Our research is about Fibromyalgia Syndrome (FMS), a chronic pain condition affecting more than 2% of the UK population, characterised by widespread pain, hypersensitivity, fatigue, poor sleep and impaired cognition.
FMS does not cause tissue destruction but is hugely debilitating and expensive - many people can’t function in their daily lives and can’t work. Like other unexplained chronic pains, FMS has been labelled a ‘sensitisation disorder’ and has often been thought psychological, but until our study findings there was no clear understanding about the biological basis for the pain of FMS.
We pursued an idea which I first developed 20 years ago2, that functional autoantibodies may cause ‘unexplained’ pain symptoms by changing the way pain nerves function, without causing tissue destruction, and that this might be demonstrated by transferring antibodies from patients to rodents and then examining the rodents for signs resembling the clinical disease.
Similar experiments have been done in other conditions – for example if one transfers antibodies from patients with myasthenia (a muscle disorder) to rodents, the rodents will develop muscle weakness3. My idea was to extend this to symptom-based disorders, defined by their lead problems of often devastating symptoms, such as pain or fatigue, absent readily discernible objective disease signs.
For the FMS study we used an injection paradigm that I had previously adapted from these myasthenia studies and used to investigate Complex Regional Pain Syndrome (CRPS), an uncommon post-traumatic pain condition4-6.
For the Guardian Top-Ten study we selected FMS patients with high symptom severity from the Pain Management Program at the Walton Centre in Liverpool. We asked them to complete questionnaires and donate blood; then we affinity-purified their serum immunoglobulin G (IgG) antibodies and sent them, together with healthy-control IgG to David Andersson and Stuart Bevan, basic pain scientists at King’s College in London, who injected the mice using our protocol and conducted detailed behavioural rodent studies.
Successively, each and every tested Liverpool patient IgG preparation was ‘positive’, in that it rendered the mice hypersensitive to pressure and cold. Unlike with our prior results in CRPS, no trauma was required to achieve this effect. After injection stop, as the mice metabolised the human IgG over time they always recovered. David and I discussed these outcomes with Camilla Svensson, who is a pain-Pharmacologist at the Karolinska Institute with extensive expertise in histopathological techniques who had a special interest in this topic.
Camilla obtained sera from Swedish patients with FMS and created three serum-IgG pools each combined from 10-15 patients. David and Stuart tested these pooled sera and - again without exemption found that they made the mice profoundly hypersensitive.
In addition to hypersensitivities to pressure and cold, the mice also developed reduced grip-strength, they moved less, and on microscopy demonstrated mild skin small nerve fibre pathology similar to clinical FMS. David’s team further demonstrated that single nociceptor fibre response-characteristics were abnormal.
Emerson Krock, a post-doc in Camilla’s team found dedicated IgG binding to cells in the mouse dorsal root ganglia, which are the sensory nerve bodies adjacent to the spinal cord, and that some cell types became activated after binding; he also confirmed FMS-IgG binding to human cadaveric DRGs.
Hardly anything worth reporting is achieved on one’s own. This study was an equal collaboration of three University teams; all three were fundamentally important to the study’s success, but the study originated in Liverpool.
So, it seems that FMS may be caused by functionally active antibodies that change the way pain nerves (‘nociceptors’) function, without leaving any other clinically detectable trace.
The experiments require replication by others, but if they are replicated the implications of these results are profound. This new evidence should pave the way for the development of a whole new range of novel diagnostic tests and immune therapies. We have now, for the first time, a valid, mechanism-driven disease model for FMS.
Perhaps our discovery might also help us and other scientists to investigate IgG roles in other symptom-based disorders. These disorders often occur independently, but Long-Covid has highlighted that ‘unexplained’ symptoms can also accompany or develop after other diseases. We can often treat destructive disease processes, but patients may nevertheless suffer from miserable, debilitating ongoing ‘invisible’ symptoms which may have a different, as yet unexplained, underlying pathophysiology. New ways of assessing and treating these problems seem now within reach.
Acknowledgement: Dr. John Wiles, Liverpool, for review and important suggestions to this blog text.