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• In reply to the authors' response to "Concerns regarding the inference that EDS is not rare"
  Alan J Hakim, Clair A Francomano, Marco Castori and Fransiska Malfait
  Published on: 13 December 2019
• Reply to “Concerns regarding the inference that EDS is not rare"
  Joanne C Demmler, Mark D Atkinson,, Emma J Reinhold, Ernest Choy and Ronan A Lyons
  Published on: 29 November 2019
• Concerns regarding the inference that EDS is not rare
  Alan J Hakim, Clair A Francomano, Marco Castori and Fransiska Malfait
  Published on: 12 November 2019

• Published on: 13 December 2019

  In reply to the authors' response to "Concerns regarding the inference that EDS is not rare"

  • Alan J Hakim, Adjunct Associate Professor in Medicine PennState University, USA
  • Other Contributors:
    • Clair A Francomano, Professor of Medical and Molecular Genetics
    • Marco Castori, Consultant and Director, Division of Medical Genetics
    • Fransiska Malfait, Associate Professor, Center for Medical Genetics

  We thank Demmler and colleagues for their reply to our concerns (dated 29th November 2019). In particular we appreciate the analysis required to demonstrate that the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) cohorts in their study shared similar characteristics across the 35 Read chapter categories. This is a valuable observation of itself.

  Demmler and colleagues say in their reply that we ‘asserted that diagnosed JHS is known to be common’. We assume they have misconstrued our opening comments about combining common with rare conditions. We used the words ‘common’ and ‘diagnosed JHS’ to describe their findings, and based on the prevalence of ‘diagnosed JHS’ in the population they studied. We recognise that this study is the first to directly report a healthcare record-based population prevalence for JHS and a healthcare record-based population prevalence for EDS.

  We read that the authors agree with our comments that it is not possible to know what proportion of people who met the Brighton criteria for JHS also meet the 2017 hEDS criteria, and, that the authors agree that further studies are required to determine how common hypermobility spectrum disorder (HSD), hypermobile EDS (hEDS), and other forms of EDS are.

  We appreciate that the authors did not “seek to remove the protected ‘rare’ status from all subtypes of EDS”, and that they “regret if their work has been misquoted on social media”. Demmler et al. also reply that...

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  We thank Demmler and colleagues for their reply to our concerns (dated 29th November 2019). In particular we appreciate the analysis required to demonstrate that the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) cohorts in their study shared similar characteristics across the 35 Read chapter categories. This is a valuable observation of itself.

  Demmler and colleagues say in their reply that we ‘asserted that diagnosed JHS is known to be common’. We assume they have misconstrued our opening comments about combining common with rare conditions. We used the words ‘common’ and ‘diagnosed JHS’ to describe their findings, and based on the prevalence of ‘diagnosed JHS’ in the population they studied. We recognise that this study is the first to directly report a healthcare record-based population prevalence for JHS and a healthcare record-based population prevalence for EDS.

  We read that the authors agree with our comments that it is not possible to know what proportion of people who met the Brighton criteria for JHS also meet the 2017 hEDS criteria, and, that the authors agree that further studies are required to determine how common hypermobility spectrum disorder (HSD), hypermobile EDS (hEDS), and other forms of EDS are.

  We appreciate that the authors did not “seek to remove the protected ‘rare’ status from all subtypes of EDS”, and that they “regret if their work has been misquoted on social media”. Demmler et al. also reply that they chose to recognise HSD as a possible diagnosis for an unknown proportion of the JHS patients. This concurs with our original point that the proportion is unknown. By the same reasoning, the proportion of hEDS would be unknown. Given this we have not changed our position in questioning why the authors stated “we conclude that EDS/HSD are not rare conditions”, when the term EDS includes these rare conditions and the authors could not know how rare or otherwise each of HSD and hEDS are.

  We also agree with Demmler et al. that HSD and hEDS individuals can have the same complex medical conditions. This was not something that we questioned. We note Demmler et al. in their reply cite our authorship (1) for which there is an associated editorial (2).

