Research funded in 2020 by The Ehlers-Danlos Society

In 2020, The Ehlers-Danlos Society funded the following studies:

To view further research funded by The Ehlers-Danlos Society, please click here.

The Ehlers-Danlos Society aspires to offer grants annually, with calls for clinical research proposals early in the year and for basic science later in the year. We will also offer grants of varying value to reflect the different nature of researcher requirements, including microgrants.

As a researcher, please look out for announcements of grant-funding rounds on our website, here.

Fall Microgrants

It is well known that chronic pain, physical disability, psychological distress, and female gender are risk factors for suicidal behaviors. These characteristics are overrepresented in people with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders (hEDS/HSD).

Although research about suicidal behaviors in this population is very scarce, available data highlight an increased rate of suicide attempts among people with hEDS/HSD. Thus, the exploration of suicidality in those affected should not be overlooked. Unfortunately, no study has focused so far on understanding more in-depth suicidality among individuals with hEDS/HSD.

Previously, we assessed suicidality in a group of patients with hEDS/HSD and characterized from a psychosocial point of view those presenting antecedents of suicidal attempts. This, with a quantitative approach. Following on from this study, we now want to explore qualitatively, how these patients understand and explain the causes of their suicidal behaviors and ideas, as well as their success or failure in overcoming the suicidal period.

For that, a semi-structured interview will be proposed to patients with antecedents of suicide attempts and suicidal ideation in order to gain a more in-depth understanding of the participants’ experiences related to what led up to their attempts/ideas. The results of this qualitative research will fill a gap in the literature and will provide important insights to clinicians for caring for vulnerable patients and preventing the relapse of suicidal behaviors.

Research Fund: $5,000
Primary Investigator:
Dr. Carolina Baeza-Velasco
Laboratoire de Psychopathologie et Processus de Santé (EA4057)
Université de Paris

One of the major concerns for patients with Ehlers-Danlos Syndrome (EDS) and related heritable collagen disorders is the lack of physician education and understanding surrounding these conditions. As such, patients often feel that their needs aren’t being met by the doctors they have entrusted with their care.

Physicians treating patients with EDS feel similar frustration, especially when trying to diagnose an adult. It is not known if this frustration for physicians stems from a lack of knowledge surrounding heritable collagen disorders or the paucity of treatment available to these patients. Physicians will be given surveys to determine their base knowledge surrounding EDS/ heritable collagen disorders as well as their Patient-Practitioner Orientation Scale (PPOS) score, which is a measurement of physician compassion. By assessing physician perceptions related to EDS, we hope to determine where physician education may be lacking.

One-on-one interviews will be also conducted with physicians to determine how to best consolidate opinions and information into a CME-accredited presentation, which will then be distributed to all physicians within the hospital network through the hospital-based e-learning platform.

Research Fund: $5,000
Primary Investigator:
Dr. Sara Strecker
Hartford Hospital

Ehlers-Danlos Syndrome (EDS) represents a family of heritable connective tissue disorders with overlapping phenotypic features that can be difficult to manage and treat. Current gaps in knowledge exist about primary care providers’ knowledge about care and management along with barriers to care and management of patients with EDS. Due to this lack of knowledge targeted educational information is limited.

The long-term goal of this research is to gain an understanding of current knowledge and barriers to improving knowledge so that targeted educational strategies can be implemented to improve awareness and comfort with the care and management of patients with EDS. The objectives of this application are to 1) characterize primary care provider understanding of care and management of patients with EDS, 2) identify barriers to improved awareness and ability to competently manage patients with EDS and 3) develop educational materials and program to improve understanding and knowledge of EDS.

We suspect that most primary care providers are not comfortable with the management of patients with EDS due to a lack of understanding, which could be improved with an increase in education. This study will assess primary care providers’ current knowledge and understanding of EDS, management experience of patients with EDS, clinical knowledge of EDS, and comfort in providing primary care services to patients with EDS.

It will also identify barriers noted by providers that prevent awareness and ability to manage patients’ EDS. With this information, we will develop a novel educational program that improves knowledge and understanding of EDS that will address barriers, and allow providers to better care for patients with EDS. We expect to provide strong evidence to improve knowledge and understanding about EDS and to empower primary care providers to manage and care for patients with EDS. We will need to understand the current knowledge and barriers that prevent better care of patients with EDS.

Our research findings will be innovative as they will raise awareness of the need for better knowledge and understanding of EDS through recognized barriers and deficits in knowledge and understanding. This study will recruit 200 participants to complete an electronic survey dispensed via email sent to local and regional primary care providers. Participants will be asked questions that evaluate primary care providers’ current knowledge and understanding of EDS, their comfort with providing care to those patients, and barriers to their understanding and management of patients with EDS.

Completion of this proposed study will provide essential information to better understand the needs of primary care providers for the management of patients with EDS. Our future direction will include the development of an educational program for providers to improve their understanding and confidence in working with patients with EDS. The education program would be piloted with several groups of physicians to evaluate strengths and weaknesses. The goal would be to develop a seminar or webinar that would be available to medical providers. If successful in our region, it could be rolled out nationally.

Research Fund: $5,000
Primary Investigator:
Dr. Jordan Jones
Children’s Mercy Kansas City

Cannabis is sometimes used therapeutically in those with chronic pain. Ehlers-Danlos syndrome (EDS) is a group of genetic disorders where chronic pain is a common feature, but the effects of cannabis on cognitive-motor skills in EDS have never been studied and the rate of use in this population is largely unknown.

