Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, 2024, Walitt et al

[Jonathan Edwards]

i think the theory is

Yes, the usual garbling.
Not even exhaustion after all?
As far as I know T regs have little or nothing to do with most autoimmunity and of course they found no autoimmunity and... it just goes wherever you want it to go, like the average review in 'Trends in Immunology', a word salad of whatever you like!

 

[siobhanfirestone]

Yes, the usual garbling.
Not even exhaustion after all?
As far as I know T regs have little or nothing to do with most autoimmunity and of course they found no autoimmunity and... it just goes wherever you want it to go, like the average review in 'Trends in Immunology', a word salad of whatever you like!

i dont know much about the t cell theories but a lot of it is newish
i think that t regs are supposed to be an inbuilt mechanism to help stop autoimmunity no?

 

[Evergreen]

The sample is too small to tell if they found anything in fact. And if they did it seems to me more like an 'odd smell' rather than smoke. It might just as well be the smell of cold damp ash.

These labels like 'activation marker' and exhaustion marker' are highly dubious at best. I fail to see how something can be an activation marker (marking increase in activity) and an exhaustion marker (showing loss of activity). And if the cells are exhausted I would expect using a checkpoint inhibitor to achieve nothing. If they activated then the situation might get worse.

Just to be clear, I have been reporting what I think Nath thinks. Not what I think!

I have no desire for years of a trial of therapies that have no prospect of working, and that could have nasty consequences. I appreciated your explanations that rituximab was unlikely to help in ME - otherwise I would have been very disappointed about the outcome of that trial.

But it sounds like they're going to happen, or at least that there's an appetite for them in the US.

 

[Sid]

0 evidence of dormant or reactivated viruses here and also terrible terrible work done in the NIH study to even demonstrate this tbh

I can't believe Nath's media comments. Trials? On the basis of a terrible n=17 study which found no evidence of a virus or anything clearly wrong with the immune system.

 

[rvallee]

I find the way Nath and others explain effort preference in interviews much more palatable than how it is written in the paper.

There's at least that other, far more likely and rational explanation, that happens to be the opposite of what is alluded in the paper's text: that the opposite of choosing the low effort is happening, that we want to make the effortful choice, but our brain, knowing better, is telling us that we shouldn't. Similar to someone trying to lift a car, and our brain knowing better is saying "uh, don't do that".

It seems to be what Nath is saying here, and it sure would have been a lot better if this had been clear in the text, but it still doesn't merit to be in the abstract or featured in any of the press releases or press material. It's a minor mostly invalid test that could hint at something but the way it was done makes it inconclusive, and that's before you consider that it was on less than 20 patients. Frankly it shouldn't have made it in the paper at all. Or any paper.

But that interpretation is equally valid based on the evidence, and actually fits with the rest of the evidence.

 

[Evergreen]

Could we talk about the anti-nuclear antibody result?

As someone already posted upthread, they found that 5% of HVs had a positive ANA compared to 24% of pwME. This was not significant in their small sample (p=0.09), but as @Jonathan Edwards commented, this could be a type 2 statistical error, and so might be significant in a larger sample.

In a long-term study of paediatric ME/CFS, Katherine Rowe reported

Twenty one per cent of the sample (n = 499) had a significantly positive titer comprising 10% with 1:160 (mildly positive), 9% between 1:320 and 1:640 (moderately positive), and 2% between 1:1,280 and 1:2,560 (strongly positive). The described patterns were speckled (65.5%), homogeneous (3.2%), nucleolar (15%) and mixed speckled/homogeneous (15.9%).

She went on:

The high titers were not associated with clinical signs or any other markers of connective tissue disorders such as high sedimentation rate, positive antibodies to double stranded DNA, or extractable nuclear antibodies, and this was confirmed by a rheumatologist. The proportion of positive titers is at least double the expected rate in this age group, and although it not unknown to have moderately strong positive titers without evidence of connective tissues disorders in pediatric rheumatology clinics, the proportion of moderate to strongly positive titers is much greater than expected (personal communication-J Akikusa, Royal Children’s Hospital, Aug 2018).

Full study here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393360/

For what it's worth I have a consistently positive speckled ANA. Antibody panels have come back negative, as they did in this study. When that happens, the doc who has ordered the test often says, Oh, it’s probably just from a recent infection. But it's always positive.

Could a positive ANA in a subset of pwME in the absence of known antibodies suggest something like viral persistence? Or something else that would or would not fit with the model proposed in this paper?

