Ehlers-Danlos syndromes and chronic pain 2017

Hypermobility, the Ehlers-Danlos syndromes and chronic pain  – D. Syx, I. De Wandele, L. Rombaut, F. Malfait – Clin Exp Rheumatol – Sept 2017

This research article explains why EDS leads to chronic pain and urges doctors to treat whatever pain symptoms arise because there is no possible cure or even slowing down of the degenerative process.

Chronic widespread pain is a common complaint among individuals affected by generalised joint hypermobility. In the absence of other conditions that cause chronic pain, these individuals are usually diagnosed with joint hypermobility syndrome (JHS).

JHS is a multifactorial trait with a strong genetic basis, but no specific genetic markers. Clinical overlap of JHS is seen with heritable connective tissue disorders, particularly with the Ehlers-Danlos syndrome, hypermobile type (hEDS).  

The Ehlers-Danlos syndromes (EDS) comprise a heterogeneous group of rare monogenic conditions that are characterised by joint hypermobility, skin and vascular fragility and generalised connective tissue friability, and are caused by genetic defects in an array of extracellular matrix genes.

The genetic basis of hEDS remains however unknown, in contrast to other well-described EDS subtypes. In view of the considerable clinical overlap with JHS, many consider it and hEDS to be a single clinical entity.

Clinical experience and a limited number of clinical studies show that chronic pain also is common in EDS patients, especially in hEDS. The specific underlying causes and mechanisms of pain in JHS and EDS remain poorly understood.

That seems strange because it’s completely obvious to me how defective and loose connective tissue could cause a great deal of pain when body parts aren’t held together properly.

Factors likely contributing to the generation and chronicity of pain include

  • nociceptive pain, directly based on structural changes in affected joints, muscle and connective tissue;
  • neuropathic pain;
  • impaired proprioception and muscle weakness; and
  • central sensitisation.

These mechanisms are not mutually exclusive, and likely more than one mechanism may be present.

Furthermore, anxiety, depression, and other variables may influence the phenotype.

Chronic pain in JHS and EDS patients often is inadequately controlled by traditional analgesics and physical therapy.

In view of the high prevalence of these underrecognised conditions, future studies addressing the nature and mediators of chronic pain are needed in order to potentially identify novel targets for therapeutic intervention and optimise treatment.

Most of these conditions were shown to be caused by biochemical and/or molecular defects in fibrillar collagen types I, III and V, or in their modifying enzymes, making EDS an exemplary heritable collagen disorder (11).

This means that EDS affects us down to the individual cell level. It’s inconceivable to me that some doctors don’t feel the pain from EDS should be treated with the most effective pain reliever: opioids.

With the advent of next generation sequencing techniques, molecular defects have recently been identified in a variety of extracellular matrix (ECM) molecules, gradually expanding the list of distinct EDS subtypes, and increasing our understanding of the underlying pathogenetic basis of EDS.

This means the damage even goes beyond cells and into the fluid around them.

These studies have recently led to a revision of the EDS classification, which now includes 13 distinct clinical EDS subtypes, for which molecular defects have been identified in 19 different genes (Table III).

Besides

  • defects in fibrillar collagens (collagen types I, III and V),
  • their modifying enzymes (ADAMTS-2, lysylhydroxylase 1 (LH1)), and
  • molecules involved in collagen folding (FKBP22),

defects have now also been identified in

  • other constituents of the ECM (e.g. Tenascin-X, collagen type XII),
  • enzymes involved in glycosaminoglycan biosynthesis (galactosyltransferase I and II (β4GalT7 and β3GalT6), dermatan 4-O-sulfotransferase-1 (D4ST1),
  • dermatan sulfate epimerase (DSE)),
  • (putative) transcription factors (ZNF469, PRDM5),
  • components of the complement pathway (C1r, C1s) and
  • an intracellular Zinc transporter (ZIP13) (12).

EDS comprises a genetically and phenotypically heterogeneous group of monogenic disorders, mainly affecting the soft connective tissues.

The major clinical characteristics of EDS include

  • skin hyperextensibility and fragility;
  • vascular fragility with easy bruisability and
  • a variable bleeding tendency;
  • joint hypermobility (usually generalised) and manifestations of generalised connective tissue fragility (10).

