Fibromyalgia: Neurological or autoimmune?

Nobody wants to be handed a problem they cannot solve, much less one they do not fully understand. Yet, this has been the reality for doctors dealing with fibromyalgia patients for decades. Of course, there are many diseases for which treatments remain scarce or ineffective – but fibromyalgia, much like its close relative chronic fatigue syndrome (CFS), has taken on an almost cult-like status due to the mystery surrounding it. It is this mystery that has led to fibromyalgia being treated like a hot potato that no clinical department wants to catch.

Dr Camilla Svensson, professor in cellular and molecular pain physiology at Karolinska Institutet, was part of a team who broke new ground in fibromyalgia research by implicating the role of human immunoglobulin G (IgG) antibodies in perpetuating the disease by transferring it to mice and observing many of the same symptoms seen in sapiens. It is too early to say whether the findings are enough to set the broader research community on a new path searching for an autoimmune cause. But the implication of specialised peripheral sensory neurons, known as nociceptors, was enough for the rheumatologists at a recent meeting she attended to explain the findings, to question once again whether fibromyalgia patients belonged in their care.

“They said great. We sometimes feel like these patients do not belong with us. Now we can send them to the neurologists.” Despite the peripheral nervous system involvement, Svensson says the neurologists at the meeting were equally unsure if they were the best specialism to care for fibromyalgia patients. “They said, if this is an autoimmune disease, these patients should probably not be with us, but at the rheumatology clinic.” From Svensson’s perspective, the answer to where fibromyalgia patients belong is unlikely to be binary, and that is not surprising. “Doctors and researchers haven’t yet fully grasped fibromyalgia, and when there is no consensus on the definite causes and few medications to try, it is difficult to determine which clinic is best suited for diagnosis and care,” she says.

She uses rheumatoid arthritis as an example of a disease for which the peripheral components could be sustaining its symptoms, much like IgG antibodies could be doing in fibromyalgia patients. “If you look at the population of [rheumatoid arthritis] patients that are successfully treated with anti-rheumatic drugs, you get a really good response from a disease activity perspective, but 30% to 50% of those individuals will still have pain.” In practice, this means the biomarkers of inflammation, like C-reactive protein levels, as well as the more obvious symptom, swollen joints, reduce – but the pain remains. If the idea of patients experiencing pain without any clear physiological reason is sounding familiar, that is because these patients are, for all intents and purposes, exhibiting fibromyalgia symptoms.

Even less surprising then is that of the 2–4% of people estimated to be fibromyalgia sufferers, researchers have indicated the comorbidity rate with rheumatoid arthritis to vary between 10% and 30%, depending on the region examined. For Svensson, this begs an important question regarding rheumatoid arthritis patients with persistent pain after effective treatment: “Is this fibromyalgia? Or is it just a central nervous system consequence of an autoimmune condition where patients have had long-lasting activity in the pain fibres, which has led to changes at the level of the spinal cord and brain?” This latter theory is based on the idea of centralised pain or centralised sensitisation, essentially meaning that the mechanisms behind the body’s pain signals are somehow impaired – although the cause of this impairment is unknown.

Potential treatments

The centralised pain explanation has been the dominant theory for a while now, which is why the research of Svensson, along with her colleagues Dr David Andersson and Professor Stuart Bevan of KCL, was so groundbreaking. In the study, the researchers injected mice with either IgG antibodies from fibromyalgia patients, or from healthy control subjects. The result was significant differences on tests designed to evaluate mechanical and cold hypersensitivity, muscular strength, and fatigue, with the negative consequences exhibited only by those given fibromyalgia IgG. The researchers also administered IgG-depleted serum as an extra control measure and found no significant differences on the tests.

These results raise an interesting question: if the human IgG of fibromyalgia sufferers is pathogenic, can immunomodulation therapy eliminate the symptoms? With strong moral and ethical reasons not to try and replicate the research using healthy humans instead of mice, Andersson and Bevan believe this could be the most definitive way to test their hypothesis that fibromyalgia is sustained by IgG antibodies in the immune system.

“If we can transfer symptoms from patients to mice using the antibodies, we would also expect removing these antibodies from patients to at least give symptomatic relief,” says Andersson. “You either need to stop the production [of antibodies] in the patient, or remove them from circulation.” Perhaps one reason the likes of Andersson, Bevan and Svensson believe fibromyalgia could have an autoimmune cause is that such a treatment would be similar to that of other diseases in this category, like systemic lupus erythematosus, Sjogren’s syndrome and autoimmune forms of encephalitis – all of which tend to be managed using immunomodulatory treatments.

The first port of call tends to be lowering the number of immune cells using drugs like corticosteroids, but in severe cases that fail to respond adequately to a pharmacological approach, plasmapheresis – a therapy that separates plasma from the blood – has been used to remove them altogether. Plasmapheresis is time-consuming, expensive and carries inherent risks (although, so does long-term corticosteroid use), but due to the absolute reduction of IgG, Andersson and Bevan see it as the natural litmus test in humans for their theory that fibromyalgia is autoimmune.

