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Mysterious pain disorder may not be only in the brain – Expert Reaction

A study in mice shows that fibromyalgia – a poorly understood condition which causes ongoing pain and fatigue in an estimated 1 in 40 people worldwide – could be caused by the immune system turning up the dial on pain-sensing nerves.

Healthy mice injected with the antibodies of fibromyalgia patients showed symptoms of the disorder, which cleared up once the antibodies were removed. The study author says it could also offer an explanation for long COVID.

The SMC asked experts to comment on the study. Feel free to use these comments in your reporting or follow up with the contact details provided.

Dr Bronwyn Lennox Thompson, Senior Lecturer, Academic Coordinator Postgraduate Programmes in Pain & Pain Management, University of Otago, Christchurch, comments:

“In this study, mice were injected with purified IgG antibodies drawn from the blood serum of people with fibromyalgia, and examined to determine whether they showed similar behavioural responses to stimuli as those in humans with the disorder. The mice demonstrated hypersensitivity to mechanical and thermal stimuli (ie they responded more quickly to a lower amount of stimulation).

“All pain is a product of interactions between the nervous system (including the brain) and other parts of the human body, so while this study suggests that the antibodies may initiate the symptoms, it doesn’t yet explain why this persists and why there are numerous spinal and brain changes in fibromyalgia.

“The response in mice suggests treatments to reduce the amount of IgG antibodies circulating in the blood might reduce symptoms in humans. These treatments typically involve separating plasma from the blood and replacing this with either saline or by treating the plasma to eliminate the IgG and returning the plasma to the body, similar to dialysis.

Long Covid patients appear to have enhanced inflammatory responses, potentially from the IgG antibodies produced in response to the virus. Long Covid symptoms are quite similar to those experienced by people with fibromyalgia.

“The major caution about this study is that it’s conducted in mice, and humans are not mice. Mice can’t describe their experiences so we’re inferring from their behavioural responses to short-term stimulation to humans who may be experiencing fibromyalgia for many years. We also may know a great deal about the possible mechanisms associated with developing fibromyalgia or long Covid, but treatments may be quite a long way off.

“What’s interesting is that although fibromyalgia has been known about since at least the early 1800s, skeptics continue to argue that it is not a “disease” but could represent distress, depression or “somatic disorder” where physical symptoms are thought to arise from psychological illness. Similar points have been made about long Covid. That women are more likely to experience both fibromyalgia and long Covid may, or may not, be relevant – there is a long history of women’s ill health being dismissed as “mental illness”.”

No conflict of interest declared.

Professor Franca Ronchese, Immune Cell Biology Programme Leader, Malaghan Institute of Medical Research, comments:

“Fibromyalgia and chronic fatigue syndrome are chronic diseases characterised by a combination of generalised pain, increased pain sensitivity, and tiredness that interferes with the ability to carry out daily activities. They affect mostly women and may occur after a trauma or following an infection. Unfortunately for the sufferers, these syndromes have remained largely mysterious with no clear cause, demonstrated mechanism, or cure. As the physical basis of these diseases could not be identified, and it was often questioned that there was one at all, treatment involved psychological counselling, anti-depressants and pain control.

“It is therefore very exciting to read this new study, which completely changes the existing paradigm for Fibromyalgia and finally opens a way forward in understanding and hopefully treating this disease. What the researchers did was purify antibodies from the blood of 44 UK and Swedish patients suffering from Fibromyalgia and matched healthy subjects. Antibodies are immune proteins produced by our body to control infections and neutralise viruses or toxins, but can in some cases turn against our body causing a multitude of autoimmune diseases. The antibodies from patients or healthy subjects were then injected into healthy mice. The surprising result of this experiment was that antibodies from patients caused mice to develop signs similar to those of Fibromyalgia including reduced physical activity, loss of muscular strength, and increased reaction to mild pain, while mice receiving antibodies from healthy subjects had none of these symptoms. The mice recovered after a few weeks once the injected antibodies eventually waned off. The authors were then able to trace the injected antibodies in mice and show that they attached themselves around nerve cells that perceive pain, making them fire more easily. Therefore, Fibromyalgia is likely similar to other autoimmune diseases where tissue damage is due to a misdirected immune response, and the specificity of this response determines the observed symptoms.

“This study generates some important predictions that need be followed up and confirmed. For example, we need to know whether larger groups of Fibromyalgia patients all share the presence of similar auto-reactive antibodies in blood, and whether these antibodies are found bound to the correct nerve cells in the patients’ bodies. We should expect that treatments that reduce the level of antibodies in blood also ameliorate the symptoms of Fibromyalgia in patients. These are all testable hypotheses and we look forward to hearing the results of such studies in the future.”

No conflict of interest declared.

Emeritus Professor Warren Tate, biochemist and molecular biologist, Brain Health Research Centre, University of Otago, comments:

“This study is an important step forward in understanding the complex disease of Fibromyalgia Syndrome that has widespread pain as a dominant feature for patients. This study shows antibodies are present in Fibromyalgia at high enough levels to invoke painful sensory hypersensitivity when transferred to mice.

“Fibromyalgia is within a group of chronic diseases like Myalgic Encephalomyelitis /Chronic Fatigue Syndrome that have also shown autoantibodies (antibodies that mistakenly target a person’s own tissues or organs). The specific autoantibodies highlighted in Fibromyalgia not surprisingly have a different response, namely widespread pain.

“Does this mean Fibromyalgia is a condition of the immune system and not the brain, as this Guardian headline reviewing the research suggests? It seems more likely the wider array of symptoms similar to Chronic Fatigue Syndrome are brain related, but the autoantibodies are an important secondary feature of the disease, just as they are in Chronic Fatigue Syndrome.”

No conflict of interest declared.