Autoimmunity and Neuroinflammation in Fibromyalgia – Verywell Health

Fibromyalgia (FM) may be an autoimmune disease, where your immune system attacks healthy cells by mistake. For years, the evidence seemed to point away from that. But now, research has shown that FM may be an autoimmune disease involving neuroinflammation, an inflammatory response within the brain and spinal cord, and small-fiber neuropathy, which is weakness and pain from nerve damage.
This article looks at how research has come back to this classification, the evidence for autoimmunity, neuroinflammation, and small-fiber neuropathy, and why these findings are important.
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For decades, fibromyalgia’s very existence was controversial. But not anymore. Early on, some doctors who believed in FM classified it as “arthritis-like.”
Many medical experts suspected autoimmunity because of the condition’s similarities to known autoimmune diseases such as lupus, Sjögren’s syndrome, rheumatoid arthritis, and multiple sclerosis.
However, early research failed to turn up the hallmarks of autoimmune disease, including:
Autoimmunity is an immune system turned against its body. Your immune system mistakes a healthy type of cell or tissue in your body for a dangerous pathogen, like a virus or bacterium. It then attacks and tries to destroy the target. This leads to tissue damage, inflammation, and other symptoms.
Later, FM was considered a pain condition that was believed to be neurological or neuro-immune. The term central sensitivity syndrome developed as an umbrella term for FM and related illnesses, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), irritable bowel syndrome (IBS), and migraine.
Now, FM is seen as a complex, multi-symptom illness. What’s more, evidence is mounting that it actually isn’t missing those hallmarks of autoimmunity:
Fibromyalgia has always borne a striking resemblance to autoimmune diseases. Research published in 2019 laid out the many factors they have in common:
Researchers may have found the smoking gun of autoimmunity in FM as well. They discovered that several autoantibodies were unusually high in people with FM, including those for:
None of these were found in every person with FM. Rates ranged from about 19% to 73%. 
Gangliosides may be an important aspect of FM autoimmunity. They’re believed to be involved in small-fiber neuropathy.
In a groundbreaking 2021 study, researchers took antibodies (immunoglobulin G, IgG) from people with FM and injected them into mice. The mice then:
Researchers say the FM IgG appeared to target white-matter brain cells (glia), gray-matter brain cells (neurons), and certain nerve fibers. This shows how immune system activity can cause neurological symptoms.

The ability to transfer FM like this is nothing short of revolutionary. On top of providing evidence about what’s causing symptoms, it could point to new diagnostic tests and treatments.

