Fibromyalgia – Are it (and ME/CFS) Autoimmune Diseases?

Geoff’s Translations

The GIST

 

Redefining Chronic Pain

Andreas Goebel of the Pain Research Institute at the University of Liverpool has been trying to redefine how we think about chronic pain for about 20 years. His journey began with a 2010 complex regional pain syndrome (CRPS) paper, which proposed that an autoimmune subgroup was present, included studies suggesting that immune treatments such as plasmapheresis and IVIG are helpful in CRPS, and most recently found that the transfer of IgG serum from fibromyalgia patients into mice replicated most of the FM symptoms in the mice.

Since then, several studies have found that passive transfer of serum from ME/CFS or long-COVID patients into mice or culture has replicated the symptoms or findings in those diseases.

This year, Goebel asked, in “Fibromyalgia syndrome—am I an autoimmune condition?“, the $64,000 question. It’s been asked before – repeatedly in ME/CFS, in particular, but more recently in fibromyalgia (FM) – and still we have no clear answer.

It seems strange that such a fundamental category – autoimmune disease – still has so much grayness to it. Maybe it’s just the nature of our complex immune system to not fit easily into boxes, or maybe the grayness, at least in part, is being driven by diseases like fibromyalgia, ME/CFS and long COVID which seem to defy traditional categorizations and are slowly tearing them apart.

A Short History of Autoimmunity

More than 80 kinds of recognized autoimmune conditions exist, and some researchers count up to 105. Despite all the studies (actually because of them), no consensus exists on exactly what constitutes an autoimmune illness. Disagreements on whether autoantibodies are driving autoimmune diseases, or are simply present, are not uncommon.

Progress in the medical field usually results in more precise definitions, but just the opposite has happened in autoimmunity. Instead of making autoimmunity more exclusive, Rose and Bona’s 1993 definition of autoimmunity opened up the criteria for it.

Wibetsky’s 1957 postulates had required that free circulating antibodies, a specific autoantigen that produced the same antibodies in animals, and specific physical changes be present.

Over time, though, Wibersky proved to be too restrictive. Rose and Bona asserted that, instead of requiring specific changes, researchers should examine the general body of evidence. The emphasis on identifying the autoantigens causing the problem was dropped.

Instead, a far simpler test case consisting of direct, indirect, and circumstantial evidence was proposed. They argued that the most compelling case for an autoimmune disorder (direct evidence) occurs when transferring an immune factor – like IgG antibodies or T-cells – into another human, animal, or culture, causes evidence of the disease in them. Next comes indirect evidence, which involved producing the same result in another animal using a specific autoantigen. Finally comes circumstantial evidence, such as finding autoantibodies, white blood cells infiltrating tissues, and a positive response to a drug.

ME/CFS – A Little History

After finding high levels of some autoantibodies, Klein and Berg, thirty years ago, proposed that ME/CFS (chronic fatigue syndrome) was a “psycho-neuro-endocrinological autoimmune disorder“. The next year, after Konstantinov et al. found increased levels of autoantibodies to nuclear envelope proteins, they proposed they had uncovered an “autoimmune component” in ME/CFS. The very next year, a high frequency of autoantibodies to insoluble cellular antigens was suggested to differentiate ME/CFS from other “rheumatic autoimmune diseases“.

More recently, a 2018 article from Euromene, “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease“, stated, “there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology.”

That same year, stating, “we think that a solid understanding of ME/CFS pathogenesis is emerging”, Blomberg et al. proposed that an infection initiates an autoreactive process in the B-cells in ME/CFS, fibromyalgia, and similar diseases.

Fibromyalgia – A Little History

On the fibromyalgia side, after finding high levels of anti-DFS70 antibodies, a 2019 Korean study proposed it may have found a “biomarker for differentiating between FM and other autoimmune diseases”.

By 2021, Martinez Lavin was asking, “Is fibromyalgia an autoimmune disorder?“, and in 2022, Shoenfeld was so convinced that FM, ME/CFS, etc., were autoimmune that he proposed a new entity called “autoimmune autonomic dysfunction syndromes” be created.