In this study, we seek to understand the immediate effects of cannabis on cognitive motor skills in those with EDS, in addition to exploring whether cannabis helps to control pain in this population. A small portion (11%) of EDS patients in a recent study from France, where both recreational and therapeutic use of cannabis is still illegal, reported using cannabis products to alleviate their chronic pain (Bénistan & Martinez, 2018).

Recent changes in the legalization of cannabis in North America have led to increased use of cannabis for both recreational and therapeutic purposes (Spindle et al., 2019). Indeed, in 2019, 18% of Canadians older than 15 reported using cannabis products within the last three months, which is notably higher than the 14% who reported the same just a year earlier, prior to its full legalization (Statistics Canada, 2019).

Across a few of our previous studies, on proprioception in EDS, we noticed that a high number of patients mentioned using cannabis products therapeutically to lessen the widespread pain they experience daily. However, there have been no studies conducted to date which have reported the prevalence of cannabis use in North Americans with EDS.

While cannabis use is often found to cause various cognitive-motor deficits, the degree of impairment is sometimes less evident among frequent users (Prashad & Filbey, 2013). Furthermore, other chronic pain populations have been found to show improvements in executive functioning following daily administration of medicinal cannabis, which was attributed to a reduction in their pain symptoms and led to an increased quality of life (Gruber et al., 2016). However, no studies have been conducted to date which have empirically evaluated the effect of cannabis use on cognitive-motor skills in EDS patients; thus, this study will be the first to compare these immediate effects in EDS to a large dataset of healthy legal users.

Research Fund: $5,000
Primary Investigator:
Ms. Holly Clayton
York University

Ehlers-Danlos syndromes (EDS) are a community of hereditary soft connective tissue disorders that include signs and symptoms of joint hypermobility, skin hyperextensibility, and other skin texture differences, and fragility of internal organs, vessels, and soft tissues.[1; 2]

Hypermobility spectrum disorders (HSD) are a group of conditions with symptomatic joint hypermobility that do not fulfill the diagnostic criteria for hypermobility type EDS.[3] The separation between HSD and hEDS is unclear; therefore, many use a single label of EDS/HSD. 90% of individuals with EDS/HSD have chronic pain.

[4] 77% of females with EDS have painful sexual intercourse (dyspareunia),[5-7] compared to 20% of females in the global population.[8; 9] Vulvodynia is chronic vulvar pain with dyspareunia.[10] Vulvodynia pain can be triggered by wearing clothing that contacts the vulva (external genitals) or by having vaginal sexual intercourse.[11] Pain from vulvodynia can be so severe that it can render sexual intercourse impossible and may drive women to have suicidal thoughts.

[12-14] EDS/HSD and vulvodynia share several comorbid conditions that have been identified separately but the association between the two has never been reported.[15] Our preliminary research of 1146 females with EDS/HSD, found 50% of the participants had vulvodynia symptoms, over 6 times that of females in the general U.S. population (8%).[15] There is little research characterizing EDS/HSD pain (location, intensity, quality, and temporality) and no research characterizing vulvodynia in EDS/HSD.

The purpose of our study is to characterize EDS/HSD pain and vulvodynia pain; and to identify patterns in pain presentation, for example, achy, intermittent, and mild pain vs. sharp, constant, and severe pain.

Our study will also examine comorbid conditions (occurring together) in EDS/HSD and vulvodynia and identify if there is a relationship between the presence of comorbid conditions and pain presentation. We will examine generalized and vulvar pain in an online survey accessed via social media. We will recruit 825 females (275 with EDS/HSD only, 275 with vulvodynia only, and 275 with EDS/HSD and vulvodynia). Pain location, intensity, quality, and the pattern will be measured with PAINReportIt®, a computerized tool used to characterize pain. The characterization of generalized and vulvar pain in females with EDS/HSD and/or vulvodynia will allow for the identification of pain patterns and comorbid condition patterns as well as allow for the development of targeted treatment methods.

Therefore, our aims are Aim 1: Characterize pain patterns across the sensory aspect of pain (location, intensity, quality, and temporality) among females with EDS/HSD only, vulvodynia only, and EDS/HSD and vulvodynia. Aim 2: Characterize patterns of comorbid conditions experienced by females with EDS/HSD only, vulvodynia only, and EDS/HSD and vulvodynia, and determine how these patterns are associated with pain patterns.

Females with and without EDS/HSD suffer from debilitating generalized and vulvar pain without effective treatment options.[3; 16; 17; 11] In order to know whom to target with which treatment strategies, it is critical to consider females’ experiences with pain and comorbid conditions holistically. This study provides a framework for developing personalized healthcare with the greatest impact on the treatment of millions living with chronic pain.

Research Fund: $5,000
Primary Investigator:
Dr. Jennifer Glayzer
University of Illinois Chicago

We aim to determine if patients with IBS/hEDSoverlap have a different mast cell profile in the gut lining compared to those with IBS without hEDS and healthy subjects.

We will determine if there is a distinct symptom profile in patients with IBS/hEDS overlap which can improve recognition of this subgroup of patients. Mast cells are a type of white blood cell that is responsible for producing inflammatory reactions in response to the detection of foreign particles in the body. They exist in both the gut lining (mucosa)as well as the connective tissue. Upon activation, mast cells release numerous chemicals which may result in inflammation in many bodily systems.

Studies have shown an increase in mucosal mast cell counts in patients with Irritable Bowel Syndrome (IBS), particularly those with predominantly diarrhea symptoms. Furthermore, it has been found that mast cells lie next to the nerves in the gut of IBS patients and this may result in tummy pain. Mast cells and Mast Cell Activation Disease (MCAD) have also been implicated in patients with hypermobile Ehlers-Danlos syndrome (hEDS).MCAD is defined as an elevated number or increased activity of mast cells, resulting in inflammatory reactions. Furthermore, an overlap between IBS and hEDS is now recognized with 54% of hEDS patients also meeting the criteria for IBS.

