Fibromyalgia is an autoimmune condition that causes pain all over the body. Does studying its mechanisms point the way to treatment options for sensory difficulties that can affect people on the autism spectrum? Dr Ben Marlow reports
In my last article in the autumn edition of Autism Eye Magazine, I discussed the use of metabolic analysis to demonstrate the impact of the body’s stress response at the start of life.
I detailed how this study showed in autistic participants compared to age-matched controls, and that this stress response was still evident at the age of five. The urine analysis showed increased levels of fatty acid oxidation among the autistic participants. It also showed a significant increase in stress response metabolites such as lactate, glycerol and alanine.1
What happens beyond those five years if that stress level continues, and what is its impact on the endocrine, metabolic and immune systems? Increasingly, researchers are publishing evidence of chronic health issues manifesting in adolescents and adults on the autism spectrum. In a paper in 2023, Professor Baron-Cohen’s team at ARC Cambridge showed that a number of health challenges are more prevalent in the autistic population.2
In my own clinic, I often see chronic clinical diagnoses involving the immune system. Autism researchers have pointed towards the idea of a ‘trained innate immune system’ in early life3, meaning our early cellular response to pathogens (viruses/bacteria) is overexaggerated and struggles to turn off.
This leaves the immune system metabolically stressed (from overuse). The overactivity also impacts cellular communication with the adaptive part of our immune system (particularly our antibody responses).
Autistic individuals display tendencies to overexaggerated responses to their environment, such as with food (intolerances), hormones (adrenaline) and pathogens in an augmented ’fight or flight’ state. This can activate our immune system and keep our bodies over-communicating danger signals. The theory is that our adaptive immunity, which is continually looking to recognise infections and protect us by producing antibodies, can begin to lose control and start producing antibodies against our own tissues. This, in turn, leads to the problem of ‘autoimmunity’.
Papers have demonstrated that mothers with poorly controlled autoimmune disease have an increased risk of their offspring having a neurodevelopmental disorder4. Studies also show that autistic individuals have a higher incidence of autoimmune disease, such as inflammatory bowel disorders, psoriasis and arthritis.5
In the clinic, I see a lot of older children who have a number of these chronic health problems. Due to the challenges of communication, body awareness and atypical presentations of these issues, reaching a diagnosis/treatment plan can difficult. I have found adolescent girls, in particular, to have a profile of ‘metabolic burnout’: chronic fatigue, brain fog, joint pain/inflammation and signs of fibromyalgia (increased pain/stiffness of muscles).
Fibromyalgia, also called fibromyalgia syndrome (FMS), is listed as a ‘Central Sensitisation Syndrome’, linked to other disorders such as migraine and interstitial cystitis. Symptoms of fibromyalgia include hyperalgesia, which is having an increased sensitivity to pain. It’s often referred to as ‘turning up the volume’ of pain.
There also can be allodynia, which is feeling pain from things that shouldn’t hurt, such as the brush of fabric against your skin, or your arm resting against your side when you sleep. Typically, this presents as augmented pain sensitivity to mechanical pressure and cold temperatures.6
Proposed mechanisms for fibromyalgia include autonomic nervous system dysfunction, dysregulation of the HPA axis (stress response) and inflammation, with increasing evidence towards an autoantibody pathology – in other words, that it is caused by a malfunctioning part of the body’s natural defences.
The increased sensitivity to a range of stimuli, such as heat and touch, experienced by those with fibromyalgia is associated with altered pain processing in the central nervous system. It is also associated with dysfunctional descending pain modulation – in other words, the body not being in full control of the pain response – and structural/functional changes in the brain.7
Dr Andreas Goebel, of the Walton Centre NHS Foundation Trust, and his team were keen to test the theory that due to the association of fibromyalgia with female patients (eight out of 10 sufferers are female) and autoimmune disorders (10-30 per cent of fibromyalgia sufferers) it may have an autoimmune base.
Immunoglobulin (Ig), purified from fibromyalgia patients, was transferred to mice. Then, a number of markers were measured. Hypersensitivity to mechanical pressure and the cold were significantly elevated compared to controls from the transfer of Ig purified from non-fibromyalgia patients. This also correlated with increased sensitisation of nociceptor C-fibres, demonstrated on mechanical activation in mice with Ig transferred from FMS patients. These symptoms in the mice fully resolved 2.5 weeks after the cessation of Ig administration, consistent with the time course for the elimination of Ig from mice.
The study also showed (via the use of staining methods to visualise fibromyalgia immunoglobulin) that the antibodies localised to the dorsal root ganglion (DRG), but neither directly to the spinal cord or brain. At the DRG, these antibodies were shown to increase activity of satellite glial cells (SGC) and bind sensory neurons, but they didn’t induce cytokine production or systemic inflammation.
The conclusion reached was antibody-dependent processes underpin the characteristic tenderness and thermal hypersensitivities experienced by fibromyalgia patients. It also showed that fibromyalgia IgG bound to SGCs and neurons in both mouse and human DRG, not localising to brain nor spine, therefore caused symptoms through peripheral mechanisms. This suggests that IgG peripheral sensitisation leads to characteristic altered CNS function; altered brain activity patterns, glial activation and multisensory hypersensitivity seen in fibromyalgia.7
Why this matters
Potentially, therapies that reduce total immunoglobulin (Ig) titre (plasmapheresis or immunoadsorption) may be effective for fibromyalgia. It may also be effective to use therapies that bind autoreactive antibodies (monoclonal antibodies), which we see being increasingly used for other autoimmune disorders.
It also raises the question whether other dysregulated sensory difficulties seen in autism (such as oversensitivity to hearing, taste or smell) may be driven by an autoimmune condition. If this is proven to be the case, they may be more amenable to pharmacological treatment, alongside more supportive management with strategies such as occupational therapy or sensory integration.
It also may help explain why some complex children with severe hypersensitivities never ‘de-sensitise’, even with graded exposure. Further research in this area is vital, as these sensory difficulties play such a huge role in limiting an autistic individual’s basic access to inclusion, learning and quality of life.
REFERENCES
1 Lingampelly, SS, Naviaux, JC, Heuer, LS et al: ‘ Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder,’ Commun
Biol 7, 536 (2024). https://doi.org/10.1038/s42003-024-06102-y
2 Ward, JH, Weir, E, Allison, C et al: ‘ Increased rates of chronic physical health conditions across all organ systems in autistic adolescents and adults,’ Molecular
Autism 14, 35 (2023). https://doi.org/10.1186/s13229-023-00565-2
3 Jyonouchi H, Sun S, Le H: ‘Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism
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4 Zawadzka A, Cieślik M, Adamczyk A: ‘The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and
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https://pubmed.ncbi.nlm.nih.gov/34768946/
5 Meltzer, A, Van de Water, J; ’The Role of the Immune System in Autism Spectrum Disorder,’ Neuropsychopharmacol 42, 284–298 (2017).
https://doi.org/10.1038/npp.2016.158
6 Goebel A, et al: ‘Passive transfer of fibromyalgia symptoms from patients to mice,’ J Clin Invest. 2021 Jul 1;131(13):e144201. doi: 10.1172/JCI144201. PMID:
34196305; PMCID: PMC8245181. https://pubmed.ncbi.nlm.nih.gov/34196305/
7 Schrepf A, et al: ‘Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study,’ Pain. 2016;157(10):2217–2225. doi: 10.1097/j.pain.
https://pubmed.ncbi.nlm.nih.gov/27420606/