 

[Jonathan Edwards]

i dont know much about the t cell theories but a lot of it is newish

I doubt there is much new. Fiona Powrie used to talk about this stuff at meetings I presented at about 15 years ago. If you take away T regs in mice you mostly get things like inflammatory bowel disease - which is unlikely to be true autoimmunity. I would not be surprised if you took them away enough you might get autoimmunity but that is a million miles away from suggesting that human autoimmune disease is tripped by T reg lack. The genetics don't indicate that as far as I am aware.

i think that t regs are supposed to be an inbuilt mechanism to help stop autoimmunity no?

That is what people who apply for grants on T regs will tell you and popular immunology is full of these fashionable memes. Real immunology is quite hard to find underneath the debris!

T cell responses are by nature very threshold dependent. You can convince any T cell to respond if you give it enough encouragement. No doubt T regs are important in balancing thresholds. But autoimmunity isn't generally dependent on T cell specificities anyway. I wouldn't be surprised if T regs where chiefly there to stop us producing unneeded immune responses to foods.[/QUOTE]

 

[siobhanfirestone]

I doubt there is much new. Fiona Powrie used to talk about this stuff at meetings I presented at about 15 years ago. If you take away T regs in mice you mostly get things like inflammatory bowel disease - which is unlikely to be true autoimmunity. I would not be surprised if you took them away enough you might get autoimmunity but that is a million miles away from suggesting that human autoimmune disease is tripped by T reg lack. The genetics don't indicate that as far as I am aware.



That is what people who apply for grants on T regs will tell you and popular immunology is full of these fashionable memes. Real immunology is quite hard to find underneath the debris!

T cell responses are by nature very threshold dependent. You can convince any T cell to respond if you give it enough encouragement. No doubt T regs are important in balancing thresholds. But autoimmunity isn't generally dependent on T cell specificities anyway. I wouldn't be surprised if T regs where chiefly there to stop us producing unneeded immune responses to foods.

[/QUOTE]

yes sadly i would say that ME might even be used as a text book example in the far distant future of just how difficult it is to work out the EXACT nature of an "immune system" disease that is not clearly or purely autoantibody driven, nor pure innate immune system driven using current methodologies and tests. Lots of random data that suggest this has something to do with the immune system, little to lock down on specific cells and mechanisms.

Alas until we have that i am coming to my own conclusions about the safety and validity of things like chemo in light of this (i dont expect anyone to respond to that here just my musings), as just how long does this "something to do with the immune system" work have to continue until a breakthrough....bah

 

[Jonathan Edwards]

Could a positive ANA in a subset of pwME in the absence of known antibodies suggest something like viral persistence? Or something else that would or would not fit with the model proposed in this paper?

As far as I know positive ANA is not likely to be related to recent viral infection or viral persistence, certainly not speckled.

The problem here is that the clinical syndromes associated with a number of ANAs, like speckled or RNP, without anti-DNA antibodies, are probably often quite limited and in some cases may be limited just to 'fatigue'. Other features like Raynaud's increase the likelihood that the ANA is relevant but it is a matter of probabilities.

When I was a rheumatologist I tended to regard anyone presenting with a positive ANA not based on anti-DNA and fatigue as having a limited, 'undifferentiated' form of lupus-type autoimmune disease. In most cases this takes a benign course apart from the fatigue.

I think I would probably have recognised that as different from typical ME with PEM and crashes but it is too long ago to be sure.


So the difficulty is that the proportion of people with positive ANA coming to an ME clinic will depend on local referral patterns and whether the rheumatologist decides this is 'ME with a chance positive ANA' or 'limited lupus-like autoimmune disease'. If like me you think the latter then PWME don't have any more ANAs then the rest.

Across the range of ME cohorts the consensus is that people with ME do not have a higher rate of ANA. One of the problems of recruiting for studies via internet is that you may well get all sorts of bias. People with fatigue and ANA may be more likely to volunteer for studies like this because, although they may technically be classifiable as having PEM most of them probably do not have the sort of PEM that would put you off getting involved in a CPET study.

It may well be that a relatively high proportion of the cohort here had what I would classify as limited lupus-like illness.

 

[Sid]

I thought Walitt was a rheumatologist. I'm very surprised he showed no interest in this.

 

[Sid]

This review from Scheibenbogen's group says the following:

2.3.1. Autoantibodies against nuclear and membrane structures
Antinuclear antibodies (ANA) were found in one study in 68 % of ME/CFS patients with the majority directed against the nuclear envelope [51]. Further studies showed ANA in 68%, 57%, 23% and 13% of ME/CFS patients [[52], [53], [54], [55]]. Ortega-Hernandez et al. found dsDNA antibodies in 12% of patients [56], but another study failed to show such antibodies in ME/CFS (0.7%) [57].

https://www.sciencedirect.com/science/article/pii/S1568997218300880

 

[Evergreen]

As far as I know positive ANA is not likely to be related to recent viral infection or viral persistence, certainly not speckled.