Things got so controversial that last year Shoenfeld and Daniel Clauw publicly debated the autoimmune question in, “Is fibromyalgia an autoimmune disorder?“. Meanwhile, also last year, Italian researchers proposed in “Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review” that FM is probably an immune-driven and often post-infectious disease.

Fibromyalgia – Are You an Autoimmune Condition”?

This year, with some new findings under his belt, Goebel asked, “Fibromyalgia syndrome—am I an autoimmune condition?”

According to Goebel, Rose, and Bona’s model provides strong evidence that fibromyalgia is an autoimmune disorder. Antibody transfer studies that have replicated symptoms in animals or produced changes in culture in FM (as well as ME/CFS and long COVID) provide direct evidence that autoimmunity is present.

Following his successful antibody transfer studies in complex regional pain syndrome, Goebel found that transferring IgG from UK and Swedish FM patients resulted in increased pain sensitivity, reduced grip strength, reduced activity, and mild damage to small nerve fibers.

Digging deeper, Goebel’s team found that the IgG antibodies from the FM patients were clustered on and presumably attacking the dorsal root ganglia (DRG) – the bundle of sensory neurons located just outside of the spinal cord through which the signals from the body flow. If you want to dysregulate pain signals from the entire body, the DRG would be the first place you might want to attack.

Glial Cells Implicated

It got better – the IgG antibodies congregated on the satellite glial cells found on the dorsal root ganglia. These glial cells – which have some similarities to microglial cells in the brain – protect, support, supply nutrients to, remove waste products from, and sometimes excite the cell bodies of sensory neurons – causing pain. Hyperactive glial cells are considered to play major roles in chronic pain, and efforts are underway to find ways to calm them down.

Critically, no IgG antibodies were found in the spinal cord or brains of the mice given the FM IgG. This is presumably a good finding as it suggests that getting drugs to these protected areas may not be necessary.

The next FM IgG transfer study largely supported Goebel’s findings. Using an “optimized protocol” and a much larger Canadian and Swedish fibromyalgia cohort, Camilla Svensson’s lab found that the degree of IgG binding to cultured SGCs correlated moderately with the patients’ pain intensities.

Directly looking for anti-satellite glial cell antibodies, she found they were associated with increased pain but that only the severe FM group had significantly elevated anti-SGC antibodies compared the mild FM group and healthy controls. She concluded:

“pathogenic autoantibodies either underlie FM in a subgroup of patients or are present at concentrations too low to be detected in our assays in individuals with mild disease.”

Noting that 60% of FM patients have small fiber neuropathy (and 40% don’t), she suggested that “multiple overlapping disease mechanisms,” including high anti-SGC antibodies in some patients, are likely contributing to FM.

Svensson’s findings suggest that the conception of FM as a purely central nervous system disease is outdated. For instance, something called “central pain inhibition (CPI) ” – which concerns the ability of the central nervous system to inhibit pain levels – was not affected at all by the antibodies. Indeed, FM studies indicate problems with central pain inhibition play a role in some FM patients but not others; i.e., not all the pain in FM may be driven by problems in the brain.

Goebel’s and Svensson’s findings suggest why central nervous system drugs used in FM, such as Lyrica, Cymbalta, and Gabapentin, can be so ineffective at times. They believe that a large subset of FM patients will benefit from drugs that affect the immune system in the periphery (the body) – not the central nervous system.

Indeed, evidence of immune dysregulation in FM continues to emerge. Verma’s 2022 Canadian study uncovered hyperactivated but exhausted immune cells and natural killer cells. These cells appear to be turning on macrophages which then attack the small nerve fibers.

The authors proposed that the peripheral nerves in FM are chronically expressing factors that draw the NK cells to attack them. Their idea that a chronic or latent infection of the nerves or an IgG-initiated upregulation of the sensory nerves brings FM, after decades of focus on the central nervous system, closer to the current conceptions of ME/CFS and long COVID.

Inflammation, Autoimmunity, FM and ME/CFS

On the other hand, the fact that large amounts of systemic inflammation are not present in FM, ME/CFS, and similar diseases suggests that these conditions are not autoimmune disorders. Some autoimmune diseases, however, do produce localized inflammation, and Goebels argues that localized inflammation of the sensory nerves in FM is driving the disease.

