Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome 2023,van Eeden et al

Abstract
Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated. We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud’s symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients. All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR. SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity. Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes.

IJMS | Free Full-Text | Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome (mdpi.com)

 

I think this paper is problematic but maybe it has some value for systemic sclerosis SSc.

People with SSc are often severely fatigued, or described being exhausted or unable to carry out daily activities even at an early stage when signs are few. This study looks at patients with limited disease but of a systemic form (indicated by nail capillaries) rather than one of the truly local forms.

It seems that a proportion of patients fulfilled CCC and maybe ICC. This may illustrate the fact that ME criteria are probably not that specific in the presence of another major disease likely to produce generalised symptoms. To me, you cannot call this ME/CFS or SSc/CFS. It is just the symptomatology of SSc.

Then there is the problem that for any given disease any symptom or symptom cluster will correlate with severity. Severity is likely to associate with generalised cell function disturbance so a correlation between fatigue and bad cells is expected. People with chronic leukaemia will show a correlation between exhaustion and bad cells etc....

It would nice to think that this might have some implications for genuine isolated ME/CFS and its pathology but I suspect not.

 

I note that they judged cell abnormality on the basis of circulating free DNA. A key feature of SSc is that cells die - especially the endothelial cells of blood vessels - which is why the nail capillaries are abnormal. So they are measuring vascular cell damage probably. There is no indication of any such damage in ME/CFS as far as I know.

Of course if someone found the same free DNA findings in even a small number of people with isolated ME it would be of great interest. But if they found abnormal nail capillaries we would just diagnose SSc!

 

Can you say more about the topic of genuine isolated ME/CFS and patients with other diseases also fulfilling ME/CFS diagnostic criteria?

The dominant narrative in the patient community for a long time was that ME/CFS research was slow to make progress because of outdated, bad diagnostic criteria. The hope was that strict and new diagnostic criteria would enable rapid progress.

If we interpret the patients in this paper as probably not truly having ME/CFS, then we would have to admit that ME/CFS cohorts, even with strict criteria, probably contain patients with illnesses like systemic sclerosis that were incorrectly diagnosed as ME/CFS. There might be hundreds of illnesses that are difficult to diagnose and can look nearly identical to ME/CFS. The proportion of these false ME/CFS cases in research cohorts could be relatively high even if from the outside it looks like strict diagnostic criteria were met.

Maybe progress is slow because this "ME/CFS mimicry" is being underestimated.
If this is true there might never be a good biomarker for ME/CFS as currently defined because there are no pure ME/CFS cohorts.

 

Whole blood mito material will be affected by muscle damage due to physical activity, was physical activity prior to sampling, per individual, quantified in some way and assessed for relationship with the other measurements? Currently jet-lagged so might be missing it.

Experienced clinicians who are friendly to biological evidence are our best tool against this problem, until we can work with those clinicians to validate sufficiently objective and disease- or even subtype- specific markers. It's a process, and there are dependable clinicians out there to help us through it

 

I'm thinking specifically about diagnostic tests here. If presumed ME/CFS cohorts also contain some cases of other illnesses that are good "ME/CFS mimics", then it might be impossible to ever devise a diagnostic test that can reach high accuracy, let's say 98%. The maximum possible might be more in the 90% range which is not quite good enough as I understand it.

 

I don't actually think we want biomarkers for anything. We want tests that reliably identify some physiological change that is likely to be related to what causes the symptoms.

Tests that agree with symptoms 98% are pretty useless because it means the symptoms are already good enough to diagnose. The best tests correlate about 80-90% with symptoms but tell you the symptoms are something to do with X. The other 10-20% of people still have symptoms and may show up on a test for Y or Z.

I sups the problem here may be that the clinicians think they ought to be looking for 'SSc/CFS' when they are actually looking for SSc fatigue. In their enthusiasm they are probably interpreting exhaustion after effort as PEM. People with SSc get that. They may get more typical PEM but I think it is hard to be sure from this.