Although hEDS patients display signs of MCAD, with symptoms such as; itching, redness, diarrhea, and tummy pain, there are no studies that have looked at alterations in the distribution and quantity of mast cells in the gut of hEDS patients and whether this correlates with IBS-like gastrointestinal symptoms, such as diarrhea and pain in the abdomen. Therefore, there are currently no management guidelines for gut symptoms in patients with MCAD and hEDS. Patients demonstrating gut manifestations of mast cell activation disease are poorly recognized and treated on the basis of presenting symptoms on a trial and error basis.

This approach often leads to patients taking many medicines. This study may result in a better understanding of the various inflammatory markers responsible for the symptoms of mast cell activation disease.

Research Fund: $5,000
Primary Investigator:
Miss Anisa Choudhary
Wingate Institute of Neurogastroenterology

Recent years have seen numerous investigators recognize a ‘quirky’ association – which is an immunological disorder of connective tissue elasticity.

This grant aims to study this association in order to generate hypotheses regarding the mechanisms that cause abnormal immune responses, that then suggest new treatment options. We will recruit participants who have been diagnosed with hEDS, hypermobility disorders (HDS), and other forms of EDS as disease controls.

A further group of controls, including participants, with disorders that involve mast cells in participants, will be assessed for the presence of mast cell–related symptoms with a symptom questionnaire developed and validated for patients with macrocytosis.

Research Fund: $5,000
Primary Investigator:
Dr. Jeremy McComish

Clinical Research Major Grant

Chronic pain and fatigue/exercise intolerance is a major complaint in individuals living with hypermobile EDS (hEDS) and may have a severe impact on quality of life and activities of daily living.

Despite this huge clinical problem, it is currently not known how or why these symptoms may arise or how they can be treated effectively. Most types of EDS are caused by alterations in collagen structure. Collagen is a major component of tendons, connecting muscles to bones to cause movement of our joints.

Lower limb tendon stiffness is reduced in EDS, which we hypothesize is the reason for reported feelings of pain and fatigue during walking in these individuals. Importantly, there is a widespread notion that exercise for these individuals should generally be avoided, due to the fear of joint dislocations, and increased extensibility of the tendons; however, evidence for this statement is lacking.

Therefore, we aim to test this hypothesis by:

1. Assessing lower limb tendon stiffness in individuals with hEDS using real-time ultrasound imaging of muscles and tendons during walking.
2. Evaluating the feasibility and effectiveness of an exercise intervention aimed at increasing tendon stiffness.
3. Quantifying the impact of altered muscle-tendon function in hEDS individuals on the energy cost of muscle contraction, muscle pain, and fatigue to better inform clinical rehabilitation practices.

There is a need for a better understanding of the impact of hEDS on activities of daily living, including walking, an easy and accessible mode of exercise for individuals with hEDS. A clearer understanding of the mechanisms of subjective fatigue, exercise tolerance, and energy expenditure is needed. This investigation proposes to compare muscle-tendon properties of hEDS and healthy controls and evaluate the impact of these properties on energy expenditure, subjective pain, fatigue, and exercise (in)tolerance. We further propose to investigate the impact of exercise training on these properties.

This information will help to inform treatment plans for individuals living with hEDS to reduce fatigue, safely engage in physical activity and improve their quality of life.

Research Grant: $148,348.10
Primary Investigator:
Dr. Jared R Fletcher
Mount Royal University
4825 Mt Royal Gate SW,
Calgary, AB
T3E 6K6,
Canada

People with hypermobile Ehlers-Danlos Syndrome (hEDS) frequently suffer from headaches, neck pain, and other neurological symptoms. However, the cause of these symptoms is poorly understood. Hypermobility of the craniocervical junction (joints between the skull and top of the spine) has been proposed as a major cause of these symptoms by causing pressure or stretch-related injury to the brainstem, nerves, and blood vessels in the neck.

This has been termed the cervicomedullary syndrome (CMS). Reports in small numbers of people with hEDS have suggested that craniocervical fusion surgery may stabilize the cervical spine and thereby dramatically improve headache and quality of life. This has not been studied in formal trials, and the rationale for surgical treatment is not widely accepted.

It is difficult to decide which (if any) people with hEDS may benefit from surgery as the symptoms of CMS have other potential causes, including migraine. The radiological measurements used in the assessment of CMS are obtained from upright dynamic magnetic resonance imaging (MRI). However, these measurements were not originally developed to be used in this condition, and we do not know the normal ranges for these values on upright MRI.

We will systematically study headache disorders, neurological symptoms, and signs in 200 people with hEDS. We will do this using structured clinical interviews, physical examination, and completion of questionnaires on pain-related disability, quality of life, autonomic symptoms, and affective scores. We will perform an upright dynamic MRI in three equal groups of 40 participants (120 in total): (1) Healthy controls without joint hypermobility or symptoms of CMS; (2) People with hEDS but no symptoms of CMS; and (3) People with hEDS and symptoms of CMS. We will record the presence of craniocervical junction abnormalities and radiological measurements of hypermobility.

In additional studies, we will look for evidence of brainstem tissue damage in people with hEDS who have symptoms suggesting CMS and radiology suggesting craniocervical hypermobility, using specialist imaging of brainstem pathways and electrical tests of brainstem function.

