, the Ehlers-Danlos syndromes and chronic D. Syx, I. De Wandele, L. Rombaut, F. Malfait

Center for Medical Genetics, ABSTRACT the nature and mediators of chronic Ghent University and Ghent Chronic widespread pain is a common pain are needed in order to potentially University Hospital, Ghent, Belgium. complaint among individuals affected identify novel targets for therapeutic in- Delfien Syx, PhD by generalised hypermobility. In tervention and optimise treatment. Inge De Wandele, PT, PhD the absence of other conditions that Lies Rombaut, PT, PhD cause , these individuals Hypermobility, joint hypermobility Fransiska Malfait, MD, PhD are usually diagnosed with joint hyper- syndrome and Ehlers-Danlos Please address correspondence to: mobility syndrome (JHS). JHS is a mul- syndromes Dr Fransiska Malfait, Center for Medical Genetics, tifactorial trait with a strong genetic Joint hypermobility (JH) implies a Ghent University Hospital, basis, but no specific genetic markers. range of joint movement that exceeds De Pintelaan 185, Clinical overlap of JHS is seen with what is considered to be normal for that 9000 Ghent, Belgium. heritable disorders, joint, taking into account the individu- E-mail: [email protected] particularly with the Ehlers-Danlos al’s age, gender and ethnicity. JH can be Received and accepted on September 8, syndrome, hypermobile type (hEDS). limited to one or a few (localised 2017. The Ehlers-Danlos syndromes (EDS) JH), but when present at multiple sites Clin Exp Rheumatol 2017; 35 (Suppl. 107): comprise a heterogeneous group of rare the term generalised JH (GJH) is pre- S116-S122. monogenic conditions that are charac- ferred (1). The presence of GJH tradi- © Copyright Clinical and terised by joint hypermobility, skin and tionally is defined by a score of at least Experimental 2017. vascular fragility and generalised con- 5 on the nine-point Beighton scale, nective tissue friability, and are caused a standardised test consisting of five Key words: joint hypermobility, by genetic defects in an array of extra- clinical maneuvers (described in Ta- Ehlers-Danlos syndrome (EDS), pain cellular matrix genes. The genetic basis ble I) (2, 3). JH is a multifactorial trait of hEDS remains however unknown, in with a strong genetic basis: in a female contrast to other well-described EDS twin study, the heritability of JH was subtypes. In view of the considerable estimated to be 70% (4). A review arti- clinical overlap with JHS, many con- cle reports prevalence of GJH between sider it and hEDS to be a single clini- 6 and 57% for women and 2–35% for cal entity. Clinical experience and a men of varying ages and ethnicities (5). limited number of clinical studies show Besides gender, age and ethnicity, envi- that chronic pain also is common in ronmental factors that influence JH in- EDS patients, especially in hEDS. The clude weight, training, trauma, surgery specific underlying causes and mecha- and various medical conditions. nisms of pain in JHS and EDS remain JH does not necessarily lead to symp- poorly understood. Factors likely con- toms, and is not a disease, nor a perma- tributing to the generation and chro- nent diagnosis. The first comprehensive nicity of pain include nociceptive pain, description of symptomatic JH in the directly based on structural changes rheumatological literature is attributed in affected joints, muscle and connec- to Kirk, Ansell and Bywaters in 1967. tive tissue; neuropathic pain; impaired They coined the term ‘hypermobility and muscle weakness; syndrome’ (HMS) and defined it as ‘the and central sensitisation. These mecha- occurrence of musculoskeletal symp- nisms are not mutually exclusive, and toms in a hypermobile, but otherwise likely more than one mechanism may be healthy person’ (6). Later, the recogni- present. Furthermore, anxiety, depres- tion of the relatively benign prognosis sion, and other variables may influence of HMS in terms of life-threatening the phenotype. Chronic pain in JHS and Funding: This work was supported by complications led to the use of the term a Methusalem Grant 08/01M01108 from EDS patients often is inadequately con- ‘benign joint hypermobility syndrome’ the Ghent University, and a grant from trolled by traditional and (BJHS) or briefly, ‘joint hypermobility Association Française des Syndromes physical therapy. In view of the high syndrome’ (JHS) (7). A set of clinical d’Ehlers-Danlos (AFSED). prevalence of these underrecognised diagnostic criteria, the ‘Brighton Crite- Competing interests: none declared. conditions, future studies addressing ria’ was established, the major criteria

