EDS and Autoimmune disease

Introduction

Ehlers-Danlos Syndrome (EDS) is a group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Among the 13 recognized subtypes, hypermobile EDS (hEDS) is the most common—but also the only form without an identified genetic marker. Traditionally considered a musculoskeletal disorder, hEDS is now increasingly recognized as a multisystem condition. One of the most important emerging themes is the frequent overlap between hEDS and various forms of immune dysfunction, including allergic disease, autoimmunity, and immunodeficiency. Understanding these immune issues is critical for improving diagnostic accuracy and developing effective treatment strategies.

The Immune Landscape of hEDS

Recent research highlights a significant co-occurrence between hEDS and immune system abnormalities. Patients often present with a combination of:

• Mast Cell Activation Disease (MCAD)
• Primary immunodeficiencies (PIDs), such as IgG subclass deficiencies and IgA deficiency
• Autoimmune diseases, including rheumatoid arthritis and lupus

These overlapping immune features contribute to the high symptom burden in hEDS and may explain its multisystem nature.

Mast Cell Activation in hEDS

Mast cells play a dual role in both protecting tissue from injury and contributing to inflammation. In hEDS, the fragility of connective tissue may trigger chronic mast cell activation, leading to a condition known as Mast Cell Activation Disease (MCAD). A major study found that 10% of patients with hEDS or Hypermobility Spectrum Disorder (HSD) had co-occurring MCAD, while 19% had MCAD combined with immunoglobulin deficiency​. Symptoms of MCAD include:

• Flushing, rashes, hives
• Gastrointestinal discomfort, diarrhea, or nausea
• Wheezing or asthma-like symptoms
• Tachycardia, dizziness, and fainting episodes—often overlapping with POTS

The activation of mast cells appears to be more prevalent in females, possibly influenced by estrogen and progesterone receptor expression on both mast cells and epithelial barriers​.

Primary Immune Deficiencies (PIDs) in hEDS

Several patients with hEDS also demonstrate primary immunodeficiencies, including:

• IgG subclass deficiencies
• IgA deficiency
• Low total IgG or impaired vaccine response

A 2022 study found that nearly half of all patients with Ig deficiency also had hEDS or HSD​. These deficiencies may contribute to frequent infections, prolonged recovery times, and persistent inflammation. Importantly, PIDs have also been linked to musculoskeletal complaints such as arthritis, which may mimic or worsen symptoms typically attributed to hEDS​.

Autoimmunity and hEDS

While not classically categorized as an autoimmune disorder, hEDS has been shown to co-occur with a range of autoimmune conditions, including:

• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis (RA)
• Sjögren’s syndrome
• Autoimmune thyroiditis

Some case reports describe individuals with all three conditions—EDS, SLE, and Myasthenia Gravis—suggesting a common thread of immune dysregulation​. Shared features include positive antinuclear antibodies (ANA), thymic abnormalities, and susceptibility to immune complex-mediated damage.

Rheumatic Disease and hEDS

Rodgers et al. found that patients with hEDS who received a comprehensive workup were far more likely to have a coexisting rheumatic disease than those who did not (67.1% vs. 9.2%)​. Commonly associated conditions included:

• Rheumatoid arthritis
• Ankylosing spondylitis
• Psoriatic arthritis
• Fibromyalgia

Notably, HLA-B27—a marker often associated with spondyloarthropathies—was found in nearly a quarter of comprehensively worked-up hEDS patients, compared to only 6.1% in the general population​.

Functional and Quality-of-Life Impacts

Foot pain and disability are common among women with EDS and have been shown to significantly impair quality of life. A recent cross-sectional study comparing women with EDS, RA, and SLE found that those with EDS had some of the lowest scores in both physical and mental quality of life assessments, even when pain severity was similar​. The authors concluded that immune and musculoskeletal overlap syndromes likely contribute to high disability and reduced function in EDS, especially when left unrecognized.

Clinical Recommendations

Based on the growing body of evidence, clinicians should consider screening for immune dysfunction in patients with hEDS or HSD. Recommendations include:

• Screening for MCAD in patients with flushing, GI symptoms, or anaphylaxis-like episodes
• Screening for IgG, IgA, and IgM deficiencies, especially in patients with frequent infections
• ANA and rheumatoid factor testing in patients with unexplained joint pain or systemic symptoms
• Consideration of autoimmune thyroid testing, particularly in women with fatigue, weight changes, or mood disorders

A multidisciplinary approach—encompassing immunology, rheumatology, allergy, and physical medicine—is essential for optimizing care in this complex patient population.

Future Directions

Further research is urgently needed to clarify the mechanisms underlying immune dysregulation in hEDS. Potential areas of exploration include:

• The role of sex hormones in modulating mast cell and immune activity
• Epigenetic changes in connective tissue-immune signaling pathways
• Personalized immunomodulatory therapies tailored to EDS subtypes

Conclusion

Immune dysfunction is common in hypermobile Ehlers-Danlos syndrome and may present as allergic, autoimmune, or immunodeficient phenotypes—or all three simultaneously. These overlapping immune issues add complexity to the clinical picture and often go unrecognized. Early diagnosis and intervention may not only improve symptoms but also prevent long-term disability. As the research continues to evolve, there is growing hope for more targeted therapies and comprehensive care strategies that reflect the true multisystem nature of EDS.

References

1. Rodgers, K. R., Gui, J., Dinulos, M. B., & Chou, R. C. (2017). Ehlers-Danlos syndrome hypermobility type is associated with rheumatic diseases. Scientific Reports, 7, 39636. https://doi.org/10.1038/srep39636
2. Islam, M., Chang, C., & Gershwin, M. E. (2021). Ehlers-Danlos Syndrome: Immunologic contrasts and connective tissue comparisons. Journal of Translational Autoimmunity, 4, 100077.
3. Chau, A. S., & Jongco, A. M. (2018). Allergic and Immunologic Dysregulation in Ehlers-Danlos Syndrome: A Case Series. J Allergy Clin Immunol.
4. Branch, C. E., & Swift, T. R. (1978). Systemic lupus erythematosus, myasthenia gravis, and Ehlers-Danlos syndrome. Ann Neurol, 4(4), 374–375.
5. Palomo-Toucedo, I. C., et al. (2023). Foot Pain and Disability in Women with Rheumatoid Arthritis, Ehlers–Danlos Syndrome and Systemic Lupus Erythematosus: Relationship with Quality of Life. J. Clin. Med., 12, 6284. https://doi.org/10.3390/jcm12196284
6. Sordet, C., Cantagrel, A., Schaeverbeke, T., & Sibilia, J. (2005). Bone and joint disease associated with primary immune deficiencies. Joint Bone Spine, 72(6), 503–514. https://doi.org/10.1016/j.jbspin.2004.07.012

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