L Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) latest paper from fluge and mella

Hufsamor

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https://www.jci.org/articles/view/1...2veCuFurNGqj7hWNr0A8QEWpXnqOyQDznQD8baDvjDYYY

Figure 1

Proposed model for ME/CFS pathomechanisms. We suggest three principal steps underlie the initiation and maintenance of ME/CFS. (i) Immune response after infection serves as a triggering event, with a role for B cells/plasma cells and autoantibodies in the underlying pathology. (ii) The vascular system and possibly GPCRs are potential targets for autoantibodies, which may affect endothelium or neurovascular control and autonomic small nerve fibers. The autoantibodies could be pathogenic IgGs or functional autoantibodies that normally occur after infection, but persist and fail to resolve over time. This disturbed homeostasis involves endothelial dysfunction in large and small arteries, impaired venous return and preload failure, and arteriovenous shunting, presumed to result in impaired autoregulation of blood flow and tissue hypoxia on exertion. (iii) Secondary compensatory efforts may add to the clinical presentation and symptoms. They include autonomic adaptations, often with increased sympathetic tone, and metabolic adaptations aiming to restore energy supply. Possible strategies for clinical trials targeting these pathways are also indicated.
 
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Possible strategies for clinical trials targeting these pathways are also indicated.
Thanks for posting!! Read thru this earlier today.

Very exciting the Progress We are Making. I think its significant progress!

Papers that suggest actual treatments! Wow what a concept!

I liked the calm logic of it all, even my husband was impressed with the figure and it made some sense to a lay person.

We must be able to at least reduce some of these auto antibodies and feel less awful. So: Make That Happen Please soon!
 
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This disturbed homeostasis involves endothelial dysfunction in large and small arteries, impaired venous return and preload failure, and arteriovenous shunting, presumed to result in impaired autoregulation of blood flow and tissue hypoxia on exertion.
I went looking for something visual- and I remain interested in the disappearance of collagen in our bodies.

so I liked this diagram because it at least shows us how collagen fibers are a key component of this vasculature.

So this damage to our physical structure- seems to be potentially linked into this dysfunction.

1626383619425.png
 

Hufsamor

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Does this hypothesis fit with observed rapid temporary remissions? Can these endothilial dysfunctions switch state dramatically over a period of a few minutes, yet show no effects from various other treatments and physical activities that affect blood flow?
This is what their paper says, but I must admit I don’t quite understand myself:
Our proposed pathomechanistic model (Figure 1) is compatible with the lack of obvious histologic inflammation in tissue samples from ME/CFS, lack of overt organ damage, and the potential for recovery — sometimes spontaneous and without sequelae.
 

Hufsamor

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I don’t have the papers in Norwegian…someone please explain what this means?

Secondary compensatory efforts may add to the clinical presentation and symptoms. They include autonomic adaptations, often with increased sympathetic tone, and metabolic adaptations aiming to restore energy supply. Possible strategies for clinical trials targeting these pathways are also indicated.
 
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anyone have an opinion about what this statement might mean- quoted from the Conclusion-

"We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output."

what are cognitive techniques?
 

SNT Gatchaman

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anyone have an opinion about what this statement might mean- quoted from the Conclusion-

"We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output."

what are cognitive techniques?
Their model suggests initiation, failure to normalise and maintenance of pathological state. They propose in summary: 1) initiation of an abnormal and prolonged immune response, typically by a virus; 2) vascular dysregulation, esp. endothelial dysfunction; 3) compensatory adaptations - autonomic and metabolic. Stage 3 produces the range of well-known (to us) symptoms - of course varying in extent and degree between patients.

They seem very clear that the disease is biological and offer potential therapies at levels 1 and 3. One of the options suggested at level 3 is a (probably deliberately) nebulous "cognitive techniques", that they offer might help a subset of patients who have moved on to established pathophysiology (as opposed to those that spontaneously recover in time from a "post-viral fatigue syndrome"). This might be by modulating the sympathetic / parasympathetic imbalance, nudging it back toward normal.

From the paper
We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output.
My opinion (very much as a newbie) is that all options are on the table for me and if there is possible benefit in things like mindfulness and meditation to help "bring balance to the Force" then I'll get over myself and give it a try. I will not try anything that is at odds with the established patient wisdom, in particular nothing acting against pacing. I also would not infer any support for e.g. LP or similar rubbish by the authors of this paper, but I have not looked hard into the background here.