If more research validates findings of autoimmunity in fibromyalgia, it could lead to diagnostic tests. For a condition that’s currently a diagnosis of exclusion, that’s an important change.
Many immunosuppressive drugs for autoimmune diseases are already on the market. That greatly expands treatment options, especially since the drugs could be used off-label right away.
It remains to be seen whether current immunosuppressants are safe and effective for FM.
Several studies have now confirmed neuroinflammation in fibromyalgia. Some also have looked at where it is in the brain and what may be driving it.
Inflammation is a complex immune response to injury and infection. It’s a necessary function. But when it becomes chronic, inflammation causes tissue damage. It’s especially harmful in the nervous system.
The nervous system and immune system work together to create neuroinflammation. FM research links several cells and one molecule to the process.
Neurological components include:
Immune system components include:
A 2021 study looked at where brain inflammation is in FM. Researchers found several areas with abnormal inflammation compared with healthy people in the control group. Some of these areas play roles in functions that are often dysregulated in people with FM. They include:
They also found abnormally low inflammation-related activity in the:
Neuroinflammation in the amygdala, left medial frontal, and left superior parietal gyri was associated with higher pain scores. Neuroinflammation in the left amygdala, left medial frontal, and left superior frontal gyri was associated with higher stress responses, which included measures of fatigue, tension, frustration, depression, somatization, and aggression.
Inflammatory markers for fibromyalgia tend to be slightly elevated. But the cells and molecules involved in the neuroinflammation of FM may provide new diagnostic markers to look for.
Drugs that suppress microglia and astrocytes may be useful for treating neuroinflammation. They include:
Other existing treatments for neuroinflammation include: 
Several other drugs are under development for neuroinflammation, most of them developed as potential Parkinson’s disease treatments. Anti-inflammatory drugs are often prescribed for neuroinflammation as well. However, they’ve historically been considered ineffective for FM pain.
Small-fiber neuropathy (SFN) is nerve damage that’s only in the small sensory nerves of the skin. It’s probably best known in relation to type 2 diabetes.
As in FM, the pain comes and goes and is described as:
Also like FM, SFN involves the abnormal pain types hyperalgesia and allodynia. Hyperalgesia makes your pain signals more intense, basically “turning up the volume” of pain. Allodynia makes things hurt that shouldn’t, like a loose waistband or a hand rubbing lightly against your skin.
SFN and fibromyalgia also have these symptoms in common:
FM research suggests some damaged nerves are part of anti-inflammatory processes. That provides another explanation for neuroinflammation.
In most SFN, pain begins in the feet and then moves upward. It’s been thought that only a small percentage of SFN begins with bodywide pain. The association between SFN and FM, which by definition includes bodywide pain, could change that belief.
The typical diagnostic test for SFN is a skin punch biopsy. A small amount of skin is removed with a circular tool and examined under a microscope. The focus is on nerve fiber density in the skin.
SFN is treatable, and small nerves continue to grow throughout life. That means they can repair damage. Standard SFN treatments are already heavily used for fibromyalgia. They include:
In a pilot study, treatment with intravenous immunoglobulin (IVIg) has been shown to improve SFN in FM. This treatment is known to be effective against autoimmune-related neuropathy. Biopsies confirmed that nerves showed less damage after treatment.
Ganglioside autoimmunity may suggest treatment options as well. Gangliosides are suspected of being involved with diabetes-related small-fiber neuropathy. Some early animal research has suggested that ganglioside-targeted treatments may improve neuropathic pain.
Currently, researchers are working on drugs called ganglioside GM3 synthase inhibitors. Evidence suggests that these may work as both oral medication and topical treatments.
Research has uncovered evidence that FM is an autoimmune disease. Neuroinflammation and small-fiber neuropathy appear to be important elements of it. Autoantibodies could provide diagnostic markers for FM. Immunosuppressants may be treatment options. Neuroinflammation and SFN also offer potential diagnostic markers. Existing treatments are on the market. Some experimental drugs are in the works as well.
These findings are finally separating fibromyalgia from a past full of controversy, disbelief, and even scorn. While diagnostic markers and treatment options are all important advances, just having validation is something many people with FM have awaited for years or even decades. Advances in research could also potentially expand treatment options for people living with FM.
Fibromyalgia isn’t classified as a neurodegenerative disease (one that destroys parts of the brain). However, it’s possible that the immune and inflammatory processes now being uncovered can cause damage to certain cells or regions in the brain. FM has long been associated with reduced gray matter in the brain. However, some research suggests it’s due to low water content and not neurodegeneration.

No, autoimmune disease currently can’t be cured. It can be successfully treated, though. Treatment for most autoimmune disease is aimed at suppressing activity in the immune system. Other treatments may help with symptoms specific to each disease.
An FM flare is a more intense period of FM symptoms. Pain and fatigue get significantly worse. You may be lethargic, unable to focus or absorb information, and have a harder time sleeping. However, FM has so many potential symptoms that it’s hard to say how one person’s flare may compare with someone else’s.

Fibromyalgia hurts so bad because neuropathy is often intensely painful. Allodynia means the nervous system interprets normal signals as painful. Hyperalgesia “turns up the volume” on pain signals, worsening pain from neuropathy, allodynia, and any other sources (such as a bad back or injury).

Learn about treatment and lifestyle changes to cope with fibromyalgia and chronic fatigue syndrome.
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