Depending on the EDS subtype and the underlying genetic defect, these manifestations and their consequences may vary from almost subclinical to severely debilitating and even life-threatening.

These reports echo clinical experience that chronic, generalised musculoskeletal pain is the most frequent complaint of patients affected by EDS, especially within the hEDS group, and the primary reason for seeking medical help. Nevertheless, further large clinical studies on the prevalence, natural history and characteristics of EDS-related pain are needed.

In our clinical experience and those of others, pain in JHS and hEDS usually starts early in life, either during childhood or in young adulthood (15, 23-26).

At first, pain is often felt as an acute and localised symptom, in relation to joint trauma, such as dislocations and sprains (27, 28) or as “growing pains”.

  • Muscle cramps, 
  • periarticular inflammation,
  • enthesopathies, such as tendinitis, tenosynovitis and fasciitis, and
  • nerve entrapment syndromes

an add to the localised musculoskeletal pain (28-30).

In later stages of life, pain becomes widespread. Arthralgias and myalgias are the most common pain presentations in young adult and adult patients (22).

The pain is most frequently localised in neck, shoulders, forearms, fingers, hips, knees and feet, likely reflecting the musculoskeletal pain pattern (22, 28). At first, pain may be limited to a few joints and/or muscles and have a migratory pattern, but it gradually becomes more persistent and assumes a more generalised distribution.

Among EDS patients, chronic widespread pain is quite common.

In 1997, Sacheti et al. interviewed 51 patients with different types of EDS, and found an incidence of chronic pain of 90%.

This was the first published report to recognise that moderate to severe pain is common in EDS, starts early in life and progresses over time (21).

A similar incidence was found in a more recent study by V oermans et al., in a cohort of 273 EDS patients affected by various EDS types. In addition, this study showed a higher prevalence of pain in hypermobile than in classic EDS (cEDS), a correlation between pain severity and hypermobility, dislocations, previous surgery and nocturnal sleep quality, and that the pain contributes to functional impairment in daily life in many patients (22).

Once pain becomes widespread, patients often lose the ability to localise its exact origin and exacerbating and relieving factors.

Common additional complaints in this stage include burning sensations, peripheral paresthesias, generalised hyperalgesia, allodynia and hypersensitivity to various stimuli, such as light, sound and odors (29, 31-33).

Besides musculoskeletal pain, patients with JHS and hEDS often report pain in nonarticular regions such as

  • headaches (21, 24, 28, 34, 35),
  • gastro-intestinal (24, 36),
  • genito-urinary and pelvic pain (37, 38).

The natural history of pain in JHS and EDS

Due to the compromised structural integrity of the connective tissues, patients suffering from EDS and JHS are prone to joint instability, leading to joint dislocations (full displacements and subluxations), and articular and softtissue injuries. As a result, occasional acute and recurrent pain is a common manifestation of JH, which may evolve to chronic widespread musculoskeletal pain (17).

Accompanying the chronic, wide-spread pain is often severe fatigue, seen in up to 84% of patients with JHS/hEDS (39). This fatigue can be sufficiently substantial to meet criteria for chronic fatigue syndrome (40).

Two important modifiers have been proposed to play a role in the generation of chronic pain: lack of proprioceptive acuity and muscle weakness.

Several studies have demonstrated impaired proprioception in JHS and EDS subjects (65-71). As proprioception is essential for joint stabilisation, patients with JH may have an increased risk for injury.

Muscle weakness, likely related to muscle hypotonia, has also been observed and may be partly due to the increased laxity of the tendons, which cannot normally transmit the power produced by muscle.

Besides nociceptive pain, several studies support a neuropathic component for EDS-related pain. A questionnaire study by Camerota et al., suggested that about 60% of hEDS and cEDS participants had ‘at least probable’ neuropathic pain (31). Voermans et al. provided evidence for compression and axonal neuropathies in various EDS types (59).

