There’s a big elephant in the room in both fibromyalgia (FM) and chronic fatigue syndrome (ME/CFS) and it’s women. The fact that a lot more women than men have these diseases must mean something, yet except for Dr. Klimas’s and Gordon Broderick’s modeling in ME/CFS, few have attempted to ask why.

These researchers do. In “Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia“, they assert that the gender imbalance tells us something vital about a disease that has often stumped the medical community.

bridging the gap

Do gender and autoimmunity hold the keys to fibromyalgia?

Fibromyalgia’s name suggests it’s a muscular disorder but it’s generally considered to be a central sensitization disorder.  It’s a neurological disease – or at least a disease with a large neurological component – treated largely by rheumatologists. It’s a real disease that all too many doctors shove into the psychosomatic slot.

One has to look no further than three FDA drugs approved for FM for evidence that the medical profession doesn’t have a handle on what’s going on. The fact that none work particularly well (30% of patients get about a 30% benefit, the authors report) suggests the drug manufacturers have been looking in the wrong places for the answer to FM.

The idea that FM is a typical central sensitization disorder (i.e. a central nervous system pain amplification disorder) doesn’t cut the mustard, either. Yes, they argue, pain amplification is present in FM, but not in the way most researchers think.

A Neuropathy-Induced Autoimmune Disease

Instead, they propose that FM is a “neuropathy-induced autoimmune disease”. These Mexican researchers believe that damage – perhaps even a small amount of damage – to nerve cells triggered the immune system to mistakenly attack the parts of the central nervous system that produce pain and other symptoms.

They’re definitely in the minority with their autoimmune hypothesis, but with autoimmune models emerging in ME/CFS, small fiber neuropathy, and postural orthostatic tacyhcardia (POTS), they may not be for long.

Damage to nerves fibromyalgia

The authors propose that nerve damage comes first – and kicks off an autoimmune process.

Autoimmunity has been discarded in FM, the researchers believe, because the inflammation found in FM is not similar to that found in many autoimmune diseases. The type of inflammation found in FM, they argue, however, is found in some autoimmune diseases. (In both MS and FM, the authors believe the inflammatory component researchers have long looked for does not show up in the blood because the disease is mostly taking place in the brain.)

Things Accumulate

Instead of being due to one specific cause, autoimmune diseases develop when risk factors accumulate. The authors

The authors laid out a number of factors which suggest an autoimmune process is present in fibromyalgia.

Being Female – Women may live longer than men but they’re also far more likely to come down with an autoimmune disorder. Approximately 80% of autoimmune patients are female.

It turns out that women are immunologically set up to have more issues with autoimmunity.

The ability to bear children has shifted women’s immune systems – making them more susceptible to autoimmune diseases. (Image by Dan Evans from Pixabay).

You can blame the kids.  The Th2 immune bias which assists with fetal health also enhances the humoral (antibody) portion of the immune system that triggers much autoimmunity.  Women also tend to have more of the immune cells that participate in autoimmunity while men tend to have more cells focused on keeping the immune system in check.

There is a plus side. Women, with their revved up immune responses, are generally better at fighting off infections.

Female Hormones – Estrogen, the main female sex hormone, is associated with enhanced antibody responses, and a reduced ability to filter out autoantibodies (weaker tolerance). Testosterone, the main male sex hormone, on the other hand, enhances immune tolerance (autoantibody removal) and reduces antibody production.

Male Trouble: the Testosterone Connection in Fibromyalgia

Age of Onset – The typical age of FM (and ME/CFS) onset – sometime in middle age – tracks with the authors’ autoimmune hypothesis, as well. Autoimmunity is a long process which often comes to fruition in middle age.

Increased Autoimmune Comorbidity – Autoimmune diseases like to play with each other and an astonishing array of  autoimmune diseases have been reported increased in FM (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjogren’s syndrome, vasculitis, polymyositis, spondylarthritis, inflammatory bowel diseases, celiac disease, and diabetes mellitus type 1).

Small Fiber Neuropathy (SFN) – a recent study suggests that the SFN commonly found in FM is very likely autoimmune in nature.

More Than Skin-Deep: The Small Nerve Fiber Problems in Fibromyalgia – A Review

Others – A 2019 study found that a substance called VGLL3 which regulates immune response genes (and has nothing to do with sex hormones) is more abundant in women.