Daniel Clauw, a rheumatologist and prominent FM researcher, has pooh-poohed the autoimmune connection, saying FM looks nothing like autoimmune disease. He has relayed that FM appears to be an oddball disease to rheumatologists, who mainly treat autoimmune diseases, and noted that the FM autoimmune charge is not led by people who treat autoimmune diseases.

While Clauw agrees that “sub-clinical inflammation” is present in FM, he notes that it’s not comparable to the systemic inflammation found in autoimmune disorders, and that neither anti-inflammatory nor autoimmune drugs used to treat autoimmune disorders are effective. Additionally, no tissue damage has been found that should be caused by an autoimmune attack.

With regard to the studies showing that serum from fibromyalgia largely replicates the disease in animals, Clauw reports that this process has rarely been found in “acknowledged autoimmune disorders” and doesn’t believe a good FM animal model is present, anyway.

Clauw may agree that localized inflammation may be present, but he clearly objects to characterizing FM as an autoimmune disease. Indeed, he believes that doing so makes a mockery of the term. Clauw believes FM is still best understood as a central nervous system disorder.

Treatment

The immune/autoimmune/central nervous system conceptions of FM and similar diseases have vast repercussions for them. An autoimmune conception of these diseases opens the door to one set of treatments, while a central nervous system conception opens the door to a mostly different set.

Goebel does not, in his short paper, discuss which drugs might be helpful in FM. While Clauw does not find autoimmune drugs useful, he does leave the door open for peripherally acting immune drugs like interleukin-6 (IL-6) and Janus kinase (JAK) inhibitors.

Verma (who also participated in Goebel’s paper) suggests that elevated levels of anti-SGC IgG could identify FM patients who might benefit from B-cell-depleting drugs, IVIG, or plasmapheresis. IVIG was the most efficacious treatment found in a recent large ME/CFS survey. In a pilot study, a different B-cell depleter, daratumumab, proved very effective in about half of ME/CFS patients.

That’s probably no surprise to Goebel, who, way back in 2010, proposed in “Immunoglobulin responsive chronic pain” that IVIG would be helpful in some chronic pain conditions. In a 2008 trial, IVIG (400 mg/kg daily for 5 days) reduced pain and tenderness and improved strength in FM patients with small fiber neuropathy (demyelinating polyneuropathy). A very small (n=7) 2020 IVIG trial found that IVIG improved FM symptoms and small fiber neuropathy as well.

We’re at the tip of the iceberg in understanding what role immune modulators will play in these diseases. If Goebel is right, they’ll play a major role in treating it. If Clauw is right, they won’t.

All in all, we should probably hope that Goebel is correct, as the number of immune-affected drug possibilities and trials far exceeds those focused on the central nervous system.

While some treatments span categories (rapamycin, besizterim, sipavibart, low dose naltrexone), current central nervous system trials in these diseases are focused mostly on rather tired antidepressant, brain stimulation and mind/body approaches. Ketamine, psilocybin and tFUS bring some new approaches, however.

https://www.healthrising.org/blog/2025/06/22/neuroinflammation-tfus-jarred_younger/

A much larger array of immune-modulating or antiviral drugs is being tested, mostly in long COVID. They include baricitinib, rapamycin, daratumumab, IVIG, plasmapheresis/immunoadsorption, sipavibart, bezisterim, leronlimab, maraviroc, Ensitrelvir, remdesivir, tocilizumab, etanercept, rovunaptabin, Rituximab, and others.

With quite a few drug trials underway, long COVID – the symptomatic sister to both ME/CFS and FM – will help our understanding of all of them.

So, in some ways, we’re back to where we started. Neither FM nor ME/CFS nor long COVID fit traditional illness categories. Fibromyalgia has never fit well into the rheumatological camp – something that some rheumatologists have made clear to their FM patients for a long time – and (as evidenced by their lack of a home at the NIH) ME/CFS and long COVID don’t fit anywhere either. Either the traditional illness categories need to be stretched or reimagined to accommodate these diseases or new categories of illness need to be found.

•  Coming up next: Digging deeper – the IgG antibody connection resolved?