Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),2021,Fluge,Mella,Tronstad

Sly Saint

Sly Saint

Senior Member (Voting Rights)
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.

https://www.jci.org/articles/view/150377
 
I was anticipating that they might have some suggestions for very specific treatment protocols in the paper.

There is this but it seems more speculative.

“Possible trials could include drugs that reduce serum IgG by targeting Fc receptor neonatal (FcRn), anti-CD38 antibodies to target long-lived plasma cells or anti-BAFF antibody to target disrupted B cell homeostasis (Figure 1).”
 
Similarly to Scheibenbogen and Wirth, Fluge and Mella propose an autoimmune mechanism involving autoantibodies to G-coupled protein receptors (GPCR), including beta-adrenergic and muscarinic ones, leading to the same downstream consequences:

We believe that the clinical symptoms in ME/CFS suggest inadequate autoregulation of blood flow according to the demands of tissues, resulting in tissue hypoxia. This is associated with lactate accumulation from limited exertion, in some patients even at rest.
[...]
In established autoimmune diseases, pathogenic IgGs often associate with complement activation, inflammation, and tissue injury. These features are not characteristic of ME/CFS. We suggest that a variant of an autoimmune mechanism affects the autonomic control of blood vessel tone and flow autoregulation. (...) In ME/CFS, a persistent functional autoantibody pattern could disturb blood vessel autoregulation and lead to secondary metabolic and autonomic adaptations (Figure 1).
​
However, going upstream of Scheibenbogen and Wirth's model, their model details how an aberrant immune response to an infectious trigger involving B cells would kick-start this autoimmune mechanism.

On the failure of the phase 3 of their rituximab trial, which suggests that B cells may not be involved in the pathophysiology of ME/CFS, they argue:

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 (Figure 1).
​
It seems that despite the negative findings of Scheibenbogen and Bergquist's validation study, both groups still consider GPCR autoantibodies as a key part of the pathophysiology of ME/CFS.

Ultimately, unless these investigators obtain significant funding to verify their hypothesis on large cohorts, I am inclined to think that learning whether ME/CFS has an autoimmune basis hinges solely on the results of the DecodeME study -- which will take a few years to complete --.
 
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cassava7 said:
Similarly to Scheibenbogen and Wirth, Fluge and Mella propose an autoimmune mechanism involving autoantibodies to G-coupled protein receptors (GPCR), including beta-adrenergic and muscarinic ones, leading to the same downstream consequences:

We believe that the clinical symptoms in ME/CFS suggest inadequate autoregulation of blood flow according to the demands of tissues, resulting in tissue hypoxia. This is associated with lactate accumulation from limited exertion, in some patients even at rest.
[...]
In established autoimmune diseases, pathogenic IgGs often associate with complement activation, inflammation, and tissue injury. These features are not characteristic of ME/CFS. We suggest that a variant of an autoimmune mechanism affects the autonomic control of blood vessel tone and flow autoregulation. (...) In ME/CFS, a persistent functional autoantibody pattern could disturb blood vessel autoregulation and lead to secondary metabolic and autonomic adaptations (Figure 1).
​
However, going upstream of Scheibenbogen and Wirth's model, their model details how an aberrant immune response to an infectious trigger involving B cells would kick-start this autoimmune mechanism.

On the failure of the phase 3 of their rituximab trial, which suggests that B cells may not be involved in the pathophysiology of ME/CFS, they argue:

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 (Figure 1).
​
It seems that despite the negative findings of Scheibenbogen and Bergquist's validation study, both groups still consider GPCR autoantibodies as a key part of the pathophysiology of ME/CFS.

Ultimately, unless these investigators obtain significant funding to verify their hypothesis on large cohorts, I am inclined to think that learning whether ME/CFS has an autoimmune basis hinges solely on the results of the DecodeME study -- which will take a few years to complete --.
Click to expand...

Well they might support their hypophesis if an phase 3 of cyclo has effect, or any anti-CD38 shows any promise, maybe in combination with anti-CD20
 
This part surpised me however:

"We speculate that cognitive techniques,
which are reported to help subgroups of
patients, might act by modulating the
sympathetic output. If so, one would
expect a greater benefit for patients with
less ongoing immune activation and less
vascular dysregulation, but with main
symptom contributions from the secondary
autonomic adaptations. Conversely,
patients with active immune disturbance
and ongoing vascular dysregulation as
the main symptom generators would have
less impact from cognitive intervention,
although psychosocial support and coping
strategies may still have a beneficial
impact on their quality of life."

That seems to be an significant leap of faith in terms of disease mechanism, dont really understand why they put it in there
 
This paper correlates almost completely with my own conclusions about the parthenogenesis of ME/CFS based on my own disease progression, lab results and general investigations.

My only addition is that I believe that there is a complement activation for clearance of soluble immune complexes and that process plays role in disease symptoms. They dismiss this in there paper but whenever there is IgG that binds it creates an immune complex it eventually needs to be cleared.