My non-fatigue symptoms are strongly dysautonomic and I observed much strangeness in the ways my circulatory system was behaving. This probably inclines me toward a vascular hypothesis, so I've certainly appreciated the relevant papers that have been published over recent weeks.
 

SNT Gatchaman

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This is what their paper says, but I must admit I don’t quite understand myself:
Our proposed pathomechanistic model (Figure 1) is compatible with the lack of obvious histologic inflammation in tissue samples from ME/CFS, lack of overt organ damage, and the potential for recovery — sometimes spontaneous and without sequelae.
I don’t have the papers in Norwegian…someone please explain what this means?

Secondary compensatory efforts may add to the clinical presentation and symptoms. They include autonomic adaptations, often with increased sympathetic tone, and metabolic adaptations aiming to restore energy supply. Possible strategies for clinical trials targeting these pathways are also indicated.
I read this paper in relation to the 2020 Wirth and Scheibenbogen paper and their 2021 follow-up.

I take it that the central hypothesis in these papers relates to profound disturbance of blood flow to e.g. muscles. Vasoconstriction and vasodilation is not happening correctly to demand. The organ (say muscle) is complaining of blood starvation, with oxygen and nutrient deficit, and waste product accumulation. That organ then "alarms" and secretes signalling molecules to attempt to correct the fault. These signals may have some useful effect locally but also spill over to the wider body. Bad symptoms follow and if bad enough: PEM/crash.

I think the suggestion is that this amount of pathophysiology is harmful, but not too harmful. I.e. it wouldn't make changes to the organ or the blood vessel that you could see under the microscope. If the abnormal vascular responses could be corrected at or close to the site of initiation, then the end organs would be back to their normal "happy" state, with no long-term harm done.

I like this idea, but that may be because it sounds quite optimistic.
 

Pyrrhus

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No abstract, so here are the first four paragraphs:

Fluge et al 2021 said:
Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (Fluge et al., 2021)
Øystein Fluge, Karl J. Tronstad, and Olav Mella
https://www.jci.org/articles/view/150377

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with unknown etiology, no validated specific and sensitive biomarker, and no standard approved effective treatment. ME/CFS has a profound impact on the quality of life of both patients and caregivers and entails high costs for society. The severity varies among patients who are able to participate to some extent in social life (mild), those who are mainly housebound (moderate) or bedridden (severe), and the very severely ill who are completely dependent on assistance for all daily living tasks, such as feeding or turning around in bed.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often starts in previously healthy individuals after an infection, the most common being infectious mononucleosis (EBV). It is more frequent in women and influenced by genetic predisposition. The main symptoms are postexertional malaise (PEM), fatigue, orthostatic intolerance, cognitive disturbances, sleep problems with inadequate restitution after rest, sensory hypersensitivity with pain, and symptoms related to autonomic and immune dysfunction. The prevalence is 0.1% to 0.8%, and ME/CFS must be distinguished from general fatigue, which is much more common in the population.

Historically, there has been limited scientific interest in ME/CFS. However, research efforts have increased in the last decade. Although this has led to different hypotheses, a firmly established pathomechanism is lacking.

Herein, we suggest a framework model for the initiation and maintenance of ME/CFS consisting of three principal steps: (a) an initial aberrant immune response; (b) an effector system for symptom generation and maintenance; and (c) compensatory adaptations. The model and possible therapeutic opportunities are summarized in Figure 1.
 

dylemmaz

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Wouldn’t this mean that Rituximab would be a treatment? I haven’t read the whole thing, yet. I’m too exhausted.
yes, it’s one of the treatments proposed. although only for a subset.

“As Rituximab targets CD20-positive cells, patients whose autoantibody production occurs in CD20-positive plasmablasts would be likely responders. In the majority of patients, however, autoantibodies may be produced in CD20-negative, long-lived plasma cells not targeted by Rituximab”
 

junkcrap50

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yes, it’s one of the treatments proposed. although only for a subset.

“As Rituximab targets CD20-positive cells, patients whose autoantibody production occurs in CD20-positive plasmablasts would be likely responders. In the majority of patients, however, autoantibodies may be produced in CD20-negative, long-lived plasma cells not targeted by Rituximab”
Anyway to tell from where one's autoantibodies are produced?