The problem here is that the clinical syndromes associated with a number of ANAs, like speckled or RNP, without anti-DNA antibodies, are probably often quite limited and in some cases may be limited just to 'fatigue'. Other features like Raynaud's increase the likelihood that the ANA is relevant but it is a matter of probabilities.

When I was a rheumatologist I tended to regard anyone presenting with a positive ANA not based on anti-DNA and fatigue as having a limited, 'undifferentiated' form of lupus-type autoimmune disease. In most cases this takes a benign course apart from the fatigue.

I think I would probably have recognised that as different from typical ME with PEM and crashes but it is too long ago to be sure.


So the difficulty is that the proportion of people with positive ANA coming to an ME clinic will depend on local referral patterns and whether the rheumatologist decides this is 'ME with a chance positive ANA' or 'limited lupus-like autoimmune disease'. If like me you think the latter then PWME don't have any more ANAs then the rest.

Across the range of ME cohorts the consensus is that people with ME do not have a higher rate of ANA. One of the problems of recruiting for studies via internet is that you may well get all sorts of bias. People with fatigue and ANA may be more likely to volunteer for studies like this because, although they may technically be classifiable as having PEM most of them probably do not have the sort of PEM that would put you off getting involved in a CPET study.

It may well be that a relatively high proportion of the cohort here had what I would classify as limited lupus-like illness.

Thank you for this.

I think 3 doctors have given me the infection explanation, and it’s given as an explanation on sites explaining causes of positive ANA, eg:

Some infectious diseases and cancers have been associated with the development of antinuclear antibodies, as have certain drugs.
https://www.mayoclinic.org/tests-pr...ew,specifically targeting each cell's nucleus.

In rheumatological patients, positive ANA in the absence of ENA or anti-DNA is usually of no specific diagnostic value, though it can suggest evolving connective tissue disease which will later be characterised by more specific autoantibodies. ANA (particularly giving a homogeneous staining pattern) are also found in chronic infections, liver disease and in some cancers. Note that treatment of patients with modern “biological” drugs such as anti-TNF (for RA or Crohns) or interferon commonly induces ANA sometimes in high levels.
https://southtees.nhs.uk/services/pathology/tests/anti-nuclear-antibody-ana/

Weak positive ANA can occur in a variety of situations where the immune system is activated e.g. in infection, malignancy or other inflammatory disorders. ANA can also be detected in healthy controls and the prevalence increases with age and if female.
https://www.yorkhospitals.nhs.uk/seecmsfile/?id=6659

So that must be based on some data.

I understand your point about the possibility of some people that currently come under the ME/CFS umbrella actually belonging elsewhere, and possibly messing up studies like this.

I have severe ME/CFS triggered by infection with PEM and crashes so I don’t think I would fit well into your limited lupus-like illness category, but who knows. I could not have participated in this study no matter how many trivial financial rewards I was offered in exchange for pinky presses!

 

[Jonathan Edwards]

I thought Walitt was a rheumatologist. I'm very surprised he showed no interest in this.

If his agenda was to show that effort choice was down in the presence of a healthy body he would have found it convenient to note that the p value was not significant. He might even not realise that the most likely interpretation of that would be type 2 error. In other words although the chances of the data being just due to chance were not small enough to be significant but the chances of it NOT being due to chance are still higher than that!

This review from Scheibenbogen's group says the following:

Trouble is none of those give control figures. The studies I am familiar with that had controls showed no difference.

 

[Jonathan Edwards]

"Some infectious diseases and cancers have been associated with the development of antinuclear antibodies, as have certain drugs."

Certain drugs, like procainamide and anti-TNF yes. The infections I think are esoteric and ANA occurs while the infection is current or for a short while after. EBV can cause a rise in all antibody levels but they return to normal. Looking at the net the link to infection is trotted out but these things are often a hang over from historic views or linked to irrelevant situations. (I have a feeling that malaria can give you a positive ANA. Hepatitis C can too.)

I have severe ME/CFS triggered by infection with PEM and crashes so I don’t think I would fit well into your limited lupus-like illness category, but who knows.

Yes, the problem with real life is that on a forum like this there are likely to be at least a few people with typical ME who have positive ANA and there may be some for whom they are related. Ultimately it is hard to be absolutely sure but a post-infective onset with typical features makes ME more likely in my mind.

 

[Evergreen]

the link to infection is trotted out but these things are often a hang over from historic views or linked to irrelevant situations. (I have a feeling that malaria can give you a positive ANA. Hepatitis C can too.)

