Beyond Bones - The Relevance of Variants of Connective Tissue (Hypermobility) to Fibromyalgia, Me/CFS and Controversies Surrounding Diagnostic Classification: An Observational Study

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

Autism and Chronic Ill Health: An Observational Study of Symptoms and Diagnoses of Central Sensitivity Syndromes in Autistic Adults

“…Autism and CSS may also be related through neuroimmune and genetic differences, particularly the recently recognised "trifecta" of conditions, including Mast cell Activation Syndrome (MCAS) [64], dysautonomia, including Postural Orthostatic Tachycardia Syndrome (POTS) [65], and joint hypermobility disorders including Hypermobile Ehlers-Danlos Syndromes (hEDS) [66]. These conditions often appear together [67] and are increasingly found to be co-morbid with or underly CSS diagnoses [25]. They have also been recognised to be associated with autism and other neurodevelopmental conditions [20,22], particularly through the work of Eccles et al [21,25,68,69], and Casanova et al (2019) recently theorised that some forms of autism could even be hereditary connective tissue disorders [70].…”

“…There is, however, growing awareness of a link between neurodivergence and genetic connective tissue disorders, particularly joint hypermobility-related disorders [20,21] and the Ehlers-Danlos syndromes [22]. These conditions often co-occur with CSS [23][24][25], but more research is needed into whether this directly translates to an association between autism and CSS.…”

The Role of Cell Adhesion and Cytoskeleton Dynamics in the Pathogenesis of the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

“…This is of importance, since the most common forms of hEDS and HSD, are currently without any diagnostic biomarker, and it is likely that further unidentified subtypes remain. This may also have implications for other related disorders such as fibromyalgia, and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which demonstrate significant overlaps with hypermobility and connective tissue abnormalities, though the association is poorly understood ( Bragée et al, 2020 ; Eccles et al, 2020 ). It is plausible therefore, that similar pathomechanisms involving fibroblast dysfunction may be contributing to the pathogenesis of these related disorders, which could be explored through their associations with membrane-bound collagen.…”

Increased rate of joint hypermobility in autism and related neurodevelopmental conditions is linked to dysautonomia and pain

“…Autism ADHD and developmental tic disorder (Tourette syndrome) often share often complex symptoms, consistent with overlapping neurodevelopmental aetiopathology. Increasingly, services need to recognise such complexity and move beyond ‘exclusive’ diagnostic categories and traditional boundaries between physical and mental health (Eccles et al, 2020) This paper sets the scene for further studies that test explicitly for meditating interactions to enable targeting of interventions to enhance quality of life across psychological and physical domains.…”