We anticipate that describing the burden of headache disorders and neurological symptoms in hEDS will increase awareness of these symptoms to healthcare providers, and better inform appropriate investigation and management. We will be the first group to establish normative ranges for the assessment of the craniocervical junction on upright dynamic MRI. We will be able to show to what degree this region of the body differs in people with hEDS compared to healthy controls. By comparing people with hEDS with and without symptoms of CMS we can study which imaging abnormalities are most related to symptoms.

The main hypothesis of this study is that craniocervical hypermobility in patients with hEDS would cause structural brainstem or spinal cord damage. If our results were in line with this hypothesis, then we would provide evidence supporting larger surgical trials that will help to deliver improved care to highly disabled patients. Alternatively, we would provide data against potentially unnecessary invasive and expensive neurosurgical treatment.

Research Grant: $149 698.13
Primary Investigators:
Dr. Manjit Matharu
University College London (UCL) Queen Square Institute of Neurology
Queen Square,
London, WC1N 3BG
United Kingdom

Health and Social Grant

Information is sparse with regard to the oral health of patients affected by Ehlers-Danlos syndromes (EDS). Systematic clinical oral investigations are missing for most of the 14 EDS types, and if available, study cohorts were small due to the rarity of the syndromes. The lack of evidence has led to various incorrect assumptions.

For example, it is repeatedly claimed that vascular (and classical) EDS are associated with a high risk for periodontitis. This statement is based on a single case report with a high risk of bias and it is more likely that this assumption is incorrect but systematic clinical investigations on periodontal manifestations in representative patient cohorts are missing. Another example is dental implants, for which few adverse side effects were anticipated. This might be true for some EDS types, but in a recent case series of individuals with periodontal EDS, we observed rapidly progressing bone loss around implants leading to implant loss after a few years. These incorrect assumptions may lead to diagnostic errors and faulty treatment in patients affected with EDS.

Various other dental and oral anomalies have been described in case reports/series and narrative reviews, which could have clinical diagnostic value if the prevalence and specificity in the different EDS types would be clarified. As members of the International Consortium on Ehlers-Danlos Syndromes and Related Disorders and through international collaboration, we have access to large cohorts of patients with different EDS types.

We aim to recruit at least 50 individuals per EDS type for clinical dental investigations in six European centers. This seems realistic for hypermobile EDS, classical EDS, vascular EDS, and periodontal EDS. Based on clinical studies we will assess oral health in people with different EDS types and develop and disseminate oral treatment strategies. Finally, patient leaflets and fact sheets for dental professionals will be designed, which will have an immediate impact on the oral health-related quality of life of EDS patients.

Research Grant: $99,159
Primary Investigator:
Dr. Ines Kapferer-Seebacher
Medical University of Innsbruck
Christoph-Probst-Platz 1,
Innrain 52 A, 6020 Innsbruck
Austria

Symptoms such as headache, neck pain, nerve pain in the arms and legs, and disturbances of heart rate and blood pressure, are thought to be derived from the upper cervical spine (upper neck) and craniocervical junction (the junction of the neck with the base of the skull) can be frightening and debilitating. It is suggested that these symptoms can result from the instability of these joints and subsequent pressure on the spinal cord and nerve roots as they pass from the cord out to the body. Clinically, both from physical examination and radiological imaging, it is difficult to establish if this is truly the case.

Whilst upright dynamic magnetic resonance imaging (MRI) is used to investigate such symptoms, there is a lack of evidence as to which measurements on MRI, if any, are truly linked to the presenting symptoms. It is also not clear if any of these measurements are commonly found in hypermobile people without symptoms. If the latter is true, then the MRI results could be unhelpful or misleading for people with symptoms. It is also not clear which tests and measures taken in clinics by doctors and physiotherapists are most useful to help guide decisions on how to help people manage th2ir symptoms. Nor is it known if or how these clinical tests and measures relate to MRI findings.

This study aims to answer these questions by comparing upright dynamic MRI of the cervical spine and craniocervical junction in two groups of people with confirmed generalized joint hypermobility. The first group is those who have symptoms that could be coming from the upper cervical spine. The second group is those with hypermobility who do not have neck problems. Everyone in both groups will be asked a series of questions and will undergo a clinical examination for head and neck, and shoulder and arm concerns that might arise. The study will use currently accepted standards of clinical assessment and validated questionnaires. The usefulness of two new questionnaires will also be assessed.

The MRI and clinical results from the two groups will be compared. Statistical techniques will be used to determine if MRI and/or clinical signs consistently identify people with neck symptoms compared to those without. Clinicians around the world can use this information in their clinics to help guide their practice, helping to improve the experience of people with these truly awful symptoms.

Research Grant: $164,393.53
Primary Investigator:
Dr. Ann McCarthy
Central Health Physiotherapy
53-64 Chancery Ln,
Holborn, London WC2A 1QS,
United Kingdom

Spring Microgrants

Hypermobility Spectrum Disorder (HSD) is a recently defined group of conditions related to the symptomatic manifestation of Generalized Joint Hypermobility (GJH) and is characterized among others by symptoms in the shoulder joint including and not limited to shoulder strength deficits, shoulder instability, and shoulder pain. This condition has negative consequences in daily living for these people, but currently, there is no optimal treatment for this population.

In an ongoing randomized controlled trial (RCT) (ClinicalTrials.gov identifier NCT03869307), we are investigating the effectiveness of a 16-week heavy strengthening exercise program in people with HSD and persistent shoulder complaints/problems. This study will use data collected in the RCT to obtain knowledge about associations between pain trajectories, exercise-induced pain flares, and exercised load in this population. In an exercise diary, the participants report pain before and after each exercise session, which makes it possible to analyze if pain decreases, increases, stays the same, and how it varies during the strengthening exercise program. In addition, associations between pain and the applied load in the specific exercise session will be studied. This information may guide healthcare professionals responsible for effective and safe treatment, in predicting response to heavy strength training, and inform a deeper understanding of possible pain patterns during exercise for this population.