  The authors also state that experts in the field considered JHS and EDS hypermobile type (EDS-HT) to be clinically indistinguishable. As it reads this statement is correct. However, it is not a universal truth. Not all cases of JHS are indistinguishable from EDS-HT. When Kirk, Ansell, and Bywaters published their observations and introduced the term Hypermobility Syndrome (3), they also described that their patient population had no evidence of any other features to suggest a hereditary connective tissue disorder (HDCT) such as EDS or Marfan syndrome.
  Hypermobility syndrome (HS) was subsequently subsumed by the term JHS. However, the Brighton criteria for JHS included other signs that were more suggestive of an HDCT (4). Ensuing publications questioned whether these additional features were more typical of the hypermobile type of EDS (Villefranche criteria) (5), and, reported inconsistency between experts in their use of diagnostic terminology. The way the criteria was structured was such that the diagnosis JHS could include individuals previously described as HS, individuals with JHS by the Brighton criteria but not having sufficient features of an HDCT, and individuals with findings more typical of the hypermobile type of EDS (then described as JHS/EDS-HT) (4, 6-9).

  In bringing together the diagnostic features of JHS/EDS-HT and the hypermobile type of EDS, the authors of the 2017 hEDS criteria recognized the need for additional descriptive diagnoses because not all individuals with JHS had signs consistent with a diagnosis of hEDS. Tinkle et al. wrote in their criteria paper (10):

  "It is, therefore, the consensus of the authors on behalf of the International Consortium on the Ehlers–Danlos Syndromes, based on the present state of our knowledge, that the two conditions [of JHS, and hEDS] are part of the same clinical spectrum ranging from apparently symptomatic GJH to individuals fitting the new diagnostic criteria for hEDS.
  Grouping all phenotypes comprised in this spectrum under the same heading may be misleading on both nosologic and therapeutic perspectives.
  For all these individuals not showing a sufficiently convincing hEDS phenotype, some alternative labels within the above‐mentioned spectrum are presented elsewhere".

  By ‘elsewhere’ they were referring to the paper by Castori et al. (11), that describes the framework for the term Hypermobility Spectrum Disorders.

  In our opinion, which we re-iterate, data that is derived from studies of JHS would require researchers to either go back and re-diagnose the subgroups of JHS if they are to report the study as HSD and hEDS, or model assumptions with regard to the relative proportions of cases that might be assumed to be HSD or hEDS.

  While still respecting the relationships between HSD and hEDS as a spectrum with definable boundaries based on criteria, researchers are able to study each individual condition, or both in parallel looking for commonality, drawing together evidence for similarity but without losing what might make one condition different from the other. We believe this is an important principle that is lost if conditions are combined together from the outset.

  With regard to prevalence studies, in our opinion it is more informative that the prevalence of hEDS is cited separate from that of other forms of EDS, not only to clearly present the prevalence of hEDS per se, but also avoid statements about EDS as a whole that might mis-represent the rare and ultra-rare nature of most of its variants.

  Finally, having worked with thousands of patients between us, we fully appreciate, and agree with Demmler et al., that these conditions require more recognition, and better understanding of the nature, and efficacy of treatment. In this regard we hope that our comments are helpful with regard to the use of terminology.

  We are grateful to BMJ Open for the opportunity to have shared our opinion, and for Demmler and colleagues' reply, and we draw our commentary to a close,

  References.

