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    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

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Do MEs cause CFS?

A.B.

Senior Member
Messages
3,780
Methylation also doesn't make sense as an etiology. People are humming along just fine until they get a viral infection then suddenly their cells can't methylate properly? So what's the cause? It can't be environmental or infectious because nobody else is affected.

This is a wrong assumption. It is well known that some people are significantly more susceptible to certain things. Drugs are a good example. There is always the possibility of an adverse reaction even in drugs that for the vast majority do not cause any problems. The reason is that at the genetic level we're all slightly different.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Thanks? I was just going by the published research showing a seven month follow up. Has anything been published showing longer?

Three year follow up has been presented and the Norwegians of course have longer follow up than that, which they are happy to discuss with other researchers, but there is no formal publication yet. They have a rolling programme of continuing open label treatment and figures so far suggest that the initial findings hold up. However, further formal double blind controlled data will need to wait for the completion of the new trial started last month.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
Rituximab would be another dead end. Although initially their fatigue would be better, B cells serve a purpose and their long term clinical outcomes wouldn't be any better. In fact, with their fatigue masked they might be worse because they are overtasking their bodies beyond their recuperative abilities.

Even if it isn't considered a viable long term treatment, it it works in a large double blinded trial, it will take a lot of explaining - we will finally see CFS and ME getting the attention they deserve by the research community.

PS, the Fluge and Mella study results clearly show show that over time, there were improvements in 10/15 patients receiving Rituximab vs 2 in the Placebo group. The fact that there was no significant difference at 3 months, but there was a difference at 6-10 months, reflects the kinetics of the clearance of whatever antibodies may have been involved. Not all antibodies are cleared out, 3 months after Rituximab infusion.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Given that Fluge/Mella have a sub-study on endothelial dysfunction assessed via flow mediated vasodilation (for reasons unknown at the moment), I thought this recent review (free full text available) gave a pretty balanced/conservative account of endothelial dysfunction and the risk for atherosclerosis in chronic inflammatory diseases including autoimmunity.

ME/CFS doesn't appear to involve high grade local or systemic inflammation but other risk factors (elevated oxidative stress; lipid abnormalities; a potential link to metabolic syndrome) have been reported not to mention the possibility of anti-endothelial cell antibodies :

Endothelial dysfunction in chronic inflammatory diseases.

Abstract

Chronic inflammatory diseases are associated with accelerated atherosclerosis and increased risk of cardiovascular diseases (CVD). As the pathogenesis of atherosclerosis is increasingly recognized as an inflammatory process, similarities between atherosclerosis and systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel diseases, lupus, psoriasis, spondyloarthritis and others have become a topic of interest. Endothelial dysfunction represents a key step in the initiation and maintenance of atherosclerosis and may serve as a marker for future risk of cardiovascular events. Patients with chronic inflammatory diseases manifest endothelial dysfunction, often early in the course of the disease. Therefore, mechanisms linking systemic inflammatory diseases and atherosclerosis may be best understood at the level of the endothelium. Multiple factors, including circulating inflammatory cytokines, TNF-α (tumor necrosis factor-α), reactive oxygen species, oxidized LDL (low density lipoprotein), autoantibodies and traditional risk factors directly and indirectly activate endothelial cells, leading to impaired vascular relaxation, increased leukocyte adhesion, increased endothelial permeability and generation of a pro-thrombotic state. Pharmacologic agents directed against TNF-α-mediated inflammation may decrease the risk of endothelial dysfunction and cardiovascular disease in these patients. Understanding the precise mechanisms driving endothelial dysfunction in patients with systemic inflammatory diseases may help elucidate the pathogenesis of atherosclerosis in the general population.

http://www.ncbi.nlm.nih.gov/pubmed/24968272
 

JalapenoLuv

Senior Member
Messages
299
Location
unknown
ME/CFS doesn't appear to involve high grade local or systemic inflammation.

Headaches are due to inflammation and they occur in most CFS patients.

"Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC." Ravindran. BMC Neurol. 2011 Mar 5;11:30. doi: 10.1186/1471-2377-11-30.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Headaches are due to inflammation and they occur in most CFS patients.

"Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC." Ravindran. BMC Neurol. 2011 Mar 5;11:30. doi: 10.1186/1471-2377-11-30.