This study is under the supervision of Associate Professor Dr. Birgit Juul-Kristensen, University of Southern Denmark, Odense, Denmark. The funding will cover the salary for a research assistant, who will type in all data from the exercise diaries (approximately 100 participants) and help with the data analysis.

Research Grant: $5,000
Primary Investigator:
Mr. Behnam Liaghat
Syddansk Universitet(University af Southern Denmark]
Campusvej 55
5230 Odense M
Denmark

Patients with hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) typically present with hypermobility in most of the joints, which is frequently associated with recurrent joint dislocations[1-3]. Some important mechanisms that are thought to play a role in shoulder dislocation are the ability to sense the shoulder joint, muscle function, and movement of the shoulder blade during arm movements.

The ability to sense the shoulder joint plays an important role in the maintenance of joint control during all arm movements [4-6], which may lead to severe shoulder complaints if left undiscovered. Poor shoulder position sense has been reported in adults with recurrent anterior shoulder instability [7], but not in adolescent swimmers with hypermobility [8]. One study has investigated dynamic shoulder-position sense without finding any significant deficits in patients with hEDS using advanced measurement methods [9, 10], while several previous studies have consistently reported deficits of dynamic knee-position sense in this patient group compared with healthy people [11, 12]. Feasible dynamic methods for clinical use, e.g. active joint reposition[13], which measures the ability to re-position the shoulder to a previous position, have shown deficits in patients with anterior shoulder instability[14], but this method has not yet been used in patients with HSD or hEDS. Abnormal movement of the shoulder blade has been found in patients with shoulder instability and dislocations[15]. Less upward rotation and more inward rotation of the shoulder blade, which are indicative of poor movement, have consistently been reported in patients with multidirectional instability during arm elevation[16-21], which may compromise arm movements and impair shoulder control[19-22]. Also, al3ered muscle activity has been found in patients with shoulder laxity, adolescent swimmers with hypermobility, and adults with MDI multidirectional instability [23-25].

While there is limited and inconclusive research on joint-position sense, no studies have, to our knowledge, simultaneously investigated joint-position sense, movements of the shoulder blade, and muscle activity of the shoulder in patients with hEDS/HSD. Investigation of these parameters during functional movements, such as shoulder elevation in different directions with and without resistance will provide a useful understanding of shoulder complaints in patients with hEDS or HSD. This knowledge will provide the basis for further investigating the effect of more specific exercise-based treatments targeting these shoulder deficits in this patient group. The aim of this study is to investigate shoulder reposition sense, movements of the shoulder blade, and muscle activity pattern in patients with hEDS or HSD with shoulder complaints such as persistent pain or instability compared to healthy controls using standardized feasible procedures.

This cross-sectional study is an international collaboration conducted by Behnam Liaghat, Ph.D. Fellow at the University of Southern Denmark, Odense, Denmark, under the supervision of Associate Professor Dr. Birgit Juul-Kristensen, University of Southern Denmark, Odense, Denmark, and will be conducted in collaboration with Professor Dr. Shea Palmer, the University of the West of England, Bristol, United Kingdom. The funding will cover travel expenses for the researchers and the included participants.

Research Grant: $5,000
Primary Investigator:
Mr. Behnam Liaghat
Syddansk Universitet(University af Southern Denmark]
Campusvej 55
5230 Odense M
Denmark

Osteoarthritis or joint wear is the deterioration in the quality of one or more joints. A joint is a place where two bones meet and move relative to each other. For smooth and pain-free movement, the ends of the bones fit together: one end usually has a rounded shape, the other a flat or hollowed-out shape. On the surface, the joint is covered with a layer of cartilage, surrounded by a case, called the joint capsule.

The joint capsule produces a gelatinous fluid that feeds the cartilage. In osteoarthritis, this structure is irreversibly damaged: the cartilage dries out and becomes crumbly. This makes the cartilage layer thinner, rougher, and less resilient. Sometimes pieces come loose, leading to the sensation of joint blockages. In addition, friction between these rougher joint surfaces and the capsule can also cause inflammation and pain (Figure).

The two main features of osteoarthritis are pain and movement restriction. In the beginning, pain occurs when loading the joint, e.g. during sports or even when walking. In a more advanced stage, there is also pain at rest that can interfere with sleep. Joint stiffness can also occur. Two types of osteoarthritis can be distinguished. On the one hand, osteoarthritis can develop in a normal joint, due to aging. It usually starts from the age of 50 and is most common in the knees, hips, and hands. This can happen to everyone. On the other hand, osteoarthritis can develop due to an illness or injury. This develops at a younger age, usually between the ages of 35 and 50, and is therefore called osteoarthritis at early-onset or premature osteoarthritis.

It has been suggested that because of the hypermobility in the joints and the frequent dislocations ((sub)luxations) and sprains, patients with Ehlers-Danlos syndrome (EDS) are prone to develop early osteoarthritis. However, no studies have been published that determine whether patients with EDS actually have early osteoarthritis and how severe it is.

It is important to investigate the occurrence of early-onset osteoarthritis in EDS patients because it can help to better understand the types of pain and pain mechanisms in EDS and because it can help to improve and specify the treatment of EDS patients regarding physiotherapy and pain medication.