  1. Copetti M, Morlino S, Colombi M, et al. Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients. Rheumatology. 2019;58:1722–1730

  2. Hakim AJ. Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder, Rheumatology (Oxford). 2019 Oct 1;58(10):1705-1706

  3. Kirk JA, Ansell BM, Bywaters EG. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26:419-425

  4. Grahame R, Bird HA, and Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). Journal of Rheumatology. 2000;27(7):1777-1779

  5. Beighton P, De Paepe PA, Steinmann B, Tsipouras P, and Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers Danlos National Foundation (USA) and Ehlers Danlos Support Group (UK). Am J Med Genet. 1998;77(1):31-37

  6. Remvig L, Jensen DV, Ward RC. Are diagnostic criteria for general joint hypermobility and benign joint hypermobility syndrome based on reproducible and valid tests? A review of the literature.J Rheumatol. 2007;Apr;34(4): 798-803

  7. Remvig L, Flycht L, Christensen KB, Juul-Kristensen B. Lack of consensus on tests and criteria for generalized joint hypermobility, Ehlers–Danlos syndrome: Hypermobile type and joint hypermobility syndrome. Am J Med Genet A. 2014:Mar;164A(3);591-596

  8. Tinkle BT, Bird HA, Grahame R, et al. The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A. 2009; Nov;149A(11):2368-2370

  9. Castori M, Dordoni C, Valiante M, et al. Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: a study of intrafamilial and interfamilial variability in 23 Italian pedigrees. Am J Med Genet A. 2014 Dec;164A(12):3010-3020

  10. Tinkle B, Castori M, Berglund, B, et al. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):48-69

  11. Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet. 2017;175C:148-157

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  Conflict of Interest:
  None declared.

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• Published on: 29 November 2019

  Reply to “Concerns regarding the inference that EDS is not rare"

  • Joanne C Demmler, Lecturer Health Data Research UK, Swansea University
  • Other Contributors:
    • Mark D Atkinson,, Research Officer, Secure Anonymised Information Linkage (SAIL) Databank
    • Emma J Reinhold, RCGP Clinical Champion for the Ehlers-Danlos Syndromes
    • Ernest Choy, Professor, Arthritis Research UK CREATE Centre, Section of Rheumatology, Division of Infection and Immunity
    • Ronan A Lyons, Professor, Health Data Research UK

  We would like to thank Hakim et al for the opportunity to continue the debate around the prevalence and definitions of conditions associated with joint hypermobility. Coming to anything like a true population prevalence for these conditions is still a long way off due to both the huge under-diagnosis (1) and ongoing evolution of the clinically-based criteria (2-4) and terminology for patients who do not have one of the known genetic mutations for classical, vascular or the other so-called rare subtypes of Ehlers-Danlos Syndrome (EDS).

  Hakim et al assert in their letter that diagnosed Joint Hypermobility Syndrome (JHS) is known to be ‘common’. We have searched the literature for reported whole population prevalence rates for JHS and have been unable to find any. Therefore our paper is the first to report a diagnosed prevalence for this condition, although this figure can also be derived for the population of Sweden, as we pointed out in our work. (5)

  We completely agree with the letter’s authors that at this point in time it is not possible to know what proportion of people who met the Brighton Criteria for JHS also meet the 2017 hEDS criteria. We hope further research may reveal this data in the future. What we can say, however, is that for the decade or so prior to 2017, experts in the field considered JHS and EDS-HT to be clinically indistinguishable (1, 6-10), indeed many clinicians used the term JHS/EDS-HT in correspondence in recognition of this. Indeed,...

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  We would like to thank Hakim et al for the opportunity to continue the debate around the prevalence and definitions of conditions associated with joint hypermobility. Coming to anything like a true population prevalence for these conditions is still a long way off due to both the huge under-diagnosis (1) and ongoing evolution of the clinically-based criteria (2-4) and terminology for patients who do not have one of the known genetic mutations for classical, vascular or the other so-called rare subtypes of Ehlers-Danlos Syndrome (EDS).

