Open Epigenetics of Post-exertional Malaise in Patients With ME/CFS: Oct 2020 [This trial is not yet open for recruitment]

Sly Saint · May 9, 2020

Sponsor Vrije Universiteit Brussel
Overall contact Andrea Polli, MSc

Summary
Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the promoter regions of those genes will be explored.

The investigators designed a randomised controlled trial with cross-over design and will enrol 80 patients with ME/CFS and 25 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups and receive either one session of aerobic exercise or a validated test designed to trigger mental stress and mental fatigue first. Then the two groups will cross over after a week wash period. The primary aim is to assess genetic and epigenetic mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.
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Eligibility Criteria
Female participants from 18 years up to 70 years old.

Inclusion Criteria: - diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Centre for Disease Control and Prevention (CDC); - age between 18 and 70 years old; - body mass index (BMI) below 30 (no obesity). Exclusion Criteria: - presence of other neurological disorders (Parkinson's disease, Multiple Sclerosis, etc); - presence of systemic disorders (lupus erythematosus, rheumatoid arthritis, etc.); - presence or history of cardiac disorders (coronary heart disease, history of heart failure, etc); - presence or history of cancer; - presence or history of neuropathic pain (e.g. pain related to herpes zoster virus); - pregnancy;
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full details here:
https://www.smartpatients.com/trials/NCT04378634

Andy · May 9, 2020

diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Centre for Disease Control and Prevention (CDC)
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So Fukuda

cassava7 · May 9, 2020

Andy said: ↑

So Fukuda
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I've sent a mail to the contact person to ask them to include CCC ontop of Fukuda.

Dear Ms Polli,

I am a person who suffers from myalgic encephalomyelitis, and I recently saw the protocol of the clinical trial on the epigenetics of PEM in ME/CFS. I would like to thank you for your interest into research on ME/CFS; good quality biomedical research is much needed to understand the disease.

I only have one concern about the current protocol. The first inclusion criterion is the following:

diagnosis of ME/CFS established by a MD experienced in the field of internal medicine and ME/CFS - according to the published international criteria developed by the Centre for Disease Control and Prevention (CDC)
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However, the CDC-1994 ("Fukuda") criteria for CFS do not require post-exertional malaise as a mandatory symptom. EUROMENE, the European network on ME/CFS, have listed this as an "objection" to using the CDC-1994 criteria [1] and have instead recommended the combined use of the Canadian consensus criteria (CCC) [2] with the CDC-1994 criteria [3]. For example, the CCC have been used successfully for the large phase 3 clinical trial of Rituximab for ME/CFS [4]; they are fit for research purposes.

Worth noting, the international consensus criteria [5] are highly specific for ME as "post-exertional neuro-immune exhaustion", which they define precisely, is the core mandatory symptom.

Since prospective participants will be evaluated by an internist MD experienced in ME/CFS, I am sure that using both CCC and CDC-1994 criteria will not be a practical difficulty. Therefore, I hope the protocol can be updated to require CCC, as a way to 1) make the trial consistent with other good quality studies on ME/CFS, 2) relieve any doubt about the ME/CFS diagnosis of included participants, 3) enable the results of the trial to be used in future research on ME/CFS.

Thank you again for setting up this interesting trial!

Sincerely,
XX

References

[1] Strand EB, Nacul L, Mengshoel AM, Helland IB, Grabowski P, et al. (2019) Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union. PLOS ONE 14(12): e0225995. https://doi.org/10.1371/journal.pone.0225995
[2] Bruce M. Carruthers, Anil Kumar Jain, Kenny L. De Meirleir, Daniel L. Peterson, Nancy G. Klimas, A. Martin Lerner, Alison C. Bested, Pierre Flor-Henry, Pradip Joshi, A. C. Peter Powles, Jeffrey A. Sherkey & Marjorie I. van de Sande (2003) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Journal of Chronic Fatigue Syndrome, 11:1, 7-115, DOI: 10.1300/J092v11n01_02
[3] Pheby, D. F. H., Araja, D., Berkis, U., Brenna, E., Cullinan, J., de Korwin, J.-D., … Wang-Steverding, X. (2020). The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report from the European Network on ME/CFS (EUROMENE). Healthcare, 8(2), 88. doi:10.3390/healthcare8020088
[4] Fluge Ø, Rekeland IG, Lien K, et al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med. 2019;170:585–593. [Epub ahead of print 2 April 2019]. doi: https://doi.org/10.7326/M18-1451
[5] Carruthers, B.M., van de Sande, M.I., De Meirleir, K.L., Klimas, N.G., Broderick, G., Mitchell, T., Staines, D., Powles, A.C.P., Speight, N., Vallings, R., Bateman, L., Baumgarten‐Austrheim, B., Bell, D.S., Carlo‐Stella, N., Chia, J., Darragh, A., Jo, D., Lewis, D., Light, A.R., Marshall‐Gradisbik, S., Mena, I., Mikovits, J.A., Miwa, K., Murovska, M., Pall, M.L. and Stevens, S. (2011), Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine, 270: 327-338. doi:10.1111/j.1365-2796.2011.02428.x
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Saz94 · May 9, 2020

Andy said: ↑

So Fukuda
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So Fukdupa

cassava7 · May 27, 2020

I resent the mail from another mail address because I'm not sure the first one went through (spam filter?). Here's Andrea Polli's response.

