Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspective

[SWAlexander]

Excerpt:
Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments. This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice.

3.2.1. Immunosuppressive Treatments​

In 2009, a cancer patient reported an improvement in their ME/CFS symptoms during chemotherapy, believed to be caused by methotrexate-induced B-cell depletion [65]. The authors suggested the potential benefit of rituximab, a monoclonal CD20 antibody which depletes B lymphocytes, as a treatment for ME/CFS. They trialled rituximab in three ME/CFS patients, all of whom reported symptom improvement. These results suggested B lymphocytes’ involvement in ME/CFS pathogenesis, providing the rationale for undertaking rituximab CTs in ME/CFS [65]. In an RCT, rituximab or saline placebo was administered twice, two weeks apart, in a total 30 ME/CFS patients [66]. There was no significant difference between the treatment and placebo groups at three months postintervention. However, a difference in symptom improvement was observed between the two groups at six to ten months postintervention. A subsequent OPT assessing maintenance doses of rituximab in 29 participants with ME/CFS found similar response rates [67]. In addition, 11 patients were still in remission at the three-year follow-up. These promising results led to a Phase III multicentre RCT in 151 ME/CFS patients [68]. Results demonstrated that repeated treatments with rituximab were not associated with ME/CFS clinical improvement and the authors hypothesized this could be due to only a subgroup of ME/CFS patients having an autoimmune mechanism [68]. To test this hypothesis, future CTs in ME/CFS patients with elevated levels of autoantibodies should be considered.

Full Test: https://www.mdpi.com/2077-0383/13/2/325

 

[Wishful]

If a treatment provides only "some improvement", likely only for some symptoms, I don't consider it an ME treatment, but rather a treatment for a downstream symptom that affects only some people. I've had several treatments that switched my ME completely off (for a short time), so I consider those treatments to have worked on the core dysfunction.

For the "efficiency of interventions", they really should stress that for most treatments, effects vary greatly between individuals, which I think is quite different from most treatments and diseases. The trials probably don't need to be different, but how the outcomes are processed and conclusions reached should be treated differently. Going into a study with the expectation of a single efficiency number is a bad start.

 

[Rufous McKinney]

we've got to make further headway on subgroups. But since A Cause has yet to be identified, this makes ID of subgroups problematic.

 

[SWAlexander]

A Cause

What symptom should be number one on the list of subgroups?

 

[Rufous McKinney]

What symptom should be number one on the list of subgroups?

I"d have to do serious thinking about that one. We have an array of research studies which sometimes mention potential subgroups. So some type of literature review analysis might inform an effort to come up wiht some preliminary ideas.

I listed below some ideas for preliminary sub groups, but I erased my baseless suggestions.

 

[Wishful]

Another problem with symptom subgroups: a lot of ME symptoms are unquantifiable. It's hard to do good research on something you can't reliably measure. I suggest not funding any research that is based on questionnaires.

 

[SWAlexander]

a lot of ME symptoms are unquantifiable

"unquantifiable" for what? How would you like research to continue?

 

[Wishful]

"unquantifiable" for what?

Well, there's no reliable clinical measurement for fatigue (not even a reliable definition for it) or for pain, or brainfog. Thus it's hard to replicate the experiment, avoid questionnaire bias, compare it to other studies, etc. We can't even guarantee that subjects actually have ME, since there's no clinical test for it. I can't offhand think of any great scientific discoveries made from non-quantifiable data. Usually it's the quantified data that leads to discovery, or at least verification.

How would you like research to continue?

I'd like to see more neurological research. Partly because I'm convinced that ME's core dysfunction involves brain cells, but also because there's still so much unknown about brain function, thus "new territory" for discoveries. We're developing new tools for studying brain function rapidly, so that's more quantifiable data we could work with. Add in some AI assistance, and maybe we'll find a clear difference between PWME and suitably unhealthy controls.

 

[SWAlexander]

Partly because I'm convinced that ME's core dysfunction involves brain cells,

I suspected years ago brain inflammation (incl. undetected encephalitis) and brain-related issues about ME/CFS.
In 2009 MECFS was called "encephalomyelitis". https://pubmed.ncbi.nlm.nih.gov/20038921/

DNA factors also play a role, as evidenced in conditions like multiple sclerosis (MS) due to inflammation.

Enlarged perivascular spaces (PVS), also known as Virchow-Robin spaces, are linked to increased cerebrospinal fluid (CSF) volume, signaling glymphatic dysfunction and abnormal CSF dynamics. Conversely, reduced CSF volume, though infrequently measured or noted, is also a concern. Diminished white and gray matter has been observed in some patients.

