Pain in the Ehlers–Danlos syndromes: Mechanisms, models, and challenges
Open accessAbstract
Chronic pain is one of the most common, yet poorly studied, complaints in people suffering from Ehlers–Danlos syndromes (EDS). This heterogeneous group of heritable connective tissue disorders is typically characterized by skin hyperextensibility, joint hypermobility, and generalized connective tissue fragility. Most EDS types are caused by genetic defects that affect connective tissue biosynthesis, thereby compromising collagen biosynthesis or fibrillogenesis and resulting in a disorganized extracellular matrix. Even though chronic pain is a major source of disability, functional impairment, and psychosocial suffering in EDS, currently used analgesics and other treatment strategies provide inadequate pain relief and thus represents an important unmet medical need. An important contributor to this is the lack of knowledge about the underlying mechanisms. In this narrative review, we summarize the current understanding of pain and the associated mechanisms in EDS based on clinical studies focusing on questionnaires and experimental pain testing as well as studies in animal models of EDS. In addition, we highlight the challenges, gaps, and opportunities in EDS‐pain research.
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- Findingown data
The authors found significantly more wind-up for painful pressure stimuli in hEDS patients than in controls.
“We found significantly more wind-up for painful pressure stimuli and significantly less exercise-induced hypoalgesia at the quadriceps (active muscle) in hEDS versus controls.”
Quote in the paperSubstantial claim - Findingnone given
Only two studies have assessed pain behavior in EDS mouse models.
“only two studies have assessed pain behavior in EDS mouse models (Table 5).”
Quote in the paperNot a substantial claim - Findingown data
The authors found significantly less exercise-induced hypoalgesia at the quadriceps (active muscle) in hEDS patients than in controls.
“We found significantly more wind-up for painful pressure stimuli and significantly less exercise-induced hypoalgesia at the quadriceps (active muscle) in hEDS versus controls.”
Quote in the paperSubstantial claim - Premisecitation
hEDS remains without a molecular explanation.
“the hypermobile type of EDS (hEDS), presumably the most common type, remains molecularly unexplained to date”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malfait et al., 2017
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- The authors state this as an assumption: hEDS is the most common type of EDS.
- Premisenone given
The molecular pathways linking EDS genetic changes to phenotypes remain largely elusive.
“the molecular pathways linking these genetic changes to the phenotypes remain largely elusive.”
Quote in the paperSubstantial claim
- Interpretationreasoning
The pleiotropic and multisystemic nature of EDS is explained by these ECM defects.
“This explains the pleiotropic and multisystemic nature of these conditions.”
Quote in the paperSubstantial claim - Premisecitation
When pain persists beyond 3-6 months or returns after tissue damage resolves, neuroplastic changes in pain pathways can produce central sensitization.
“when pain persists for more than 3-6 months or resurfaces after the tissue damage has resolved, neuroplastic changes in the pain processing pathways (Figure 1B) may lead to a hypersensitive state of the somatosensory system, a phenomenon called central sensitization”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Basbaum et al., 2009
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- cites Latremoliere & Woolf, 2009
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- cites Woolf, 2011
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- Interpretationreasoning
A lack of knowledge about the underlying mechanisms is an important contributor to inadequate pain relief in EDS.
“An important contributor to this is the lack of knowledge about the underlying mechanisms.”
Quote in the paperSubstantial claim - Premisecitation
Both hEDS and HSD can be associated with extra-musculoskeletal manifestations including chronic fatigue, pelvic floor problems, bladder dysfunction, dysautonomia, immune alterations, gastrointestinal dysfunction, behavioral disturbances, and psychological distress.
“both hEDS and HSD can be associated with a multitude of extra-musculoskeletal functional manifestations, including chronic fatigue, pelvic floor problems, bladder dysfunction, various dysautonomic features, alterations of the immune system (including mast cell activation syndrome), gastro-intestinal dysfunction, behavioral disturbances, and psychological distress”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Castori et al., 2017
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- cites Malfait et al., 2020
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- cites B. Tinkle et al., 2017
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- Premisecitation
Chronic pain lasting longer than 3 months was or is part of the diagnostic criteria for hEDS in both the Villefranche and 2017 classifications.
“(chronic) pain (described as either 'joint pain, 'musculoskeletal pain', or 'chronic widespread pain' lasting for longer than 3 months), was/is part of the diagnostic criteria for hEDS, both in the Villefranche (Beighton et al., 1998) and the 2017 EDS classification (Malfait et al., 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Beighton et al., 1998
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- cites Malfait et al., 2017
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- Interpretationreasoning
This focus complicates molecular pathomechanism studies because the genetic basis of hEDS/JHS is unknown.
“This complicates studies investigating the molecular pathomechanisms underlying pain in EDS or JHS/HSD, since the genetic basis of hEDS/JHS remains unknown.”
Quote in the paperSubstantial claim - Premisecitation
A case report and a small series of hEDS/JHS, vascular EDS, and classical EDS patients described decreased intra-epidermal nerve fiber density, a sign of small fiber neuropathy.
“One case report and a study in a small series of hEDS/JHS patients (n= 20), three vascular EDS and one classical EDS patient described decreased intra-epidermal nerve fiber density, which is a sign of small fiber neuropathy”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Cazzato et al., 2016
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- cites Pascarella et al., 2016
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- Premisenone given
Little research has been done on the prevalence, characteristics, etiology, and mechanisms of pain in EDS/JHS/HSD despite it being a major clinical problem.
“surprisingly little research has been done on the prevalence, characteristics, etiology, and mechanisms of pain in EDS and JHS/HSD”
Quote in the paperSubstantial claim - Interpretationcitation
Clinical experience indicates chronic pain is one of the most frequent complaints in EDS, especially hEDS.
“These reports echo clinical experience that chronic pain is one of the most frequent complaints of patients affected by EDS, especially hEDS.”
Quote in the paperNot a substantial claim - Premisecitation
Di Stefano et al. found hyperalgesia to cold and heat in 27 adult JHS/hEDS patients.
“Di Stefano et al. also found hyperalgesia to cold and heat in 27 adult JHS/hEDS patients”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Di Stefano et al., 2016
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- Premisecitation
Overlapping conditions such as chronic fatigue, sleep disturbances, irritable bowel syndrome, depression, and anxiety often co-exist with chronic pain in EDS/JHS/HSD.
“overlapping conditions such as chronic fatigue, sleep disturbances, irritable bowel syndrome, depression and anxiety often co-exist”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Bulbena et al., 2017
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- cites Fikree et al., 2017
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- cites A. Hakim et al., 2017
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- Premisecitation
If left untreated or inadequately treated, chronic pain in EDS/JHS/HSD often harms physical, social, and emotional function and substantially reduces quality of life.
“If left un-or inadequately treated, it often has a detrimental effect on physical, social, and emotional function in affected individuals, with a substantial deterioration of their quality of life”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Bovet et al., 2016
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- cites Johannessen et al., 2016
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- cites Scheper et al., 2016
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- Interpretationreasoning
Multiple etiologies of pain may co-exist in many cases.
“In many cases, however, multiple etiologies of pain may co-exist.”
Quote in the paperSubstantial claim - Interpretationreasoning
Micro- and macrotrauma in joints, tendons, and ligaments may further reduce proprioceptive acuity, increasing the likelihood of additional injuries.
“Both micro-and macrotrauma in the joints, tendons and ligaments may further diminish proprioceptive acuity, increasing the likelihood of additional injuries.”
Quote in the paperNot a substantial claim - Premisecitation
People with hEDS or JHS/HSD are predisposed to dislocations and repetitive soft-tissue traumas such as overstretching and tearing of ligaments and tendons due to ligamentous laxity, joint instability, lack of proprioceptive acuity, and reduced muscle strength and endurance.