I think Fluge and Mella are on the right track and there will be a breakthrough for patients in five years. I personally think that anti CD-38 Daratumumab or similar will be key here and in other autoimmune diseases as well with the occasional and CD-20 Rituximab infusions to stop memory cells to become new plasma cells.

Finally I think there is a ongoing trigger that maintains this autoreactivity in ME/CFS and other autoimmunity conditions. Mostly likely HHVs (human herpesvirues) or HERVs (human endogenous retroviruses).
 
Marky said:
This part surpised me however:
Click to expand...
They might just want to be able to document that they have never said that a single treatment should be assumed to help “every person with ME”. Preparing for the CBT-gangs arguments against future medicine testing on sub groups? I doubt researchers on any other disease ever have to think of such precautions, though.
 
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This quote sounds very logical based on my subjective experience with the illness:
"We believe that the clinical symptoms in ME/CFS suggest inadequate autoregulation of blood flow according to the demands of tissues, resulting in tissue hypoxia. This is associated with lactate accumulation from limited exertion, in some patients even at rest."

Could it be that the fault is located on the brain level? The part of the brain that controls the blood flow in the body is the medula oblongata, according to this study, so it would be interesting if anybody knows if this part of the brain has been studied in ME before?

A fault in autoregulation of blood flow doesn't neccessarily have to be brain based of course, but it's one possible explanation, and not the most implausible based on my limited knowledge of these matters?
 
Campanula said:
This quote sounds very logical based on my subjective experience with the illness:
"We believe that the clinical symptoms in ME/CFS suggest inadequate autoregulation of blood flow according to the demands of tissues, resulting in tissue hypoxia. This is associated with lactate accumulation from limited exertion, in some patients even at rest."

Could it be that the fault is located on the brain level?
Click to expand...

I'm not convinced that it is. The unusual results on the 2 day CPET at the ventilatory threshold are not explained by autonomic disregulation that would result in impaired blood pressure or a delayed rise in heart rate upon standing from supine position (null results after a maximal exercise test).

(note, "Autoregulation" doesn't necessarily mean by the brain.)

Arterial flow (and heart rate) is regulated centrally, but capillary flow is regulated peripherally, so the "shunting" as discussed can have a peripheral, rather than central cause.
 
Campanula said:
Could it be that the fault is located on the brain level? The part of the brain that controls the blood flow in the body is the medula oblongata, according to this study, so it would be interesting if anybody knows if this part of the brain has been studied in ME before?
Click to expand...
I'm quoting myself because I found something of interest on the medulla oblongata. Turns out it has been researched in ME/CFS already, and one study found that this part of the brainstem doesn't communicate very well with the other parts of the brainstem during exertion.

From Health Rising:
"It turned out that the people with ME/CFS demonstrated something of a “communication breakdown”. Different parts of their brainstem weren’t talking well with each other. Nor was their brainstem communicating well with other parts of the brain.

The most problematic connection for people with ME/CFS was between both parts of the medulla oblongata and the left cuneiform nucleus. While it was difficult to pin down the exact impact, Barnden reported that weakened connections between these two areas of the brain could produce such issues as maintaining movement, sleep quality, autonomic function and cortical arousal levels, which affect memory, learning and problem solving."

This is obviously preliminary at this point, with only one study that I know of finding this result related to the medulla oblongata, but I find it interesting none the less. Some other studies from the same researcher, Barnden, also seem to suggest that the brainstem could be involved.
 
Medical Express: Myalgic encephalomyelitis associated with cellular energy strain

quote:
"For those suffering from ME, this means that we now have a somewhat better understanding of the disease, and the study provides possible explanations for the differences in patient responses to various types of symptomatic treatments or dietary changes," says Tronstad.

In the long term, he also hopes that these findings can make it easier to find biomarkers for the disease, and to find effective treatments and eventually a cure.

"Today we have no established treatment for ME, and we want to understand more of what happens in the bodies of ME patients. If we know that the autoregulation of blood flow is involved in the disease, we can search for markers and autoimmune mechanisms that are specifically connected with the blood supply", says the professor.
 
The Norwegian ME Association organised an ME conference last November in Oslo. They have now uploaded the lecture professor Øystein Fluge held on disease mechanisms in ME/CFS. I thought the paper he and his team published last spring was difficult to understand, and have missed a lecture for us patients. Finally here it is! But sadly only in Norwegian.



Here's a summary and apologies for any clumsy translation:

He starts with saying that he has one foot in oncology and one in ME, and that it's two very different worlds. One gives you a highway into health care, and then there's ME. This is thought provoking and one of the reasons to continue in this field.

The only thing that will turn this field around are hard medical facts showing what ME is. He is very clear that he is presenting a hypothesis and spends a little time on explaining what that is, and the importance of having hypotheses confirmed or refuted.

