Theories on Causes


Presentation by Valeria Giorgi; Report written by Janice Sumpton

This paper addresses the theories on causes of fibromyalgia discussed at the 2021 International Virtual Congress on Controversies in Fibromyalgia.  Keep in mind these are theories and that context is important. The size of the study can make a huge difference in the results. Research study sizes should  be neither too big nor too small since both have limitations that can compromise the conclusions drawn from the studies. If a study is too small it may prevent the findings from being extrapolated (or being able to predict if the results are accurate). If the study is too large, it may amplify the results in a way that is not clinically relevant.  These theories show there is still a long way to go before a definitive cause is found for fibromyalgia. 

Role of Genetics in FM:

  • Overall estimated heritability of 13.9% in 26,749 pts with FM
  • Younger pts (≤ 50yr) had a much stronger genetic component to their FM score 23.5% and FM pts (> 60yr) had the lowest (7.5%).
  • The FM score did not differ significantly by sex

Reference: Dutta D. et al. Heritability of the Fibromyalgia Phenotype varies by age. Arthritis Rheumatol 2020;72:815-23.

Interplay of Central and Peripheral Nervous Systems:

  • Interplay between potential mechanisms causing FM and nociplastic changes in FM
  • The grey boxes show different possible causes of FM (slide photo below)
  • The red boxes show major nociplastic changes* 
  • There is a reciprocal relationship both top down and bottom up (eg: increased pain perception negatively affects sleep)

*Nociplastic Pain Definition: A clinical definition of pain arising from altered nociception despite no evidence of tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing pain.

Reference: Kosek E et al. Pain 2016;157:1382-1386.

Reference: Sarzi-puttini P et al. Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat Rev Rheumatol 2020;16:645-660.

The Gut Microbiome and Its Biomarkers:

  • Systematic review on FM and relationship to the gut microbiome +/or biomarkers of gut bacteria 
  • 11 studies that included 618 FM pts and 635 controls (no FM)
  • 5 broad areas of research in this review include Helicobacter pylori, gut microbiota, metabolomics, intestinal hyperpermeability and small intestinal bacterial overgrowth
  • As yet no single gut-FM biomarker has been identified and validated
  • More study is needed

Reference: Erdrich S et al. Determining the association between fibromyalgia, the gut microbiome and its biomarkers: a systematic review. BMC Muscul Dis 2020;21:181.

Role of Mast Cells:

  • From skin biopsies of FM pts there was an increase in mast cells, Corticotropin Releasing Hormone (CRH) and Substance P
  • The activation of the mast cells releases cytokines and lipids that can increase low-grade inflammation
  • Stress can result in the generation of CRH

Reference: Conti P et al. Impact of mast cells in fibromyalgia and low-grade chronic inflammation: can IL-37 play a role? Dermatol Ther.  2020;33(1):e13191.

A Small Study looked at Comorbidity of mood disorders:

  • bipolar and panic disorder was found in 46.6% (55/118) of FM pts
  • if you expand to include pts with minor bipolar disorder and subthreshold panic then comorbidity of psychiatric disorders increased to 68.6% (81 of 118 pts with FM).

Reference: Alciati A et al. Comorbidity between bipolar and panic disorder in fibromyalgia syndrome. JClin Med 2020;9:3619

Small-Fibre Neuropathy and Neuropathic Pain: Differential Diagnosis and Therapeutic Approach – presented by Andrea Truini

  • 57 FM pt had skin biopsies to determine if small-fibre pathology leads to clinically important somatosensory stem abnormalities
  • 30% of pts had a small-fibre pathology
  • Found negligible impact (eg. FM pts with small-fibre pathology did not show any sensory deficits therefore, existence of small-fibre neuropathy likely does not play a noteworthy role in symptoms of FM

Ref: Fasolino A et al. Small-fibre pathology has no impact on somatosensory system function in patients with fibromyalgia. Pain 2020;161(10):2385-2393.