Fibromyalgia and refractory pain in rheumatic diseases

Fibromyalgia is one of the most common causes of chronic pain worldwide. There is no diagnostic test available, and patients are diagnosed based on how severe and widespread their pain is and whether they have other symptoms, such as fatigue, sleep problems and depression. Treatment of fibromyalgia is focused on exercise and education, which help patients become more active and cope better with pain. Drugs that are used to treat pain in fibromyalgia are effective in some patients, but often cause problematic side effects and regularly become less effective with time. Fibromyalgia has a severe impact on quality of life, but the fact that patients look healthy can make it difficult for them to qualify for benefits and to convince their environment about how they feel. Although fibromyalgia affects more than 1 in 50 people, the cause of disease remains unknown. A better understanding of the cause of fibromyalgia, is likely to dramatically accelerate development of improved treatments and invention of diagnostic tests. We have discovered that the body's normal defence mechanism, the immune system, is responsible for pain in fibromyalgia patients. Immune cells produce proteins called antibodies, which would normally be used to help us destroy bacteria and other parasites, thereby helping us fight infections, and to become immune to them. Our results show that fibromyalgia patients make antibodies that attack their own bodies, rather than infections. These antibodies stimulate pain-sensing nerves throughout the body, making patients too sensitive to pressure, temperature and thereby experiencing unrelenting pain. In our pilot experiments, we have purified antibodies from fibromyalgia patients (without other health conditions) and healthy volunteers and injected these to mice. Remarkably, mice that were given patient antibodies developed similar symptoms to the patients that the antibodies were taken from, whereas antibodies from healthy volunteers were without effect.
While about 2% of the general population (mostly women) suffer from fibromyalgia, around 25% of people rheumatic disease suffer from this difficult chronic pain condition. Rheumatic disease can often be well controlled by drugs, but fibromyalgia and the pain it causes throughout the body does typically not improve by treatment. During this project we will determine whether fibromyalgia in rheumatic patients is also caused by antibodies that cause pain. Our results are very likely to lead to development of the first simple diagnostic tests, and this will dramatically reduce the stressful period of time, often a couple of years that it currently takes for patients to be diagnosed. It is also very likely that our work will lead to improved treatment of fibromyalgia, and some of the possible treatments are already used in other conditions caused by antibodies that attack our own bodies.

Fibromyalgia syndrome (FMS) is a common chronic primary pain syndrome with a prevalence exceeding 2% in the general population. FMS is characterized by chronic widespread pain in combination with other neurological symptoms, such as fatigue, sleep disturbances, anxiety, depression, and memory problems. FMS is more common in women than men, and much more prevalent in patients with autoimmune rheumatological conditions. Patients report very poor scores for health-related quality of life, and the available therapies are of limited efficacy.
We have recently discovered that FMS in patients without comorbidities (primary FMS) is caused by autoantibodies and that sensory, anatomical, and motor symptoms can be transferred from patients to mice by administration of IgG. These findings are likely to initiate a paradigm shift in our understanding and management of FMS and have enabled us to embark on detailed cellular and molecular investigations of FMS. Our studies of single afferents in skin-nerve preparations and current-clamp investigations of dorsal root ganglion (DRG) neurons show that FMS IgG produces neuronal hyperexcitability. Transcriptomic analysis of sensory ganglia has identified a single candidate ion channel, and the observed electrophysiological changes in DRG neurons mirror those expected to be caused by dysregulation of the candidate ion channel.
About 20-30% of patients with rheumatoid arthritis, ankylosing spondylitis, and Behcet's disease meet the diagnostic criteria of FMS. While the rheumatic disease in these patients is often well-controlled clinically, FMS is typically refractory to treatment. The proposed studies will determine whether the same mechanisms that we have identified in primary FMS, are also responsible for comorbid FMS in patients with rheumatic diseases. The results of the proposed studies will expand our earlier conclusions and may establish FMS as an autoimmune disease in its own right.