  Hakim et al assert in their letter that diagnosed Joint Hypermobility Syndrome (JHS) is known to be ‘common’. We have searched the literature for reported whole population prevalence rates for JHS and have been unable to find any. Therefore our paper is the first to report a diagnosed prevalence for this condition, although this figure can also be derived for the population of Sweden, as we pointed out in our work. (5)

  We completely agree with the letter’s authors that at this point in time it is not possible to know what proportion of people who met the Brighton Criteria for JHS also meet the 2017 hEDS criteria. We hope further research may reveal this data in the future. What we can say, however, is that for the decade or so prior to 2017, experts in the field considered JHS and EDS-HT to be clinically indistinguishable (1, 6-10), indeed many clinicians used the term JHS/EDS-HT in correspondence in recognition of this. Indeed, in guidance released by The Ehlers-Danlos Society alongside the 2017 reclassification, it is stated that “if someone was diagnosed with hEDS before the 2017 criteria, there’s no cause to seek a new diagnosis unless they decide to participate in new research or need to be reassessed for some other reason”. (11(p.1)) For these reasons, we would maintain that grouping patients with JHS and EDS-HT is legitimate. However, in order to accurately reflect the current classification, notwithstanding the fact that the hEDS criteria are being revised at the present time, we chose to recognise the term Hypermobility Spectrum Disorders (HSD) as a possible diagnosis for an unknown proportion of these patients. The same 2017 guidance states that “treatment is more important than labels” (11( p.1)) With this sentiment we wholeheartedly agree. We cannot know how many of the patients in this historical cohort meet which clinical criteria now, nor indeed at the time they were given these labels. But we can say that there are many more people than previously realised who are suffering from symptomatic generalised joint hypermobility and its associated multisystemic features (8), by whatever definition. It is patients and their symptoms which we believe we should be focusing on until such time as we have a clearer understanding of the presumed underlying genetic factors.

  To test Hakim et al’s hypothesis that the characteristics of the JHS and EDS groups could differ, we decided to repeat our case-control calculations, combining all ages but separating the two diagnostic groups, and we present this data in figures 1 and 2. We find it interesting that the two groups show such homogeneity, with no significant differences across the 35 Read chapter categories, other than in additional musculoskeletal diagnoses and musculoskeletal medications for those with JHS within the 12 months before and after diagnosis. We believe this adds to the previously held opinion that JHS and the hypermobile form of EDS as assessed by the previous Villefranche or Berlin criteria are clinically indistinguishable. We did find a difference in the age and gender characteristics of the two populations (see figures 3 and 4), possibly related to patterns of referral depending on age and symptomatology, which could potentially explain the observed difference in musculoskeletal findings. This is speculation, however, and we would encourage exploration of our cohorts by other researchers who may be able to elucidate this further. The speculation by Hakim et al that it is possible that no one with a previous diagnosis of JHS would meet the 2017 hEDS criteria seems unlikely to us, based on our clinical experience and the observations of others since 2017 (12-14) (Eccles, J A, written communication, 6th and 14th November 2019), but others must draw their own conclusions until such time as we have further research data on this question. We thank the respondents for their intriguing calculation that if just 15% of people with a previous diagnosis of JHS now meet the 2017 hEDS criteria, this would be sufficient to find EDS not to be rare. We ourselves made no attempt to model or guess at the proportions, but simply reported the available coded data.

  Where Hakim et al refer to the proportion of ‘the EDS cohort’ which have hEDS versus the other subtypes, it is unclear whether they are referring to our data or to people with EDS in general. We were careful to set out in detail where patients had a subtype of EDS recorded and where they did not. Whilst we might all presume that the overwhelming majority of patients with the header code EDS in fact have the hypermobile form, we cannot make this assumption without supporting evidence. Given how few individuals had a coded subtype other than hypermobile, we made the decision to include all people with EDS in our study. We have been very careful to consistently talk about a combined prevalence of EDS and JHS in our paper and stated that other subtypes of EDS are genuinely rare and regret if this has been misquoted on social media.