“People with hEDS or JHS/HSD are predisposed to dislocations and repetitive soft-tissue traumas, such as overstretching and tearing of ligaments and tendons (Rombaut, De Paepe, Malfait, Cools, & Calders, 2010;Rombaut et al., 2012), due to their ligamentous laxity and joint instability, lack of proprioceptive acuity and reduced muscle strength and endurance.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Rombaut et al., 2010
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- cites Rombaut et al., 2012
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- Premisereasoning
Experimental research on increased endogenous pain facilitation and/or reduced inhibition is scarce in hEDS and JHS/HSD.
“Experimental research into increased endogenous pain facilitation and/or reduced inhibition, mechanisms underlying central sensitization, is equally scarce in hEDS and JHS/HSD.”
Quote in the paperSubstantial claim - Premisecitation
Nociceptive pain directly related to injuries, often triggered by sports injuries or surgery, is frequently encountered in hEDS and JHS.
“Nociceptive pain directly related to these injuries (often triggered by external factors such as sports injuries or surgery (Castori et al., 2013)) is frequently encountered in hEDS and JHS.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Castori et al., 2013
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- Premisecitation
Chronic widespread pain in EDS/JHS/HSD is associated with high use of analgesics, surgery, and physical therapy.
“The chronic, widespread pain in EDS and JHS/HSD is associated with high use of analgesics, surgery, and physical therapy”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Castori et al., 2012
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- cites Castori et al., 2013
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- cites Chopra et al., 2017
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- Premisecitation
In this stage, pain distribution and description often overlap with fibromyalgia.
“In this stage the pain distribution and description often overlap with fibromyalgia”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites B.T. Tinkle & Levy, 2019
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- Premisereasoning
Comprehensive cutaneous innervation data for other molecularly solved EDS types are not available, representing a gap.
“comprehensive cutaneous innervation data on other molecularly solved EDS types are currently not available, thereby representing a gap in the study of pain in EDS.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Microtrauma in frail connective tissues may cause subclinical damage often without a recognized trauma history.
“microtrauma in the frail connective tissues may cause subclinical damage that is often not supported by a recognized history of trauma.”
Quote in the paperSubstantial claim - Premisecitation
Besides musculoskeletal pain, headaches, abdominal pain, pelvic girdle pain, and dysmenorrhea are frequently reported in hEDS or JHS/HSD.
“Besides musculoskeletal pain, other pain phenotypes, especially headaches, abdominal pain, pelvic girdle pain, and dysmenorrhea are frequently reported in individuals suffering from hEDS or JHS/HSD”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Ali et al., 2020
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- cites Chopra et al., 2017
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- cites Fikree et al., 2017
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- Premisecitation
Scheper et al. provided evidence that generalized hyperalgesia begins in childhood by studying pain pressure thresholds in 43 children/adolescents with hEDS/JHS.
“Scheper et al. provided evidence for onset of the generalized hyperalgesia in childhood, by studying PPTs 43 children/adolescents with hEDS/JHS”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Scheper et al., 2017
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- Premisecitation
A few studies found experimental evidence for central sensitization in the chronification of generalized pain in JHS or hEDS.
“A few studies found experimental evidence for central sensitization in the chronification of generalized pain in individuals with JHS or hEDS.”
Quote in the paperNot a substantial claim - Premisecitation
Sequestered ECM components or degradation products can act as damage-associated molecular patterns, which are endogenous danger signals recognized by pattern recognition receptors of the immune system.
“a variety of sequestered ECM components or their degradation products can act as damage-associated molecular patterns (DAMPs) (Schaefer, 2014), which function as endogenous danger signals and are recognized by Pattern Recognition Receptors (PRRs) of the immune system.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schaefer, 2014
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- Premisecitation
Individuals with hEDS and JHS/HSD frequently experience high levels of anxiety and depression.
“individuals with hEDS and JHS/HSD frequently experience high levels of anxiety and depression”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Baeza-Velasco et al., 2015
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- cites Smith et al., 2014
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- Premisecitation
Transcutaneous sine wave stimuli elicit a hypersensitive response of myelinated Aδ and Aβ fibers, but not of unmyelinated C fibers, in Tnxb-/- mice.
“Transcutaneous sine wave stimuli elicited a hypersensitive response of myelinated Aδ and Aβ fibers, but not of unmyelinated C fibers.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okuda-Ashitaka et al., 2020
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- Premisecitation
Tnxb-/- mice show no thermal hypersensitivity.
“and also found mechanical allodynia but no thermal hypersensitivity.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Okuda-Ashitaka et al., 2020
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- Premisereasoning
Temporal summation of pressure pain and conditioned pain modulation for pressure stimuli have not yet been investigated in EDS/HSD.
“However, temporal summation of pressure pain and conditioned pain modulation responses for pressure stimuli have not yet been investigated.”
Quote in the paperSubstantial claim - Interpretationreasoning
The nervous system and associated pain-related behaviors are compromised in mouse models of EDS.
“Together, these findings illustrate that the nervous system and associated pain-related behaviors are compromised in mouse models of EDS”
Quote in the paperSubstantial claim - Premisecitation
Animals, most commonly mice and rats, are widely used as models to study pain.
“animals, most commonly mice (Mus musculus) and rats (Rattus norvegicus), are widely used as models to study pain (Mogil, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mogil, 2009
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- Rests on an assumption: Experimental pain studies in people with EDS are limited by ethical considerations, their subjective nature, and difficulties in obtaining neuronal tissues and cells for molecular studies.
- Premisecitation
Tnxb-/- mice show an increased number of P-ERK and NADPH-diaphorase positive neurons in the dorsal horn of the spinal cord, suggestive of spinal central sensitization.
“In addition, Tnxb -/-mice showed an increased number of P-ERK and NADPH-diaphorase positive neurons in the dorsal horn of the spinal cord, suggestive of spinal central sensitization (Okuda-Ashitaka et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okuda-Ashitaka et al., 2020
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- Interpretationreasoning
Research into pain-related behaviors in animal models of EDS is only in its infancy.
“Research into pain-related behaviors in animal models of EDS is only in its infancy.”
Quote in the paperSubstantial claim - Premisecitation
These mouse models provide valid models for their human counterparts.
“While these models have been found to provide valid models for their human counterparts”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vroman et al., In press
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- Premisecitation
Both male and female Col5a1+/- mice, a model for classical EDS, are hypersensitive to mechanical stimuli in the hind paws and abdominal area.
“both male and female Col5a1 +/-mice, a model for classical EDS (Wenstrup et al., 2006), are hypersensitive to mechanical stimuli in the hind paws and abdominal area but not to thermal stimuli.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Syx et al., 2020
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- Interpretationreasoning
An intact ECM plays a potentially important role in proper innervation and pain processing.
“further highlight the potentially important role of an intact ECM for proper innervation and pain processing.”
Quote in the paperSubstantial claim - Premisecitation
Sensory neurons express the same pattern recognition receptors, such as Toll-like receptors, which can induce painful pathways upon activation.
“Sensory neurons have been shown to express the same PRRs (e.g., Toll-like receptors (TLRs)), which can induce painful pathways upon activation”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Feldman et al., 2012
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- cites Lacagnina et al., 2018
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- cites Miller et al., 2015
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- Premisecitation
Col5a1+/- mice are not hypersensitive to thermal stimuli.
“are hypersensitive to mechanical stimuli in the hind paws and abdominal area but not to thermal stimuli.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Syx et al., 2020
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- Premisecitation
Tnxb-/- mice, a model for classical-like EDS, show mechanical allodynia.