 

In the absence of a marker, what we mainly lack is an adequate screening tool for PEM. A questionnaire that doesn't lead patients too much, perhaps along the lines of the HADS scale (which I think uses techniques such as asking the same question in different ways).

In most cases PEM ought to be distinctive enough to rule in ME, in the absence of signs of another condition. With decent screening tools and experienced clinicians, surely it shouldn't be any harder to diagnose than other chronic conditions that lack reliable biomarkers, and surely there shouldn't be any greater a proportion of misdiagnosed patients in trial cohorts.

We just need the tools and the, um, clinicians.

 

Not mutually exclusive.

Also, yes, if a biological feature being used as a diagnostic is one that's related to the underlying causal mechanism, it is probably more likely to work, in principle. Of course. However, does that notion then preclude other features that are consequences, not causes, of underlying pathology, from also working well as diagnostic tools? Of that, I am not so sure.

 

That isn't the point, @DMissa.
The point is that it is a common fallacy to think that medicine is looking for very high levels of correlation. If you are able to establish such high levels it means that you already have the confidence you need for making an accurate diagnosis. If the test does not relate to some insight into process it is pointless.

And yes of course 'related to what causes' in no way precludes consequences - they relate to causes.

The point is that the popular concept of 'biomarker' isn't really what physicians need. It has become a popular meme and it is often assumed that the better the correlation the better the test. This is very far from so. Unfortunately people doing clinical research often do not think very logically. Which is why we have things like Chalder Fatigue Scores.

 

In the case of ME/CFS, though, a biomarker which correlates highly with the accepted diagnostic criteria would secure victory against psychologists, insurers and benefits assessors, so it’s perfectly reasonable for us to be almost as excited about biomarkers as the prospect of a cure, and very sensible to focus on biomarkers for the hallmark symptom of PEM.

 

But only if we have reason to think it relates to causation. We tend to assume it must do but it need not. 98% of people with fibromyalgia may have high levels of one or other painkiller in the blood but it wouldn't be a useful biomarker.

In reality, what people will take seriously as a biomarker is likely to be credibly related to causation. And its usefulness will lie in whether it really does reliably relate to causation - which trumps any relevance of the correlation rate. A biomarker for process P that is responsible for PEM in 37% of people with ME would be great. A biomarker that is actually a red herring that someone claims to have found in 99% PWME is worse than useless because the one with PEM who is not positive loses their benefits.

Victory against psychologists will only come from something that is credibly relevant to cause.

 

So then we should be looking for a biomarker for PEM?

I think I can feel when PEM starts in the body. The last time it started just hours after exertion. It's initially barely perceptible but increases over time.

If I can feel it, it shouldn't be difficult to find a biomarker.

 

Yes, that makes sense, although you don’t have to be John Stuart Mill to prefer a world where 99% of pwME access benefits and 1% are shafted, to the one we have currently.

 

I wonder if we should bear in mind that diseases like Alzheimer's don't have a biomarker. OK a Doctor will reasonably diagnose Alzheimer's long before a scan [even if you could run one] would identify amyloid plaque accumulating in the brain.
I wonder if the solution is to try to work with the APPGs to "force" a change in policy i.e. a Doctors diagnosis of ME/CFS should be enough to access benefits? The existence of long covid/post covid may encourage the Government to:

• provide access to benefits to those with ME/CFS; and/or
• restrict providing benefits to those with ME/CFS - due to concern that it would open the flood gates etc.

But yes it's ridiculous that people can't access benefits because they cannot prove they have ME/CFS.

 

The problem is that in theory benefits are based on capacity, not diagnosis, which is as it should be - but that leaves a lot of room for prejudice against particular diagnoses, especially those without biomarkers, to influence capacity assessments.

 

Fair point i.e. they can highlight concerns, and they are cross-party [more difficult for the Government to dismiss], but they can't force the Government.