The Gist

  • Fibromyalgia largely remains a mystery. We know that central sensitization is involved but how it came to be remains a mystery. Plus, other parts of the body are involved.
  • These researcher propose that FM is an “neuropathy-induced autoimmune disease”; i.e. the disease starts with damage to the nerves and over time morphs into an autoimmune disorder when the immune system responds incorrectly to the “cellular debris” produced during the nerve damage.
  • The authors note that women are much more likely to come down with FM and autoimmune diseases than men.
  • Women are immunologically and hormonally set up to have more problems with autoimmunity.
  • They produce more antibodies – the main drivers of autoimmunity – and are less effective at regulating them than men. (They also tend to be more effective at fighting off infections.)
  • They produce more estrogen – which increases the antibody response – and less testosterone – which dampens the antibody response – than men.
  • The common occurrence of FM during middle age also tracks with other autoimmune diseases.
  • The authors proposed that researchers screen tissues, blood and cerebral spinal fluid for evidence of autoantibodies.

An Autoimmune Model

These researchers propose that an infection or some other factor which damages the nerves starts the autoimmune process off. The damage in and around the nerve may not be large at all but if it liberates too many antigens (the structures on cells that antibodies latch onto) for an antibody-dominant, poorly regulated immune system to handle, trouble may follow.

Antibodies that attack our cells are formed all the time but our immune system has ways to filter them out. It can get overwhelmed when too many antigens are present and form antibodies which mistakenly attack our cells.

The authors believe something similar to FM is happening in multiple sclerosis (MS). Multiple sclerosis, they report, can, in its early stages, be “more or less” controlled with antiviral drugs like interferon. As the immune system reacts more and more to the “cellular debris” produced by the infection, the disease changes. What began as a pathogenic attack has morphed into an autoimmune reaction.

Continuous stress provides another way to feed an incipient autoimmune process because ongoing stress suppresses the immune response (including apparently the part of the immune response which removes autoantibodies) leaving the body more open to infections and autoimmunity.

Proving Autoimmunity

If FM is understood to be an autoimmune disorder, treatment options would greatly expand.  Proving that is going to take some doing, however, and we’ll see if the small FM research community responds to their call. The authors propose:

  • Screening the tissues in the nervous system that are involved in pain amplification for autoantibodies.
  • Screening of the blood and cerebral spinal fluid for autoantibodies or autoreactive white blood cells.

Time will tell if they’re right or not but the interest in autoimmunity in FM, ME/CFS and related diseases is growing. Check out some of the autoimmune doings going on in these diseases.

Autoimmune Doings In and Around Fibromyalgia

  • A small paper recently charted the positive effects IVIG had on small fiber neuropathy in FM.
  • Another study found that the type of small fiber neuropathy found in FM tends to be associated with autoimmune diseases.
  • Novel Sjogren’s Syndrome autoantibodies were recently found in about a third of FM patients.
  • Jill Schofield MD recently released a paper charting how she treats autoimmune small fiber neuropathy – a form of small fiber neuropathy that could be quite prevalent in FM and ME/CFS.
  • Jonas Bergquist has reportedly confirmed Carmen Scheibenbogen’s autoantibody findings in FM.
  • Dysautonomia International has launched an IVIG study in POTS – a disease with an apparently large autoimmune subset.

Treatment Takeaways

  • Given the rapid and ongoing development of drugs to treat autoimmunity, showing that FM is an autoimmune disease would likely greatly expand the treatments available.
  • A recent paper suggested that IVIG may be helpful for FM patients with small fiber neuropathy.

What is Fibromyalgia?

We’re left with the question: what is fibromyalgia? We know that central sensitization is present but why has that happened? And why is a peculiar form of small fiber neuropathy so common? How about the prominent gender imbalance? Why do so many people with other pain conditions develop FM? Why is migraine so common?

Mysteries abound in FM. Sympathetic nervous system activation, herpesviruses, mitochondrial problems, blood flows to the muscles, autoimmunity, hormonal issues, metabolic problems, etc. have all been posited to play a role.  What seems clear is that like ME/CFS, FM is a complex disease that affects many systems. Whoever figures out FM will have to account for all of that. Autoimmunity is one hypothesis which probably could.


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