Is joint hypermobility linked to self-reported non-recovery from COVID-19? Case–control evidence ... , 2024, Eccles et al

[SNT Gatchaman]

What are the alternative hypothesis for blood blood in the extremities in POTS again? I know SFN is a potential cause but is there anything else?

Off the top of my head —

• Beta-adrenergic receptor auto-antibodies
• Something messing up acetylcholine or its receptors
• Something messing up nitric oxide generation
• Impaired endothelial generation of ATP, leading to reduced NO generation and availability to vascular smooth muscle cells
• Damage / impairment of the vasa vasorum (the small blood vessels in the wall of the capacitance vessels themselves), possibly by microclots

 

[Eddie]

Off the top of my head —

• Beta-adrenergic receptor auto-antibodies
• Something messing up acetylcholine or its receptors
• Something messing up nitric oxide generation
• Impaired endothelial generation of ATP, leading to reduced NO generation and availability to vascular smooth muscle cells
• Damage / impairment of the vasa vasorum (the small blood vessels in the wall of the capacitance vessels themselves), possibly by microclots

Thanks, seems like a good list. You'd think these hypothesis wouldn't be that hard to test, I guess it just takes money, time and some rigorous trial protocols that have been lacking. Doesn't seem like immune modulating drugs, mestinon, or nicotine has been that effective.

Also I meant to say blood pooling not blood blood .

 

[Hutan]

Come on @Hutan, the things you mention make no sense in terms of explaining why PWME are unwell. There are people with gross collagen abnormalities of all sorts who do not feel as if they have ME. You can dream up 'vague indications' for anything. Why on earth should flexibility make you more vulnerable to ME?

I'm not saying I believe all or even any of the postulated hypotheses. But, there may be possible issues with collagen or associated tissues that are different to the 'gross collagen abnormalities' that you are thinking of. There could be something only slightly related to collagen's stretchiness, something to do with its immune modulating properties, edit - maybe the percentages of the different sorts of collagen* - that could slightly increase the vulnerability to ME/CFS.

The body is really complicated and there is a lot to find out. I think the balance of probability is that it is as you say. But still, I think the fence is a reasonable place to sit about many things to do with ME/CFS while we wait for more good research.

* Immune Modulatory Properties of Collagen in Cancer
Edit to add that paper's conclusion: (ECM is extracellular matrix)

The ability of the ECM to influence immune cell behavior constitutes a novel research field, which could be termed matrix immunology. Here we have reviewed the current knowledge about the ability of collagen to directly or indirectly affect T cell activity. The majority of the reviewed studies focus on collagen type I, which is the most abundant of the collagens. It should, however, be noted that other less abundant collagen types could have different effects on the activity of immune cells.

In addition to collagen, the ECM also contains many other components that all potentially could influence the cells in contact with it. Some of these components, such as versican, extracellular matrix protein-1 (ECM1) and hyaluronan, have already been suggested to have direct immune modulatory function (194–196). The current knowledge about the ability of different ECM components including hyaluronan to modulate immune activity has been excellently reviewed by (197). However, for most ECM components it is still unknown if they can influence immune cell activity.

The immune modulatory functions of the ECM could influence the development and progression of cancer as well as the outcome of cancer therapies. Consequently, future studies within this field could reveal targets for new cancer therapies. Finally, it should be noted that the importance of the ECM in regulating immune activity extends beyond the cancer research field, since the dysregulation of immune activity is a key feature of multiple other pathological conditions.

 

[Evergreen]

In the teensy NIH study (Walitt et al. 2024), there was no difference in Beighton scores between pwME and healthy volunteers. It’s in Supplementary Data file 5:

Characteristic HV (n=21) ME/CFS (n=17) p-value

Beighton Score [mean (SD)] 0.6 (1.0) 1.4 (2.2) 0.1

The Mudie et al. study in ME/CFS suggests to me that there is no connection between hypermobility and ME/CFS, but that people with EDS and ME/CFS may be more severely affected than people with ME/CFS but not EDS, and that could be worth looking at in better studies. (All self-reported in Mudie et al.) https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1324879/full#h4

This is Mudie et al's table 3 of people with ME/CFS and with or without hypermobility, but not EDS:

And this is table 2 from Mudie et al:

There is no table in Mudie et al comparing those with and without EDS. I think in table 1 (not shown in this post), which compares those with and without hypermobility, the few statistically significant differences are likely attributable to the higher rate of EDS in those with hypermobility.