Yes, I can see how that would happen. Once the panel comes back negative they lose interest completely, and really just want to explain it away. And with malaria or hepatitis C, presumably the ANA decreases again at some point, rather than staying up indefinitely?

Yes, the problem with real life is that on a forum like this there are likely to be at least a few people with typical ME who have positive ANA and there may be some for whom they are related. Ultimately it is hard to be absolutely sure but a post-infective onset with typical features makes ME more likely in my mind.

I'm fine with the uncertainty. A strong autoimmune family history might make it a 50:50 toss-up. And I was just reading that some people's SLE onset coincides with a viral infection - I didn't know that before. Either way, no-one's solving any of it yet!

 

[Sid]

Trouble is none of those give control figures.

Autoantibodies to nuclear envelope antigens in chronic fatigue syndrome
American study with a CFS group (n=60) and two controls groups. Control group 1 consisted of allergy and depression patients. Control group 2 was healthy controls and blood donors. 68% of the ME/CFS group was ANA-positive. Only 10% and 15% of control groups 1 and 2 were, respectively. However, they considered titres of only 1:50 positive which is quite weak. 28% of the CFS group had a positive Shirmer so maybe they just had undiagnosed Sjogren's (which can cause huge fatigue).

Antinuclear antibodies in patients with chronic fatigue syndrome
Japanese study. "We reported anti-68/48kD protein antibodies utilizing SDS-PAGE/ immunoblot method. These autoantibodies were found in 13% of 114 CFS patients and 0% in healthy subjects (p < 0.05)."

Antinuclear autoantibodies (ANA) in Gulf War-related illness and chronic fatigue syndrome (CFS) patients
Wessley. "CFS patients had a similar prevalence of ANA (18%, 18/100) to the matched healthy control subjects (16%, 18/111). In the CFS group the positive samples were mainly of speckled pattern (9/18); some had the nuclear pattern (7/18) and the rest had other patterns (2/18)."

Clinical laboratory test findings in patients with chronic fatigue syndrome
Another American study. 579 CFS cases meeting Fukuda criteria and 147 blood donor controls "who denied chronic fatigue". 15% of the CFS group were ANA+, 0% of controls.

 

[Jonathan Edwards]

I think those just show how dependent rates are likely to be on recruitment routes, @Sid. Maybe blood donors aren't allowed to give blood if they are ANA positive !! Otherwise the 0% looks a bit spooky.

My memory is that the UK ME Biobank, which has the advantage that it was not recruited to prove any particular point pre or post hoc, did not show an increase.

Rheumatology clinics are full of young women with fatigue and maybe sore joints whose GP has got a positive ANA but God knows what that means, other than that it would be easy to call them all ME and write a paper.

 

[Evergreen]

Antinuclear autoantibodies (ANA) in Gulf War-related illness and chronic fatigue syndrome (CFS) patients
Wessley. "CFS patients had a similar prevalence of ANA (18%, 18/100) to the matched healthy control subjects (16%, 18/111). In the CFS group the positive samples were mainly of speckled pattern (9/18); some had the nuclear pattern (7/18) and the rest had other patterns (2/18)."

This one sounds convincing, as the healthy controls for the CFS group were matched for age and gender. But then I remember that in the PACE trial, the King's centre's patients do not sound representative of the wider patient population.

Eg, in the PACE Trial Management Group meeting 16 minutes:

At King’s a larger portion of patients opt for CBT over the trial. King’s also has a higher portion of referral with mis-diagnoses or previous treatment.

King’s has a high number of patients excluded on SF36 scores.

Edited to correct meeting number.

 

[dave30th]

It just seems that the press have gone out of their way to get positive quotes about this study, particularly from those who are supported by the patient community, and yet there are so many obvious caveats.

Important to remember that we don't know what else these researchers said to the journalists--so we shouldn't take any quotes from them saying the study is good for X reason to mean they didn't also say the study is terrible for Y reason--even if that latter part is not quoted.

 

[Jonathan Edwards]

Important to remember that we don't know what else these researchers said to the journalists--so we shouldn't take any quotes from them saying the study is good for X reason to mean they didn't also say the study is terrible for Y reason--even if that latter part is not quoted.

I was approached by journalists saying 'This looks like a damp squib that the science community is going to forget. But maybe an opportunity to flag up that ME is being taken seriously and some research is being done. Do you agree?' So I said yes and tried to think of something that ordinary people might connect to that was at least within the message of the paper.

After some further dialogue we all agreed that picking it apart would just make everyone miserable and maybe make enemies unnecessarily, for no real benefit so stick to plan A.

PACE was a major disaster that influenced care for a decade. This is not going to make any difference to what others do, I think. If Nath wants to try toxic drugs I am not sure how much that will have to do with the study. I rather suspect he will not have the courage.