  We completely agree with Hakim at al that ‘further studies are required to determine how common HSD, hEDS, and other forms of EDS are’, however at the present moment, after the 2017 reclassification but whilst we are awaiting a revision and validation of the hEDS criteria, such studies, at least at an epidemiological level, are virtually impossible, especially when one considers the inconsistency between these diagnostic labels and the clinical codes available. No new clinical codes have been introduced post the 2017 classification to distinguish between JHS/EDS-HT and HSD/hEDS or to expand on the sub-coding of EDS. (15) The definitions of ‘Hypermobility Spectrum Disorders’ remain confusing, and to date, there has been no research which has been able to demonstrate a difference between those who meet the hEDS criteria and those who fall into HSD12 (16-18).

  We reject the assertion that we combined JHS and EDS populations in order ‘to identify a larger absolute value for prevalence’. At all times we worked from the clinical guidance about these conditions, although obviously constrained by the historical nature of the coded data. We do not seek to remove the protected ‘rare’ status from all subtypes of EDS, but from the data available to us, we made what we felt to be the most accurate calculations we could, and our paper passed through the full rigours of open peer review prior to publication. It should not be forgotten, again, that the vast majority of patients remain without a diagnosis. (1) In terms of NHS England hEDS is already effectively excluded from the provision of specialist commissioning for rare diseases. (19(p.26)) But because it is still believed to be ‘rare’, there is also a lack of appropriate locally commissioned services tailored to the needs of this group. Our work in no way intends to disrupt the pathways or support available for people who require genetic sequencing to confirm subtypes of EDS with known mutations, and nor should it. We do hope that as a result of our work, clinicians, commissioners, educators and others will come to realise the significance, and higher prevalence than previously realised, of hypermobility-related conditions.

  Figure 1: see here https://blogs.bmj.com/bmjopen/files/2019/11/figure-1.jpg
  Odds ratios of Read chapter diagnoses within 12 months before and after EDS or JHS diagnosis. Presented are all results that affect at least 5 cases or 20 controls. Chapters are as follows: A: Infectious/parasitic diseases; B: Neoplasms; C: Endocrine.butr./metab./immun. Disease; D: Blood/blood forming organs disease; E: Mental disorders; F: Nervous system / sense organ disease; G: Circulatory system disease; H: Respiratory system disease; J: Digestive system disease; K: Genitourinary system disease; L: Pregnancy / childbirth /puerperium; M: Skin/ subcutaneous tissue disease; N: Musculoskeletal / connective tissue; P: Congenital anomalies; R: Symptoms, signs, ill-defined conditions; S: Injury and poisoning; T: Causes of injury and poisoning; U: External causes of morbidity and mortality; Z: Unspecified conditions

  Figure 2: see here https://blogs.bmj.com/bmjopen/files/2019/11/figure-2.jpg
  Odds ratios of Read chapter prescriptions 12 months before and after EDS or JHS diagnosis. Presented are all results that affect at least 5 cases or 20 controls. Chapters are as follows: a: Gastro-intestinal drugs; b: Cardiovascular drugs; c: Respiratory drugs; d: Central Nervous System drugs; e: Drugs used in Infections; f: Endocrine drugs; g: Obs/Gynae/Uti drugs; h: Chemotherapy/ Immunosupp drugs; i: Heamatology/Dietetic drugs; j: Musculoskeletal drugs; k: Eye drugs; l: ENT drugs; m: Skin drugs; n: Immunology drugs and vaccines; o: Anaesthetic drugs; p: Appliances and reagents (dressing etc.)

  Figure 3: see here https://blogs.bmj.com/bmjopen/files/2019/11/figure-3.jpg
  Age at first coded diagnosis of EDS by age group and gender in the case-control cohort.

  Figure 4: see here https://blogs.bmj.com/bmjopen/files/2019/11/figure-4.jpg
  Age at first coded diagnosis of JHS by age group and gender in the case-control cohort.