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Table I. Beighton score used for the evaluation of joint hypermobility. biochemical and/or molecular defects in fibrillar types I, III and V, Negative Unilateral Bilateral or in their modifying enzymes, mak- Passive dorsiflexion of the 5th finger >90° 0 1 2 ing EDS an exemplary heritable colla- Passive flexion of the thumbs to the forearm 0 1 2 gen disorder (11). With the advent of Hyperextension of the elbows >10° 0 1 2 next generation sequencing techniques, Hyperextension of the knees >10° 0 1 2 molecular defects have recently been Forward flexion of the trunk with knees fully 0 Present identified in a variety of extracellular extended and palms resting on the floor 1 matrix (ECM) molecules, gradually expanding the list of distinct EDS sub- Table II. Brighton Criteria for Joint Hypermobility Syndrome (JHS) (8) and Villefranche types, and increasing our understand- Criteria for Hypermobile EDS (hEDS) (11). ing of the underlying pathogenetic ba- Brightoni Criteria (JHS) Villefranche Critera for hEDS sis of EDS. These studies have recently led to a revision of the EDS classifica- Major Criteria Major Criteria tion, which now includes 13 distinct - Beighton score ≥ 4/9 (currently or historically) - Beighton score ≥ 5/9 clinical EDS subtypes, for which mo- - > 3 months in > 4 joints - Skin involvement (hyperextensibility and/or smooth, velvety skin) lecular defects have been identified in Minor Criteria 19 different genes (Table III). Besides - Beighton score of 1-3 Minor Criteria defects in fibrillar (collagen - Arthralgia in 1-3 joints or , , - Recurring joint dislocations or - Chronic joint/limb pain (> 3 months) types I, III and V), their modifying en- - Dislocations/ in more than 1 joint, or - Positive family history zymes (ADAMTS-2, lysylhydroxylase in 1 joint on more than one occasion 1 (LH1)), and molecules involved in - ≥ 3 lesion A major criterion has high diagnostic collagen folding (FKBP22), defects (e.g. epicondylitis, , ) specificity and the presence of one or - Marfanoid habitus more major criteria is either necessary for have now also been identified in other - Skin striae, hyperextensibility, thin skin, papyra- clinical diagnosis or highly indicative. constituents of the ECM (e.g. Tenas- ceous scarring A minor criterion is a sign of lesser diag- cin-X, collagen type XII), enzymes - Eye signs: drooping eyelids or myopia or anti- nostic specificity. The presence of one or involved in glycosaminoglycan bio- mongolid slant more minor criteria contributes to the di- - History of varicose veins, hernias, uterine/rectal agnosis. However, in the absence of major synthesis (galactosyltransferase I and prolapses criteria they are not sufficient to establish II (β4GalT7 and β3GalT6), dermatan the diagnosis 4-O-sulfotransferase-1 (D4ST1), der- For a diagnosis of JHS, the presence of both ma- matan sulfate epimerase (DSE)), (pu- jor criteria, one major and two minor, four minor, or two minor criteria plus one or more first-degree tative) transcription factors (ZNF469, affected relative(s) is needed. The diagnosis of PRDM5), components of the comple- JHS needs clinical and/or molecular exclusion of ment pathway (C1r, C1s) and an intra- overlapping heritable connective tissue disorders. cellular Zinc transporter (ZIP13) (12). Despite advances in our understanding being the presence of GJH and chronic clinical characteristics of EDS include of the genetic basis of EDS, one of the musculoskeletal pain (8). Besides GJH skin hyperextensibility and fragility; initially recognised and most preva- and pain, it was recognised that JHS vascular fragility with easy bruisability lent EDS subtypes, hypermobile EDS patients show mild signs of connec- and a variable bleeding tendency; joint (hEDS), remains molecularly unex- tive tissue fragility and laxity, including hypermobility (usually generalised) plained. hEDS shows considerable clini- skin hyperextensibility, hernia, vari- and manifestations of generalised con- cal overlap with JHS, as reflected in the cose veins, uterine or rectal prolapse nective tissue fragility (10). Depending two sets of diagnostic criteria that have and marfanoid habitus (Table II). As on the EDS subtype and the underly- been used over the past two decades (Ta- such, JHS shows overlap with several ing genetic defect, these manifestations ble II) (8, 11). The similarities between heritable connective tissue disorders and their consequences may vary from these conditions have created the notion (HCTD), such as and almost subclinical to severely debilitat- that JHS and hEDS may constitute a sin- , but most nota- ing and even life-threatening. gle pathological entity (7, 13). Both con- bly with the Ehlers-Danlos syndromes In 1997 six main EDS subtypes were ditions lack specific genetic profiles by (EDS). JHS is sometimes considered defined, including the classical, vas- which the diagnosis can be confirmed, a mild form of HCTD, but no specific cular, hypermobility, , and, as a result, researchers and clini- genetic markers have been identified to arthrochalasia and dermatosparaxis cians have struggled with the terms JHS date (7, 9). subtype, and clinical diagnostic crite- and hEDS over the decades, and they EDS comprises a genetically and phe- ria were established for each of these have often been used interchangeably, notypically heterogeneous group of subtypes (known as the ‘Villefranche both in routine clinical care and in clini- monogenic disorders, mainly affecting Classification for EDS’). Most of these cal research studies (13, 14). the soft connective tissues. The major conditions we.re shown to be caused by The recently published revised EDS

Clinical and Experimental Rheumatology 2017 S-117 Hypermobility, the Ehlers-Danlos syndromes and chronic pain / D. Syx et al.

