Inflammation-induced pain and fatigue in fibromyalgia and ME/CFS and role of variant connective tissue, 2023, Eccles, Harrison, Davies et al

[Tom Kindlon]

https://ard.bmj.com/content/82/Suppl_1/129.2

Inflammation-induced pain and fatigue in fibromyalgia and ME/CFS and role of variant connective tissue

J. Eccles1 , M. Amato1 , K. Themelis2 , L. Quadt2 , H. Critchley1 , N. Harrison3 , K. Davies4 .

1 Brighton and Sussex Medical School, Neuroscience, Falmer, United Kingdom; 2 University of Warwick, Psychology, Coventry, United Kingdom; 3 University of Cardiff, CUBRIC, Cardiff, United Kingdom; 4 Brighton and Sussex Medical School, Clinical and Experiemental Medicine, Falmer, United Kingdom

Annals of the Rheumatic Diseases 2023;82:129.

Abstract

Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathophysiological mechanisms are under debate. It remains unclear whether dysregulated inflammation, induced either by an exogenous stimulus (eg a virus or other stressor), or autoimmunity, is of prime importance [2].

Objectives: 1. To determine in a novel human model the effects of an in vivo inflammatory challenge in the induction of pain and fatigue in fibromyalgia and ME/CFS compared to controls. 2. Explore potential mediators and moderators involved.

Methods: Data were available for 48 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 22 matched controls, who had undergone a placebo controlled inflammatory challenge (typhoid vaccination) as part of ISRCTN78820481. Participants underwent full research diagnostic evaluation including a hypermobility assessment. Subjective pain and fatigue were assessed after saline injection and typhoid vaccination (VAS). Linear regression models were used to explore predictors, with adjustment for potential confounders (age/gender) and baseline levels as appropriate.

Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1) pain and 2) fatigue induced by challenge and mediators/moderators included change in IL-6 induced by inflammatory challenge and hypermobility features.

Results: Being a patient rather than control significantly predicted inflammation-induced fatigue (B=14.89 (95%CI 3.29-26.50), t=2.56, p=0.013) and pain (B=12.88 (95%CI 0.65-25.10), t=2.11, p=0.039) after adjusting for levels induced by placebo.

Induced pain was independently predicted by level of IL-6 induced by inflammatory challenge (B=23.44 (95%CI 5.15-41.72),t=2.57, p=0.013) as was induced fatigue (B=10.63 (95%CI 2.84-18.41), t=2.73, p=0.008) Mediated moderation analyses suggested the link to induced pain and fatigue through induced inflammation was associated with hypermobility features (Index of mediated moderation 11.02 (95%CI 1.45-22.73) and 6.20 (95%CI 0.07-13.64) respectively))

Conclusion: To our knowledge this is the first human study to evaluate directly the effect of an exogenous inflammatory challenge (typhoid vaccination) in a combined group of Fibromyalgia and ME/CFS patients. Il-6 was shown to be a critical mediator. This work strongly supports the hypothesis that inflammation is key to the pathophysiology of ME/CFS. We are evaluating associated CNS inflammation in the model, as well as other associations, such as autonomic dysfunction and hypermobility. Further understanding the mediators involved in the condition should in future open the way to testing targeted anti-inflammatory therapy.

 

[Jonathan Edwards]

I don't think this tells us anything other than that if you are a patient with ME or fibromyalgia it is a worse experience being given typhoid vaccine - which would be unsurprising for all sorts of reasons. I suspect it would be worse for people with MS or motor neurone disease or lots of other things. I don't think it tells us anything about ME.

I also think there is a huge problem with expectation here. If you are a patient your expectations will be different from if you are a healthy control. If you have been told you have hypermobility your expectations are likely to be different again. The hypermobility gurus provide their patients with all sorts of expectations - with little or no evidence base.

 

[Tom Kindlon]

The results are supposedly based on some sort adjustment for placebo. Hopefully there will be a full paper with more info on all the details.

 

[Jonathan Edwards]

The results are supposedly based on some sort adjustment for placebo.

Yes, but I don't think that impacts on my concerns at all. Most people can tell the difference between a typhoid jab and a dummy - which would be a sort of nocebo if anything I guess.

The abstract does not say anything about PWME having higher inflammatory mediator responses as far as I can see. We would expect people with higher responses to feel worse symptoms - as is found - but there is no particular indication that this is different for ME? I get the impression that they are trying to wring some interesting results out of some old data that did not show the things that would really have explained what is going on in ME - like much higher CRP responses across the board, for instance.

 

[AknaMontes]

Is it not obvious from all the other research to date that ME is far more complex than just inflammation?!

 

[Jonathan Edwards]

It might be much simpler, @AknaMontes !