 

[Jonathan Edwards]

The Mudie et al. study in ME/CFS suggests to me that there is no connection between hypermobility and ME/CFS, but that people with EDS and ME/CFS may be more severely affected than people with ME/CFS but not EDS

If I remember rightly there is no evidence for any of the patients in the Mudie study actually having EDS. I think it was just that someone had told them they had - which is hopelessly inadequate since so many 'ME physicians" diagnose EDS on anyone with loose joints.

It is also extremely difficult to compare severity on reports of symptoms. To have any biological value one would need objective evidence of a difference in disability using altimetry or whatever.

 

[Evergreen]

If I remember rightly there is no evidence for any of the patients in the Mudie study actually having EDS. I think it was just that someone had told them they had - which is hopelessly inadequate since so many 'ME physicians" diagnose EDS on anyone with loose joints.

It is also extremely difficult to compare severity on reports of symptoms. To have any biological value one would need objective evidence of a difference in disability using altimetry or whatever.

Agree on both counts.

I haven't seen a methodologically sound study that suggests a link between ME/CFS and either hypermobility or EDS, however either is defined.

I think it's also possible that physicians are more likely to diagnose EDS when someone's ME/CFS is severe. And/or that people with severe ME/CFS see more physicians in their search for help and so are more likely to end up in the office of a physician who thinks there's a link.

Would it be possible to do a study of pwME/CFS and pwEDS where a physician is blinded to whether people have ME/CFS or not and has to do a physical exam only to establish if certain features of EDS that are not part of ME/CFS are present, like velvety skin or wide scars and take a history only of things like of organ tearing, whether symptoms started with an infection or not?

 

[Jonathan Edwards]

Would it be possible to do a study of pwME/CFS and pwEDS where a physician is blinded to whether people have ME/CFS or not and has to do a physical exam only to establish if certain features of EDS that are not part of ME/CFS are present, like velvety skin or wide scars and take a history only of things like of organ tearing, whether symptoms started with an infection or not?

'Velvety skin' is such a subjective thing you can diagnose it in almost anyone. People with true EDS with skin changes have visibly abnormal patches of redundant skin or scars. But those who have skin changes are not hEDS, they are genuine monogenic EDS cases and probably mostly have identifiable gene defects.

I have not come across anyone with ME with a known EDS gene defect. By chance there will be a few - maybe 100 people in the UK with both. There might well be one or two on this forum, but there will also be people with all sorts of other uncommon diseases by chance.

I would hope that the DecodeME GWAS study will confirm the absence of any findings of a link to EDS genes that seemed to be the conclusion of the preliminary look see in the Leeds Biobank on about 2,000 cases.

 

[Kitty]

I think it's also possible that physicians are more likely to diagnose EDS when someone's ME/CFS is severe.

It seems plausible. When people have naturally flexible connective tissue, low body weight and can't use their muscles much, it probably exaggerates joint discomfort and subluxations. By the time my mam was 90, thin and frail, the head of her right femur would barely stay put—but she had bendy joints and hip dysplasia, not EDS.

I have EDS on my medical record because I spent decades needing my right hip shoved back into place, but if it's ever X-rayed, it probably looks like my mam's (and my aunt's, sister's, and several cousins'). Some of us have right shoulder blades so winged they look a bit like they belong to people with FSHD, but it's just another skeletal quirk. It makes me wonder how many of those who diagnose EDS actually look at the joints themselves.

 

[Hutan]

In the teensy NIH study (Walitt et al. 2024), there was no difference in Beighton scores between pwME and healthy volunteers. It’s in Supplementary Data file 5:

Characteristic HV (n=21) ME/CFS (n=17) p-value

Beighton Score [mean (SD)] 0.6 (1.0) 1.4 (2.2) 0.1

That study was hopelessly flawed in its cohort matching. The HV had a big percentage of people over 50; the ME/CFS cohort had a big percentage of people between 18 and 30. And even with that age skew, there was no difference in Beighton scores.

The following diagram is from a nice 2017 Australian study:
Beighton scores and cut-offs across the lifespan: cross-sectional study of an Australian population
that suggested that the Beighton assessment was never meant to be used in individual clinical assessment and isn't very good. And that an arbitrary cut off of 4 for general joint hypermobility is particularly useless. A mean of 1.4 in the teensy NIH study ME/CFS cohort doesn't seem to be indicating an epidemic of joint hypermobility in people with ME/CFS but perhaps was slightly higher than would have been expected. I know the Beighton score is a bad measure, but surely if you are going to go to the expense of gathering the data, you'd adjust the results for age and sex.




That 2017 Australian study commented that there seems to be racial differences in the prevalence of high Beighton scores, with higher scores reported in West Africa and Korea. I'm not aware of higher rates of ME/CFS in South Korea.