The glymphatic system, a vessel network, clears waste from cell apoptosis and neurotransmitter demyelinating diseases, which can be caused by viruses or bacteria, from the central nervous system (CNS), predominantly during sleep. An MRI can detect enlarged perivascular spaces exceeding 1 mm in diameter, as determined by structural magnetic resonance imaging. Previously considered benign, enlarged perivascular spaces (EPVS) in the brain are now linked to various clinical conditions (e.g., MS, Autism).

However, a definitive assessment of brain damage is only possible through an autopsy.

 

[Wishful]

Another path I'd like research to follow: figure out not only what percentage of PWME have specific symptoms, but also what percentage don't have specific ME symptoms. I'm thinking of my lack of physical symptoms, which a few other people have also reported. If that's just a very tiny percentage, then it might be a unique ability to block the mechanism of physical limitation. However, if it's a significant percentage, it might mean that the mechanism is downstream of the core dysfunction rather than part of it. Right now research is spread over a wide range of possibilities. Data to rate the likelihood of a path being involved in the core dysfunction would be helpful.

 

[SWAlexander]

but also what percentage don't have specific ME symptoms.

Your question could be valuable for the "NANDSC ME/CFS Research Roadmap Working Group".
https://www.ninds.nih.gov/about-nin...l/nandsc-mecfs-research-roadmap-working-group

 

[Osaca]

Another path I'd like research to follow: figure out not only what percentage of PWME have specific symptoms, but also what percentage don't have specific ME symptoms. I'm thinking of my lack of physical symptoms, which a few other people have also reported. If that's just a very tiny percentage, then it might be a unique ability to block the mechanism of physical limitation. However, if it's a significant percentage, it might mean that the mechanism is downstream of the core dysfunction rather than part of it. Right now research is spread over a wide range of possibilities. Data to rate the likelihood of a path being involved in the core dysfunction would be helpful.

Whilst I agree that in general it would be interesting to study some outliers or anomalies, that only makes sense if you have unlimited means and have already understood the common principles of any illness. Otherwise you might just end up studying some very rare effects that have nothing to do with ME/CFS (for example some very rare genetic disease). According to all research physical symptoms appear to be at the core for almost anyone that has ME/CFS according to the CCC and there isn't any evidence that says otherwise.

In diseases that are already far better understood and have a diagnostic criteria not reliant on self-reported symptoms such research studying anomalies can indeed be very fruitful (even in MS, which is far better understood, it probably doesn't make too much sense to focus research on those patients that are seronegative for EBV apart from acknowledging that EBV isn't a necessary factor for the development of MS). Studying outliers is essentially what the BPS crew has been wanting to do for decades by focusing on psychological symptoms and applying Fukuda or worse criteria instead of the CCC.

I certainly understand your sentiment, given that you appear to be an outlier, at least regarding your symptom description, and I certainly also have some things I would think would be interesting to study and worthy of describing, however that can only be the case once core symptoms such as PEM and brain dysfunction have been studied in depth and well-characterised via some measurement technique. This has never been the case.

What I certainly agree with is that questionnaire focused research is not primarily needed. There's still a certain room for questionnaires directed at trying to understand specific dysfunctions better, for example trying to accurately describe different types of brain-fog/brain-dysfunction or even characteristing PEM better (this will probably require an abundance of expertise accompanied with a lot of feedback by patients), but ulimately the reason to do this is to characterise said dysfunctions via tests for example an array of different cognitive perfomance test. Studies only asking you to tick a box at "Do you have brain dysfunction?" are completely worthless and a waste of resources.

Regarding the original posts and possible subgroups, for now that's unfortunately largely a useless discussion, because there's no way to meaningfully characterise such subgroups. Given the heterogeneity of a syndromic illness it does seem quite likely to me that there are indeed different subgroups or even people that are now considered to have ME/CFS and in the future will be considered to have an entirely different illness. But trying to infer anything from that on the efficacy of different treatments, as patients like to do, is no different than if Wesseley were to say "GET cures everyone with ME/CFS, my study showed it worked for a subgroup and the other subgroups just didn't try hard enough". That is simply not how meaningful research could ever work.

