugh ND, Ko AI, Iwasaki A, Ring AM. Diverse Functional Autoantibodies in Patients with COVID-19. medRxiv [Preprint]. 2020 Dec 12:2020.12. Link: https://pubmed.ncbi.nlm.nih.gov/33330894/