Therefore, we set up a research study to investigate with radiography (X-rays) whether patients with classical EDS, classical-like EDS, and hypermobile EDS, between 35 and 50 years old, have early-onset osteoarthritis in the hands, knees, and hips and whether this is different between these types of EDS and compared to healthy persons. Also, the mobility of the joints is measured to investigate whether there is a relationship between the degree of (hyper)mobility in a joint and the presence of early-onset osteoarthritis in that joint in EDS patients.

Currently, 31 EDS patients have been tested, but to have reliable results it is desirable to expand the patient group. Funding for this study will be used to pay the X-rays of newly enrolled EDS patients and to pay a statistician who will analyze the results.

Research Grant: $5,000
Primary Investigator:
Dr. Lies Rombaut
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,
Belgium

Diseases of the connective tissue, including Ehlers-Danlos disease (EDS), are systemic and negatively affect multiple tissues and organ/systems. In fact, although EDS is characterized by various skin features (including hyper-extensibility, fragility, softness, bruising, abnormal scarring) and joint hypermobility, it often causes joint and muscle pain in addition to a variety of other symptoms. These, including symptoms affecting the respiratory system, are less studied but can significantly reduce the quality of life of EDS patients. A few, sparse studies have reported an increased number of respiratory symptoms (wheezing, coughing, chest pain,breathing difficulties), lung diseases and even asthma in patients with EDS. However, data on the prevalence and/or incidence of these cases are not available and no in-depth studies on the respiratory system of EDS patients have been performed. We recently characterized the respiratory phenotype in a mouse model of recessive osteogenesis imperfecta (OI), a disease that causes severe bone fragility but also skin alterations, with some overlapping features with EDS. OI is most often caused by alterations in type I collagen, the most abundant protein in our body and an essential structural component of our connective tissues.

Our study showed that type I collagen expressed in the lung tissue presents similar defects to those seen in bone and skin; moreover, we demonstrated that OI mice have both morphological and functional respiratory defects with important implications for patients with this disease. Indeed, previous theories suggested that the respiratory function is impaired because of the musculoskeletal issues caused by OI. Instead, our study indicated that collagen defects directly impact lung structure and function. Therefore, our working hypothesis is that collagen alterations such as those impacting type I collagen in OI or type V or III collagen in EDS also primarily affect the respiratory system with deleterious pathophysiologic consequences that could help explain the symptoms observed in these patients.

We believe it is critical to begin to study these important aspects of the disease. We thus propose to utilize a well-described mouse model of classic EDS (carrying mutations in the Col5a1 gene) and determine potential alteration in its respiratory function and respiratory mechanics using the forced oscillation technique, a powerful tool permitting the experimental assessment of lung function in a comprehensive, detailed, precise and reproducible manner. Our pilot study provides an opportunity to explore these aspects in a mouse model with the ultimate goal to translate the new knowledge into improvements in the respiratory management and care of EDS patients.

$5,000
Primary Investigator:
Dr. Roy Morello
University of Arkansas for Medical Sciences
4301 W Markham St,
Little Rock, AR 72205,
United States

Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder with thirteen clinical subtypes mainly characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Mutations in a protein called FKBP22 cause kyphoscoliotic EDS (kEDS). Individuals with kEDS have a broad spectrum of phenotypes, such as the curved spine, excess joint flexibility, poor muscle tone, stretchy skin, hearing loss, and breakable aorta. The mechanism by which reduced or abnormal FKBP22 leads to kEDS is unknown and represents a critical gap in our knowledge. I have recently discovered that the FKBP22 protein binds to some of the 28 different collagens but not others. Understanding how and where FKBP22 differentially binds collagens has never been explored. Determining the nature of these interactions would contribute to a fundamental understanding of kEDS disease mechanisms and contribute to the development of novel therapeutic interventions.

$5,000
Primary Investigator:
Dr. Yoshihiro Ishikawa
The Regents of the University of California, San Francisco
505 Parnassus Ave,
San Francisco, CA 94143,
United States

The spider: mapping your symptoms
Patients with joint hypermobility report joint pain as their main symptom. However, their lives are often affected by many other problems situated outside the muscles and joints as well. Fatigue, feeling unwell after exercise, feeling faint in an upright position, abdominal pain, slow bowel transit, diarrhea, and urinary incontinence are examples of additional ‘non-musculoskeletal symptoms.

Since 2017, these bothersome symptoms have been acknowledged by the international EDS consortium and are referred to as the comorbidities of hypermobility. Unfortunately, when seeking treatment, many patients feel as if these symptoms are neglected at first because they are not taken into consideration when diagnosing HSD and EDS. The reason is that diagnosis of EDS is based on more structural symptoms, such as abnormal scarring and fragility of soft tissues.

Although the functional symptoms do not have a central place in the diagnostic procedure, researchers found that they lower quality of life importantly. In fact, the impact of symptoms like fatigue, difficulty regulating blood pressure, and stomach and bowel problems is often as large as the impact of pain. Furthermore, evidence is growing that subgroups exist in patient with HSD and in hEDS and that these may need different treatment strategies. For instance, a Dutch-Australian research team evaluated 101 children with hEDS/HSD and detected three subgroups. The most severely affected subgroup reported a larger number of non-musculoskeletal symptoms and was more likely to have a worse disease trajectory growing up. A similar finding was described in adults by Belgian researchers. To register the non-musculoskeletal symptoms (comorbidities) of joint hypermobility in a standardized way, the ‘Spider’ was developed.

