Stimulated by Clauw et al 2023 and Cho et al 2023.[1,2]
FM – fibromyalgia
key to acronyms
IF – impact factor
SGC – satellite glial cell
DRG – dorsal root ganglion
MSK – musculoskeletal
HR – hazard ratio
aHR – adjusted hazard ratio
I was curious to see this debate on FM published in Autoimmune Reviews (IF 13.6) at the end of August,[1] and I thought it was ironic that on the same day a huge retrospective cohort study from Korea addressed a related theme in the American Journal of Ophthalmology (IF 4.2).[2]
I have followed the fascinating research that has identified IgG in the serum of FM patients that seems to activate SGCs in DRGs (see Transfer of FMS with IgG),[3] and subsequent research correlating the levels of these antibodies with severity of symptoms (See FM and anti-SGC IgG 2023).[4] So, I was surprised to see a famous name in the pain world dismiss this research because “…these studies are not likely to be helpful in determining whether FM is an autoimmune disease” and if FM is an autoimmune disease, “Then so is headache, irritable bowel, TMD, and low back pain – because it is widely acknowledged that the pathophysiology of these pain syndromes is similar.”
It is always dangerous to rely on a phrase like ‘widely acknowledged’, particularly when your antagonist has cited clear experimental data in support of the need to rethink the current dogma. It is annoying that this new data does not fit with the current categorisation of FM as a form of nociplastic pain, and that ICD-11 has only recently (early 2022) introduced the term chronic primary pain (See Chronic primary MSK pain 2022) especially for conditions like FM, where a focal cause is elusive.
That brings me to the second paper on FM to pop up on the 25th August. This one involves the entire population of Korea between the years 2012 and 2021, of whom, 606 153 had a diagnosis of FM. 102 900 had a prior diagnosis of FM during the washout period of the study, leaving 479 892 newly diagnosed with FM during the study period. An age and sex matched random sample of patients who had sought consultation for a pain condition but not been diagnosed with FM served as the control.
The outcome of interest was the incidence of optic neuritis in these groups, and this proved to be considerably higher in the patients diagnosed with FM (HR 2.11). In their discussion the authors suggest this result can be explained by the common pathophysiology of autoimmunity-related neuroinflammation between the two diseases.
The increased incidence of optic neuritis was slightly higher in men than women and peaked in men in their 60’s (aHR 3.37) and women in their 20’s and 30’s (aHR 2.07). The authors suggest a fall in testosterone may be implicated in men, since this hormone has myelin-repairing and anti-inflammatory properties. The case for women is unsurprisingly more complex. Oestrogens have antioxidant neuroprotective effects on the optic nerve, so one might expect a similar pattern of risk to that in men; however, in FM growth hormone deficiency is common, and this can lead to a reduction in the production of female hormones. This effect of growth hormone deficiency is likely to have a bigger impact on female hormones when their production is highest ie in early adulthood, hence the higher relative incidence in earlier adulthood.
This is observational data, so comes with all the relevant caveats, but an increased risk of over 2-fold is hard to dismiss. I think we need a Mendelian randomisation study to probe for causative links, but in the meantime, I am happy to bang an iconoclastic drum supporting FM as an autoimmune disorder in earshot of the conservative pain hierarchies who invented nociplastic pain and chronic primary MSK pain, two labels we don’t really need if we examine our patients properly.
References
1 Clauw D, Sarzi-Puttini P, Pellegrino G, et al. Is fibromyalgia an autoimmune disorder? Autoimmun Rev Published Online First: 25 August 2023. doi:10.1016/j.autrev.2023.103424
2 Cho HR, Lee GK, Lee J-Y. Increased risk of optic neuritis in patients with Fibromyalgia: nationwide population-based cohort study in South Korea. Am J Ophthalmol Published Online First: 25 August 2023. doi:10.1016/j.ajo.2023.08.015
3 Goebel A, Krock E, Gentry C, et al. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest 2021;131:144201. doi:10.1172/JCI144201
4 Krock E, Morado-Urbina CE, Menezes J, et al. Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms. Pain 2023;164:1828–40. doi:10.1097/j.pain.0000000000002881
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