Table III. The 2017 revised classification of the Ehlers-Danlos syndromes, inheritance by EDS, especially within the hEDS pattern, and genetic basis (12). group, and the primary reason for seek- EDS subtype Abbreviation IP Gene ing medical help. Nevertheless, further large clinical studies on the prevalence, Classical EDS cEDS AD Major: COL5A1, COL5A2 Type V collagen natural history and characteristics of Rare: COL1A1 Type I collagen EDS-related pain are needed. Classical-like EDS clEDS AR TNXB Tenascin-X Most studies on EDS pain have subse- Cardiac-valvular EDS cvEDS AR COL1A2 Type I collagen quently focused on hEDS. Moreover, Vascular EDS vEDS AD Major: COL3A1 Type III collagen as discussed, several of these studies Rare: COL1A1 Type I collagen do not distinguish between hEDS and Hypermobile EDS hEDS AD Unknown Unknown JHS, and consider these a single clini- Arthrochalasia EDS aEDS AD COL1A1, COL1A2 Type I collagen cal entity (13, 14). Dermatosparaxis EDS dEDS AR ADAMTS2 ADAMTS-2 In our clinical experience and those Kyphoscoliotic EDS kEDS AR PLOD1 LH1 FKBP14 FKBP22 of others, pain in JHS and hEDS usu- Brittle Cornea Syndrome BCS AR ZNF469 ZNF469 ally starts early in life, either during PRDM5 PRDM5 childhood or in young adulthood (15, Spondylodysplastic EDS spEDS AR B4GALT7 β4GalT7 23-26). It is often triggered by appar- B3GALT6 β3GalT6 ent external factors such as injury, SLC39A13 ZIP13 surgery, sport activities, psychological Musculocontractural EDS mcEDS AR CHST14 D4ST1 distress or various comorbidities (25). DSE DSE At first, pain is often felt as an acute Myopathic EDS mEDS AD or AR COL12A1 Type XII collagen and localised symptom, in relation to Periodontal EDS pEDS AD C1R C1r C1S C1s joint trauma, such as dislocations and (27, 28) or as “growing ”. IP: inheritance pattern; AD: autosomal dominant; AR: autosomal recessive. Muscle cramps, periarticular inflamma- tion, enthesopathies, such as tendinitis, nosology has addressed this inconsist- It has been estimated that among indi- tenosynovitis and , and nerve ency and has regrouped both condi- viduals with GJH, approximately 3.3% entrapment syndromes can add to the tions within the hypermobile type of of women, and 0.6% of men develop localised musculoskeletal pain (28-30). EDS, with a much better-defined set of chronic complaints (6, 18, 19). These In later stages of life, pain becomes clinical criteria (12). The terms HMS incident rates may well be an under- widespread. and and JHS are abandoned and replaced estimation, in view of the general una- are the most common pain presenta- by the term ‘hypermobility spectrum wareness of clinicians regarding GJH- tions in young adult and adult patients disorders’ (HSD). HSD is intended as related pain (20). Among EDS patients, (22). The pain is most frequently local- an alternative label for patients with chronic widespread pain is quite com- ised in neck, shoulders, forearms, fin- symptomatic JH who do not have any mon. In 1997, Sacheti et al. interviewed gers, hips, knees and feet, likely reflect- rare form of EDS or who do not meet 51 patients with different types of EDS, ing the musculoskeletal pain pattern the new criteria for hEDS (12, 15, 16). and found an incidence of chronic pain (22, 28). At first, pain may be limited This review discusses published stud- of 90%. This was the first published to a few joints and/or muscles and have ies that still used the ‘old’ JHS and report to recognise that moderate to a migratory pattern, but it gradually hEDS terminology and criteria, hence severe pain is common in EDS, starts becomes more persistent and assumes the term JHS, and not HSD, is used early in life and progresses over time a more generalised distribution. Once throughout the manuscript (21). A similar incidence was found in pain becomes widespread, patients of- a more recent study by Voermans et al., ten lose the ability to localise its exact The natural history of pain in in a cohort of 273 EDS patients affected origin and exacerbating and relieving JHS and EDS by various EDS types. In addition, this factors. Common additional complaints Due to the compromised structural in- study showed a higher prevalence of in this stage include burning sensations, tegrity of the connective tissues, pa- pain in hypermobile than in classic EDS peripheral paresthesias, generalised hy- tients suffering from EDS and JHS are (cEDS), a correlation between pain se- peralgesia, allodynia and hypersensi- prone to joint instability, leading to joint verity and hypermobility, dislocations, tivity to various stimuli, such