The idea that ME subtypes explain treatments only working for some—thoughts?

jonathan_h

jonathan_h

Established Member (Voting Rights)
Whether it’s Ampligen, LDN, or CoQ10, it’s not uncommon to see pwME attribute the range of outcomes from popular treatments to (theoretical) differences in the biopathology of people’s ME. The logic goes: those who benefit from a treatment share some common feature of their disease process that the treatment is acting on, and the non-responders don’t have that feature.

I have mixed feelings about this idea. On the one hand, it’s a convenient excuse for treatments which truly don’t work. We know from clinical trials that if you give a group of pwME a placebo for a decent while, a significant number of them will have their health improve in that duration for whatever reason. So, to my understanding, our expectation for a popular treatment which literally does nothing should be that there are a significant number of people talking about how their ME improved while taking it. The idea that those who apparently benefit from a treatment are *necessarily* a subtype of “responders” seems false.

On the other hand, there are a couple of treatments I have tried over the years which I’m moderately confident have benefitted me: low-dose abilify, which expanded my energy envelope by a little for some months, and natto-serra, which improves my body-wide aching muscle pain. Many pwME have tried these treatments and felt zero benefit. While I’m open to the possibility I’m confusing correlation and causation, I think that’s unlikely for a few reasons: symptomatic improvement in these specific ways is rare for me, benefit was closely linked temporally to starting the treatments, and in the case of natto-serra, the benefit has disappeared and returned when I’ve stopped and restarted taking it, respectively. So I find myself wondering: am I in an ME subtype that responds to these treatments?

Interested in how others think about this.
 
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Yes, when researchers start reaching for the 'sub-type' idea post-hoc it raises skeptical thoughts. We've seen some pretty bad papers supposedly reporting on ME/CFS subtypes.

That said, it is to be expected that cohorts of people diagnosed with ME/CFS will include some people who have other health problems, and perhaps even that ME/CFS is several different diseases. If the cohorts are big enough, a result that has some of the ME/CFS people with a biomarker that's clearly different to the controls and some of the ME/CFS people looking exactly like the controls would still be exciting. So would a chart from a decent (blinded) trial that shows us that some ME/CFS people responded to a treatment and other ME/CFS people did not.

On the issue of treatments and responders to date, my set point is skepticism. Part of that is probably living through the Phase 3 rituximab trial. I was hopeful that it would work, that it would be the answer. And it wasn't, even though we saw some people improving. I think some of the people really did improve and possibly even some of them truly did respond to the rituximab - but the latter must surely have been a very small number to not move the dial compared to the placebo. I know this illness fluctuates and I know how easy and seductive the idea of some treatment helping is.

As far as people finding treatments that help them goes, if adults research the options, aren't coerced or misinformed, and feel able to stop if something isn't helpful, then whatever makes people's lives better. Watching what happens when you go off the drug and then go back on it, several times, sounds like a good thing to do. Tracking objective markers for quite a while could help with the certainty.

I think parents need to be really careful about experimenting on their child with ME/CFS. I recall some research by Katherine Rowe where she found many young people reflecting on their experience of having ME/CFS as a child commented that they wished their parents had not tried all sorts of treatments. I think the need for parents to feel that things are getting better for their child, and the child wanting the parent to not be upset can really skew proper assessments of risk and outcomes. I think in that case, it would be very tempting for a parent to feel that they had found a treatment for their child, for their child's ME/CFS sub-type, even if there was quite a lot of evidence, anecdotal and otherwise, that it did not work for people with ME/CFS generally.
 
It would not surprise me if there turned out to be some sub-types of ME. There are for many diseases. It might even be the normal situation.

But each disease group still has something in common. Cancers, for example, are a failure to restrain cell growth.

None of which excuses simplistic arbitrary sub-typing to explain away inconsistent results.
 
Given that "causes" vary , it's the end state that is common .

There are probably many biological pathways to this end state , which may be modulated by genetics / epigenetics, so things working / not working didn't seem that odd to me - just frustrating .