The end result of this questionnaire is a graph shaped like a spider web, that shows health care professionals which issues require further assessment and should be treated as a priority. For instance, if patients have severe digestive problems or symptoms related to blood pressure regulation, these should be addressed first before starting intensive physiotherapy or physical training. In addition, the spider can be used to track how a patient’s health is evolving over time and to monitor the effects of treatment.

Finally, researchers will also be able to use the spider, since it provides insight into the prevalence of non-musculoskeletal symptoms in HSD and EDS, and reveals whether differences exist between patient groups with HSD, hEDS, and other EDS-types. In many countries, patients with EDS diagnoses are more likely to receive acknowledgment, assistance and reimbursement for treatment than patients with HSD. The faulty assumption that hEDS is more severe than HSD could be confuted by symptom registration on a large scale. Because little is known about the genetic background of HSD and hEDS, the spider could be an interesting tool to shed light on the differences and similarities between both pathologies. Finally, the spider could be helpful to detect groups of similar patients within large populations with the same diagnosis. Researchers hope to understand whether patient subgroups with different symptoms also have a different genetic background.

$5,000
Primary Investigator:
Miss Inge De Wandele
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,
Belgium

For diagnosis and research it is very useful to be able to look at the skin of patients with Ehlers-Danlos syndrome and Hypermobility Spectrum Disorders using a transmission electron microscope. To be able to do this, a small sample of skin is processed and a very thin slice is taken and put in the microscope. Using this type of microscope, it is possible to look at a cross section through the cells and collagen of the dermis (skin layers) at very high magnification, to see if they are normal or not. By comparison, with a scanning electron microscope it is possible to see the surface of tissues at high magnification in three dimensions. Scanning electron microscopy gives interesting results, but for the study of the dermis, is less useful. Even when both of these types of microscope are used, it is still very difficult to tell what is happening in the skin in three dimensions. However, a microscope was recently developed where, in an automated fashion, slice after slice is taken from a biopsy and the cut surface is photographed after each slice has been taken. This makes it possible to build up a three-dimensional picture of the cells, collagen strands and elastic fibres. Using multiple slices and a computer to build up a three-dimensional image is called computer tomography which is what x-ray, CT and magnetic resonance imaging body scanners do – which is especially useful when looking at organs. However, when wishing to look at cells and collagen at the microscopic level, electron tomography is required. It is our expectation that by looking at skin biopsies from patients suffering with Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders using this new piece of equipment (Serial Block Face Scanning Electron Microscope) it will help scientists understand more about the molecular biology of these conditions. Only a few research institutions in the UK own these new microscopes. This grant application, in large part, is to pay for the services of one of these universities, with interpretation in large part being the job of those applying for this microgrant. The institution we have approached is the University of Manchester Wellcome centre of Cell-Matrix research.

$5,000
Primary Investigator:
Mr. Bart Wagner
Sheffield Teaching Hospitals
Royal Hallamshire Hospital,
Glossop Rd, Broomhall,
Sheffield, S10 2JF
United Kingdom

Chronic pain is present in the majority of patients suffering from Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) and is a major reason to seek medical help. It has a detrimental effect on the quality of life and psychosocial well-being of EDS/HSD patients. Despite its high prevalence, little is known about the precise origins and mechanisms contributing to EDS-related pain and the pain is usually inadequately controlled by currently used treatments. An important reason for this is the lack of studies investigating the mechanisms and pathways that initiate and maintain EDS-related pain. Animal models can give valuable insights into mechanisms and pathways that are affected in human disorders. Zebrafish has emerged as a promising animal model to reliably study pain-related behavior and associated mechanisms, since their nervous system shows great similarity to humans. Our group recently created zebrafish models for the rare spondylodysplastic EDS (spEDS) subtype due to defects in B4GALT7 and B3GALT6, and the musculocontractural EDS (mcEDS) subtype due to CHST14 mutations. Both subtypes are caused by defects in the biosynthesis of proteoglycans, which are important molecules providing structural support to connective tissues but are also involved in other biological functions, such as during development of the nervous system. Since clinical practice and some reports suggest that patients with spEDS and mcEDS suffer from chronic pain, we want to use these zebrafish models for our pain studies. A first step in the elucidation of the alterations in the pain pathways associated with these EDS subtypes is to assess whether the zebrafish models experience pain. Therefore, the general aim of this proposal is to document pain- and stress-related behavior in spEDS and mcEDS zebrafish. To obtain this information, the spontaneous free-swimming behavior of these zebrafish will be carefully monitored and analyzed. If pain-related behavior is observed, we will try to ameliorate the observed pain-related behavior by administering several types of pain medication to the water and check if th3s reverses the behavior. In addition, the spEDS and mcEDS zebrafish will be crossed with a specific reporter line allowing to visualize the nervous system. Alterations in neuronal development will be evaluated in this way. When successful, this proof-of-concept data will set the stage for further in depth analyses. This proposal is part of a large, ongoing and collaborative research line at the Center for Medical Genetics Ghent (Belgium), aiming to better understand the molecular and cellular pathways and mechanisms that contribute to pain in EDS, with the ultimate goal to identify targets for safer, more efficient and (potentially) disease-tailored approaches for pain relief.