The only thing that would seem sensible to me, that would be extremely easy and hasn't been done sufficiently is being better at collecting all available data on each patient (cause of illness onset for instance specific viral infections, do they have POTS or other "notable" symptoms, a "higher probability of autoimmunity" for example repeatedly highly positive ANAs or via patient history for example via a history of autoimmunity and even genetic markers which could be useful if DecodeME reveals anything, etc.), but I wouldn't go so far as to say that, that in any way is useful to indentify subgroups and it might as well lead nowhere but it still makes sense to have it as part of the data as long as you don't draw false conclusions from additional data (for example by not sufficiently correcting for multiplicities or by slicing and dicing your data until you obtain a result).

 

[Wishful]

According to all research physical symptoms appear to be at the core for almost anyone that has ME/CFS according to the CCC and there isn't any evidence that says otherwise.

I just checked the ICC, and under "Energy production/transportation impairments: At least one symptom", there are 4 options, none of which are "reduced stamina or strength" or anything like that. The CCC also lacks a requirement for "reduced stamina or strength". "Muscle weakness" is listed under "Neurosensory, perceptual and motor disturbances", which to me implies a neurological cause, not a muscle tissue or blood flow cause. Think of a robot arm not working properly: it could be the motors or power delivery, or it could be the control system. So no, the research (or at least criteria) does not claim that physical dysfunction (reduced ATP production or whatever) is a core part of ME.

Whilst I agree that in general it would be interesting to study some outliers or anomalies, that only makes sense if you have unlimited means and have already understood the common principles of any illness. Otherwise you might just end up studying some very rare effects that have nothing to do with ME/CFS

I accept that as a valid argument. However, it's one of those "grey areas"; I'm not claiming that ME research should be based only on outliers, but it also shouldn't ignore them completely. I think in engineering terms, so if I was trying to diagnose a fault in a device, and if one seemed to display the same symptoms but several devices lacked a factor common to most failed devices, I'd put fairly strong weight on that factor not being the cause. How important that weight is depends on the number of other possible causes to explore, the chance that the failure is really the same for all devices and not just similar in appearance, etc. No one is letting me decide research funding, so it's not an issue. No one was interested in my offer to be studied to find out why I had other ME symptoms without physical limitations. I also offered to be studied while cumin was working as PEM blocker, but not one was interested in that either. A lost opportunity IMO.

 

[Osaca]

I just checked the ICC, and under "Energy production/transportation impairments: At least one symptom", there are 4 options, none of which are "reduced stamina or strength" or anything like that. The CCC also lacks a requirement for "reduced stamina or strength". "Muscle weakness" is listed under "Neurosensory, perceptual and motor disturbances", which to me implies a neurological cause, not a muscle tissue or blood flow cause. Think of a robot arm not working properly: it could be the motors or power delivery, or it could be the control system. So no, the research (or at least criteria) does not claim that physical dysfunction (reduced ATP production or whatever) is a core part of ME.

I agree that "reduced stamina or strength" doesn't appear to be part of the criteria, however the CCC includes "There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability" which in my eyes includes "reduced stamina or strength". I think we might be miscommunicating since I didn't know what your "lack of physical symptoms" was referring to (and you certainly don't have to reveal that to me). If someone has a "lack of (any) physical symptoms" they cannot have ME/CFS according to the CCC ("any" is what I introduced since I'm not sure what exact physical symptoms you are referring to). If someone lacks some very specific physical symptoms that don't contradict the CCC then based on these vague criteria they of course still have ME/CFS.

I'm not sure what you mean by "physical dysfunction". Physical fatigue is the first necessary criterium in the CCC other physical dysfunctions are necessary conditions as well.

I accept that as a valid argument. However, it's one of those "grey areas"; I'm not claiming that ME research should be based only on outliers, but it also shouldn't ignore them completely.

Whilst I certainly understand your perspective (if there was more funding available or a higher quality in research I might even agree with you) I actually think research for now has to neglect anomalies that might be irrelevant to ME/CFS if there's evidence that it might be less likely that someone with such "anomalies" has ME/CFS. Unless there's a better understanding of the general concepts of ME I see this as the only approach. And that is although my background is similar to yours, a background where outliers shouldn't be ignored but instead be looked at even harder.

No one is letting me decide research funding, so it's not an issue.

Me neither and I'm certainly not pretending that anything I am saying is of particular value.

I also offered to be studied while cumin was working as PEM blocker, but not one was interested in that either. A lost opportunity IMO.

Of course I gave your cumin experience a test, without any positive results for myself. I don't think research will get anywhere for now if it spends funding on anecdotal stories that are completely irreproducible (at the same time I think much of the current research funding is still being wasted and I certainly was happy that you shared your cumin experience). How would one ever study cumin as PEM blocker if one doesn't even know what PEM is? How should they detect the termination of a signal when they don't even know what signal they are looking for in a sample size of n=1?