I think it's also possible that physicians are more likely to diagnose EDS when someone's ME/CFS is severe. And/or that people with severe ME/CFS see more physicians in their search for help and so are more likely to end up in the office of a physician who thinks there's a link.

Would it be possible to do a study of pwME/CFS and pwEDS where a physician is blinded to whether people have ME/CFS or not and has to do a physical exam only to establish if certain features of EDS that are not part of ME/CFS are present, like velvety skin or wide scars and take a history only of things like of organ tearing, whether symptoms started with an infection or not?

I agree, I suspect many diagnoses of hEDS are the product of young women with ME/CFS or some autoimmune condition going to see a doctor who likes to make hEDS diagnoses. I doubt that any studies trying to investigate the diagnostic preferences of doctors will get us very far.

I reckon the way to go with investigating the hypermobility hypothesis is to forget about hEDS diagnoses and Beighton scores and instead get into looking at the biology, the biochemistry, the immune function of the extracellular cellular matrix. Is collagen in capillary walls affected during an infection; is it different in ME/CFS? There is plenty there that is interesting to investigate.
e.g. a small 2004 study of fibromyalgia found lower levels of intramuscular collagen, suggesting 'this may lower the threshold for muscle micro-injury and thereby result in non-specific signs of muscle pathology'.

 

[Sean]

I have not come across anyone with ME with a known EDS gene defect. By chance there will be a few - maybe 100 people in the UK with both. There might well be one or two on this forum, but there will also be people with all sorts of other uncommon diseases by chance.

For example, I was born with post-axial polydactyly on both hands (something like this, non-functional, and removed soon after birth). What are the odds of having that plus getting ME later in life? Vanishingly small.

But pretty sure they have no causal relationship.

 

[SNT Gatchaman]

For example, I was born with post-axial polydactyly on both hands (something like this, non-functional, and removed soon after birth). What are the odds of having that plus getting ME later in life? Vanishingly small.

But pretty sure they have no causal relationship

It's not completely beyond the realm of possibility that there's a shared risk moving the ME vulnerability needle. From Genetic overview of postaxial polydactyly: Updated classification (2023, Clinical Genetics) —

So far, 11 loci (PAPA1-PAPA11) and seven human genes have been reported to cause non-syndromic postaxial polydactyly in humans, including the ZNF141, GLI3, IQCE, GLI1, FAM92A1, KIAA0825, and DACH1.

GeneCards links for those is —

ZNF141
GLI3
IQCE
GLI1
FAM92A1
KIAA0825
DACH1

FAM92A1 is aka CIBAR1 —

Acts as a positive regulator of ciliary hedgehog signaling (By similarity). Probable regulator of ciliogenesis involved in limb morphogenesis (PubMed:27528616, 30395363). In cooperation with CBY1 it is involved in the recruitment and fusion of endosomal vesicles at distal appendages during early stages of ciliogenesis (PubMed:27528616, 30395363). Plays an important role in the mitochondrial function and is essential for maintaining mitochondrial morphology and inner membrane ultrastructure (PubMed:30404948). In vitro, can generate membrane curvature through preferential interaction with negatively charged phospholipids such as phosphatidylinositol 4,5-bisphosphate and cardiolipin and hence orchestrate cristae shape

I haven't come across polydactyly ever highlighted in ME patient histories though, so I very much doubt there'd be anything there. Perhaps there's a rare mutation that allows polydactyly and non-lethal mitochondrial impairments?

 

[Evergreen]

I doubt that any studies trying to investigate the diagnostic preferences of doctors will get us very far.

Oh that wasn't what I intended! What I was pondering was whether a study could be done that would control for diagnostic preferences, by not allowing the assessor to know whether the participant had a diagnosis of ME/CFS or EDS, and getting them to just work through a carefully honed checklist of physical signs and possibly a couple of history items. The purpose would be to see whether pwME really do have more signs of EDS than the general population - and so would need to include participants from the general population too, which I didn't explicitly say.

Mr Evergreen tells me that I switch topics with no warning, and I think that's what I did in my post, oops.

 

[ME/CFS Skeptic]

Had another look at the Eccles study and the hypermobility was based on self-report:

GJH was determined using the 5-part Hakim and Grahame self-report questionnaire (5PQ)

Non-recovery was also based on self-report so perhaps the association found may simply reflect that some people tend to report more problems than others.

 

[Ash]

A very small number of children have major laxity problems with certain joints - often just one pair - knees or shoulders for instance. Subluxation and gait problems can occur. I used to see people like this about once in ten years. They have very real problems with that specific joint but otherwise tend to be quite normal.

How were they managed?

 

[Jonathan Edwards]

How were they managed?

Sometimes with sophisticated splints, sometimes with surgery.