Recently, an increased rate of upper limb nerve (sub)luxations was demonstrated in JHS/hEDS, which may contribute to some peripheral neuropathic features of pain, such as paresthesias (29). Henderson et al. reported that laxity of the cervical spine can lead to direct compression of the spinal cord (60). Recently, a decreased intraepidermal nerve fibre density was demonstrated in skin biopsies derived from EDS/ JHS patients, providing evidence for the existence of small fibre neuropathy (61, 62).

Psychological influences are important in an individual’s experience of a painful stimulus, modifying the risk, perception, and response to acute pain and the risk to develop chronic pain. Pain is intimately related to fear and anxiety.

The chronic, widespread pain in JHS/ hEDS is associated with high use of analgesics, surgery and physical therapy (22, 47). Nonetheless, it is generally refractory to these interventions; consequently it often has a detrimental effect on physical, social and emotional function in affected individuals, with a substantial deterioration of their quality of life (23). Psychological dysfunction and emotional problems are common, including depression and anxiety (28, 48-52).

Evidence for pain-related fear in hypermobile subjects was provided by Rombaut et al., who reported fear of falling among women with JHS/hEDS (73), and Celletti et al. who reported that kinesiophobia is a common symptom in JHS/hEDS (74, 75).

The pathogenesis of pain in hypermobility and EDS

The specific underlying causes and mechanisms of pain in JHS and EDS patients remain poorly understood. No pathophysiological model has been identified yet, although evidence has been presented for several types of mechanisms, including nociceptive and neuropathic components, as well as pain sensitisation, as seen in musculoskeletal pain of many aetiologies. Furthermore, more than one aetiology may often be involved, as is seen in many pathological entities.

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. This often aggravates functional disability and leads to depression, which in turn reduces pain tolerance and promotes further pain

This is why it’s so important to treat pain and reduce it enough to stay active and able to do physical therapy.

In addition to these nociceptive and neuropathic components, an important role for central sensitisation in the chronification of generalised pain has been found in many individuals with JHS and hEDS. The earliest reports concerning central sensitisation emerged from studies indicating evidence for generalised hyperalgesia in patients with these conditions (32, 33, 63). [see Hyperalgesia in With Hypermobility and EDS]

Unpublished data from our research group in a cohort of hEDS/JHS patients provide further evidence for central sensitisation, by showing increased wind-up to repeated stimuli and decreased exercise-induced analgesia (64).

Nociceptive pain directly related to affected ligaments and tendons, joints, muscles and connective tissue, is frequently encountered, and often presents at early stages of acute and localised pain. Joint instability due to congenital capsuloligamentous laxity predisposes patients to dislocations and to repetitive soft-tissue traumas, such as ligamentous and tendinous overstretching and tears (21, 22, 53).

In addition, microtraumata may cause subclinical damage that is often not supported by a recognised history of joint trauma.

The extremely high prevalence of chronic musculoskeletal pain in patients with EDS and with other HCTD leads one to hypothesise that abnormalities in the ECM can contribute to the generation and chronification of pain (77).

The ECM is composed of structural and non-structural proteins, such as fibrillar proteins (collagens), glycoproteins (fibronectin, tenascins) and several classes of proteoglycans (heparan sulfate, chondroitin/dermatan sulfate and keratan sulfate proteoglycans) embedded in a hydrogel matrix

Conclusion

Many cases of chronic widespread pain evolve from local nociceptive and neuropathic musculoskeletal problems, characterised by a period of massive peripheral input in the (sub)acute to chronic stage (82).

In response, the central nervous system modulates the sensitivity of the somatosensory system. Once central sensitisation is established, it is sustained or aggravated by new peripheral input (83). In EDS, central sensitisation may arise as a consequence of the continuous stimulation of peripheral nociceptors by mediators released from the aberrant ECM.

It has been reported that a variety of sequestered ECM components can act as damage-associated molecular patterns (DAMPs) (84), which function as endogenous danger signals and are recognised by pattern recognition receptors (PRRs) of the immune system.

for instance, functional deficits have been observed in peripheral nerves of collagen type VI deficient mice, which were paralleled by impaired nociception because of disorganised C-fibre nociceptors (78).

Chronic widespread pain is an important and underrecognised complaint in individuals displaying generalised joint hypermobility.