 

[Wishful]

loss of physical and mental stamina

The wiki copy says "fatigue" instead of stamina, and there's no clear definition of "fatigue", so it doesn't necessarily mean inadequate ATP in muscles. When I had bad PEM, I certainly didn't feel like exerting myself, but my muscles were able to do the exertion. So does neurological "feeling of muscle fatigue" count or absolutely not count?

As for my lack of physical limitations, I mean that my ME didn't reduce my ability to ride 40 km, or dig soil for hours, or do other such strenuous activities. The pain or malaise made me not want to overcome those feelings to exert myself, but my body seemed capable. That seems quite different from the majority of PWME. I'm not alone, since other people reported having ME but able to do bodybuilding that sounded quite impressive. I do suffer from mental fatigue; when my ME flares up I can't focus on reading for very long or do other such cognitive tasks. IIRC, when I checked years ago, the CCC had a criteria of physical or mental fatigue, not and.

I earlier said the criteria was a circular argument. The criteria was put together by collecting data on what symptoms PWME report. How did they select who made up those PWME whose symptoms determined the criteria? I assume it was by seeing who met the criteria. A agree there needs to be some criteria, and I don't at this point see any options other than this circular argument, but the limitations means that it is not an absolute determination of who actually has the disease known as ME. I recall seeing versions of criteria that accept that there are some exceptions to the rules. The criteria are a tool that serve some purpose, but it's not a perfect, absolutely trustworthy tool.

Exceptions are a potentially very valuable tool too, but also not absolutely trustworthy. In the absence of the perfect tool for the job, you have to decide which flawed tool is the best choice.

How would one ever study cumin as PEM blocker if one doesn't even know what PEM is?

I'd do it as taking as many samples and scans that I could think of, before, during, and after exertion, with cumin and without. Maybe there would be a significant difference in one or more factors, which poses the question: why does that happen? If the data doesn't provide an immediate clue, save it to compare with other data later. Maybe someone has the same response to dandelion root, so compare the data and look for correlations. This sort of data collection should be even more valuable as AI develops and can search vast amounts of data for connections.

 

[Rufous McKinney]

Studies only asking you to tick a box at "Do you have brain dysfunction?" are completely worthless and a waste of resources.

totally agree

Regarding the original posts and possible subgroups, for now that's unfortunately largely a useless discussion, because there's no way to meaningfully characterise such subgroups.

it seems that before you can describe sub-groups: you must be able to describe the overall Group, first.

(A few studies done to date, that I seem to recall, seem to suggest perhaps there are two subgroups. I cannot seem to recall any suggesting five, or ten possible subgroups.)

 

[Rufous McKinney]

in a sample size of n=1?

there was that recent publication over one SINGLE woman with odd symptoms and her doctor published and NIH did all these tests on her.

Why was her n=1 so very special?

I had mild something Epstein Barr for most of my life. I could work full time, I could hike all day. I worked harder than most of my healthy colleagues. I could also outsmart smart lawyers, much of the time.

None of this is the case now, as I got worse in 2017.

But prior to 2017 I was doing far worse for about ten years. And I recall when I lost my brain compass. I was never lost, I hiked professionally cross country through old growth forests no trails, no route and you do not get lost EVER

It was around 2010, my brain compass broke. So that was a very early symptom of mild ME getting much worse, (sleep issues also worse)...so brain cleansing had something to do with all THAT.

The compass in our brains is a real thing, but they aren't designing a simple test for that one.


I am reasonably convinced that a major component of whats wrong with us, is tied to a lack of proper brain cleansing.

 

[lenora]

What's amazing to me is the sheer numbers of patients with undiganosed diseases (orphan diseases) that fit in with our symptoms. So, so many of them....and yet we know for sure that they aren't from the same cause.

No wonder doctors can't make a diagnosis....I've been living with and trying to figure this out for more than 40 years, and I'm still no closer. I think each of us has to figure out what our worst symptoms are, what helps them the most and then go from there.

True, there are a lot of symptoms that we don't all share. Fatigue is the big one, but if you look at all the orphan diseases, that is a common factor. Perhaps we should come up with a description of what fatigue really means....I know for a fact that many people share our type of fatigue. Mine isn't as bad as it once was, but then I haven't undergone surgery, really never go out and don't do meals or household chores. Does that mean I don't have fatigue. I would have to say "no" to that....it's just that I've learned to adjust to it.

