Beyond Bones - relevance of variants of connective tissue (Hypermobility) to Fibromyalgia, ME/CFS - Eccles et al Feb 2020

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Sly Saint

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BEYOND BONES - THE RELEVANCE OF VARIANTS OF CONNECTIVE TISSUE (HYPERMOBILITY) TO FIBROMYALGIA, ME/CFS AND CONTROVERSIES SURROUNDING DIAGNOSTIC CLASSIFICATION: AN OBSERVATIONAL STUDY

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract
Objectives: To understand the relevance of symptomatic hypermobility and related connective tissue variants to the expression of symptoms in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The study further tested if specific subfactors within the diagnostic classification of hypermobility predict clinical presentations.

Design: We report part of a larger case-control study exploring mechanisms of chronic pain and fatigue in Fibromyalgia and ME/CFS (https://doi.org/10.1186/ISRCTN78820481) Setting: an NHS Clinical Research Facility. Participants: A subsample of 87 participants were assessed for symptomatic hypermobility by a trained clinician; 63 presented with a clinical diagnosis of either Fibromyalgia and or ME/CFS confirmed at screening; 24 participants were confirmed as healthy controls. Main outcome measures: 1) Brighton Criteria for joint hypermobility syndrome and 2017 hEDS diagnostic criteria. 2) ACR 2010 Diagnostic Criteria for Fibromylagia and Canadian and Fukada diagnostic criteria for ME/CFS. 3) Self report measures of subjective pain, fatigue and interoceptive sensibility.

Results: Twenty of the 63 patients (32%) presented with a clinical diagnosis of Fibromyalgia; 24 (38%) with a clinical diagnosis of ME/CFS and 19 (30%) with dual diagnoses of fibromyalgia and ME/CFS. After evaluation using clinical research tools, 56 patients (89%) met ACR diagnostic criteria for fibromyalgia; 59 (94%) Canadian Criteria for ME/CFS; and 61 (97%) Fukada Criteria for ME/CFS.

After research evaluation 52 patients (85%) in fact met diagnostic criteria for Fibromyalgia and ME/CFS on all three sets of tools (ACR, Canadian, Fukada). In addition, 51 patients (81%) and 9 (37.5%) healthy controls met Brighton Criteria for joint hypermobility syndrome and 11 (18%) and 2 (8%) of patients and controls respectively, on the 2017 hEDS criteria.

Of these patient participants with symptomatic hypermobility only 12 (23.5%) had received a prior diagnosis of hypermobility. Across all participants meeting Brighton Criteria, 13 (22%) also endorsed a hEDS diagnosis. Membership of the patient group was predicted by meeting the Brighton Criteria for joint hypermobility syndrome (p=<0.001, OR 7.08, 95% CI 2.50 to 20.00), but not by meeting the hEDS criteria.

The historical, rather than current Beighton score correlated with; 1) total pain reported on the McGill Pain Questionnaire (short form), (r= 0.25, n= 73, p=0.03); 2) Widespread Pain Index (derived from ACR diagnostic criteria) (r=0.26, n= 86, p=0.01); 3) ACR symptom severity (r=0.27, n=85, p=0.01); 4) Fatigue Impact (r=0.29, n=56, p=0.28); and 5) interoceptive sensibility (r=0.30, n=56, p=0.02. Conclusions: Symptomatic joint hypermobility is relevant to symptoms and diagnosis in Fibromyalgia and ME/CFS. These conditions are poorly understood yet have a considerable impact on quality of life.

Further work is needed to determine the prevalence of hEDS within the general population and define the critical clinical dimensions within symptomatic hypermobility. It is important to note the high rates of mis/underdiagnosis of symptomatic hypermobility in this group. Moreover, we need to clarify the role of variant connective tissue in dysautonomic and inflammatory mechanisms implicated in the expression of pain and fatigue in fibromyalgia and ME/CFS. Our observations have implications for diagnosis and treatment targets. Study registration: ISCRTN78820481
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https://www.medrxiv.org/content/10.1101/2020.02.21.20025072v1
 
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Setting: an NHS Clinical Research Facility
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Given the nonsense that the NHS uses internally over those diagnoses, I would not put any trust whatsoever in what this setting can produce, unfortunately. The study doesn't appear particularly bad, but at some point incompetence catches up to you and destroys credibility far too much to take anything from an ideological playground as being relevant.