  References

  1. Grahame R. Hypermobility: an important but often neglected area within rheumatology. Nature Clinical Practice Rheumatology 2008;4(10):522-24. doi: 10.1038/ncprheum0907
  2. De Wandele L, Rombaut L, Coussens M, et al. A suggestion for refining the new diagnostic criteria for hypermobile EDS. International Symposium on the Ehlers-Danlos Syndromes. Ghent, Belgium, 2018.
  3. Rombaut L, De Wandele L, Coussens M, et al. The 2017 diagnostic criteria for hEDS: the Ghent data and experience, and a suggestion for refining the new diagnostic criteria for hEDS. International Symposium on the Ehlers-Danlos Syndromes. Ghent, Belgium, 2018.
  4. Grahame R. Should comorbidities be included in the hEDS criteria? International Symposium on the Ehlers-Danlos Syndromes. Ghent, Belgium, 2018.
  5. Cederlöf M, Larsson H, Lichtenstein P, et al. Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers-Danlos syndrome or hypermobility syndrome and their siblings. Bmc Psychiatry 2016;16 doi: 10.1186/s12888-016-0922-6
  6. Gazit Y, Jacob G, Grahame R. Ehlers-Danlos Syndrome-Hypermobility Type: A Much Neglected Multisystemic Disorder. Rambam Maimonides Medical Journal 2016;7(4) doi: 10.5041/rmmj.10261
  7. Tinkle B, Castori M, Berglund B, et al. Hypermobile Ehlers-Danlos Syndrome (a.k.a. Ehlers-Danlos Syndrome Type III and Ehlers-Danlos Syndrome Hypermobility Type): Clinical Description and Natural History. American Journal of Medical Genetics Part C-Seminars in Medical Genetics 2017;175(1):48-69. doi: 10.1002/ajmg.c.31538
  8. Castori M, Tinkle B, Levy H, et al. A Framework for the Classification of Joint Hypermobility and Related Conditions. American Journal of Medical Genetics Part C-Seminars in Medical Genetics 2017;175(1):148-57. doi: 10.1002/ajmg.c.31539
  9. Castori M, Dordoni C, Valiante M, et al. Nosology and Inheritance Pattern(s) of Joint Hypermobility Syndrome and Ehlers-Danlos Syndrome, Hypermobility Type: A Study of Intrafamilial and Interfamilial Variability in 23 Italian Pedigrees. American Journal of Medical Genetics Part A 2014;164(12):3010-20. doi: 10.1002/ajmg.a.36805
  10. Tinkle BT, Bird HA, Grahame R, et al. The Lack of Clinical Distinction Between the Hypermobility Type of Ehlers-Danlos Syndrome and the Joint Hypermobility Syndrome (a.k.a. Hypermobility Syndrome). American Journal of Medical Genetics Part A 2009;149A(11):2368-70. doi: 10.1002/ajmg.a.33070
  11. The Ehlers-Danlos Society. Hypermobile Ehlers-Danlos syndrome (hEDS) vs. Hypermobility Spectrum Disorders (HSD): What’s the Difference? no date [Available from: https://ehlers-danlos.com/wp-content/uploads/hEDSvHSD.pdf.
  12. Huynh J, Saboda K, Sanoja A, et al. Patient-reported symptoms do not differ between people who do and do not meet hEDS criteria. International Symposium on the Ehlers-Danlos Syndromes. Ghent, Belgium, 2018.
  13. McGillis L, Clarke H, Hussey L, et al. Experiencing utilizing the 2017 criteria for diagnosis of Ehlers-Danlos syndrome: a Canadian perspective. International Symposium on the Ehlers-Danlos Syndromes. Ghent, Belgium, 2018.
  14. Rosen C, O'Connor C, Schwartz S, et al. Application of the 2017 hypermobile EDS diagnostic criteria in a paediatric population. International Symposium on the Ehlers-Danlos Syndromes. Ghent, Belgium, 2018.
  15. Facts and Dimensions. New UK Health Dimensions Database For Use by all NHS Organisations no date [Available from: https://factsanddimensions.co.uk/.
  16. Chiarelli N, Ritelli M, Zoppi N, et al. Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers-Danlos Syndromes. Genes 2019;10(8) doi: 10.3390/genes10080609
  17. Zoppi N, Chiarelli N, Binetti S, et al. Dermal fibroblast-to-myofibroblast transition sustained by alpha v beta 3 integrin-ILK-Snaill/Slug signaling is a common feature for hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Biochimica Et Biophysica Acta-Molecular Basis of Disease 2018;1864(4):1010-23. doi: 10.1016/j.bbadis.2018.01.005
  18. Copetti M, Morlino S, Colombi M, et al. Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients. Rheumatology 2019;58(10):1722-30. doi: 10.1093/rheumatology/kez029
  19. NHS England. Highly specialised services 2018 2018 [Available from: https://www.england.nhs.uk/commissioning/wp-content/uploads/sites/12/201....

