Quantitative measures of tissue mechanics to detect hypermobile Ehlers-Danlos syndrome and hypermobility syndrome disorders: a systematic review

A subject librarian with expertise in systematic reviewing advised on the selection of electronic databases and the search strategy. The electronic databases selected were AMED, CINAHL+, EMBASE, MEDLINE and SportDiscus. Search terms and associated synonyms (Table 1) were developed through group discussion and advice from the subject librarian.

The diagnostic terms of hEDS and HSD were included as well as previous diagnoses of JHS, EDS-HT and Ehlers-Danlos type III, as it was expected that limited literature would be retrieved using the 2017 hEDS and HSD diagnostic terms [1, 2]. The search was limited to the English language and the time period January 1, 1998 to January 31, 2019 because the Villefranche nosology and Brighton criteria were only in the public domain from 1998. Two researchers conducted the electronic database searches to minimise potential errors.

Inclusion criteria, agreed a priori through group discussion, were as follows: (1) confirmed diagnosis of hEDS/HSD (or equivalent diagnoses of EDS-HT, EDS type III or JHS) using internationally recognised criteria; (2) healthy control group as a comparator and (3) objective measures of tissue stiffness, extensibility or elasticity of muscle, tendon, connective tissue or skin. There were no limitations on study type, other than including only primary research.

All duplicates and non-human studies were removed. Study titles were then screened against the inclusion criteria at a meeting of all researchers. The abstracts of the remaining studies were all screened by individual team members, followed by another group meeting to agree which would be included for full-text review. Any disputes were discussed and resolved by consensus. Snowballing of the reference lists of remaining studies was undertaken to identify potential additional studies and these were screened in the same way. The remaining studies underwent full-text review by individual team members, with the final studies to be included in the review then agreed at a meeting of the research group. The search and selection processes were recorded as per PRISMA guidelines [19].

The ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) checklist [20] was chosen as a framework to facilitate critical appraisal in this review. Although the STROBE checklist is not a critical appraisal tool per se, as an international reporting standard, it addresses the key aspects of design, conduct and analysis of cross-sectional studies. As such, it was considered a valuable framework to judge the quality of the included studies. Each individual team member completed the STROBE checklist for each of the final included studies. Further information about each study was recorded using a standardised data extraction form. Data extracted included study design, country, aims, tissue(s) investigated, diagnostic criteria, sample size, sex, age, ethnicity, patient recruitment, statistical analysis and a final summary. A final version of the STROBE checklist and data extraction table for each study was then agreed through discussion and consensus.

Table 2 summarises the characteristics of the included studies, including participant demographics. Three studies investigated a higher percentage of women than men, with only Remvig and colleagues [14] not detailing the sex of participants. One study excluded men altogether [16], stating that 90% of hEDS patients are women. Most studies recruited convenience samples from existing clinical records, with only Alsiri and colleagues [15] recruiting prospectively from physiotherapy referrals.

Age ranges varied from 18 to 89 years, which is an important factor when measuring the mechanical properties of skin, because of collagen changes with age. For example, Luebberding and colleagues [22] identified greater laxity and reduced elasticity in skin after 40 years of age. An additional relationship was observed between reduced skin elasticity in women and hormonal changes over time, particularly during the menopause. These observations are important because all four studies in this review included women over 40 years (although Remvig and colleagues [14] capped the age at 42 citing age-related collagen changes for this decision). Age could therefore be a confounding factor for each of the studies and further research should be conducted to understand its impact on the data.

Reporting of ethnicity can improve judgements of external validity, particularly as to whether the sample represents the diversity of affected populations [23]. Ethnicity is particularly important in this case because hypermobility is known to be more prevalent in African and Asian groups as compared to white populations [24]. However, ethnicity of participants was reported in only one study [15].

The STROBE statement (Table 3) identified that overall there was robust reporting and analysis of results, including declarations of limitations and/or recommendations for future practice and research. Omissions in some reports related to criteria 5, 9 and 10. Only Alsiri and colleagues [15] provided robust details for criterion 5 (‘Describe the setting, locations and relevant dates, including periods of recruitment, exposure, follow-up and data collection’). Two studies [14, 15] supplied details for criterion 9 (‘Describe any efforts to address potential sources of bias’). Only one study [15] provided evidence for criterion 10 (‘Explain how the study size was arrived at’). This demonstrates that the common omissions are related to time scales and recruitment processes, blinding to reduce bias and sample size calculations. Alsiri and colleagues [15] was the only study to meet all STROBE criteria, indicating a high-quality study report.

Details about the recruitment process are important as they provide context for the reader and clarity about whether participants are suitable for answering the study objectives. Only Alsiri and colleagues [15] provided sufficient detail about the study setting, including such details as the dates during which data collection was conducted.

Blinding is the most effective way of preventing investigator effects or expectation effects but there was a lack of blinding in two of the four studies [16, 21]. It should be noted that blinding was incomplete in both of the studies that attempted it [14, 15]. For example, in Alsiri and colleagues [15], the examiner knew the diagnostic category of each participant and blinding only applied to data analysis. Remvig and colleagues [14] reported blinding examiners to previous skin signs and to each other’s results but it was not reported if the examiners were aware of specific diagnoses or if analysis was conducted blind.

Sample size calculations allow researchers to generalise results and it has been suggested that a sample size calculation should be a prerequisite to any clinical research study [25]. The study by Alsiri and colleagues [15] was the only one to conduct an a priori sample size calculation. They used data from a previous PhD study [26] to guide the calculation, identifying that 20 participants were needed. They proceeded to recruit and retain appropriate numbers to fulfil the calculated numbers. As the sample size of the other three studies was not justified, the results may have been subject to type II errors.