Funding:
This project was primarily funded by a Versus Arthritis Grant (21994), with additional support provided by a studentship awarded by Action for M.E. and match-funded by Brighton and Sussex Medical School. The work was also supported by a charitable donation from the Fibroduck Foundation. Jessica Eccles was supported by the National Institute of Health Research (CL-2015-27-002).
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I) Prevalence of hypermobility
The most notable result seems to be that they found that 80% of patients met Brighton Criteria for joint hypermobility syndrome. That seems very high and makes me wonder if there was a significant selection bias. The paper reads:

"Patients were recruited by advertisement from local support organisations for Fibromyalgia and ME/CFS, local rheumatology clinics and via social media and bulletin boards."​

Would be good to know how the advertisement looked like. Did it, for example, mention hypermobility or hEDS?

It seems a bit strange that the authors do not mention exclusions of the patients they examined. Usually, if you recruit patients suspected of having ME/CFS and do the required clinical examination, you'll find patients who have similar symptom but actually have another condition that can explain the results. Here it seems that 97% who responded to the advertisements turned out to have ME/CFS according to the Fukuda criteria and 94% according to the Canadian Consensus Criteria. That seems quite high.

I also don't think that the assessment of hypermobility was done by researchers/clinicians who were blinded to ME/CFS status - perhaps this could have inflated the prevalence figures of hypermobility a bit as well.

II) Symptomatic hypermobility
The authors say that "It is important to note the high rates of mis/underdiagnosis of symptomatic hypermobility in this group." But how do we know that the hypermobility is symptomatic if ME/CFS patients have symptoms anyway? If 37.5% of healthy controls met Brighton Criteria for joint hypermobility than perhaps a lot of ME/CFS patients who met the criteria don't experience any disabling symptoms as a result of it as well.

One way to know more is to look at correlations between ME/CFS symptoms and hypermobility indicators, but the authors note that:

"Across all participants there were no associations between current (i.e. present) Beighton score and baseline pain, fatigue and interoceptive questionnaires."
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They then go on to focus on Historical Beighton scores (i.e ever being able to perform the relevant manoeuvre) where there were some correlations, but this seems less relevant than the current Beighton score.

The authors also mention that:

"Endorsing both major criteria of Brighton Criteria was significantly associated with fulfilling Canadian criteria for ME"​

I'm no expert in this but from quickly googling the Brighton criteria it seems that "Arthralgia for longer than 3 months in 4 or more joints" is one of the two major criteria, so no surprise that this predicts ME/CFS/FM status. After al, criteria for healthy controls included having a score no more than 3/10 on a pain visual analogue scale. Except for easy bruising, no other minor Brighton criteria (dislocation, skin hyperextensibility of skin etc.) were significantly predictive of ME/CFS.
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III) hEDS prevalence
The prevalence of hEDS was also determined and reported as follows:
Two (8%) of healthy controls met 2017 hEDS criteria, compared to 11 (18%) of the patients
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The authors didn't report a significance test for this presumably because their sample size was too small. They write: "Our control group is too small to make more than anecdotal statements regarding hEDS prevalence." They did note that "A diagnosis of hEDS did not predict presence of Fibromaylgia and or/ME/CFS, nor did individual elements of the diagnostic criteria."
 
Patients were recruited by advertisement from local support organisations for Fibromyalgia and ME/CFS, local rheumatology clinics and via social media and bulletin boards."

Would be good to know how the advertisement looked like. Did it, for example, mention hypermobility or hEDS?
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A good demonstration that self selected samples are useless for prevalance /epidemiology studies.
 
For what it’s worth:
I satisfy all ME, ME/CFS and CFS criteria. I tend to have nearly every symptom listed that a man can have.
But I’ve never had any hypermobilty in any joints. In fact, things went in the opposite direction despite being quite active in the early years and spending a lot of time doing stretching.
 