“Okuda-Ashitaka et al. studied tenascin-X knockout (Tnxb -/-) mice, a model for classical-like EDS, and also found mechanical allodynia but no thermal hypersensitivity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okuda-Ashitaka et al., 2020
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- Premisecitation
Transcriptome analysis in mouse models of nerve injury- and inflammation-induced pain identified ECM organization as a central molecular pathway in chronic pain development.
“Transcriptome analysis in mouse models of nerve injury-and inflammation-induced pain have identified ECM organization as a central molecular pathway in chronic pain development”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Parisien et al., 2019
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- Interpretationreasoning
Other emotional and cognitive mechanisms likely contribute to chronic pain in EDS and JHS.
“Besides avoidance strategies, other emotional and cognitive mechanisms likely contribute to chronic pain in EDS and JHS.”
Quote in the paperNot a substantial claim - Premisecitation
Rombaut et al. reported fear of falling among women with JHS/hEDS.
“Rombaut et al., (2011) who reported fear of falling among women with JHS/hEDS”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rombaut et al., 2011
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- Premisecitation
Anxiety and depression may increase the experience of pain.
“these emotions may increase the experience of pain”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Linton & Shaw, 2011
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Celletti et al. reported that kinesiophobia is common in JHS/hEDS.
“Celletti et al. (2013) who reported that kinesiophobia is a common symptom in JHS/hEDS”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Celletti et al., 2013
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- Premisecitation
The authors and others have provided evidence for alterations in ECM architecture and organization on dermal biopsies from people with different EDS types, both in vivo and in vitro.
“We and others have provided evidence for alterations in the ECM architecture and organization on dermal biopsies from people with different types of EDS, both in vivo (transmission electron microscopy and immunohistochemistry on skin) and in vitro (immunofluorescence on dermal fibroblast cultures)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Chiarelli et al., 2019
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- cites Malfait et al., 2013
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- cites Syx et al., 2019
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- Premisecitation
Formalin injection in the hind paw of Tnxb-/- mice evokes an increased pain response during the first acute phase (0-5 min) and early during the second inflammatory phase (16-30 min) compared to wild-type.
“A chemical pain stimulus with formalin injection in the hind paw evoked an increased pain response during the first (acute) phase (0-5 min) and early during the second (inflammatory) phase (16-30 min) in Tnxb -/-mice, compared to wild-type.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okuda-Ashitaka et al., 2020
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- Premisecitation
Several mouse models of molecularly elucidated EDS types have been generated and characterized over the past few decades.
“Several mouse models of molecularly elucidated EDS types have been generated and characterized over the past few decades (Vroman et al., In press).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vroman et al., In press
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- Premisecitation
Methods to assess behavioral changes in response to chemical, thermal and electrical stimuli have been developed to model both acute and ongoing (chronic) pain in zebrafish.
“Methods to assess behavioral changes in response to stimuli of chemical, thermal and electrical origin have been developed to model both acute and ongoing (chronic) pain in zebrafish (Ohnesorge, Heinl, & Lewejohann, 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ohnesorge, Heinl, & Lewejohann, 2021
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- Premisecitation
Central sensitization in hEDS is caused by alterations in endogenous pain facilitation and inhibition.
“Still, these data further confirm that central sensitization in hEDS is caused by alterations in endogenous pain facilitation and inhibition (De Wandele et al., under review).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites De Wandele et al., under review
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- Premisecitation
For most EDS types, one or several mouse models have been developed.
“For most EDS types, one or several mouse models have been developed (Vroman et al., in press).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vroman et al., in press
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- Premisecitation
Zebrafish models for cardiac-valvular EDS (col1a2-/-) and spondylodysplastic EDS (b4galt7-/- and b3galt6-/-) mimic features of the respective human EDS counterparts.
“Recently, the use of zebrafish in EDS research has been introduced by our lab with the description of several zebrafish models for cardiacvalvular EDS (col1a2 -/-) (Gistelinck et al., 2018) and spondylodysplastic EDS (b4galt7 -/- (Delbaere, Van Damme, et al., 2020) and b3galt6 -/- (Delbaere, De Clercq, et al., 2020)), which mimic features of the respective human EDS counterparts.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Gistelinck et al., 2018
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- cites Delbaere, Van Damme, et al., 2020
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- cites Delbaere, De Clercq, et al., 2020
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- Interpretationreasoning
Recent observations of altered pain-related behaviors and innervation in classical and classical-like EDS mouse models underscore their potential as preclinical models to investigate and unravel pathways and mechanisms underlying EDS-related pain.
“Recent observations of altered pain-related behaviors and innervation in the classical and classical-like EDS mouse models underscore their potential as preclinical models to investigate and unravel the pathways and mechanisms underlying EDS-related pain”
Quote in the paperSubstantial claim - Premisecitation
Zebrafish can facilitate the screening for potent analgesics in translational pain research by allowing larger throughput compared to other vertebrate models.
“Furthermore, zebrafish can facilitate the screening for potent analgesics in translational pain research by allowing larger throughput compared to other vertebrate models (Kalueff et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kalueff et al., 2016
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- May combine two claims. 35
- Classified as probably not a substantial claim. 19
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Findingown dataThe authors did not detect differences in conditioned pain modulation between hEDS patients and healthy controls, in contrast to Leone et al.
“In contrast to Leone et al., we did not detect differences in conditioned pain modulation between hEDS patients and healthy controls.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Leone et al., 2020
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PremisecitationCurrently used analgesics provide inadequate pain relief in EDS, representing an unmet medical need.
“currently used analgesics provide inadequate pain relief and thus represents an important unmet medical need”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Syx et al., 2017
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PremisecitationChronic pain in EDS is a major source of disability, functional impairment, and psychosocial suffering.
“Even though chronic pain is a major source of disability, functional impairment and psychosocial suffering in EDS”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Syx et al., 2017
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PremisecitationAll EDS-related defects compromise collagen biosynthesis, fibrillogenesis, and/or supramolecular organization of collagen fibrils in the ECM at some level, altering the physical properties of the ECM in essentially all tissues and organs.
“All these EDS-related defects compromise collagen biosynthesis, fibrillogenesis and/or supramolecular organization of collagen fibrils in the ECM at some level, with alterations in the physical properties of the ECM in essentially all tissues and organs.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Malfait et al., 2020
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- cites Malfait et al., 2017
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PremisecitationAcute nociceptive pain in EDS/JHS/HSD can arise from subluxations or dislocations, soft tissue injury, surgery, muscle or tendon rupture, skin tears, abnormal wound healing, bruising, pneumothorax, and internal organ prolapses.
“Depending on the type, these may for instance include subluxations and dislocations of large and small joints, soft tissue injury, surgical interventions, muscle or tendon rupture, skin tears, abnormal wound healing, repetitive bruising, pneumothorax and internal organ prolapses”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malfait et al., 2020
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PremisecitationThe 2017 EDS classification limits hEDS to individuals with features indicating a systemic and/or Mendelian connective tissue disorder.
“the revised 2017 EDS classification now emphasizes that among individuals with otherwise unclassified joint hypermobility, the term hEDS should be limited to individuals with features indicative of a systemic and/or Mendelian connective tissue disorder”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malfait et al., 2020
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PremisecitationThese manifestations are recognized as joint hypermobility-associated comorbidities with varying evidence, but their biological link to tissue alterations is unclear.
“These concurring manifestations are now recognized, with different levels of evidence, as 'joint hypermobilityassociated comorbidities', but the biological connection to tissue alterations is not clear”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malfait et al., 2020
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PremisecitationChronic pain is among the most frequent and least studied complaints in people with EDS.
“Chronic pain is one of the most common, yet poorly studied, complaints in people suffering from Ehlers-Danlos syndromes (EDS).”