as light, dislocations (full displacements and previous surgery and nocturnal sleep sound and odors (29, 31-33). Besides subluxations), and articular and soft- quality, and that the pain contributes to musculoskeletal pain, patients with tissue injuries. As a result, occasional functional impairment in daily life in JHS and hEDS often report pain in non- acute and recurrent pain is a common many patients (22). These reports echo articular regions such as headaches (21, manifestation of JH, which may evolve clinical experience that chronic, gener- 24, 28, 34, 35), gastro-intestinal (24, to chronic widespread musculoskeletal alised musculoskeletal pain is the most 36), genito-urinary and pelvic pain (37, pain (17). frequent complaint of patients affected 38). Accompanying the chronic, wide-

S-118 Clinical and Experimental Rheumatology 2017 Hypermobility, the Ehlers-Danlos syndromes and chronic pain / D. Syx et al. spread pain is often severe , seen quently causing overload in other areas with JH may have an increased risk for in up to 84% of patients with JHS/hEDS of the movement apparatus (25, 54). injury. Muscle weakness, likely related (39). This fatigue can be sufficiently Other contributors to nociceptive pain to muscle hypotonia, has also been ob- substantial to meet criteria for chronic may include multiple surgical proce- served and may be partly due to the fatigue syndrome (40). The underly- dures (22), reduced bone mass (55-57) increased laxity of the , which ing cause is unclear and likely multi- and premature (58); the cannot normally transmit the power factorial, but muscle weakness (41, 42), impact of the latter two on the pheno- produced by muscle. In addition, the sleep disturbance due to nocturnal pain type of JHS/hEDS however remains a fear of provoking pain and injury may (22), concentration problems (39) and matter of debate. lead to decreased levels of activity, ulti- cardiovascular dysautonomia (43-46) Besides nociceptive pain, several stud- mately resulting in deconditioning and may be contributing factors. ies support a neuropathic component exercise intolerance (42). The chronic, widespread pain in JHS/ for EDS-related pain. A questionnaire Psychological influences are important hEDS is associated with high use of an- study by Camerota et al., suggested in an individual’s experience of a pain- algesics, surgery and physical therapy that about 60% of hEDS and cEDS ful stimulus, modifying the risk, per- (22, 47). Nonetheless, it is generally participants had ‘at least probable’ ception, and response to acute pain and refractory to these interventions; con- neuropathic pain (31). Voermans et al. the risk to develop chronic pain. Pain is sequently it often has a detrimental ef- provided evidence for compression and intimately related to fear and anxiety. fect on physical, social and emotional axonal neuropathies in various EDS In the literature on chronic pain, the function in affected individuals, with a types (59). Recently, an increased rate fear-avoidance model may explain in substantial deterioration of their quality of upper limb nerve (sub)luxations was part the disabling role of pain-related of life (23). Psychological dysfunction demonstrated in JHS/hEDS, which may fear in many patients. It states that a and emotional problems are common, contribute to some peripheral neuro- highly fearful person learns to avoid including depression and anxiety (28, pathic features of pain, such as pares- activities that he or she perceives as 48-52). thesias (29). Henderson et al. reported harmful or pain-provoking (72). Evi- that laxity of the cervical spine can lead dence for pain-related fear in hyper- The pathogenesis of pain to direct compression of the spinal cord mobile subjects was provided by Rom- in hypermobility and EDS (60). Recently, a decreased intraepider- baut et al., who reported fear of falling The specific underlying causes and mal nerve fibre density was demonstrat- among women with JHS/hEDS (73), mechanisms of pain in JHS and EDS ed in skin biopsies derived from EDS/ and Celletti et al. who reported that patients remain poorly understood. No JHS patients, providing evidence for kinesiophobia is a common symptom pathophysiological model has been the existence of small fibre neuropathy in JHS/hEDS (74, 75). Over the long identified yet, although evidence has (61, 62). term, avoidance behavior that results been presented for several types of In addition to these nociceptive and from fear of pain leads to disuse and mechanisms, including nociceptive and neuropathic