Me too Dolphin, but it is interesting that three of the members of our local ME support group, who each have had a diagnosis of ME for many many years, have recently been diagnosed with EDS: a new member also shares some of their characteristics.
 
Dolphin said:
For what it’s worth:
I satisfy all ME, ME/CFS and CFS criteria. I tend to have nearly every symptom listed that a man can have.
But I’ve never had any hypermobilty in any joints. In fact, things went in the opposite direction despite being quite active in the early years and spending a lot of time doing stretching.
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Me too. I don't believe I have EDS but looking at the chart in post #7 above I am surprised at the number of things I would say yes to. Despite the fact I consider myself to be quite a "stiff" person. I especially noticed this in yoga class where there were other women of a similar age.

2 of my siblings tick a lot of those boxes and I was always envious of how flexible they were. A couple of their offspring have been officially diagnosed with hypermobility.

Maybe a link, maybe not. There are other autoimmune disorders in the family that are just as likely to be connected as this is to ME.
 
In contrast to this poorly structured little study there are some big population based studies now indicating that hypermobility has little or no relation to ME/CFS or chronic pain syndromes. It may be worth noting that Dr Eccles is a psychiatrist specialising in mind-body interaction and the BPS people had a major input into floating the idea that there was a link, based again on poorly conducted studies. This is the bio bit of BPS for them.
 
I can't remember if I read it or imagined it, but I thought that lax and deconditioned muscles could give hypermobility. Despite being unable to do very much I was able to touch the floor with my hands with ease. I stopped doing it because I decided it was more a sign of damaged muscle than fitness or ability.

I have no idea where this notion came from or if it is true.
 
Mithriel said:
I can't remember if I read it or imagined it, but I thought that lax and deconditioned muscles could give hypermobility.
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Muscle condition/deconditioning is quite different to flexibility. Stretching less should lead to less flexibility, though joint laxity is another story.

I have neither joint flexibility, nor joint laxity and the idea that I could ever touch the floor with the palms of my hands is well, a fantasy at best.

edit- without bending my knees, dear smarty-pants!
 
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Mithriel said:
I can't remember if I read it or imagined it, but I thought that lax and deconditioned muscles could give hypermobility.
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Generally speaking not. But the Beighton manoeuvres for hypermobility are a mixed bag that probably test a combination of e.g. ligamentous length, ligamentous elasticity, bone congruity, and musculotendinous length. I am pretty sure that Carter and Beighton had no real idea why they were choosing the 9 points they did. It is all a mess and almost certainly of no real interest.
I suspect that muscle bulk does not get in the way of any of the Beighton manoeuvres. Ballet dancers who can put their hands flat on the floor usually have highly developed musculature. Elbow flexion may be limited by a large biceps/brachialis complex but flexion is not used to judge mobility.
 
Snow Leopard said:
Muscle condition/deconditioning is quite different to flexibility. Stretching less should lead to less flexibility, though joint laxity is another story.

I have neither joint flexibility, nor joint laxity and the idea that I could ever touch the floor with the palms of my hands is well, a fantasy at best.

edit- without bending my knees, dear smarty-pants!
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Michiel Tack said:
It's quite easy to do, the trick is to bend your knees.
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Sorry for being OT, but this reminded me of the Dara O'Briain stand-up where he makes fun of flexibility as a type of fitness. "Yes I can touch the floor. I. Have. Knees." :laugh:
 
Interesting looking at the lead author's professional biography:
Dr Jessica Eccles MB ChB, Dip(French), MA, MSc, MRCPsych, PhD, PGCert HE

Clinical Senior Lecturer and MQ Arthritis Research UK Fellow
E: J.Eccles@bsms.ac.uk
T: +44 (0)1273 877700
Location: Trafford Centre for Medical Research, University of Sussex, Brighton, BN1 9RR

E: neuroscience@bsms.ac.uk

Areas of expertise: Brain-Body Interactions, Joint hypermobility, Liaison Psychiatry

Research areas: Neuroscience, Psychiatric manifestations of connective tissue disorders, Mechanisms of chronic pain and fatigue
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So she is a liaison psychiatrist and researcher with a focus in her research on looking for links between joint hypermobility and psychiatric conditions.
 
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