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  Conflict of Interest:
  None declared.

  • Back to top
• Published on: 12 November 2019

  Concerns regarding the inference that EDS is not rare

  • Alan J Hakim, Adjunct Associate Professor in Medicine College of Medicine, PennState University, USA
  • Other Contributors:
    • Clair A Francomano, Professor of Medical and Molecular Genetics
    • Marco Castori, Consultant and Director, Division of Medical Genetics
    • Fransiska Malfait, Associate Professor

  Dear Sir or Madam

  Re. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison.
  Demmler J C, Atkinson M D, Reinhold E, Choy E, Lyons R A, Brophy S T
  BMJ Open 2019;9:e031365

  We write concerning the paper by Demmler et al., published in BMJ Open. We wish to raise the following concerns:

  1. With regard to combining the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) populations for analysis.

  If one combines data from a cohort that is found to be ‘common’ (in this case ‘diagnosed JHS’) with one that is found to be ‘rare’ (in this case ‘diagnosed EDS’), the new combined cohort (i.e. diagnosed JHS/EDS) will be common. To then consider the rare cohort common is a fallacy.

  Also, although individuals in a population with a previous diagnosis of JHS (i.e. prior to the 2017 international classification (1,2)) might have Hypermobile EDS (hEDS) by the current classification, it is not known how JHS segregates into Hypermobility Spectrum Disorder (HSD) and hEDS. A JHS population would need to be reassessed to confirm this, or modelling assumptions of the data would need to be applied.
  In addition, it is not known what proportion of the EDS cohort have hEDS versus the rare Mendelian types of EDS. As such, there is no way of knowing whether or by what proportion the two cohorts represent the same or similar or dif...

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  Dear Sir or Madam

  Re. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison.
  Demmler J C, Atkinson M D, Reinhold E, Choy E, Lyons R A, Brophy S T
  BMJ Open 2019;9:e031365

  We write concerning the paper by Demmler et al., published in BMJ Open. We wish to raise the following concerns:

  1. With regard to combining the Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos syndromes (EDS) populations for analysis.

  If one combines data from a cohort that is found to be ‘common’ (in this case ‘diagnosed JHS’) with one that is found to be ‘rare’ (in this case ‘diagnosed EDS’), the new combined cohort (i.e. diagnosed JHS/EDS) will be common. To then consider the rare cohort common is a fallacy.

  Also, although individuals in a population with a previous diagnosis of JHS (i.e. prior to the 2017 international classification (1,2)) might have Hypermobile EDS (hEDS) by the current classification, it is not known how JHS segregates into Hypermobility Spectrum Disorder (HSD) and hEDS. A JHS population would need to be reassessed to confirm this, or modelling assumptions of the data would need to be applied.
  In addition, it is not known what proportion of the EDS cohort have hEDS versus the rare Mendelian types of EDS. As such, there is no way of knowing whether or by what proportion the two cohorts represent the same or similar or different conditions.

  Given the distribution of JHS to EDS in this study is approximately 6 to 1, the combined cohort would likely share the characteristics of the JHS cohort in a case-control analysis.
  By combining the two populations to explore association with other aspects of health and wellbeing the opportunity to compare differences between the two groups is lost. Do the populations in this study differ? What evidence is there that JHS and EDS are behaving statistically in the same way or differently with regard to the parameters collected?