All studies had robust inclusion and exclusion criteria which indicated attempts to mitigate potential confounding factors. Exclusion criteria included skin disease, malignancies and limb trauma, all of which could affect skin/tissue mechanics. Pregnancy and recent childbirth were exclusions employed by Alsiri and colleagues [15] and Rombaut and colleagues [16]. An increase of relaxin levels during pregnancy, and shortly after birth, is associated with increased joint laxity. Relaxin regulates the remodelling of tissue structures such as bone, synovium, cartilage, ligaments and tendons [27]. Exclusion of pregnant women, and those that have recently given birth, therefore attempts to reduce the risk of this confounding factor. However, there is also evidence that increased relaxin levels during menstruation in normally menstruating young women were associated with a reduction in patellar tendon stiffness [28]. The role of relaxin on tissue stiffness in women with hEDS/HSD may therefore be important to consider in future research [16].

There were a variety of methods shown to distinguish between the tissue mechanics of adults with hEDS/HSD and healthy controls. These methods were applied to a range of different tissues. The following discussion evaluates the potential clinical utility of such methods.

Remvig and colleagues [14] used two established techniques for measuring skin extensibility, elasticity and stiffness—the suction cup method (SC) and the soft tissue stiffness meter (STSM). They explored if the devices could differentiate between EDS-HT, BJHS and controls. The study identified a difference between the three groups in skin extensibility of the volar aspect of the forearm using the SC method when the arm was extended but not flexed. However, on post hoc testing, there were no differences between individual groups. There were no differences in skin elasticity between groups using the SC method. The STSM found differences in skin consistency on the volar aspect of the forearm between groups with the elbow both extended and flexed. People with EDS-HT had lower stiffness than controls but there were no differences between BJHS and control. There were no differences in skin consistency as measured with the STSM on the dorsal aspect of the forearm. Arokoski and colleagues [29] previously demonstrated the feasibility of the custom-built STSM used in the study. Other soft tissue meters are now commercially available, are practical and have generally been evaluated positively [30, 31]. Further evaluation of such devices in the assessment of hEDS/HSD is recommended. Given the observation that differences were observed in the volar aspect of the forearm but not the dorsal aspect [14], a range of anatomical structures should be tested in future research.

Rombaut and colleagues [16] investigated the mechanical properties of the plantar flexor muscle-tendon tissues in people with EDS-HT and controls. Achilles tendon stiffness was measured as a function of tendon lengthening (assessed using diagnostic ultrasound) and isometric plantar flexor muscle force (assessed using an isokinetic dynamometer). Stiffness of the Achilles tendon was significantly reduced in adults with EDS-HT (EDS-HT 12.3 ± 4.84 N/mm versus controls 15.6 ± 4.43). The clinical utility of such methods may be more challenging due to the specialist equipment and training required.

Alsiri and colleagues [15] used strain elastography to examine passive stiffness in the Achilles tendon, patellar tendon and five muscles. The technique involves pressing an ultrasound probe rhythmically over the site of interest and the digital capture of the ultrasound image (an elastogram) of the compression of the underlying tissues (strain). Analysis involved highlighting an area of the elastogram which represented the area of interest and another reference area of subcutaneous fat. A strain index was automatically calculated for each area, with the upper boundary representing the area of interest and lower boundary representing the subcutaneous fat. From this, the strain ratio (upper boundary/lower boundary) was calculated. The elastograms are also colour coded, producing a map of soft (coloured red), intermittent (green) and hard tissues (blue). Alsiri and colleagues [15] calculated the proportion of red, green and blue pixels within each target tissue using an image processing software. The upper boundary of the strain index successfully distinguished between people with HSD and healthy controls at three test sites: brachioradialis muscle, patellar tendon and Achilles tendon. The strain ratio distinguished between groups at two test sites: brachioradialis muscle and patellar tendon. There was a higher proportion of soft tissues in the biceps brachii and Achilles tendon and a lower proportion of hard tissues in the biceps brachii, brachioradialis and Achilles tendon in people with HSD, when compared to healthy controls. Of these sites, the Achilles tendon seemed particularly promising as differences were observed using three outcomes—the strain index and the proportion of both soft and hard tissues. Although elastography seems to be becoming more popular, with an increasing evidence base, its clinical utility might still be questioned due to the specialist equipment and training required. Nevertheless, it is clearly sensitive to soft tissue changes in hEDS/HSD and warrants further investigation. An alternative to strain elastography, namely shear wave elastography, has the potential to provide even more objective findings [32] and could form the basis of future research.

The design and conduct of the review were extremely rigorous, with all steps of the procedure subject to multiple researcher oversight, discussion and consensus. The review was limited to the English language, however, and may have excluded relevant studies as a result. Heterogeneity of diagnostic criteria and terminology made it difficult to identify the patient populations investigated, although we are confident that the studies included were appropriate to the inclusion criteria.

Future research should further investigate the potential use of handheld tissue stiffness meters and ultrasound methods to contribute towards the diagnosis of hEDS/HSD. The former devices may be particularly useful in clinical practice as they require minimal training. Appropriate clinimetric properties, such as sensitivity and specificity and receiver operating curve analysis, should be explored. In the absence of a gold standard diagnostic test, comparisons should be made against the international diagnostic criteria for hEDS [1] and framework for HSD [2]. Additionally, it is recommended that attention is paid to recruiting representative samples in terms of age, gender and ethnicity. Future studies should include blinding to avoid investigator bias and should perform prospective study size calculations.