It's a " systems " condition , and other systems science areas are complex due to the interplay between different variables , feedback loops and the different types of expertise required to understand impacts and mechanisms. ( eg climate science ) . This makes research more difficult, especially with the dearth of funding ME/CFS has .


I can see ME/CFS being either many separate similar conditions yet to be unravelled , or like MS a condition with subtypes .

I'm hopeful that genetic research such as decodeME, the various " omics" , gut studies etc and the use of AI will start the unravelling needed to get to mechanisms .
Without mechanisms we can't develop and target treatments.
 
There are two very different arguments.

On the one hand there’s the possibility of ME/CFS having different downstream effects, having different subtypes or even being a collection of different illnesses. This seems like an extremely reasonable hypothesis to me for which the very reasonable following argument, which is commonly seen in many other illnesses, can be made

A) subtypes exist -> different treatments addressing ME/CFS work for different people​

However, this is a completely different logical argument than saying

B) different treatments addressing ME/CFS work for different people -> subtypes exist​

which is what is usually the reflection of the lived experience of people experimenting with different treatments or also what some of the post-hoc studies @Hutan mentions do.

I also think people on S4ME are very knowledgable on ME/CFS and have done their due diligence to confirm they have ME/CFS by ruling out other medical conditions. However, this is not always the case for the internet in general, which is the source of anecdotal evidence for many people, including myself. I’ve seen polls on the internet for ME/CFS patients where not only more than half of the people didn’t fulfill the CCC, but the majority of people hadn’t even heard of the existence of diagnostic criteria for ME/CFS before. In most scenarios one probably doesn’t actively engage too much with these patients as engagement with "veterans" of this disease seems more common, however I wouldn’t underestimate a substantial confirmation bias in anybody who reads a story that confirms his own lived experience even when the source might be "less credible".

I think Natto-Serra is a good example of this. It seemed to be very popular and I saw it mentioned everywhere across the internet roughly a year ago. I wasn’t able to read the source of every claimed success, but for many, including myself, there was sufficient anecdotal evidence to give it a try, just as I am willing to try “x,y and z” if I find a sufficiently reasonable argument to do so. Since then the popularity of Natto-Serra has declined. The same can be said about almost any other supplement/treatment where waves of popularity can be witnessed. Of course there are supplements/treaments for which the evidence is more overwhelming and for which trials are very warranted, LDA being one of those. I would also never discount anybody’s lived experience, for example you being able to reliably induce a symptomatic improvement. However, I wouldn’t argue that that is a solid argument for different subtypes existing especially, because one can just as well argue that the improvement stems from any different currently physiologically immeasurable effect.

As @Hutan mentions every cohort of people, especially those present on the internet, rather than in well conducted RCTs, of any disease, will always include some people who have other health problems, possibly just some downstream effects caused by ME/CFS, as well. Sometimes something as mundane as a simple deficiency.

I’m by no means suggesting that for example what you are experiencing with Natto-Serra couldn’t be addressing a core ME/CFS process. There is ample evidence that vascular/microvascular/endothelial/coagulation problems could be present in at least a subset of ME/CFS patients and it wouldn’t be unreasonable to assume that, in possibly a further subset of patients, Natto-Serra is somehow addressing these problems. However, I don’t think that alone can be used to argue for oneself belonging to a certain subtype.

After all even healthy people make all sorts of different claims of things that are beneficial to their health, with a multitude of possibilities of why this could be the case, ranging from placebo effects to addressing some deficiencies. Unfortunately, proper investigations are always needed to find out what’s truly going on since making argument B) requires a verification of the statement “different ME/CFS treatments work for different people” which is impossible to do without solid evidence.
 
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jonathan_h said:
Whether it’s Ampligen, LDN, or CoQ10, it’s not uncommon to see pwME attribute the range of outcomes from popular treatments to (theoretical) differences in the biopathology of people’s ME. The logic goes: those who benefit from a treatment share some common feature of their disease process that the treatment is acting on, and the non-responders don’t have that feature.
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In some cases I wonder if a the person really have ME or is it a different condition that is misdiagnosed - I believe, for example, that people with MS will sometimes get a ME diagnosis early on. ME is relatively easy for a doctor to diagnose but jumping to that conclusion can stop other lines of investigation.