“The next step will be for clinical investigators to run clinical trials with plasmapheresis to see how that impacts their symptoms,” says Bevan. “It’s something we would dearly like to see done,” adds Andersson.

Cerebrospinal fluid pressure

If plasmapheresis is shown to improve fibromyalgia symptoms, the case for an autoimmune basis to the disease will be stronger, and patients will continue to be sent to the rheumatology department. But another branch of researchers have been advancing a different theory for a while now. Dr Mieke Hulens, working at faculty of kinesiology and rehabilitation sciences at the University of Leuven, is one of those researchers. Eschewing the idea of an autoimmune cause completely, she believes the key to understanding fibromyalgia lies in the spine, or more specifically the cerebrospinal fluid (CSF) that circulates around the brain and spinal cord. The lynchpin of her theory is based on the existence of Tarlov cysts – fluid-filled sacs found on the nerve roots of the spine.

“Tarlov cysts are an under-recognised condition because most doctors believe they are clinical findings that have no importance and do not cause any symptoms,” she says. “But we have found that almost all of the patients who have Tarlov cysts, have chronic pain.” The occurrence of the cysts, Hulens explains, is due to increased cerebrospinal pressure, which she posits to cause irritation to the nerves and even cause nerve damage. To support the theory, she and seven other researchers conducted a study that put 197 patients diagnosed with fibromyalgia, CFS or both conditions, under an MRI scanner looking for Tarlov cysts. The prevalence was 39% among the cohort, but Hulens says even those who did not have them showed other signs of increased cerebrospinal pressure. “A lot of the patients had dilated nerve root sheaths, but they didn’t look like cysts yet,” she explains.

An accompanying element of Hulens’ theory is that the reason symptoms often cross over with fibromyalgia and CFS patients is that the two diseases share a common pathophysiology – increased cerebrospinal pressure.

In another study, published at the start of this year, she sought to explain this link by connecting small fibre neuropathy, thought to be a potential cause of pain and abnormal skin sensations present in both fibromyalgia and CFS patients, with the pathological impact of Tarlov cysts. In the small retrospective study, she and her fellow researchers used intraepidermal nerve fibre density (IENFD) data from 17 patients, all of which had Tarlov cysts. They found that 82% of patients had an IENFD value below 5%, which is an indication of small fibre neuropathy. CSF pressure, her paper contends, initiates formation of the cysts, but also damages axons and neurons inside nerve root sheaths and dorsal root ganglia (DRG) – a cluster of neurons in a dorsal root of a spinal nerve. This is not the first time that DRG has been implicated in the pathophysiology of fibromyalgia, and Hulens believes it could explain the small fibre neuropathy. Another part of her theory is grounded in the upright, mostly standing position human beings tend to be in day-to-day. She contends that hydrostatic pressure in the CSF is the highest in the lowest nerve roots, which is why Tarlov cysts tend to be more prominent in the sacral nerve roots and may explain why those suffering with fibromyalgia and CFS often report bowel and bladder issues along with their widespread pain.

An autoimmune cause?

For Hulens part, the answer to whether fibromyalgia has an autoimmune cause is an unequivocal no. “It’s always been linked to viruses or autoimmune disease, but everybody gets different viruses and everybody has IgGs against them. I don’t think that’s a cause,” she says.

The root cause, she believes, is likely a hereditary predisposition in the genes that leads to increased CSF pressure. She points to research from 2004 led by University of Cincinnati psychiatry and behavioural neuroscience professor Lesley Arnold that found the family members of patients with fibromyalgia were eight times more likely to have the disease than those of patients with rheumatoid arthritis. “It’s a bit like increased blood pressure,” she adds. “That’s hereditary too, but increased blood pressure is very easy to measure, so there have been very large epidemiological studies showing that even moderate increases in blood pressure are harmful.”

In contrast, Hulens says there is a belief that only very high cerebrospinal pressure is harmful because little is known about the effects of moderate increases. “Those [moderate increases] are the patients with fibromyalgia and CFS,” she believes.

Although it is anecdotal, in her role as a physical medicine and rehabilitation physician, Hulens says many of her patients get symptom relief through a redcution in sitting, and using a reclining chair when they do, to reduce the amount of CSF pressure, which elevates in traditional seated positions where the feet make contact with the floor. Beyond that, she says treatments that lower CSF pressure range from drugs with “significant side effects” and “disappointing” therapeutic benefit, to extreme methods like installing a shunt or conducting a lumbar puncture, both of which carry risks – especially shunting, which can result in CSF leakage.

Discussions about the element of risk in procedures indicated from both sides of the fibromyalgia research spectrum: autoimmune and neurological, help to bring the discussion back to patient care. Those that suffer from the disease, says Svensson, are speaking up for themselves, as she observed in a meeting about potential treatments. “The patient representatives were very vocal in the discussion, saying ‘let us decide if it’s worth taking the risk, because we don’t have a life today,’” she recounts. “That left me so touched and motivated to continue this work.”