Of course, this particular symptom will be underrecognized because doctors, in general, do not give full credence to a patient’s complaints of pain.

The majority of these individuals are diagnosed with JHS, a multifactorial condition with a strong genetic basis. Although the specific genetic basis of JHS has not been elucidated, JHS shows signs of generalised connective tissue fragility, and as such overlaps with the HCTD, especially the Ehlers-Danlos Syndromes.

Moreover, painful injuries have been shown to induce unique ECM alterations at acute and chronic time points after the injury, such as elevation of matrix metalloproteinase (MMP) levels resulting in microglial activation (79), and alterations in integrin signaling (80). Furthermore, the ECM has been demonstrated to be a key player in central nervous system (CNS) neuroplasticity and connectivity (77).

Recently it has been demonstrated that sensory neurons can express the same PRRs (e.g. toll-like receptors (TLRs), which can induce painful pathways upon activation (85-87). As such, it could be hypothesised that the abnormal ECM associated with EDS is a potential source of DAMPs, which can chronically stimulate peripheral nociceptors, thereby leading to sensitisation and driving pain.

These monogenic disorders result from molecular defects in constituents of the ECM, and chronic widespread pain is a major complaint in many EDS patients as well.

The specific underlying causes and mechanisms of pain in these patients are not well understood. Nociceptive pain, neuropathic pain and central sensitisation all contribute to the evolving pain phenotype.

Patients with EDS harbour defects in different components of the ECM, including collagens, glycoproteins and proteoglycans (Table III) (12). The resulting abnormalities in connective tissue integrity and functioning could have a devastating impact on the nervous system.

Overall, it is clear that several types of pain etiology coexist in JHS/EDS patients, based on the contribution of nociceptive, neuropathic, and sensitisation mechanisms and that multiple biological and psychological factors contribute to the evolving pain phenotype.

Like for other chronic pain conditions, genetic factors (e.g., in genes encoding connective tissue proteins and/or genes involved in pain neurotransmission), environmental factors, but also psychological and emotional factors have been proposed to influence the pain phenotype.

These proteins, such as collagen types I, III, V, tenascins and proteoglycans as well as their receptors, are distributed throughout the connective tissue of the central and peripheral nervous system and play important structural and functional roles (81).

Management of the often severe, changing and highly debilitating pain in hypermobile patients is currently insufficient.

Perhaps this is because doctors are no longer prescribing opioids for pain. Especially with EDS, when pain is both nociceptive and systemic, opioids may be the only drug strong enough to allow patients a decent quality of life.

Traditional pain medications do not adequately treat most patients, probably because the underlying mechanisms are different and/or more complex than for most other pain conditions.

Studies investigating pain thresholds in healthy individuals highlight a prominent role for common genetic variations in proteins involved in various aspects of pain neurotransmission (88, 89).

Connective tissue allows the body to sense tensile and compressive forces and pressure (e.g., proprioception, pain perception), enabling the individual to react appropriately with a protective response. Hence, the defective ECM in EDS might compromise the formation of the (peripheral) nervous system and contribute to the increased vulnerability of peripheral nerves to stretching or pressure (59).

Given the complex nature of pain in JHS and EDS patients, our fragmented understanding of the mechanisms underlying pain, and the absence of reports on effectiveness of treatment modalities in large cohorts, management of acute and chronic pain in these patients is challenging and currently insufficient (26).

As EDS arises from genetic defects in diverse components of the ECM, it provides a unique model to study the pathophysiological connection between the ECM and pain.

This could help to identify mediators and pathways that initiate and/or maintain pain in EDS patients, and the mechanisms by which these affect molecular and/or cellular changes in the nervous system.

It requires a patient-tailored and multidisciplinary approach, combining pharmacological intervention with physical and psychological therapy, in order to treat the causes of pain and minimize the pain sensation, with a common goal to improve quality of life and daily functioning.

Collectively, this knowledge might expose possible analgesic targets. In the long run, these insights might not only be beneficial for EDS patients, but will also shed more light on more common chronic musculoskeletal pain conditions, including JHS, but also fibromyalgia and osteoarthritis.

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