Indeed, migraine like headaches appear to be quite common in ME/CFS but that doesn't equate to peripheral inflammatory disorders assocaited with very hight levels of PICs and frank tissue damage.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I assume this was presented at a conference? Does anyone know of a freely accessible summary of the results?

I do not think there is any official summary. They have a lot of data and I think it would be difficult to produce a meaningful brief summary. I suspect material is being submitted for publication on the continuing treatment protocol but that can take time.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
@Jonathan Edwards

I have a quick question, what effect on gene expression should be expected for an enzyme that is targeted by an autoantibody? (if the answer is 'it depends', then what examples are there in the literature that I should look for?)
 

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards

I have a quick question, what effect on gene expression should be expected for an enzyme that is targeted by an autoantibody? (if the answer is 'it depends', then what examples are there in the literature that I should look for?)

Are you asking about transcription of the enzyme gene itself? That would depend on whether bidning of the antibody to the enzyme interfered with a feedback from the enzyme's activity on transcription factor binding. An antibody that blocked an enzyme might lead to increased enzyme production as part of a homeostatic feedback loop through transcription.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
OK Leopardtail, I know what you are saying and there is a lot of justification for it.

But let's turn this into an exercise. We need a proposal of intent for a grant application to investigate methylation in ME and applicants are allowed 500 words to convince some intelligent funders to invite a formal proposal. I am the intelligent funders' advisor, who looks at the proposals of intent. (You may realise that this is not so very far away from reality.) If the case for studying methylation is solid enough then anyone with familiarity in the field should be able to put the case. When some new avenue opens up in research it is usual for every Tom Dick and Harry on the planet to put in a proposal to work on it. The case needs to relate the problem seen at the widest angle to something very specific and testable through a tight series of argued steps. Could you persuade me in 500 words?
real life has had me offline for a few weeks, there is a piece of research that needs to be done (in my view). I'll give this some thought when I can give it enough time to condense it down into 500 words.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia

Hip

Senior Member
Messages
17,820
1. ME1 is due to antibodies to certain nuclear proteins that can enter cells and disturb function on a body-wide basis. ANA is positive and usually speckled in pattern. (The proteins are likely to come under what are called ENA antigens, which are not always strictly nuclear but no matter.) The fatigue of ME1 is basically the same as in primary Sjögren’s syndrome and other ANA-linked illnesses that have names. I have met many people in this group. Some might suggest that they are well enough described to take them out of the ‘unknown causes’ that are MEs but a lot of these people end up labelled as ‘CFS with an ANA’. The fatigue may be a bit different from other groups.

Prof Edwards, I am just trying to get an understanding of and handle on your ME1.

Would you be able to symptomatically characterize this type of ME/CFS in its onset and early stages? In your experience, is ME1 easy to symptomatically distinguish from the infectious onset types of ME/CFS (symptomatically meaning other than by tests such as the ANA)?

For example, in the infectious onset of ME/CFS, you typically see either an immediate onset of ME/CFS symptoms within days of contracting the triggering infection; or the onset is more gradual, slowly arising in the week or months that follow the initial infection.

Are there any typical triggering factors or characteristic onset symptoms associated with ME1, in as far as you have been able to ascertain?

And do these ME1 patients suffer from the chronic sore throat of ME/CFS? My own chronic sore throat was caused by the virus that appeared to trigger my ME/CFS; the sore throat was the very first symptom this virus produced when I first caught it (and at the time of course I thought that it was nothing more than just a sore throat that would soon go away). However, my initial sore throat remained, and is still present to a degree even a decade later.

So I wonder whether the chronic or recurring sore throat often found in ME/CFS might be peculiar to the infectious onset-type ME/CFS, and thus be usable as a differential diagnosis between ME1 and the other MEs you enumerate which have infectious associations.
 
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Snowdrop

Rebel without a biscuit
Messages
2,933
@Hip
I know your question is directed to J Edwards. I would be glad to fit nicely where it would be clear to catagorise me for diagnostic purposes but I wouldn't fit in the above I think. I did have a sore throat for some years (it took me a while to realise this :rolleyes: I wish I'd paid more attention) But I also did not have a infectious onset that I am aware of. Already before clear CCC definition symptom onset I had not been experiencing many infections that others got around me.

In my opinion I think that it is possible that for some it is still a discreet trigger that could identify a sub-set but it wouldn't (by my experience) completely clear things up.