  We surmise that the authors in part combined the two populations to identify a larger absolute value for prevalence that informs the need for education, training and healthcare resources. It is increasingly recognized that complex combinations of health concerns arise in HSD and hEDS alike. We recognise why HSD and hEDS would be considered together in this context.
  However, by their nature the rare types of EDS will have different specific concerns that influence different education and training needs, and healthcare resource allocation. Rare disease status has significant impact on the way healthcare services plan care (e.g. direct commissioning of specialised services in the UK); or the way organisations support research ( e.g. The Office of Rare Diseases, The National Center for Advancing Translational Sciences, USA), for example.

  Regardless of combining the prevalence, it remains necessary that we understand the size effect for each of the different patient populations, as specific needs may differ.

  2. With regard to interchanging the term JHS with HSD and hEDS, and determining the prevalence of EDS:

  The authors switch from the term JHS to a combination of HSD and hEDS. We recognize this inference. Nevertheless, at this time there is no evidence to inform how JHS segregates into HSD or hEDS, and this uncertainty was not clarified in the paper. There is no modelling of the data that might support inferences with regard to such segregation.
  What proportion of the JHS group might add to the overall prevalence of hEDS? How does that modelling affect the prevalence of EDS over all when added to the EDS cohort data?
  For example, by our estimate approximately 15% of the JHS cohort would need to have hEDS for this prevalence figure plus that from the EDS cohort to reach a population size of 50 per 100000 for EDS as a whole in this study. Even then that would be 1 in 2000 of the general population; and given that some of the EDS cohort would not have hEDS this would also infer that hEDS per se is rare as it would be a proportion of that EDS population.
  If none of the JHS population had hEDS the prevalence calculation for EDS using only the EDS cohort data demonstrates EDS to be rare.
  There are other ways to model the data, but we hope that this demonstrates our point.

  Until reasonable evidence is available as to the segregation of JHS into hEDS and HSD, we believe studies such as that of Demmler et al. should present the data as found for JHS, or define the assumptions and models they are using to reach their conclusions. In addition, studies should avoid clustering JHS and EDS. The term EDS is a pleural (i.e. Ehlers-Danlos syndromes), grouping together disorders under the title.

  Further studies are required to determine how common HSD, hEDS, and other forms of EDS are. Shared knowledge among members of the international medical and scientific community suggest that HSD is likely common; that more work is required to determine if hEDS is common or not; and, that other Mendelian types of EDS are rare or ultra-rare.

  3. Concerning the combining the populations and the paper's Conclusion.

  The authors conclude that “EDS/HSD are not rare conditions…”. This is asserted because the authors have combined the JHS and EDS populations. We question the reasoning for combining the populations above, but wish, here, to raise further concern about interpretation.

  We are aware that this publication is being cited in public forums as saying ‘EDS is common’. At this time, from the data presented, there is no evidence to support that statement, for either hEDS or the rarer types of EDS. Even were it found that hEDS is not rare, it is that observation that would make most sense to assert given many forms of EDS are between rare and ultra-rare.

  While there is no direct statement from the authors that ‘EDS is common’, we suggest that the opinion has arisen because of the way the whole paper, including the conclusion has been presented.

  We respectfully request that the editors of BMJ Open and the paper’s authors consider the above.

  Yours faithfully,

  Dr. Alan J Hakim, Adjunct Associate Professor of Medicine, College of Medicine, PennState University, USA, & Consultant Rheumatologist, London

  Dr Clair A. Francomano, Professor of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA

  Dr. Marco Castori, Consultant and Director, Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy

  Prof. Fransiska Malfait, Associate Professor, Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

  References:

  Malfait F, Francomano C, Byers P, et al. 2017. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet 175C:8–26.

  Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. 2017. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet 175C:148-157.

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  Conflict of Interest:
  None declared.

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