He starts of with some general observations:

He thinks of ME as a reversible disease in principle.
There are usually no apparent organ damage or classic inflammation in tissue.
The clinical picture is quite similar.
Patients describe reduced anaerobic threshold.
What are primary and what are secondary changes in a complex clinical picture?

Several aspects point towards the immune system being involved.
  • ME often occurs after an infection and often in otherwise completely healthy people.
  • 3-4 times more female patients, which are typical for diseases in the immune system.
  • A slight increased risk of lymphoma which could point to a chronic activated immune system.
  • High occurrence of autoimmune diseases in family members (40-55%?).
  • Data from overlapping conditions as POTS, orthostatic hypotension, CRPS, fibromyalgia, Long Covid suggest an autoimmune basis. He doesn't think this is classic autoimmune disease, but related.

He then gives a short introduction to the immune system. B-cells create antibodies, T-cells attack other cells. In autoimmune diseases the immune response is directed towards the body's own proteins and then called auto-antibodies.

Is ME/CFS an auto-antibody mediated response that disturbs the blood regulation to tissue?

Their working hypothesis:
- Immune disturbance after an infection
- affected auto regulating of blood flow, which gives tissue hypoxia
- Lack of energy, PEM
- Secondary metabolic adaptions and secondary autonomic adaptions

B-cells create auto-antibodies. They mature in the bone marrow and are called plasma cells when fully developed. Rituximab binds to the molecule CD20 which are on all B-cells when they develop. Rituximab thus remove B-cells that are not fully developed yet. Rituximab also remove some newly fully developed B-cells as they might still have some CD20 on them. Long lived plasma cells on the other hand, don't have CD20 and are therefore not affected by Rituximab.

Cyclophosphamide is a cytotoxic therapy and is thought to reduce the maturation of activated B-cells into anti-body producing plasma cells.

They believe there is a pattern of auto antibodies after an infection that disturbs the blood vessel function.
Potential therapeutic targets could be:
  • B cell depletion - Anti-CD20 antibody
  • Cytotoxic drugs - Cyclophosphamide
  • Plasma cell survival factors - Anti-BAFF antibody
  • Plasma cells - Anti-CD38 antibody, Proteasome inhibition
  • Immunoglobin manipulation - FcRn targeting, Immunoadsorption, IVIG

They still believe Rituximab may have an effect, but that they're drowning a bit in variations. Some could be placebo, but there are also huge fluctuations in symptoms.

Perhaps it's best to attack either later in the development of B-cells on plasma level or on autoantibody level. They hope to be able to continue with interventions soon.

One of the slides presents following model:

Pattern of autoantibodies after infection?
Persistent, affecting vascular function

Endothelial dysfunction - Large and small arteries
Arteriovenous shunting - Impaired oxygen extraction
Impaired venous tone and return - preload failure

Impaired auto regulation of blood flow on exertion - tissue hypoxia

​
Next slide explains further:
Reduced auto regulation of blood flow

When the blood flow increase, the artery should dilate with the help of among other Nitric Oxide. This ability is reduced in patients.

Reduced venous return to heart resulting in reduced cardiac output in activity/strain.

Arteriovenous anastomosis
"Shunts" blood directly from small arteries to small veins to small arteries, without blood through the capillary system. Not enough oxygen to tissue.​

When you have too low blood flow and too little oxygen in the tissue, the body will initiate ways to compensate for this. This will lead to an activation of the autonomic nervous system and some metabolic changes. More usage of amino acids and fats, and less of glucose as energy source. This compensation is similar of metabolic adaptation to hunger, hypoxia, endurance exercise.

When it comes to therapeutic interventions which can lead to long term changes they're thinking of interventions aimed at the underlying immune response. Also to reduce or remove the cause: auto antibodies affecting venous function and blood flow with resulting tissue hypoxia.

Interventions aimed towards secondary adaptions will have a more short lived effects. This could be pyridostigmine, diets, supplements, cognitive mechanisms.

Towards the end he wonders if ME is due to disease causing auto reactive antibodies (IgG) or a pattern of persistent natural autoantibodies after an infection or another trigger.

He refers to a study from 2020 titled "Diverse Functional Autoantibodies in Patients with COVID-19" which with a new technology called REAP (Rapid Extracellular Antigen Profiling) showed dramatic increase of auto antibody response after Covid-19. Could there be similar mechanisms in other infections?

Could ME/CFS entail a pattern of immune response/functional auto antibodies that don't "calm down" after the infection is over, but instead persist and disturb the vascular auto regulation of blood flow?

He ends with talking about effects of cognitive therapy and presents a possible model of primary symptoms (blood vessel function, tissue hypoxia with strain/activity) and secondary symptoms (sympathetic activation, metabolic). Perhaps those with only persistent secondary symptoms, where the primary symptoms are resolved, may spontaneously improve. But one should be careful with cognitive interventions aimed at those patients who have both primary and secondary symptoms. They will have less benefit of CBT, can perhaps even deteriorate from it.
 
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