components, an impor- muscle deconditioning, which gener- neuropathic components, as well as tant role for central sensitisation in ates further loss of muscle strength pain sensitisation, as seen in musculo- the chronification of generalised pain and flexibility. This often aggravates skeletal pain of many aetiologies. Fur- has been found in many individuals functional disability and leads to de- thermore, more than one aetiology may with JHS and hEDS. The earliest re- pression, which in turn reduces pain often be involved, as is seen in many ports concerning central sensitisation tolerance and promotes further pain pathological entities. emerged from studies indicating evi- (76). Besides avoidance strategies, Nociceptive pain directly related to af- dence for generalised hyperalgesia in other emotional and cognitive mecha- fected and tendons, joints, patients with these conditions (32, 33, nisms likely contribute to chronic pain muscles and connective tissue, is fre- 63). Unpublished data from our re- in EDS and JHS (25). quently encountered, and often presents search group in a cohort of hEDS/JHS The extremely high prevalence of at early stages of acute and localised patients provide further evidence for chronic musculoskeletal pain in patients pain. Joint instability due to congenital central sensitisation, by showing in- with EDS and with other HCTD leads capsuloligamentous laxity predisposes creased wind-up to repeated stimuli and one to hypothesise that abnormalities patients to dislocations and to repetitive decreased exercise-induced analgesia in the ECM can contribute to the gen- soft-tissue traumas, such as ligamentous (64). eration and chronification of pain (77). and tendinous overstretching and tears Two important modifiers have been The ECM is composed of structural and (21, 22, 53). In addition, microtraumata proposed to play a role in the genera- non-structural , such as fibril- may cause subclinical damage that is tion of chronic pain: lack of proprio- lar proteins (collagens), glycoproteins often not supported by a recognised ceptive acuity and muscle weakness. (fibronectin, tenascins) and several history of joint trauma. The occurrence Several studies have demonstrated im- classes of proteoglycans (heparan sul- of microtraumata on joint surfaces may paired proprioception in JHS and EDS fate, chondroitin/dermatan sulfate and lead to adaptation and compensation subjects (65-71). As proprioception is keratan sulfate proteoglycans) embed- of movement and gait patterns, conse- essential for joint stabilisation, patients ded in a hydrogel matrix. A clear role

Clinical and Experimental Rheumatology 2017 S-119 Hypermobility, the Ehlers-Danlos syndromes and chronic pain / D. Syx et al. has been demonstrated for the ECM in tors released from the aberrant ECM. Conclusion general nociception; for instance, func- It has been reported that a variety of Chronic widespread pain is an impor- tional deficits have been observed in sequestered ECM components can act tant and underrecognised complaint peripheral nerves of collagen type VI as damage-associated molecular pat- in individuals displaying generalised deficient mice, which were paralleled terns (DAMPs) (84), which function joint hypermobility. The majority of by impaired nociception because of as endogenous danger signals and are these individuals are diagnosed with disorganised C-fibre nociceptors (78). recognised by pattern recognition re- JHS, a multifactorial condition with a Moreover, painful injuries have been ceptors (PRRs) of the immune system. strong genetic basis. Although the spe- shown to induce unique ECM altera- Recently it has been demonstrated that cific genetic basis of JHS has not been tions at acute and chronic time points sensory neurons can express the same elucidated, JHS shows signs of gener- after the injury, such as elevation of PRRs (e.g. toll-like receptors (TLRs), alised connective tissue fragility, and matrix metalloproteinase (MMP) levels which can induce painful pathways as such overlaps with the HCTD, es- resulting in microglial activation (79), upon activation (85-87). As such, it pecially the Ehlers-Danlos Syndromes. and alterations in integrin signaling could be hypothesised that the abnor- These monogenic disorders result from (80). Furthermore, the ECM has been mal ECM associated with EDS is a molecular defects in constituents of the demonstrated to be a key player in cen- potential source of DAMPs, which can ECM, and chronic widespread pain is a tral nervous system (CNS) neuroplasti- chronically stimulate