Then where drugs help with symptom relief people seem to get a range of symptoms so if a particular symptom isn't that bad for an individual then a drug may not have a big effect. But given the range of symptoms does this imply subtyping or is it a more complex common mechanism that can lead to different symptoms in different people and even different symptoms at different times.

Perhaps one question we should ask is how consistent are drugs in other illnesses. Would you expect to try a few different things to find one that works with a different condition.
 
jonathan_h said:
Whether it’s Ampligen, LDN, or CoQ10, it’s not uncommon to see pwME attribute the range of outcomes from popular treatments to (theoretical) differences in the biopathology of people’s ME. The logic goes: those who benefit from a treatment share some common feature of their disease process that the treatment is acting on, and the non-responders don’t have that feature.

I have mixed feelings about about this idea. On the one hand, it’s a convenient excuse for treatments which truly don’t work. We know from clinical trials that if you give a group of pwME a placebo for a decent while, a significant number of them will have their health improve in that duration for whatever reason. So, to my understanding, our expectation for a popular treatment which literally does nothing should be that there are a significant number of people talking about how their ME improved while taking it. The idea that those who apparently benefit from a treatment are *necessarily* a subtype of “responders” seems false.

On the other hand, there are a couple of treatments I have tried over the years which I’m moderately confident have benefitted me: low-dose abilify, which expanded my energy envelope by a little for some months, and natto-serra, which improves my body-wide aching muscle pain. Many pwME have tried these treatments and felt zero benefit. While I’m open to the possibility I’m confusing correlation and causation, I think that’s unlikely for a few reasons: symptomatic improvement in these specific ways is rare for me, benefit was closely linked temporally to starting the treatments, and in the case of natto-serra, the benefit has disappeared and returned when I’ve stopped and restarted taking it, respectively. So I find myself wondering: am I in an ME subtype that responds to these treatments?

Interested in how others think about this.
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I've broken it down into 2 related Qs - the sub-types bit, then the 'claiming it' in research as a get out of jail free card vs 'where it is a finding'.

Question 1:
I'm certainly open to the idea that the diagnosis (even with PEM) has been a dumping pot for decades particularly in the UK. And that because of the terrible guidelines/attitudes it has been used in the following way: certain GPs or other HCPs label a person for no reason, perhaps even before meeting them perhaps because someone else didn't like their face or perhaps demographic or not liking face, and from thereon after said person receives no investigations or anything and even if past tests or history shows something that is 'wiped' by the label.

By which I mean person walks in with blood tests showing abnormalities, other tests showing pathophysiology that you wouldn't repeat (as it won't change) but would still be there if you did and yet by virtue of the new 'CFS label' and BPS individuals and the push through certain edits from certain people enforcing GP pathways that person now apparently has no pathophysiology. Which of course isn't true but seems to work in that strange land. And serves as an edict for all other illness barring any red flag someone might worried about it looking really bad and obvious if they missed, or something they might get paid for (whether or not patient has it in case of really bad GPs).

SO there is probably no other group who are more likely to have other comorbidities, as well as there being different issues in individual bodies for something which I suspect is related to the body being 'bombarded' in some way that could well mean that various proportions will also find e.g. if they had a vulnerable gut or tendency to allergy or ENT issues or migraines means that it takes those down too (at the least re: 'subtype'). I'm sure there have also been 'downstream' effects as I've become more ill and had it for longer too.