$5,000
Primary Investigator:
Dr. Delfien Syx
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,
Belgium

Hypermobility is a common body type and it is estimated to affect 20% of the population . Only 10% of people with hypermobility are symptomatic which often causes a confusion regarding the nature of pain in these patients . Furthermore there is an anecdotal impression among some doctors that patient with rare forms of EDS , such as classical or vascular type , do not suffer with pain or significant musculoskeletal issues. Others believe that this is simply a presentation of fibromyalgia with oversensitivity to pain in anxious patients who happen to be hypermobile. We have observed an increase in the rate of orthopaedic surgical procedures undertaken in patients attending the hypermobility clinics compared to those attending the general rheumatology and chronic pain clinics. This indicates that mechanical pathology rather than pain oversensitivity plays an important role in their symptoms. We have performed a retrospective review of medical records of 350 patients attending a hypermobility clinic at our tertiary referral centre, University College London Hospital, between January 2018 and December 2018. We found that the mean age was 36 years , 37 % had EDS(hypermobile, classical, vascular or other rare type) with 13% had documented genetic mutations 83 patients (24%) had undergone orthopaedic interventions including 9 who had EDS with confirmed genetic mutations. 54% of patients who had surgical intervention were under the age of 40. The total number of surgical procedures in the cohort was 227 (equating to 0.6485 interventions per patient). Of those requiring operative intervention, the average number of interventions per patient was 2.73. One third of patients had surgery on two or more joint groups, including 8 patients (2%) who had surgery in four or more joint groups. Knees (24%) and hips (23%) were the most common sites for operative intervention with 9% having surgery on their shoulders. 29% of pts had significant hypermobility with a Beighton score of 7 and above but there was no correlation between Beighton score and number of surgical procedures. Only 2% of cases were referred from an orthopaedic team thereby excluding a referral bias. We have highlighted that patients with hypermobility related disorders have a significant number of orthopaedic surgical procedures on multiple sites and at a young age, with indication of mechanical pathology playing an important role in their symptoms. The Beighton score did not appear to be a reliable predictor of surgical intervention. This is not surprising given that the score only covers 5 joint areas and excludes common surgical sites such as the hips and shoulders. This study was accepted as an oral presentation at EULAR (the main European rheumatology meeting) in June 20202 and received a very good feedback We would like to apply to this grant to perform subgroup analysis and get a professional statistical advise to be able to publish this in one of the main rheumatology journals. We are aiming to complete this by June 2021

$5,000
Primary Investigator:
Dr. Hanadi Kazkaz
University London Hospital
12 Queen Square, Holborn,
London, WC1N 3BG
United Kingdom

Vascular Ehlers-Danlos (vEDS) is an inherited connective tissue disorder caused by a deficiency in type III collagen. Patients with this disorder have spontaneous rupture of blood vessels, often resulting in sudden death at a young age. The risk of rupture is difficult to monitor or predict and there are no treatments for prevention of rupture in vEDS. The issue of what type and how much exercise is safe for patients with vEDS is of high concern among patients who want to do whatever they can to prevent spontaneous rupture. The most conservative answer in terms of reducing stress on the blood vessels is to avoid all exertional activity, but this robs the patient of the many health benefits of exercise. The best available exercise recommendations in vEDS are derived from those for other connective tissue related vascular diseases, such as Marfan syndrome and Loeys Dietz Syndrome. However, these syndromes are defined by a reliable pattern of aneurysm formation, followed by dissection and rupture and do not mimic the unpredictable vascular ruptures seen in vEDS. Currently, vEDS patients are advised to avoid “burst” exertions and contact sports, which generally translates to avoiding all competitive sports and significant weightlifting. However, the exercise guidelines in this disease are severely lacking in evidence-based recommendations.
In our lab, we have a mouse model of severe vEDS which we have utilized to begin to investigate questions with respect to two major categories of exercise: dynamic or “cardiovascular” (running, swimming, biking, etc) and static or “isometric” (pull-ups, pushups, planks, resistance training). To assess the effects of cardiovascular exercise, we used treadmill running. To assess the effects of isometric exercise, we utilized inverted suspension with mice supporting their own weight against gravity for an extended interval. In our preliminary studies, we noted that consistent moderate cardiovascular exercise did not result in an increased rate of vascular rupture in these mice. We also discovered that isometric exercise actually increased overall survival, particularly in female mice. None of the female vEDS mice on an isometric exercise regimen died, which is significantly different than the 50% mortality rate observed in non-exercised vEDS controls. This points to isometric exercise as a potential beneficial adjunct in the treatment plan of vEDS patients. Financial support from an EDS Society microgrant would allow us to further investigate these preliminary findings and determine a mechanism for these observed differences that will inform further research in and future recommendations on exercise for patients living with vEDS.

$5,000
Primary Investigator:
Dr. Rebecca Sorber
Johns Hopkins University School of Medicine
733 N Broadway,
Baltimore, MD 21205,
United States

Additional Research

Professor Qasim Aziz at Barts and The London School of Medicine and Dentistry has been caring for patients with EDS for many years. He has heard consistent stories of his patients’ symptoms improving with a change of diet. Some patients have improved a great deal and are living happy lives again. It’s now time to test, in a scientific study, whether changes in diet really can improve EDS symptoms in adults. Latest statistics from Professor Aziz’s London clinic show that, on average, EDS symptoms start at the age of 12 but the condition is not diagnosed until the age of 24.

hEDS is also associated with a range of gut disorders, including acid reflux and irritable bowel syndrome. There are no drugs that target connective tissue abnormality. Current treatments include medications to reduce symptoms, alongside physiotherapy for muscle and joint issues.

Good nutrition is essential for connective tissue repair and general healing. Certain nutrients are needed for the body to make collagen and support connective tissue function. Identifying specific nutrients needed for connective tissue function is important.

The Ehlers-Danlos Society and The Ehlers-Danlos Support UK fundraised together, jointly, towards research into Diet and EDS in 2018 and 2019. All donations made through The Ehlers-Danlos Society were transferred to The Ehlers-Danlos Support UK in 2020, who is managing a research study into Diet and EDS.

$7,997

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