Systematic Literature Review

Both patients and the medical community have long hypothesized over the interconnectedness of the triad of Ehlers Danlos Syndrome, Mast Cell Activation and dysautonomia. Indeed, when this review was proposed at the last scientific meeting of the Ehlers Danlos Society, it attracted an abundance of interest and attention for clinicians and patients alike. We know that eastern medical systems repeatedly mention connective tissue and mast cell in the same context. Thus, searches must be broadened beyond Western medical ideals. Indeed, previous reviews of this nature have also concluded that broader and more systematic work should be pursued, recognising that this would require an international approach, and extensive time investment (Kucharik et al, 2019; Kohn, 2020; Monaco et al, 2022; Wang et al, 2021). Looking at other medical systems, we may provide answers which can jumpstart research worldwide. Considering the above, this proposed global systematic literature review expands upon these earlier outputs to include all languages and medical systems to determine what, if any pathophysiological mechanisms there are between the triad of Ehlers-Danlos Syndrome, Mast Cell Activation and Dysautonomia. This will further our understanding of which hypotheses exist for these connections and thus better direct further studies in this pursuit.

Overall, this project aims to:

1. Determine where two or more of the following conditions (Ehlers-Danlos Syndrome Hypermobility Spectrum Disorders, Mast Cell Activation, and Dysautonomia) are discussed as concomitant pathologies in scientific literature.
2. Determine possible pathophysiological mechanism(s) of Ehlers-Danlos Syndrome, Hypermobility Spectrum Disorders, Mast Cell Activation, or Dysautonomia.
3. Determine whether Ehlers-Danlos Syndrome, Hypermobility Spectrum Disorders, Mast Cell Activation, and/or Dysautonomia have been described within any other medical system under different names.

Project management will be overseen by the two PIs with support from our affiliate research centres. The team will meet bi-weekly to ensure key milestones are met and outcomes are produced with maximum impact. The protocol for this study has already been listed on PROSPERO.

Co leading this project are distinguished members of the Ehlers Danlos society’s international consortium Dr Isabelle Brock and Dr Sally Pezaro. Dr Pezaro recently led A scoping review and expert co-creation of evidence-based clinical guidelines for the management of childbearing with hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders in partnership with Dr Brock.

We intend to work collaboratively with a much wider interdisciplinary team, which has extensive experience in conducting rigorous systematic literature reviews. We will also engage with stakeholders and representatives from allergy immunology, gastrointestinal, pulmonology, rheumatology, endocrinology, orthopedics, genetics, and gynecology throughout. Our core team covers the disciplines of medicine, midwifery, patient perspective, acupuncture, and veterinary medicine.

Approach

Via rigorous methodologies and guided via the Joanna Briggs Institute, we will conduct a systematic review of the literature to comprehensively answer the following question: “In what ways are the Ehlers Danlos Syndromes, Mast Cell Activation and dysautonomia interrelated in terms of both concomitant pathologies and pathophysiological mechanism(s)?

In this task we will not be limited by language, nor by medical model. This review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Search databases include: CINAHL, Cochrane, Elsevier, MEDLINE, PubMed, Scopus, Trip, EThOS, ABIM, DHARA, AYUSH, Google Scholar, TCMID, COJ, ECOJ, KMbase, KTKP, and Jintu. There will be no date or publication restrictions. The search will be repeated prior to final analysis and publication. Editors and authors will also be contacted to access any new data required.

Search terms: These will be finalized in partnership with stakeholder groups and will include previous nomenclature for all conditions in 24 languages.

The Mixed Methods Appraisal Tool (MMAT) will be used to assess the quality of any primary studies included. PRISMA guidelines will be used to direct reporting. The full protocol for this review has been registered with the international Prospective Register of Systematic Reviews (PROSPERO).

Analysis: We will conduct a framework analysis whereby each of the conditions is used as a template under which to group and cross reference common themes to be synthesized from the literature.

Patient Involvement

Aside from the academic imperative for this work, people who have lived experience with EDS and HSD have called for this work to ascertain whether or not there is a link between hypermobility, dysautonomia and mast cell disorder symptoms to inform improved symptom management. Indeed, requests have come from our conference presentations, alongside clinical encounters. Patient voices have been involved with this project from inception through the development of keywords, search strategies, budgeting, and planning. We have lived experience members in our team. Our plans involve the inclusion of patient participants throughout (e.g. in the review of articles, report writing and dissemination of findings). We will also hold regular in-person focus groups and surveys with patients to determine:

• What we should be looking for
• How we need to remain flexible and adaptable in the process.
• What questions patients/public have with regards to the triad
• How patients/public want to see any results/recommendations presented.

Patients and other stakeholders may also be asked to review documents, dissemination materials and publications prior to their launch outside of planned focus groups. Participants involved in all these activities will be compensated in the form of online shopping vouchers. We will conduct meetings online to reduce our carbon footprint and also to promote inclusion and widen participation where possible. We are committed to decolonial feminist approaches which promote equity and justice for all. This will underpin the work we do and ensure inclusivity throughout.

Expected Outcomes/ Impact

Any correlations and relationships identified in the review would be published open access and used to inform clinical care and future research, leading to treatment protocols where conditions overlap. The rigor of our approach will enable us to evaluate how we have met our overall aims. Nevertheless, we recognise that this review will require updating periodically.

Our patient and public engagement thus far suggest this is a highly anticipated project and one which would create impact in the field where currently evidence is limited, particularly in terms of bringing together a global picture as we propose to do here.

As one can see this is a huge undertaking in this global approach and thus needs funding.

Thank you for your help with any donation.

If you would like to fund the entire project please contact Dr. Brock at research@connective-tissue-issues.com directly.