THEN we have the issue that until someone does a really good job of studying PEM and knowing exactly when it starts (during?) vs the level of exertion vs threshold (which would I guess mean some measure showing 'stress body has been put under' instead of the current 'measure arbirtrary level of exercise, without a good way of measuring the person's threshold who is doing it', oh plus not including how exhausted they might already be getting there and the weeks leading up to it) and understanding all the different 'other' potentially 'within ME/CFS' comorbidities like POTS or if someone is carrying 'still recovering from covid 6months ago' vs 'having been put through a year of hellish overwork' I can certainly see how at the medication level something could be well worth having but particularly only to certain groups. Just due to the quirks of what is bundled under the condition. And of course these 'episodes' can load one 'standard ME' which might be 'matched' with another individual into e.g. 10yrs of being quite different if someone has had a bad run of these things after another. As I suspect it's a vulnerable system taking 'another hit' in another way and so on. Whether if it is that they will end up calling that 'types' or 'sub-types' or there will be a more appropriate term I don't know but it certainly feels relevant for ME.

But also when you note not just the different severities and 'situation' re: whether someone can pace at all or is permanently struggling beyond threshold, but things like sleep reversal (type of PEM not 'behavioural' can train way out of it, but trying to do that makes that worse and more embedded) seems to be something very much a dominant feature for a certain proportion and definitely not one for others.

Question 2:
I'd say the suggestion of 'it might only be subtypes' is reasonable but only where someone is using a decent methodology rather than 'fishing' and in particular where the pattern shows a sub-group who 'benefit very obviously and significantly' - particularly where it can be well-triangulated with more objective measures etc - vs 'the rest' .

In my naivity thinking medicine did science I assumed that by the time trials were run then this type of exploratory research had been done first, and that 'size of impact' mattered in order that it was worthwhile identifying homogoneous groups within groups. That doesn't necessary mean it is unusual for this illness. I'm aware for example for RA of some who are 'atypical' and some who didn't respond to the newer treatments and had to stick with the old, and vice versa. But just thinking about e.g. PPIs or nasal sprays for rhinosinusitis people will try different ones and some will end up with others suiting them better for reasons that might not be about 'the illness' but individualities of the body and situation?

But then I grew up in science being observation-based too, and whilst I understand when you get to trials its inference using only quant across average it's weird how this bit gets skipped so much when people are putting models together - it's one thing finding a med helps, but another thing claiming cause, which does need more back and forth between that deductive testing (and inference) to explain why it makes sense. You'd therefore also expect the results from these things to be inputting useful data (and hope they'd share the raw with others looking into similar areas for the sake of progressing it) not just for replication but also so that the models and any splits or groupings or 'other factors' to be refined - and for it's impact on methodology if it might affect sample or what you might need to control (or be aware of as another factor) in an experiment.

So where it is being done genuinely it is worthwhile but I have little faith in the one-liner or 'manifesto' ramble from someone's personal bigotry rather than it pulling out why such findings contradict or update an assumed mechanism on a model etc

I suspect the tendency to not look for harms either has made the research on the non-pharm side really poor at this too because they aren't really caring about anything other than trying to achieve an averaged effect that can just about tick their box on claimed impact. Which tells us little about whether it is useful or in the mechanism. You wouldn't expect people to fish out a 8% subjective (with no blinded placebo) difference in 20% of people and make claims. But if on a trial where most didn't really show any difference there was a 20% of people who could suddenly take 30min showers standing up every day for a year when they were bed-bound and scraping their way through one a week sitting down that might be worth further describing and looking into what differentiates them. A one-liner about 'might be sub-types' isn't that level of analysis or consideration of how they performed.
 
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People who share a diagnosis of a certain disease (well established pathology) based on the most objective findings via tests and scans, don’t necessarily respond the same to medications that they might be given, even those with a proven track record of some level of effectiveness for improving outcomes for patients with this disease.
There are always patients who respond unusually well or unusually poorly.

The things patient with ME who don’t have any of the above knowledge on their side attempt to experiment with are things to meddle with biological processes that can be guessed to be occurring based upon knowledge borrowed from other areas and the symptoms an individual is experiencing.

I am all for this guessing and feeling around in the dark for something that might help. When you have nothing else. Fortunately there is now easier access to information that will help inform any individual of potential risks as well as benefits. But it has to be taken into account that being sick makes it harder to calculate these things or the assimilate the knowledge to start with.