- Also stated in: § Pain in EDS and HSD, a challenging problem · plain
“One of the major complaints of individuals suffering from EDS and JHS/HSD is pain (Castori et al., 2013;Chopra et al., 2017;A. J. Hakim & Grahame, 2004;Syx, De Wandele, Rombaut, & Malfait, 2017).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Castori et al., 2013
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- cites Chopra et al., 2017
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- cites Syx et al., 2017
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- Also stated in: § Pain in EDS and HSD, a challenging problem · plain
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PremisecitationMost EDS types are caused by genetic defects that affect connective tissue biosynthesis, impair collagen biosynthesis or fibrillogenesis, and produce a disorganized extracellular matrix.
“Most EDS types are caused by genetic defects that affect connective tissue biosynthesis, thereby compromising collagen biosynthesis or fibrillogenesis and resulting in a disorganized extracellular matrix (ECM).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Malfait et al., 2020
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- cites Malfait et al., 2017
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PremisecitationEDS are rare inherited connective tissue disorders marked by generalized joint hypermobility, skin hyperextensibility and fragility, abnormal wound healing, easy bruising, and widespread connective tissue friability.
“The Ehlers-Danlos syndromes (EDS) comprise a group of rare heritable connective tissue disorders, clinically hallmarked by generalized joint hypermobility, skin hyperextensibility and fragility, abnormal wound healing, easy bruising and widespread connective tissue friability”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malfait et al., 2020
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PremisecitationIndividuals with symptomatic joint hypermobility who do not meet 2017 hEDS criteria and lack another joint hypermobility-associated condition are classified as HSD, and the term JHS is no longer used.
“Individuals with symptomatic joint hypermobility who do not fulfil the 2017 diagnostic criteria for hEDS (and who do not have signs and symptoms of another joint hypermobilityassociated condition) are now considered to fall into the group of 'Hypermobility Spectrum Disorders' (HSD) (Castori et al., 2017), and the term JHS is no longer used.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Castori et al., 2017
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PremisecitationTo date, 13 EDS types are recognized, 12 of which have been molecularly elucidated, caused by defects in 20 genes.
“To date, 13 distinct EDS types are recognized, 12 of which have been molecularly elucidated, caused by defects in 20 different genes”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Malfait et al., 2020
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- cites Malfait et al., 2017
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Premisenone givenThe prevalence of these comorbidities in other molecularly defined EDS types has not been documented.
“The prevalence of these comorbidities in other molecularly defined types of EDS has not been documented.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenNo pathophysiological pain model has been identified for EDS, though theoretical arguments and some evidence support nociceptive, neuropathic, and central sensitization/nociplastic mechanisms.
“No pathophysiological pain model has been identified yet for EDS, although theoretical arguments and some evidence has been presented for several types of mechanisms, including nociceptive pain, neuropathic pain (Raja et al., 2020), and central sensitization with the development of nociplastic pain”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAvailable treatments for pain in EDS provide modest relief at best and carry adverse events and health risks.
“available treatments provide modest relief at best, and are associated with undesirable adverse events and health risks”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Syx et al., 2017
Not checked in the free run.
May combine two claims.
PremisecitationArthralgia is frequently described in weight-bearing joints such as hips, knees, and ankles, in joints used in repetitive tasks such as shoulders, wrists, and hands, and in the neck, back, and temporomandibular joints.
“Arthralgia is frequently described in weight-bearing joints such as hips, knees, and ankles, in joints involved in repetitive tasks, such as shoulders, wrists and hands, and in the neck, back and temporomandibular joints”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Benistan & Martinez, 2019
Not checked in the free run.
- cites Rombaut et al., 2010
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- cites B. T. Tinkle & Levy, 2019
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May combine two claims.
PremisecitationMuscle cramps, enthesopathies such as tendinitis, tenosynovitis, and fasciitis, and nerve entrapment syndromes can add to localized musculoskeletal pain.
“Muscle cramps, enthesopathies, such as tendinitis, tenosynovitis and fasciitis, and nerve entrapment syndromes can add to the localized musculoskeletal pain”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Aktas et al., 2008
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- cites Granata et al., 2013
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- cites Rombaut et al., 2010
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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenPain in EDS gradually becomes less localized and takes on a widespread and chronic character.
“Pain in EDS gradually becomes less localized and takes on a wide-spread and chronic character.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningVery little is known about pain prevalence and mechanisms in pediatric, adolescent, and male EDS/JHS/HSD populations, or in other EDS types.
“very little is known about pain prevalence and mechanisms in pediatric, adolescent, and male EDS and JHS/HSD populations, nor in individuals affected with another type of EDS.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationReduced bone mass and premature osteoarthritis may contribute to nociceptive pain in hEDS and JHS/HSD, but their impact on the pain phenotype remains unclear.
“Other contributors to nociceptive pain in hEDS and JHS/HSD may include reduced bone mass (Banica et al., 2020;Dolan, Arden, Grahame, & Spector, 1998) and premature osteoarthritis (Jonsson et al., 2009), but the impact of the latter two on the pain phenotype remains to be elucidated.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Banica et al., 2020
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- cites Dolan et al., 1998
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- cites Jonsson et al., 2009
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May combine two claims.
PremisecitationMyalgias are commonly reported at this stage, with tender myotendinous insertion points and muscle tension.
“Myalgias are also commonly reported at this stage, with tender myotendinous insertion points and muscle tension”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rombaut et al., 2010
Not checked in the free run.
May combine two claims.
PremisereasoningMost pain studies in EDS/JHS/HSD focused on adult females with hEDS, JHS, or mixed diagnoses, likely because this group allows sufficient sample size.
“Most of the studies that have investigated pain in EDS or JHS/HSD focused on adult females with hEDS, JHS or mixed hEDS/JHS diagnoses, likely reflecting the relative ease of studying a substantial patient sample size necessary for statistical analysis within this group.”
Quote in the paperSubstantial claim- The authors state this as an assumption: hEDS is the most common type of EDS.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSacheti et al. first reported a 90% incidence of chronic pain in 51 patients with different EDS types.
“Sacheti and coworkers were the first to report a 90% incidence of chronic pain in 51 patients with different EDS types”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sacheti et al., 1997
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThis 90% incidence was later confirmed in other questionnaire studies.
“This incidence was later confirmed in a few other questionnaire studies”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Benistan & Martinez, 2019
Not checked in the free run.
- cites Rombaut et al., 2010
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- cites Voermans et al., 2010
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May combine two claims.
PremisecitationIn this later stage, common additional complaints include burning sensations, peripheral paresthesias, generalized hyperalgesia, allodynia, and hypersensitivity to light, sound, and odors.
“Common additional complaints in this stage include burning sensations, peripheral paresthesias, generalized hyperalgesia, allodynia, and hypersensitivity to various other stimuli, such as light, sound and odors”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Benistan & Martinez, 2019
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- cites Castori et al., 2013
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- cites Syx et al., 2015
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May combine two claims.
PremisecitationSome questionnaire studies provide evidence for a neuropathic component to hEDS- or JHS-related pain, but another questionnaire study could not confirm this.
“a few questionnaire studies provided evidence for a neuropathic component to hEDS-or JHS-related pain (Benistan & Martinez, 2019;Camerota, Celletti, Castori, Grammatico, & Padua, 2011;Rombaut et al., 2015;Voermans, Knoop, & van Engelen, 2011), although this could not be confirmed in another questionnaire study (Di Stefano et al., 2016).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Benistan & Martinez, 2019
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- cites Camerota et al., 2011
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- cites Di Stefano et al., 2016
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May combine two claims.
PremisecitationOnly three published studies have assessed temporal summation of pain and one has examined conditioned pain modulation in this patient population.
“To date, only three published studies assessed pain facilitation using temporal summation of pain (Benistan & Martinez, 2019;Di Stefano et al., 2016;Leone et al., 2020) and one study examined conditioned pain modulation (Leone et al., 2020) in this patient population.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Benistan & Martinez, 2019
Not checked in the free run.