At different times in our life, we're apt to handle fatigue in a much different manner. Right now, I'm handling it in the best way I know possible, but when I was much younger and had children, I had to meet their needs...and I did. I still don't know if I had more energy (since it can come and go) or I had a higher duty to perform. I really couldn't give an honest answer to that. This illness can and does change for a lot of us, and that makes it all the more difficult for a doctor to make a diagnosis.

It seems that the more we learn, the harder it all gets. But isn't that called progress? Yours, Lenora

 

[Osaca]

The wiki copy says "fatigue" instead of stamina, and there's no clear definition of "fatigue", so it doesn't necessarily mean inadequate ATP in muscles.

This appears to an official source which says "There is an inappropriate loss of physical and mental stamina" (I also don't think PEM is related to an actual lack of physical energy in terms of ATP. Thinking hardly requires more actual energy (ATP) than not thinking and yet induces PEM for most people, which seems to be a far more complex issue than lack of ATP, I actually prefer your faulty circuit analogy).

I fully agree with you on these criteria being nothing but a circular argument in the absence of a better argument. Hopefully they can someday be replaced by something responding to measurements. However, that currently makes it even more important to study properties that are being described and not some outliers. That doesn't mean that outliers can't or don't have ME (or what is currently considered to be ME according to the CCC). It just means that studies have to focus on reducing all sorts of noise.

That doesn't only mean they have to apply the strictest criteria (the CCC) it also means that IMO you have to even further and the following things should be fulfilled when looking for most study cohorts: Minimum illness duration of at least 1 year, at least 60% females, no pre-ME/CFS comorbidities, not overweight, no psychological problems, no psychological problems pre-ME/CFS, athletic pre-ME/CFS, working full-time pre-ME/CFS, no smoking, no drinking, not older than 65 (to high of an increase of possibly additional and undetectable health problems), few post-ME/CFS comorbidities, higher severity level than mild.

That may mean that such cohorts aren't a perfect representation of the general illness and it even means I myself am not participating in studies since I recently developed an additional autoimmune disease on top of ME/CFS and as such my study measurements could introduce artifacts not related to ME/CFS.

It's certainly not perfect but reducing possible noise has to be the top priority (and as someone interested in AI you could only agree with this) alongside better methodologies.

ay it seems that before you can describe sub-groups: you must be able to describe the overall Group, first.

Precisely. To study properties of a subsets you first have to know something about the whole set. We know nothing about the whole set.

there was that recent publication over one SINGLE woman with odd symptoms and her doctor published and NIH did all these tests on her.

Why was her n=1 so very special?

Honestly, this person was just probably just extremely lucky and persistent. For some reason the doctor cared more about her then doctors usually care or have to time care for a single patient, possibly because they had an excellent relationship, maybe this person was wealthy, but probably most importantly because this woman had been suffering from conditions completely unrelated to ME/CFS which society cares about more. I guess if she had been an n=1 ME/CFS case she likely would have just been ignored like everybody else.

 

[junkcrap50]

there was that recent publication over one SINGLE woman with odd symptoms and her doctor published and NIH did all these tests on her.

Why was her n=1 so very special?

Could you link the paper of the case study? Or more info about what NIH tests and things were done? I hadn't heard of this story.

Honestly, this person was just probably just extremely lucky and persistent. For some reason the doctor cared more about her then doctors usually care or have to time care for a single patient, possibly because they had an excellent relationship, maybe this person was wealthy, but probably most importantly because this woman had been suffering from conditions completely unrelated to ME/CFS which society cares about more. I guess if she had been an n=1 ME/CFS case she likely would have just been ignored like everybody else.

I don't know about this case specifically, but I can comment more generally. Extremely lucky is the answer. Having caring doctors & wealth are not much help for this disease. I've seen a few ME/CFS & Long Covid cases online where the patient or parents of the ME/CFS/LC patient are doctors or scientists themselves and have wealth to do any treatment & testing and it's gained them no advantage.

Potentially if you have super wealth, like greater than $50 million, you might have some success or advantage but it's unknown as we've seen no ME/CFS patient like that, lol. The only way I could see that being helpful is if you were conducting or replicating lab-bench ME/CFS research on yourself. Or you would donate to a ME/CFS reseacher on the condition they run your blood/cells/samples through their research and provide you results. So, essentially, at that point, you would be self-funding lab-bench, n=1, ME/CFS research on yourself. And even then what can you do in regards to treatment? You would have to self experiment with untested, much less unapproved, drugs.