I don't think positive or negative outcomes is likely to tell us anything about ME in terms of how coherent it might be found to be or not be.

I don’t think we can likely get close enough to the pathology from this direction. I mean I don’t think we can infer anything about ME from individuals labelled with ME responding or not responding because there are too many variables to account for.


But people with his diagnosis might experience certain symptoms that may or may not be helped by one or more experimental nutritional supplements or drugs.

I think it does provide the individual experimenting with some useful clues with which to care for themselves as best as possible in these unfavourable circumstances.

I think pooling our knowledge on experiments can be very useful for possible avenues of research, but I don’t think it should be used to place patients into particular categories in terms of their presumed type of disease. Because although you might get this right you might also get it wrong. Or get it partially right and still miss something important.

For personal theorising and speculation, spontaneous thought , intuitive revelation, it’s never too early. But for categorising individuals or illness it’s too early. It’s usually too early.
 
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I benefitted from taking CoQ10 years ago because my blood levels were low. Might be indirectly related to M.E. and oxidative stress(which was very high on my test panel), just like it would with other pathologies.

It almost feels like a 'boost', but certainly isn't a permanent effect, in fact when I was able to do more it just gave me PEM.

Same with when I took magnesium/taurine injection off and on for a few years. Got a boost of energy and smoother gait when my levels went back to normal range, but it certainly didn't improve PEM which is the disordered physiological process.
 
jonathan_h said:
We know from clinical trials that if you give a group of pwME a placebo for a decent while, a significant number of them will have their health improve in that duration for whatever reason.
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The improvement may not be real; it might only be the result of how "improvements" are judged. Without a reliable quantitative measure of "health", we can't judge whether it really changes before/after. In another thread I pointed out that you can probably bias the results by doing the pre-test in a depressing room, and the post-test in a cheerful room, and that won't be mentioned in the study.

I think there's a core mechanism common to all PWME. Given the complexity of the human body, it's reasonable for some people to have different reactions to factors and different sets of downstream effects. For example, if a person has intestinal walls more responsive to cytokines, ME might result in more cytokines and thus more symptoms from gut inflammation and leakage. So, there will be sub-groups based on responses and downstream effects. As someone else pointed out, not everyone responds exactly the same to any drug, so you can divide them into subgroups too. That doesn't mean that there are different subgroups of core mechanisms for ME. There will also be other diseases which share some responses and downstream effects that some PWME have.

I still have hope that there will be a treatment or cure for the core mechanism of ME, which will work for the majority. My experiences with temporary remissions convinces me that there is one fairly simple switch, and if you manage to switch it off, all the ME symptoms are gone.
 
From having had three people in my family with ME/CFS (onset for all three at the same time, and therefore almost certainly the same cause, the same disease) and having had ME/CFS for nearly 11 years now, I observe that:

* individual experiences with the same disease do differ e.g. impact on sleep reversal, recovery
* symptoms are really variable over time e.g. the importance of gastro issues has changed a lot

Seeing that variability, I am left feeling that there can be quite a lot of phenotypic variation but the disease is still ME/CFS. Not to say it isn't useful to find out why that phenotypic variation occurs.
 
Creekside said:
The improvement may not be real; it might only be the result of how "improvements" are judged. Without a reliable quantitative measure of "health", we can't judge whether it really changes before/after. In another thread I pointed out that you can probably bias the results by doing the pre-test in a depressing room, and the post-test in a cheerful room, and that won't be mentioned in the study.

I think there's a core mechanism common to all PWME. Given the complexity of the human body, it's reasonable for some people to have different reactions to factors and different sets of downstream effects. For example, if a person has intestinal walls more responsive to cytokines, ME might result in more cytokines and thus more symptoms from gut inflammation and leakage. So, there will be sub-groups based on responses and downstream effects. As someone else pointed out, not everyone responds exactly the same to any drug, so you can divide them into subgroups too. That doesn't mean that there are different subgroups of core mechanisms for ME. There will also be other diseases which share some responses and downstream effects that some PWME have.

