Bridging Dx Gap for [hEDS] and [HSD]: Evidence of Common Extracellular Matrix Fragment in Plasma Potential Biomarker, 2024, Ritelli et al

Full Title: Bridging the Diagnostic Gap for Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: Evidence of a Common Extracellular Matrix Fragmentation Pattern in Patient Plasma as a Potential Biomarker, 2024, Marco Ritelli et al

ABSTRACT
Diagnosing hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD), common overlapping multisystemic conditions featuring symptomatic joint hypermobility, is challenging due to lack of established causes and diagnostic tools. Currently, the 2017 diagnostic criteria for hEDS are used, with non-qualifying cases classified as HSD, although the distinction remains debated.

We previously showed extracellular matrix (ECM) disorganization in both hEDS and HSD dermal fibroblasts involving fibronectin (FN), type I collagen (COLLI), and tenascin (TN), with matrix metalloproteinase-generated fragments in conditioned media. Here, we investigated these fragments in patient plasma using Western blotting across diverse cohorts, including patients with hEDS, HSD, classical EDS (cEDS), vascular EDS (vEDS), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and healthy donors, uncovering distinctive patterns.

Notably, hEDS/HSD displayed a shared FN and COLLI fragment signature, supporting their classification as a single disorder and prompting reconsideration of the hEDS criteria. Our results hold the promise for the first blood test for diagnosing hEDS/HSD, present insights into the pathomechanisms, and open the door for therapeutic trials focused on restoring ECM homeostasis using an objective marker.

Additionally, our findings offer potential biomarkers also for OA, RA, and PsA, advancing diagnostic and therapeutic strategies in these prevalent joint diseases.

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What do the forum's experts think about this?

 

I find it puzzling.

The authors start off by describing hEDS and HSD as 'multi systemic'. (The word used to be multi system and I am a bit suspicious about its re-birth in the context of 'uncertain' diseases as multi-systemic'.) But both these diagnoses imply that only one system is involved. If there is mo0re than just hypermobility then it isn't just HSD or hEDS - unless of course you move the goalposts yet again.

As to suggesting that hEDS and HSD are the same, my thought is that they probably are because they are both used to describe people with hypermobility and pains or fatigue without any clear evidence of a monogenic origin (i.e. true EDS). The great majority of people given these diagnoses are likely to have normal polygenic hypermobility and very likely pain or fatigue for unrelated reasons.

But if this group has a special pattern of matrix protein fragments in the blood it would be of interest.

Coming to the data, this is where I am most puzzled because the impression is given that people either have certain fragments or do not. And people with 'OA' have a fragment that normal people do not. But pretty much all normal people over fifty have some form of 'OA'. Moreover, it seems peculiar that the fragments should be either just present or absent. I would expect all grades of presence of all fragments, just with some difference in proportions. The trouble is that the Western blot pictures we are given are 'typical examples' of presumably the cases with clearest results.

If the results are real then it shows something quite interesting about hyper mobile people with pain. I doubt it has any particular relevance to ME/CFS. To be able to interpret it I think we need a cohort with equal hypermobility and no particular pain problems. The majority of people with hypermobility do not have significant pain or fatigue problems. And for good measure maybe a population with pain and or fatigue and maybe even ME/CFS, but without hypermobility.

 

I think the bendiness is a bit of a distraction for these patients, like how fatigue isn't really the main problem for a lot of us despite what the name CFS might suggest. Mostly, I hear complaints like "I'm allergic to everything and it's turning into anaphylaxis" or "my rectum is prolapsing into my vagina" or "I can't defecate normally and no doctor can tell me why" or "I have some form of OI or exercise intolerance and keep nearly blacking out". And rightly or wrongly, hEDS sounds to these patients like a unifying reason for these various woes, and other abnormalities people have noticed in themselves across their life.

 

If the results are real, you were wrong about “all that pseudoscience” that led them there, I guess.

 

If the results are real then it indicates the there is a common polygenic state with hypermobility and unusual fibronectin degradation. Which is possible, if surprising. The 'pseudoscience' relates to the attribution of all sorts of symptoms like fatigue, widespread pains, allergy, OI, gut problems etc. to this state without any evidence. The fibronectin fragment would tell us nothing about those if they are spurious associations.

And my main grouse has been calling this EDS, which it wouldn't be. As they say, it is just a common presumably polygenic hypermobile state.

 

Sounds interesting but the perfect separation in such a large sample almost seems like to good to be true. Especially considering that pain and hypermobility form a continuum with HSD and hEDS using an arbitrary cutoff. The paper writes: