Biomarkers and Inflammation in Ehlers-Danlos Syndrome

Ehlers-Danlos syndromes (EDS) are a diverse family of heritable connective tissue disorders traditionally characterized by hypermobile joints, stretchy skin, and tissue fragility. But beneath this surface-level definition lies a far more intricate story—one that's beginning to unfold thanks to emerging research on inflammation and biomarkers. Among the subtypes, hypermobile Ehlers-Danlos syndrome (hEDS) stands out as the most common, yet also the most elusive. Unlike its rarer counterparts, hEDS has no known genetic mutation, making diagnosis and understanding of its pathophysiology particularly challenging.

But this is beginning to change.

The Fibronectin Fragment and ECM Clues

Recent discoveries have revealed a potential molecular fingerprint of hEDS and Hypermobility Spectrum Disorders (HSD). In 2025, a study published in the American Journal of Medical Genetics reported the detection of a 52 kDa fibronectin fragment in the plasma of individuals with hEDS and HSD. This fragment was absent in both healthy individuals and those with other disorders. It suggests a shared and specific underlying mechanism in hEDS and HSD—possibly tied to abnormal extracellular matrix (ECM) remodeling.

Proteomic analysis further revealed consistent patterns of ECM degradation, including increased fragments of collagen and tenascin-X. These findings not only move the field closer to a long-sought objective biomarker but also raise the possibility that hEDS and HSD may represent a spectrum of the same underlying biological process.

Inflammation: More Than a Side Effect?

Traditionally, hEDS has been described as a structural connective tissue disorder—mechanical in origin. Yet mounting evidence suggests that inflammation plays a critical and underappreciated role. In a comprehensive review, Caliogna and colleagues outlined elevated inflammatory markers in EDS patients, including cytokines, chemokines, and microRNAs that regulate immune response and oxidative stress.

These pro-inflammatory patterns may help explain the chronic fatigue, widespread pain, and neurological symptoms that so often accompany hEDS. Some researchers even posit that hEDS may share pathogenic overlap with autoimmune and rheumatologic diseases.

That theory gained further traction in a retrospective study by Rodgers et al., who found that individuals with hEDS were significantly more likely to be diagnosed with comorbid autoimmune and inflammatory diseases—including ankylosing spondylitis, rheumatoid arthritis, fibromyalgia, and psoriasis. Notably, 23.9% of hEDS patients who received comprehensive workups were positive for the HLA-B27 antigen, a genetic marker strongly associated with inflammatory arthritis.

Vascular EDS and Systemic Inflammation

Though genetically distinct from hEDS, vascular EDS (vEDS) offers additional insight into the role of inflammation in EDS more broadly. Morissette et al. conducted one of the most detailed examinations of inflammatory biomarkers in vEDS. Their study found significantly elevated levels of transforming growth factor-beta (TGF-β1 and TGF-β2), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and adhesion molecules (VCAM-1, ICAM-1). Mean platelet volume was also increased, suggesting ongoing vascular damage and platelet activation.

Interestingly, these inflammatory markers correlated with disease severity and were more elevated in patients who had already experienced vascular complications. This systemic inflammatory signature hints that the vasculopathy of vEDS may involve more than simple connective tissue fragility—perhaps a chronic, maladaptive wound-healing response tied to dysregulated ECM and immune signaling.

A Path Forward: Diagnosis and Therapy

What do these findings mean for the future of EDS care?

First, they offer hope for earlier and more accurate diagnosis—particularly for hEDS, which currently lacks a genetic test and is often diagnosed years after symptom onset. A reliable plasma biomarker like the 52 kDa fibronectin fragment could transform clinical practice.

Second, the inflammatory and immune involvement in EDS raises the possibility of new treatment avenues. Anti-inflammatory strategies, immunomodulatory therapies, or interventions targeting TGF-β signaling may benefit subsets of patients who have long been told there’s “nothing wrong” on standard labs or imaging.

Finally, these findings challenge the narrative that hEDS is merely a “benign hypermobility” issue. Instead, we’re beginning to understand it as a complex systemic disorder—one that disrupts structural proteins, immune balance, and homeostatic signaling throughout the body.

The connective tissue may be the canvas, but inflammation is increasingly revealing itself as one of the main artists painting the clinical picture of EDS.

References

Caliogna, L., Guerrieri, V., Annunziata, S., Bina, V., Brancato, A. M., Castelli, A., Jannelli, E., Ivone, A., Grassi, F. A., Mosconi, M., & Pasta, G. (2021). Biomarkers for Ehlers-Danlos Syndromes: There Is a Role? International Journal of Molecular Sciences, 22(18), 10149. https://doi.org/10.3390/ijms221810149

Milewicz, D. M., Reid, A. J., & Cecchi, A. C. (2014). Vascular Ehlers-Danlos syndrome: exploring the role of inflammation in arterial disease. Circulation: Cardiovascular Genetics, 7(1), 5–7. https://doi.org/10.1161/CIRCGENETICS.114.000507

Morissette, R., Schoenhoff, F., Xu, Z., Shilane, D. A., Griswold, B. F., Chen, W., Yang, J., Zhu, J., Fert-Bober, J., Sloper, L., Lehman, J., Commins, N., Van Eyk, J. E., & McDonnell, N. B. (2014). Transforming Growth Factor-β and Inflammation in Vascular (Type IV) Ehlers–Danlos Syndrome. Circulation: Cardiovascular Genetics, 7(1), 80–88. https://doi.org/10.1161/CIRCGENETICS.113.000280

Ritelli, M., Chiarelli, N., Cinquina, V., Bertini, V., Piantoni, S., Caproli, A., Della Pina, S. E. L., Franceschini, F., Zarattini, G., Gandy, W., Venturini, M., Zoppi, N., & Colombi, M. (2025). Bridging the Diagnostic Gap for Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: Evidence of a Common Extracellular Matrix Fragmentation Pattern in Patient Plasma as a Potential Biomarker. American Journal of Medical Genetics Part A, 197, e63857. https://doi.org/10.1002/ajmg.a.63857

Rodgers, K., Gui, J., Dinulos, M. B. P., & Chou, R. C. (2017). Ehlers-Danlos syndrome hypermobility type is associated with rheumatic diseases. Scientific Reports, 7, 39636. https://doi.org/10.1038/srep39636

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