I still have hope that there will be a treatment or cure for the core mechanism of ME, which will work for the majority. My experiences with temporary remissions convinces me that there is one fairly simple switch, and if you manage to switch it off, all the ME symptoms are gone.
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Or you seem to hear from the description of clinics ‘follow up’ that it’s sent to them remotely (and those who don’t want to / see benefit in a reply might be those with bad feedback or nothing good to report) to do when they feel able to be being handed a sheet after travelling to and finding a clinic they’ve never been to before. I think there is reasonable argument to say that at least with subjective there should at least be a second start measure taken eg 3rd visit in when people have had their induction and gif their bearings of what they’ve signed up to and their journey etc
 
This thread has me thinking that I need to introduce some blinding into my own trials of medications. I think this would not do much for some drugs, which have obvious side effects, but could be worthwhile for others. I'm imagining buying some opaque capsules, crushing up some pills (for non-coated medications) to fill capsules, filling an equal number of capsules with a filler and then asking someone else to put them in two different bottles for me. Has anyone figured out an easier way to do this?
 
LarsSG said:
I'm imagining buying some opaque capsules, crushing up some pills (for non-coated medications) to fill capsules,
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There are two forms of generic empty gel capsules you can buy. The clear one for non-enteric medications, and the opaque white ones for enteric (coated) medications.

For blinding the white ones have the advantage of hiding the contents, so you can't tell what is in them.

I don't know if non-enteric can be taken in an enteric capsule.
 
LarsSG said:
This thread has me thinking that I need to introduce some blinding into my own trials of medications. I think this would not do much for some drugs, which have obvious side effects, but could be worthwhile for others. I'm imagining buying some opaque capsules, crushing up some pills (for non-coated medications) to fill capsules, filling an equal number of capsules with a filler and then asking someone else to put them in two different bottles for me. Has anyone figured out an easier way to do this?
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When medication has a dramatic effect you can probably rely on unblinded self reporting, the problem is with something that has a slight effect or no effect.

I suspect trying to blind yourself would just get too complicated, wouldn’t it be better trying to focus on either objective outcomes or alternatively look at longer time scales.

For example when having B12 injections I sometimes feel a bit better and sometimes don’t, however I suspect the effect is generally on how I feel rather than any significant increase in activity. So I could not initially be certain if they did any good. It was only over several years of being uncertain if the injections had an effect or not, that I came to the conclusion that being in B12 deficit leads to me feeling a bit more groggy, which is helped by the injections, and that maintenance doses stop me going into deficit again, but otherwise have no noticeable impact on how I feel when not in deficit. (Obviously there is the possibility of a sort of second order placebo effect where I am thinking I experience this pattern because of my current theory about the effect of B12 injections only having a subjectively noticeable effect and then only when I am in deficit, but that maintenance dosages stop me going into deficit.)

Though such slight effects on how we feel are of some value in dealing with such a horrid condition, they are not going to change the face of treatment for ME. So if a medicine only seems to have a slight subjective effect, as long as there are no side effects, does it matter if any improvement is real or self delusion? Why not just keep on taking it as long as the effect, real or placebo, leaves you thinking things are a bit better, but recognise that either interpretation is possible.
 
Perhaps it is useful to look at other diseases with an established pathophysiology. As an example, various treatments will work for some, but not all, people with the same subtype of MS (e.g. relapsing-remitting) or mitochondrial disease, such as low dose naltrexone or L-carnitine. This does not mean that the underlying pathophysiology is different.

It may well be that there are different subtypes of ME/CFS, and Choutka & Awasaki’s comprehensive review of post-acute infection syndromes lends plausibility to this hypothesis in that they highlight that although these syndromes share the same core symptoms of exertion intolerance and fatigue, their presentations differ depending on the triggering infectious agent. For instance, people with post-giardasis ME/CFS may report more gastrointestinal symptoms. However, the response (or lack thereof) to certain treatments is not a sufficient test to infirm or confirm the existence of ME/CFS subtypes.
 
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