- cites Di Stefano et al., 2016
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- cites Leone et al., 2020
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationChronic musculoskeletal pain has long been recognized as a major complaint in JHS and was included in diagnostic criteria.
“Chronic musculoskeletal pain has long been recognized to be a major complaint in JHS and it was included in the diagnostic criteria”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Grahame et al., 2000
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- cites Kirk et al., 1967
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May combine two claims.
PremisecitationFemale Col5a1+/- mice show altered climbing behavior with decreased grip strength.
“In addition, female Col5a1 +/-mice showed altered climbing behavior with decreased grip strength.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Syx et al., 2020
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevalence rates of many different pain conditions are higher in women than in men.
“It has been widely reported that the prevalence rates of many different pain conditions are higher in women than in men”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kim & Kim, 2020
Not checked in the free run.
May combine two claims.
PremisecitationAn ECM network surrounds and supports neuronal cells including nociceptors and non-neuronal cells in the PNS and CNS, where it can regulate synapse formation and function, modulate neuronal excitability, and play a role in CNS neuroplasticity and connectivity.
“An ECM network also surrounds and supports neuronal cells, including nociceptors, and non-neuronal cells in the PNS and CNS (Barros, Franco, & Muller, 2011), where it can regulate synapse formation and function, modulate neuronal excitability and play a role in CNS neuroplasticity and connectivity”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Barros et al., 2011
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- cites Tajerian & Clark, 2015
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe ECM consists of collagens, glycoproteins, proteoglycans, elastin, and microfibrillar proteins, which with producing cells form connective tissue throughout the body.
“The ECM consists of collagens, glycoproteins, proteoglycans, elastin and microfibrillar proteins, which, together with the cells that produce them (e.g., fibroblasts), forms the connective tissue that is found throughout the body”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Frantz et al., 2010
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSex differences in chronic pain prevalence have been well-established.
“Intriguingly, sex differences in chronic pain prevalence have been well-established (Mogil, 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mogil, 2020
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAccording to the fear-avoidance model, a highly fearful person learns to avoid activities perceived as harmful or pain-provoking.
“According to the 'fearavoidance model', a highly fearful person learns to avoid activities that he or she perceives as harmful or pain-provoking”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vlaeyen & Linton, 2000
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May combine two claims.
InterpretationreasoningAn abnormal ECM may contribute to the generation and chronification of pain in EDS by compromising development or support of the peripheral nervous system and by inducing molecular or cellular changes in nociceptors and the PNS.
“Therefore, it is possible that an abnormal ECM contributes to the generation and chronification of pain in these conditions, potentially driven by dual factors: the abnormal ECM may (i) compromise the proper development and/or support of the (peripheral) nervous system, contributing to increased vulnerability of the peripheral nerves; and (ii) induce molecular and/or cellular changes in the nocice”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCol5a1+/- mice have decreased intraepidermal nerve fiber density, with fewer nerves crossing the epidermis and reduced total nerve length compared to wild-type.
“Visualization of nociceptors in the glabrous skin of the footpad revealed a decreased intraepidermal nerve fiber density, with fewer nerves crossing the epidermis and a reduced total nerve length of Col5a1 +/-mice compared to wild-type (Syx et al., 2020).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Syx et al., 2020
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationStudies assessing pain inhibition after exercise in EDS/HSD are lacking, but are of major interest because exercise therapy is a cornerstone of treatment.
“studies assessing pain inhibition after exercise in EDS and HSD are currently lacking but are of major interest as exercise therapy is a cornerstone in treatment”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Engelbert et al., 2017
Not checked in the free run.
May combine two claims.
InterpretationreasoningOver the long term, avoidance behavior from fear of pain leads to disuse and muscle deconditioning, further loss of strength and flexibility.
“Over the long term, avoidance behavior that results from fear of pain leads to disuse and muscle deconditioning, which generates further loss of muscle strength and flexibility.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThese studies found increased wind-up to pinprick and thermal stimuli and reduced conditioned pain modulation with thermal stimuli.
“These studies found evidence for increased wind-up to pinprick and thermal stimuli and reduced conditioned pain modulation with thermal stimuli.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Benistan & Martinez, 2019
Not checked in the free run.
- cites Di Stefano et al., 2016
Not checked in the free run.
- cites Leone et al., 2020
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May combine two claims.
PremisecitationPeripheral tissue injuries cause ECM remodeling and induce pain with alterations in ECM modifying enzymes such as matrix metalloproteinases.
“peripheral tissue injuries have been shown to cause ECM remodeling and induce pain with alterations in ECM modifying enzymes, such as matrix metalloproteinases”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Tajerian & Clark, 2015
Not checked in the free run.
- cites Tajerian & Clark, 2019
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAnimal models of nociception date back to the late 19th century and have been crucial in understanding pain processes and discovering pain-relieving therapies.
“Animal models of nociception date back to the late 19 th century and have been crucial in our understanding of pain processes and in the discovery of painrelieving therapies (Gregory et al., 2013;Minett, Quick, & Wood, 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Gregory et al., 2013
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- cites Minett, Quick, & Wood, 2011
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May combine two claims.
InterpretationreasoningThis often aggravates functional disability and leads to depression, which reduces pain tolerance and promotes further pain.
“This often aggravates functional disability and leads to depression, which in turn reduces pain tolerance and promotes further pain.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChronic pain is usually more severe for women than men with the same disease condition.
“and that chronic pain is usually more severe for women than men with the same disease condition (Kim & Kim, 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kim & Kim, 2020
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationZebrafish model is increasingly used in neurobiological and nociceptive research.
“and this model is increasingly used in neurobiological and nociceptive research (Malafoglia, Bryant, Raffaeli, Giordano, & Bellipanni, 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malafoglia, Bryant, Raffaeli, Giordano, & Bellipanni, 2013
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFor zebrafish, it is now clearly established that they can perceive pain, both in early and adult stages.
“Also for zebrafish, it is now clearly established that they can perceive pain, both in early and adult stages”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Malafoglia, Bryant, Raffaeli, Giordano, & Bellipanni, 2013
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationInitial discussions questioned whether fish were able to perceive pain, but identification of nociceptors using electrophysiology and neuroanatomical approaches in rainbow trout together with other mounting evidence changed this view.
“Initial discussions questioned whether (zebra)fish were able to perceive pain, but the identification of nociceptors using electrophysiology and neuroanatomical approaches in rainbow trout (also a teleost) together with other mounting evidence changed this view (Sneddon, 2002(Sneddon, , 2003(Sneddon, , 2015)).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Sneddon, 2002
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- cites Sneddon, 2003
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- cites Sneddon, 2015
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The authors state this as an assumption.
hEDS is the most common type of EDS.
“the hypermobile type of EDS (hEDS), presumably the most common type”
The paper relies on this without support.
Most published studies on hEDS/JHS/HSD use the old JHS and hEDS criteria and terminology and often do not distinguish hEDS from JHS.
“most published studies included still use the old JHS and hEDS criteria and terminology, and often do not make the distinction between hEDS and JHS.”
The paper relies on this without support.
Experimental pain studies in people with EDS are limited by ethical considerations, their subjective nature, and difficulties in obtaining neuronal tissues and cells for molecular studies.
“Because experimental pain studies in people with EDS are limited by several factors, such as ethical considerations, their subjective nature, and difficulties in obtaining neuronal tissues and cells for molecular studies”
The paper relies on this without support.
Animals cannot report pain, so indirect behavioral methods are needed to assess nociception in rodents.
“Since animals cannot report pain and thus pain cannot be directly evaluated in rodents, a range of indirect behavioral methods have been developed to reliably assess and quantify signs of nociception in these non-communicating subjects.”