peripheral nocic- major complaint in many EDS patients city and connectivity (77). eptors, thereby leading to sensitisation as well. The specific underlying causes Patients with EDS harbour defects in and driving pain. and mechanisms of pain in these pa- different components of the ECM, in- Overall, it is clear that several types of tients are not well understood. Nocice- cluding collagens, glycoproteins and pain etiology coexist in JHS/EDS pa- ptive pain, neuropathic pain and central proteoglycans (Table III) (12). The tients, based on the contribution of no- sensitisation all contribute to the evolv- resulting abnormalities in connective ciceptive, neuropathic, and sensitisa- ing pain phenotype. Like for other tissue integrity and functioning could tion mechanisms and that multiple bio- chronic pain conditions, genetic factors have a devastating impact on the nerv- logical and psychological factors con- (e.g., in genes encoding connective tis- ous system. These proteins, such as tribute to the evolving pain phenotype. sue proteins and/or genes involved in collagen types I, III, V, tenascins and In addition, there are many genetic and pain neurotransmission), environmen- proteoglycans as well as their recep- environmental factors that contribute tal factors, but also psychological and tors, are distributed throughout the con- to pain development. Genetic determi- emotional factors have been proposed nective tissue of the central and periph- nants of variability in pain sensitivity to influence the pain phenotype. eral nervous system and play important for instance, that are independent of the Management of the often severe, structural and functional roles (81). degree of joint hypermobility, could changing and highly debilitating pain Connective tissue allows the body to influence the pain phenotype. Studies in hypermobile patients is currently sense tensile and compressive forces investigating pain thresholds in healthy insufficient. Traditional pain medica- and pressure (e.g., proprioception, pain individuals highlight a prominent role tions do not adequately treat most pa- perception), enabling the individual to for common genetic variations in pro- tients, probably because the underlying react appropriately with a protective teins involved in various aspects of mechanisms are different and/or more response. Hence, the defective ECM in pain neurotransmission (88, 89). complex than for most other pain con- EDS might compromise the formation Given the complex nature of pain in ditions. of the (peripheral) nervous system and JHS and EDS patients, our fragmented As EDS arises from genetic defects contribute to the increased vulnerabil- understanding of the mechanisms un- in diverse components of the ECM, it ity of peripheral nerves to or derlying pain, and the absence of re- provides a unique model to study the pressure (59). ports on effectiveness of treatment mo- pathophysiological connection be- Many cases of chronic widespread dalities in large cohorts, management tween the ECM and pain. This could pain evolve from local nociceptive of acute and chronic pain in these pa- help to identify mediators and path- and neuropathic musculoskeletal prob- tients is challenging and currently in- ways that initiate and/or maintain pain lems, characterised by a period of mas- sufficient (26). It requires a patient-tai- in EDS patients, and the mechanisms sive peripheral input in the (sub)acute lored and multidisciplinary approach, by which these affect molecular and/or to chronic stage (82). In response, the combining pharmacological interven- cellular changes in the nervous system. central nervous system modulates the tion with physical and psychological Collectively, this knowledge might ex- sensitivity of the somatosensory sys- therapy, in order to treat the causes of pose possible targets. In the tem. Once central sensitisation is es- pain and minimize the pain sensation, long run, these insights might not only tablished, it is sustained or aggravated with a common goal to improve quality be beneficial for EDS patients, but will by new peripheral input (83). In EDS, of life and daily functioning. Manage- also shed more light on more common central sensitisation may arise as a con- ment of JHS and EDS-related pain has chronic musculoskeletal pain condi- sequence of the continuous stimulation excellently been reviewed in several tions, including JHS, but also fibromy- of peripheral nociceptors by media- recent papers (25, 26, 90, 91). algia and osteoarthritis.

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