 

[Hutan]

The abstract does not say anything about PWME having higher inflammatory mediator responses as far as I can see.

Yes, although it does say that being a patient predicted levels of pain and fatigue, and that pain and fatigue was predicted by post-injection IL-6 levels.

Induced pain was independently predicted by level of IL-6 induced by inflammatory challenge (B=23.44 (95%CI 5.15-41.72),t=2.57, p=0.013) as was induced fatigue (B=10.63 (95%CI 2.84-18.41), t=2.73, p=0.008)

I assume from the absence of a statement about IL-6 levels in the patients that pre- and post-injection levels of IL-6 probably weren't statistically different in patients as compared to controls - but it will be interesting to see the whole paper. The sample size is quite small, especially the control group, given there is the typhoid injection and saline placebo arms - that might have affected the ability to find something statistically significant.

It's an interesting question - do people with ME/CFS have an unusual response to an immune challenge? Has that been looked at before?

 

[SNT Gatchaman]

do people with ME/CFS have an unusual response to an immune challenge? Has that been looked at before?

Not sure if you mean pain response or more generally an abnormal immune response to challenge. From Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations (2020, The Journal of Clinical Investigation, thread 1, thread 2) —

Changes in T cell metabolism are driven by specific signaling pathways and are highly regulated. Proper metabolic programs at rest and following an immune challenge are essential for optimal T cell effector function, proliferation, and viability.

Dysfunction in immunometabolism can contribute to the establishment and/or maintenance of human disease. Increased T cell metabolism or ROS production can contribute to inflammation and/or autoimmunity. Conversely, hypometabolism, or a failure to increase metabolism following an immune challenge, can help maintain a chronic infection or cancer progression. Specifically, chronic infection can lead to T cell exhaustion, in which metabolism and, in turn, effector functions are impaired.

Concluding —

It is clear that the immune system plays a role in ME/CFS. Our data indicate that there are existing reductions in resting T cell metabolism in patients. In particular, CD8+ T cells had altered mitochondrial membrane potential and an impaired metabolic response to activation. Both CD4+and CD8+ T cells had significant reductions in glycolysis. This hypometabolism in T cells aligns with other findings of hypometabolism in ME/CFS cells. Furthermore, patients with ME/CFS appeared to have altered relationships between plasma cytokine abundance and T cell metabolism, in which proinflammatory cytokines unexpectedly correlated with hypometabolism. Such a dysregulation may indicate that ME/CFS T cells have lost responsiveness to some proinflammatory cytokines. Along with hypometabolism in immune cells, this is consistent with a possible ongoing infection, though such an infectious agent has not yet been identified. A high priority moving forward will be to determine the mechanism behind hypometabolism in ME/CFS T cells as well as how altered metabolism affects the function of these cells.

 

[SNT Gatchaman]

See also
Altered immune metabolism in myalgic encephalomelitis/chronic fatigue syndrome (2019, PhD thesis related to above)
Abnormal immune system response in the brain of women with Fibromyalgia after experimental endotoxin challenge (2023)

 

[DMissa]

impaired metabolic response to activation.

The kinetics of transient activation by immunological stimulus are different between individuals. And yes this extends to cells in vitro, we have seen it in the lab. Without a time-course that captures the curve for each individual it's therefore hard to know what to make of results obtained at only one time point after transient stimulation. Have a look at supplemental figure 1. See the big spread in data points when the samples were activated? That is possibly because at the time of measurement, each sample is sitting at a different point in their personal response curve to the stimulus. Some may be before, at or around, or after their peak response, to varying degrees in each case. Overnight stimulation is long enough that each of these possibilities seems reasonable.

 

[Hutan]

Not sure if you mean pain response or more generally an abnormal immune response to challenge. From Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations (2020, The Journal of Clinical Investigation, thread 1, thread 2) —

It (the 2020 paper from Hanson's lab) is a really interesting paper, concluding as it does that CD8+ T cells have an impaired response to activation and that that is indicative of a chronic infection. A lot has been pointing in that direction lately - a chronic infection or the body thinking it has one. However, the researchers just stimulate the t-cells in vitro; I was thinking more of an immune challenge being applied to whole people, in vivo, as was done in the paper that is the subject of this thread.

 

[SNT Gatchaman]

Have a look at supplemental figure 1. See the big spread in data points when the samples were activated? That is possibly because at the time of measurement, each sample is sitting at a different point in their personal response curve to the stimulus.

Thank you.

We confirmed our activation method via flow cytometric analysis of the early activation marker CD69 on our cells (Supplemental Figure 1). Both ME/CFS and healthy control T cells had significantly increased CD69 MFI after overnight stimulation (Supplemental Figure 1). We did not always have a sufficient number of T cells to include a subject in every assay.

 

[Tom Kindlon]