The paper relies on this without support.
Pain is a major problem in individuals with hEDS and JHS/HSD, associated with increased morbidity, reduced functionality, reduced quality of life, and increased use/abuse of pain treatments.
“Pain is undoubtedly a major problem in individuals suffering from hEDS and JHS/HSD and is associated with increased morbidity, reduced functionality, and reduced quality of life, and with increased use and abuse of pharmacological and non-pharmacological pain-relieving treatments.”
The paper relies on this without support.
These pain treatments often have only moderate effect and may be associated with severe complications and health risks.
“Yet these treatments often only have only a moderate effect at best and may be associated with severe complications and health risks.”
The paper relies on this without support.
Virtually no experimental pain studies have been performed in people with molecularly elucidated forms of EDS.
“To date, virtually no experimental pain studies have been performed in people with molecularly elucidated forms of EDS.”
The paper relies on this without support.
Multisystemic connective fragility in people with molecularly elucidated EDS predestines them to repeated micro- and macrotrauma.
“Yet, the multisystemic connective fragility in these people also predestines them to repeated micro-and macrotrauma.”
The paper relies on this without support.
Most studies on hypermobility-related pain focused on hEDS/JHS patients.
“In addition, since most studies on hypermobility-related pain focused on hEDS/JHS patients”
The paper relies on this without support.
Diagnosis of hEDS/JHS is much more frequent in females than in males.
“and since the diagnosis of these conditions is much more frequent in females than in males”
The paper relies on this without support.
Most information on pain prevalence and mechanisms has been gathered in adult females.
“most information on pain prevalence and pain mechanisms has been gathered in adult females”
The paper relies on this without support.
Little information is available on pain prevalence and mechanisms in male and/or pediatric/adolescent populations with molecularly elucidated types of EDS or with HSD.
“and little information is available on pain prevalence and mechanisms in male and/or pediatric/adolescent populations with molecularly elucidated types of EDS or with HSD.”
The paper relies on this without support.
The exact reason for the sex-divergence observed for hEDS and JHS/HSD remains elusive.
“The exact reason for the sex-divergence observed for hEDS and JHS/HSD remains currently elusive.”
The paper relies on this without support.
Research regarding mechanisms governing sex-related differences in pain in general is still in its infancy due to bias in biomedical research, which has largely been performed in males.
“Research regarding the mechanisms governing sex-related differences in pain in general is still in its infancy due to the bias in biomedical research, which has largely been performed in males.”
The paper relies on this without support.
Animal models, especially rodents, have been great allies in advancing insights into pathophysiological mechanisms of disease and can serve as preclinical models for development and assessment of pharmacological treatments.
“Animal models, especially rodents, have been great allies in advancing our insights into the pathophysiological mechanisms of disease and can serve as preclinical models for the development and assessment of pharmacological treatments.”
The paper relies on this without support.
Many advances have occurred in rodent pain assessment techniques.
“Also in the field of pain research, many advances have occurred in rodent pain assessment techniques.”
The paper relies on this without support.
Increasing evidence points to comparable processes in fish.
“Although rodent (mammalian) animal models are dominating research on nociception and pain, increasing evidence points to comparable processes in fish.”
The paper relies on this without support.
Zebrafish is widely used as an animal model in many research areas such as disease modelling, regeneration and toxicology.
“The tropical freshwater teleost or bony fish, Danio rerio (zebrafish), is widely used as an (vertebral) animal model in many research areas such as disease modelling, regeneration and toxicology.”
The paper relies on this without support.
Zebrafish popularity is fueled by advantages such as small size, easy genetic manipulation, high fecundity, external fertilization, large offspring, transparency of rapidly developing embryos and low maintenance cost.
“Its popularity is fueled by several advantages, such as small size, easy genetic manipulation, high fecundity, external fertilization, large offspring, transparency of rapidly developing embryos and low maintenance cost.”
The paper relies on this without support.
Electrophysiology, optogenetic tools and transgenic lines that label specific neuronal subsets are available in zebrafish field.
“In addition, electrophysiology, optogenetic tools and transgenic lines that label specific neuronal subsets are also available in the zebrafish field.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Central sensitization, as seen with generalized chronic widespread pain, will secondarily promote visceral hypersensitivity.
“Thirdly, central sensitization, as seen with generalized, chronic widespread pain, will secondarily promote visceral hypersensitivity. 13”
From Hypermobile Ehlers–Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know (2022) · cites this paper as [13]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
The Voermans pain study has conflicting publication years
MinorThe table labels the Voermans study of pain in EDS patients as 2011, while the paper's reference for the Voermans pain study is dated 2010. Its separate 2011 Voermans reference concerns neuropathic pain.
“| Voermans et al. | 273 EDS patients | Questionnaires | Pain in 90% (98% JHS/hEDS | | 2011 | (53 undefined”
“100. Voermans, N. C., Knoop, H., Bleijenberg, G., & van Engelen, B. G. (2010). Pain in ehlers- danlos syndrome is common, severe, and associated with functional impairment.”
The stated use of the Villefranche classification exceeds the interval before its revision
MinorThe paper says the 1998 classification was used for over two decades, but it identifies its replacement as the revised 2017 classification. That interval is 19 years.
“These discoveries laid the foundation for the 1998 Villefranche EDS Nosology, which was used for over two decades”
“the revised 2017 EDS classification now emphasizes”
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Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system
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Pain in Ehlers-Danlos Syndrome Is Common, Severe, and Associated with Functional Impairment
Voermans, N. C., Knoop, H., Bleijenberg, G., & van Engelen, B. G. (2010) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2009.12.026 · Cited by 237 · see citing works
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Toll-like receptors and their role in persistent pain
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Pain management in the Ehlers–Danlos syndromes
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A Review of Pain Assessment Methods in Laboratory Rodents
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Chronic pain is a manifestation of the Ehlers-Danlos syndrome
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Murine Model of the Ehlers-Danlos Syndrome
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Painful Pathways Induced by TLR Stimulation of Dorsal Root Ganglion Neurons
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Gastrointestinal involvement in the Ehlers–Danlos syndromes
Fikree, A., Chelimsky, G., Collins, H., Kovacic, K., & Aziz, Q. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31546 · Cited by 159 · see citing works
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Psychiatric and psychological aspects in the Ehlers–Danlos syndromes
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Disability in Adolescents and Adults Diagnosed With Hypermobility-Related Disorders: A Meta-Analysis
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Chronic fatigue in Ehlers–Danlos syndrome—Hypermobile type
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Self-citationZebrafish neurobehavioral phenomics for aquatic neuropharmacology and toxicology research
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Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes
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In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP
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Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies
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Self-citationAssessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry
