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Fibromyalgia found to most likely be caused by autoimmune disorder

The study found that Fibromyalgia is an immune system disease rather than a neurological dysfunction, as previously thought. Patients with fibromyalgia antibodies cause greater pain sensitivity, muscular weakness, decreased mobility, and a decrease in the number of tiny nerve fibers in the skin. Once the antibodies were removed from their systems, the mice injected with them recovered within weeks.

Many of the symptoms of fibromyalgia syndrome (FMS) are caused by antibodies that increase the activity of pain-sensing nerves throughout the body, according to new research from King’s College London’s Institute of Psychiatry, Psychology & Neuroscience (IoPPN) in collaboration with the University of Liverpool and the Karolinska Institute.

The findings suggest that fibromyalgia is an immune system disease rather than a neurological dysfunction, as previously thought.

The study, which was published early in July in the Journal of Clinical Investigation, shows that patient antibodies cause greater pain sensitivity, muscular weakness, decreased mobility, and a decrease in the number of tiny nerve fibers in the skin, all of which are symptoms of FMS.

The mice acquired an increased sensitivity to pressure and cold, as well as a decreased movement grip strength, after being injected with antibodies from patients with FMS, according to the researchers. Mice injected with antibodies from healthy persons, on the other hand, were unaffected, showing that patient antibodies cause, or at least contribute to, the disease.

Furthermore, once the fibromyalgia antibodies were removed from their systems, the mice injected with them recovered within a few weeks. This data clearly implies that medicines that lower patient antibody levels are likely to be successful. Such treatments are already available and are used to treat various autoantibody-related diseases.

“The implications of this study are profound. Establishing that fibromyalgia is an autoimmune disorder will transform how we view the condition and should pave the way for more effective treatments for the millions of people affected. Our work has uncovered a whole new area of therapeutic options and should give real hope to fibromyalgia patients,” said Dr David Andersson, the study’s primary investigator from King’s IoPPN.

“Previous exploration of therapies has been hampered by our limited understanding of the illness. This should now change. Treatment for FMS is focussed on gentle aerobic exercises, as well as drug and psychological therapies designed to manage pain, although these have proven ineffective in most patients and have left behind an enormous unmet clinical need.”

According to current estimates, FMS affects at least one in every 40 individuals globally (80% of whom are women), and is characterized by extensive discomfort throughout the body, as well as tiredness (often known as ‘fibro fog’) and mental anguish. It most often affects people between the ages of 25 and 55, however it can also affect children.

“When I initiated this study in the UK, I expected that some fibromyalgia cases may be autoimmune. But David’s team have discovered pain-causing antibodies in each recruited patient. The results offer amazing hope that the invisible, devastating symptoms of fibromyalgia will become treatable,” said Dr Andreas Goebel, the study’s principle clinical investigator from the University of Liverpool.

“Antibodies from people with FMS living in two different countries, the UK and Sweden, gave similar results, which adds enormous strength to our findings. The next step will be to identify what factors the symptom-inducing antibodies bind to. This will help us not only in terms of developing novel treatment strategies for FMS, but also of blood-based tests for diagnosis, which are missing today,” said Professor Camilla Svensson, the study’s primary investigator from Karolinska Institute.

Dr Craig Bullock, the head of Research, Discovery and Innovations at Versus Arthritis said “Fibromyalgia affects millions of people in the UK and can have a devastating impact on quality of life. It causes pain all over the body, fatigue, disturbed sleep and regular flare-ups where symptoms get even worse.”

“Fibromyalgia is a particularly difficult condition to diagnose and manage because its causes are unknown. This research shows that antibodies found in human blood can cause fibromyalgia-like symptoms in mice, suggesting that these antibodies play a crucial role in the condition. Further research is needed but this offers hope to the millions of people with fibromyalgia that an effective treatment could be found in the relatively near future.”

The study was published July 1st, 2021 in the Journal of Clinical Investigation.

Abstract. Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

Results. Passive transfer of sensory hypersensitivities. IgG purified from the serum of individual FMS patients and healthy control (HC) subjects recruited from the Walton Centre (Liverpool, United Kingdom [UK]) was administered to female mice by intraperitoneal injection for 4 consecutive days (8 mg per day). This dose regimen was based on the original studies identifying myasthenia gravis as an autoantibody-mediated disorder (29, 30), and more recent studies of complex regional pain syndrome (26, 31). Because FMS is characterized by hypersensitivity to mechanical pressure, we examined paw withdrawal thresholds in mice using the Randall-Selitto paw-pressure test following IgG transfer. IgG from each of the 8 individual patients, but not from any of the 6 HC subjects, rapidly produced mechanical hypersensitivity (Figure 1, A–F). In addition to pressure sensitivity, patients frequently report that pain is exacerbated by cold temperatures, and quantitative sensory testing has demonstrated an increased cold pain sensitivity in FMS (1, 2, 4, 16). In good agreement with patient observations, administration of IgG from 7 of the 8 FMS patients gave rise to a significantly increased sensitivity to noxious cold in mice (Figure 1, G–L). Both mechanical and cold hypersensitivities were typically established within 24–48 hours after the first injection and were maintained for more than 1 week. The observed hypersensitivities produced by IgG preparations from different FMS patients showed similar amplitudes and time courses (Figure 1, A–L, and Supplemental Figure 1, A and B; supplemental material available online with this article;, which is reflected in the averaged mechanical and cold sensitivities produced by IgG from these 8 individual FMS patients and 6 HC subjects measured over 10 days (Supplemental Figure 1, C and D). FMS IgG also generated hypersensitivity to stimulation with calibrated von Frey filaments, a widely used test of mechanical nociception in mice (Figure 2A). Fibromyalgia pain is characteristically widespread, and studies of the bodily localization of pain have identified the thigh as one of the most commonly affected sites (32, 33). We therefore examined the pressure sensitivity of the thigh using the Randall-Selitto device (Figure 2B), to determine whether FMS IgG affects the pressure sensitivity of sites other than the hind paw in mice. In this test, FMS IgG produced significant mechanical hypersensitivity in the thigh compared with treatment with IgG from HCs (Figure 2B).

Goebel A, Krock E, Gentry C, Israel MR, Jurczak A, Urbina CM, Sandor K, Vastani N, Maurer M, Cuhadar U, Sensi S, Nomura Y, Menezes J, Baharpoor A, Brieskorn L, Sandström A, Tour J, Kadetoff D, Haglund L, Kosek E, Bevan S, Svensson CI, Andersson DA. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 2021 Jul 1;131(13):e144201. doi: 10.1172/JCI144201. PMID: 34196305; PMCID: PMC8245181.

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