Dear [cassava7],

Thanks for your interest and well-supported arguments. You are right re the diagnostic criteria, and we are aware of that.
We decided to use the more general Fukuda’s criteria as inclusion criteria for two reasons:

they are still the most commonly used ones and we were also interested to compare our results to published research.

To compare the three diagnostic criteria you mentioned. In fact, participants will also be assessed according to CCC and IOM criteria (e.g. filling modified DePaul Symptoms Questionnaire), we just didn’t use them as inclusion criteria.

Hope this answers your concern,
Kind regards,

Andrea

---

Andrea Polli
PhD Researcher
Vrije Universiteit Brussel
Katholieke Universiteit Leuven
FWO Fellow

Pain in Motion (PiM) Group
http://www.paininmotion.be/
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My response:

Dear Andrea,

Thank you for your answer It is good to know that the CCC and IOM criteria will also be applied.

My concern about the inclusion criteria impacting the validity of the study still holds, though. As the study will evaluate the effects of PEM, the diagnostic criteria used for the inclusion of participants must require PEM, otherwise its results could be contested simply on this basis. The study could certainly reveal interesting aspects of PEM so having its validity undermined only because of this easily fixable point would be most unfortunate.

As a simpler solution than changing the inclusion criteria to CCC or IOM, you could use the so-called modified CDC-1994 criteria with PEM as a mandatory symptom.

Best,
[cassava7]
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adambeyoncelowe · May 27, 2020

cassava7 said: ↑

I resent the mail from another mail address because I'm not sure the first one went through (spam filter?). Here's Andrea Polli's response.

My response:
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I think you make a very good point. The US has specifically said PEM should be mandatory in its IOM report, so the likely outcome is that any study with optional PEM could be downgraded.

wigglethemouse · Jan 30, 2021

Neil McGregor gave a talk at the 2019 Australia ME/CFS Conference and it was recorded. In it he discusses a hypothesis that PEM could cause low acetate that affects HDAC1 and HDAC2 (and SMAD1,4,5) which then affects gene transcription of some genes found relevant to ME/CFS in other studies causing less protein to be made.
https://mecfsconference.org.au/videos/neil-mcgregor/

McGregor then published this paper that discusses HDAC
Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases
https://www.mdpi.com/2075-4418/9/3/70/htm#B6-diagnostics-09-00070
Thread : https://www.s4me.info/threads/post-...on-in-me-cfs-cases-2019-mcgregor-et-al.10260/

The talk and paper is of relevance as this study is looking at HDAC in PEM.

McGregor discusses that the only HDAC study in ME that he could find was Jason et al 2011 which showed 4 fold elevated HDAC2 in elderly CFS patients.
Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome
https://www.sciencedirect.com/science/article/abs/pii/S0889159111001255?via=ihub
Sci-Hub : https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0889159111001255?via=ihub

Will be interesting to see what this study finds.

wigglethemouse · Jan 31, 2021

Cort wrote about HDAC in relation to McGregors study

The Tie That Binds…
McGregor then shifted gears and proposed – using a gene expression exercise study by Whistler et. al. – that the tie that binds all this together may be massive levels of something called histone deacetylation (performed by histone deacetylase enzymes or HDACs). He noted that histone acetylation/deacetylation regulated the top twenty genes found altered in Whistler’s study. A similar outcome was found in a genetic polymorphism study.

That suggested to him that people with ME/CFS are having trouble “acetylating”; i.e. using acetyl groups to regulate our gene expression. Only one study has addressed this issue, and it found HDAC2 and HDAC3 levels three and four times higher in ME/CFS than normal.

McGregor then tied it all together with a nice bow. Bringing us back to square one, he proposed that the HDAC problems in ME/CFS result from the problems with glycolysis.

Glycolytic inhibition, it turns out, increases HDAC activity. Low lactate and pyruvate levels – because they are HDAC inhibitors – allow HDAC levels to rise. HDAC then causes deacetylation and silences the transcription of many genes.

McGregor has found dramatically reduced urea, acetate and allantoin levels in ME/CFS. Acetate, McGregor believes, is a particularly critical factor. Acetate comes into play because it plays a crucial role in the transcription of our DNA – and the subsequent production of protein in the cell. The histone deacetylation he believes is present in ME/CFS inhibits DNA transcription, thus reducing protein production in the cell – which makes the cells go all twitchy when faced with a challenge.

The big question in ME/CFS, then, in McGregor’s mind is what the heck is whacking that very first stage in energy production – glycolysis. That’s where the key to this disease, he believes, will be found. He reported that he’s now searching for the causes of the glycolytic problems in ME/CFS and hopes to have more information on that this fall.
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Source : https://www.healthrising.org/blog/2...gregor-metabolism-chronic-fatigue-glycolysis/

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Open Epigenetics of Post-exertional Malaise in Patients With ME/CFS: Oct 2020 [This trial is not yet open for recruitment]

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