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Self-citationReducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy
Jayaraj, N. D., Bhattacharyya, B. J., Belmadani, A. A., Ren, D., Rathwell, C. A., Hackelberg, S., Hopkins, B. E., Gupta, H. R., Miller, R. J., & Menichella, D. M. (2018) · Journal of Clinical Investigation · doi:10.1172/jci92117 · Cited by 90 · see citing works
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The nociceptive innervation of the normal and osteoarthritic mouse knee
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Self-citationThe zebrafish as a model for nociception studies
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Behavioral Measures of Pain Thresholds
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Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis
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Molecular Mechanisms of Sex-Related Differences in Arthritis and Associated Pain
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Neuropathic pain is a common feature in Ehlers-Danlos syndrome
Camerota, F., Celletti, C., Castori, M., Grammatico, P., & Padua, L. (2011) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2010.09.012 · Cited by 61 · see citing works
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Symptomatic Joint Hypermobility
Tinkle, B. T., & Levy, H. P. (2019) · Medical Clinics of North America · doi:10.1016/j.mcna.2019.08.002 · Cited by 58 · see citing works
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Self-citationPain in hypermobile Ehlers‐Danlos syndrome: New insights using new criteria
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Expanding the clinical and mutational spectrum of the Ehlers–Danlos syndrome, dermatosparaxis type
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Self-citationBi-allelic AEBP1 mutations in two patients with Ehlers–Danlos syndrome
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Self-citationCurrent Methods to Investigate Nociception and Pain in Zebrafish
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The relationship between benign joint hypermobility syndrome and carpal tunnel syndrome
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Entrapment neuropathies and polyneuropathies in joint hypermobility syndrome/Ehlers-Danlos syndrome
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The role of the extracellular matrix in chronic pain following injury
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Evidence of small fiber neuropathy in a patient with Ehlers–Danlos syndrome, hypermobility-type
Pascarella, A., Provitera, V., Lullo, F., Stancanelli, A., Saltalamacchia, A. M., Caporaso, G., & Nolano, M. (2015) · Clinical Neurophysiology · doi:10.1016/j.clinph.2015.12.004 · Cited by 27 · see citing works
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Animal Models of Ehlers–Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential
Vroman, R., Malfait, A., Miller, R. E., Malfait, F., & Syx, D. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.726474 · Cited by 20 · see citing works
Self-citationSyx, D., Miller, R. E., Obeidat, A. M., Tran, P. B., Vroman, R., Malfait, Z., Miller, R. J., Malfait, F., & Malfait, A.-M. (2020) · Pain · doi:10.1097/j.pain.0000000000001935 · Cited by 19 · see citing works
Self-citationBanica, T., Coussens, M., Verroken, C., Calders, P., De Wandele, I., Malfait, F., Zmierczak, H.-G., Goemaere, S., Lapauw, B., & Rombaut, L. (2020) · Osteoporosis International · doi:10.1007/s00198-019-05269-z · Cited by 19 · see citing works
Self-citationMechanical allodynia in mice with tenascin-X deficiency associated with Ehlers-Danlos syndrome
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Self-citationEhlers-Danlos syndromes: Revised nosology, Villefranche, 1997
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Thwaites, P. A., Gibson, P. R., & Burgell, R. E. (2022) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15927 · Cited by 59 · see citing works
International Perspectives on Joint Hypermobility
Nicholson, L. L., Simmonds, J. V., Pacey, V., Wandele, I. D., Rombaut, L., Williams, C., & Chan, C. L. (2022) · JCR Journal of Clinical Rheumatology · doi:10.1097/rhu.0000000000001864 · Cited by 42 · see citing works
Self-citationFarrell, S. F., Kho, P. F., Lundberg, M., Campos, A. I., Rentería, M. E., de Zoete, R. M. J., Sterling, M. M., Ngô, T. T., & Cuéllar-Partida, G. (2022) · Journal of Pain · doi:10.1016/j.jpain.2022.10.005 · Cited by 28 · see citing works
Resource utilization and multidisciplinary care needs for patients with Ehlers–Danlos syndrome
Jones, J. T., Black, W. R., Cogan, W., & Callen, E. F. (2022) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.2057 · Cited by 23 · see citing works
“Chronic musculoskeletal pain is one of the most common complaints in those with EDS (Malfait et al., 2021), which is likely why pain management, PT/ OT, and rheumatology are the top three requested specialties as they all share a common focus on musculoskeletal health.”
BackgroundPlacing joint hypermobility in context: traits, disorders and syndromes
Morlino, S., & Castori, M. (2023) · British Medical Bulletin · doi:10.1093/bmb/ldad013 · Cited by 31 · see citing works
“24 Understanding the existence of specific pathophysiological mechanisms and/or some convergence with other rheumatic diseases is crucial for improving treatment strategies and QoL of people with symptomatic JHM. ‘The Spectrum’ is a theoretical concept incorporating all phenotypes of JHM related to…”
BackgroundInfluentialTenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome
Okuda‐Ashitaka, E., & Matsumoto, K. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1107787 · Cited by 20 · see citing works
“Pain is a common and severe symptom in patients with various types of EDS (Chopra et al., 2017; Syx et al., 2017; Malfait et al., 2021).”
BackgroundWhalen, K. C., & Crone, W. (2022) · Journal of Pain Research · doi:10.2147/jpr.s377790 · Cited by 20 · see citing works
“More research needs to be done to discover the pathophysiology of pain in EDS to better formulate treatments for pain.(8)”
BackgroundAnalysis of matrisome expression patterns in murine and human dorsal root ganglia
Vroman, R., Hunter, R. S., Wood, M. J., Davis, O., Malfait, Z., George, D., Ren, D., Tavares‐Ferreira, D., Price, T. J., Miller, R. J., et al. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1232447 · Cited by 15 · see citing works
Self-citationSanti, M. D., Zhang, M., Asam, K. R., Yu, G., Dong, P. M., Sheehan, D. H., Aouizerat, B. E., Thomas, C. M., Viet, C. T., & Ye, Y. (2024) · Journal of Pain · doi:10.1016/j.jpain.2024.104615 · Cited by 17 · see citing works
Willich, L., Bohner, L., Köppe, J., Jackowski, J., Hanisch, M., & Oelerich, O. (2023) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-023-02877-1 · Cited by 14 · see citing works
“Due to the not uncommon lack of knowledge about the frequent occurrence of TMD in patients with EDS and the associated non-treatment of these, general medical problems, as well as the chronicity of pain, could also occur in the long term to the typical symptoms [6, 11, 34].”
BackgroundHermans, S. M. M., Knoef, R., Schuermans, V. N. E., et al. (2022) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-022-03466-x · Cited by 13 · see citing works
“Patients with EDS often suffer from chronic pain as a major source of disability [20].”
BackgroundThe Ehlers–Danlos Syndromes against the Backdrop of Inborn Errors of Metabolism
Damme, T. V., Colman, M., Syx, D., & Malfait, F. (2022) · Genes · doi:10.3390/genes13020265 · Cited by 13 · see citing works
“pain and fatigue are complications of generalized joint hypermobility and are reported in all types of EDS [16].”
BackgroundSelf-citationTrieste, L., Cannizzo, S., Palla, I., Triulzi, I., & Turchetti, G. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.986218 · Cited by 10 · see citing works
Pain in Ehlers–Danlos Syndrome: A Non-Diagnostic Disabling Symptom?
Guerrieri, V., Polizzi, A., Caliogna, L., Brancato, A. M., Bassotti, A., Torriani, C., Jannelli, E., Mosconi, M., Grassi, F. A., & Pasta, G. (2023) · Healthcare · doi:10.3390/healthcare11070936 · Cited by 8 · see citing works
“Correlation of EDS pain and management [49,50].”
Camerota, F., Mariani, R., Cordiano, G., Trani, M. D., Lodato, V., Ferraris, A., Pasquini, M., & Celletti, C. (2023) · Brain Sciences · doi:10.3390/brainsci13071042 · Cited by 10 · see citing works
Colman, M., Syx, D., Wandele, I. D., Rombaut, L., Wille, D., Malfait, Z., Meeus, M., Malfait, A., Oosterwijck, J. V., & Malfait, F. (2023) · Journal of Pain · doi:10.1016/j.jpain.2023.06.015 · Cited by 8 · see citing works
Self-citationDickinson, M., Erridge, S., Warner-Levy, J. J., Clarke, E., McLachlan, K., Coomber, R., Holden, W., Rucker, J., Platt, M. W., & Sodergren, M. H. (2025) · ACR Open Rheumatology · doi:10.1002/acr2.70024 · Cited by 7 · see citing works
“The t -tests with Bonferroni corrected P values for paired comparisons between baseline and the follow-up intervals are shown in Supplementary Tables 1 – 17.”
InfluentialDiagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines
Xu, K., Li, G., Wu, Z., Zhang, J., Wu, N., & On behalf of the Chinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes (2024) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-024-03121-0 · Cited by 7 · see citing works
Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review
Pliego-Arreaga, R., Cervantes‐Montelongo, J. A., Silva-Martínez, G. A., Tristán-Flores, F. E., Pantoja-Hernández, M. Á., & Maldonado-Coronado, J. R. (2024) · Biomolecules · doi:10.3390/biom14040472 · Cited by 8 · see citing works
“Furthermore, the functions of other ECM constituents, such as tenascin XB (TNXB), vitronectin (VTN), and proteoglycans and glycosaminoglycans (GAGs), are explored within the context of regulating connective tissue equilibrium and understanding pathogenesis [21–36].”
BackgroundDolsø, M., Juul‐Kristensen, B., Skou, S. T., Søgaard, K., Søndergaard, J., Juhl, C. B., & Liaghat, B. (2023) · Musculoskeletal Science and Practice · doi:10.1016/j.msksp.2023.102798 · Cited by 6 · see citing works
“2 symptoms reported by patients with HSD is important, because it can support the development of optimal treatment (Johnson and Robinson, 2010; Malfait et al., 2021).”
BackgroundLindholm, S., Petersson, S., Molander, P., & Björk, M. (2025) · European Journal of Pain · doi:10.1002/ejp.70000 · Cited by 4 · see citing works
“…the sensitivity of the somatosensory system; thus, a wide-spread nociplastic pain develops, aggravated by new peripheral input, and negatively impact activity and function in daily life and cause difficulties performing activities (Chopra et al. 2017; Malfait et al. 2021; Syx et al. 2017).”
Chew, M. T., İlhan, E., Nicholson, L. L., Kobayashi, S., & Chan, C. L. (2024) · Disability and Rehabilitation · doi:10.1080/09638288.2024.2351180 · Cited by 3 · see citing works
“Pain mechanisms in EDS are complex and enigmatic, including a combination of nociceptive, neuropathic and nociplastic pain [4].”
Halverson, C. M. E., & Doyle, T. A. (2023) · Disability and Rehabilitation · doi:10.1080/09638288.2023.2200039 · Cited by 3 · see citing works
“While several previous studies have examined this topic from the perspectives of clinicians [28,29], our data provide distinctive insight by examining it from the perspective of the patients themselves.”
ResultTörnblom, H. (2022) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.17134 · Cited by 1 · see citing works
Hermisson, J., Schreiner, C., Weichselbaumer, S., Werner, M., Hackl, V., Roth, J., Leiss, S., Maukner, A. C., Wojczewski, S., Hainzl, A., et al. (2026) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-026-01155-6 · Cited by 1 · see citing works
“Gelenkschutz und Stabilisierung sind daher als Bestandteil multimodaler und pflege-rischer Maßnahmen zu berücksichtigen [24].”
Beckwith, R., & Stephens-Lewis, D. (2025) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2025.105084 · Cited by 1 · see citing works
Butt, M. F., Dervin, H., Hoshino, S., Yazaki, E., Gerard, P., Sweis, R., Sifrim, D. A., Aziz, Q., Zárate-López, N., & Fikree, A. (2026) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2026.04.019 · Cited by 1 · see citing works
(2023) · doi:10.1101/2023.02.24.23286404 · Cited by 1 · see citing works
“Strikingly, pain is highly prevalent in heritable connective tissue disorders (HCTD) caused by monogenic defects in ECM genes, including the Ehlers-Danlos syndromes (EDS) [45; 68; 86] and osteogenesis imperfecta [4], both collagen-related disorders, and Marfan syndrome [85], caused by defects in fibrillin-1.”
BackgroundSelf-citationEhlers-Danlos syndrome: From bedside to bench
(2024) · Frontiers research topics · doi:10.3389/978-2-8325-4557-7
Gibbons, V. A., Batubo, V. I., & Woodberry, K. M. (2026) · Cureus · doi:10.7759/cureus.113374
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Distinct dermal fibroblasts direct mechano-chemical signaling to the epidermis during pregnancyPreprint
Kobayashi, Y., Sunadome, K., Maki, K., Fukunaga, H., Matsubara, H., Ohkubo, S., Maki, R., Yoshikawa, M., Tata, A., Tata, P. R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.11.675503
“In addition, the deficiency of Tnxb gene is known to induce classical-like EDS (clEDS1) that causes hyperextensible skin ( 21 , 22 ).”
Emerging Clinical Concepts in Pain Management of Ehlers-Danlos Syndrome
Banerjee, R. C., Ramsey, M. E., Buras, B. E., Potharaju, P., Shekoohi, S., Abd-Elsayed, A. A., & Kaye, A. D. (2026) · Current Pain and Headache Reports · doi:10.1007/s11916-026-01532-1 · Cited by 1 · see citing works
“Neuropathic pain Burning pain, paresthesias, allodynia; small fiber involvement Serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, and gabapentinoids guided by phenotype [4, 20, 23].”
InfluentialSebastian, R., Wright, T. B., Lee, S. H., & Gattu, K. (2026) · Cureus · doi:10.7759/cureus.103015 · Cited by 1 · see citing works
Genetic Variants and Clinical Phenotyping in 39 Pediatric Patients with Neuropathic Pain
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Guidance on Home-Based Care for People with Severe ME/CFS: A Transdisciplinary Expert Statement
Hermisson, J., Schreiner, C., Weichselbaumer, S., Werner, M., Hackl, V., Roth, J., Leiss, S., Maukner, A. C., Wojczewski, S., Hainzl, A., et al. (2026) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-026-01182-3
“Therefore, joint protection and stabilization should be considered as part of multimodal and care interventions [23].”
The matrisome of the murine and human dorsal root ganglion: a transcriptomal approachPreprint
Vroman, R., Hunter, R. S., Wood, M. J., Davis, O., Malfait, Z., George, D., Ren, D., Tavares‐Ferreira, D., Price, T. J., Malfait, A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.22.513341
“Clinically, there are also examples of collagen-related diseases with unexplained neurological effects such as pain [9].”
BackgroundSelf-citationBrandt, L., Kondratek, M., Kim, L., Ohanian, H., Schneck, K., Vukasovich, C., Woźny, A., & Ziskey, C. (2026) · International Journal of Rehabilitation Research · doi:10.1097/mrr.0000000000000713
- Authors
- Malfait, F., Colman, M., Vroman, R., De Wandele, I., Rombaut, L., Miller, R. E., Malfait, A., & Syx, D.
- Affiliations
- Ghent University Hospital (BE)
- Center for Medical Genetics Ghent University Hospital Ghent Belgium
- Rush University Medical Center (US)
- Corresponding author
- Malfait, Fransiska
- ORCID
- Venue
- American Journal of Medical Genetics Part C: Seminars in Medical Genetics
- Publisher
- Wiley
- Published
- 2021-11-19
- Volume
- 187
- Issue
- 4
- Pages
- 429-445
- ISSN
- 1552-4868 (ISSN-L)
- 1552-4876
- OpenAlex
- W3211477955
- Cited by
- 41
- References
- 104
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 10
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- American Journal of Medical Genetics Part C Seminars in Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Funders
- Fonds Wetenschappelijk Onderzoek (11B7921N, 12Q5920N, 1842318N, 3G041519)
- Rush University
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR070328, R01AR060364, R01AR064251, R01AR077019‐01A1)
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
- Keywords
- Ehlers-Danlos syndrome, chronic pain, connective tissue diseases, pain mechanisms, analgesic treatment, collagen synthesis, extracellular matrix, joint hypermobility
- MeSH terms
- Connective Tissue Diseases, Ehlers-Danlos Syndrome, Humans, Joint Instability, Pain, Skin Abnormalities
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