Ehlers-Danlos Syndromes (EDS) are a group of hereditary disorders primarily affecting connective tissues, which provide structure and support throughout the body. These conditions are characterized by defects in collagen production or processing, leading to hypermobile joints, stretchy skin, and tissue fragility. Inflammation is the body’s complex biological response to harmful stimuli, typically involving immune cells and chemical mediators. Although EDS is fundamentally a structural disease, research suggests that the mechanical instability inherent to EDS drives a complex, low-grade inflammatory response. This chronic inflammation may explain many systemic symptoms experienced by patients.
Ehlers-Danlos Syndrome: A Systemic Condition
The primary genetic defects in EDS weaken the body’s structural scaffolding, leading to joint instability and tissue fragility throughout the body. While joint hypermobility is the most visible feature, the impact of compromised connective tissue is far-reaching, affecting virtually every organ system. This systemic involvement moves the condition beyond a simple musculoskeletal disorder.
Patients frequently experience widespread non-structural manifestations suggesting chronic disruption. These issues include profound chronic pain and debilitating fatigue, which are common complaints in clinical practice. Many individuals with EDS also contend with autonomic dysfunction, such as Postural Orthostatic Tachycardia Syndrome (POTS), and chronic gastrointestinal problems. The presence of these multi-systemic symptoms often prompts patients and clinicians to search for an inflammatory cause that links these seemingly disparate issues.
Identifying Specific Inflammatory Markers
Research into EDS, particularly the hypermobile type (hEDS), has identified specific biomarkers indicating systemic immune involvement, though the profile is distinct from typical inflammatory diseases. Standard markers of acute systemic inflammation, such as C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR), are frequently normal in hEDS patients. This often leads to misdiagnosis, as the inflammation present is not the high-level, acute type seen in conditions like rheumatoid arthritis.
However, circulating immune mediators suggest a state of chronic immune dysregulation. Studies have found altered cytokine signaling in hEDS patients, including specific pro-inflammatory cytokines like Interleukin-6 (IL-6), which show altered expression patterns in EDS fibroblast cells. In vascular EDS (vEDS), markers such as Monocyte Chemoattractant Protein-1 (MCP-1) and adhesion molecules (VCAM-1, ICAM-1) are often significantly elevated, pointing to chronic vascular damage and activation.
A significant source of measurable inflammation in EDS is the frequent co-occurrence of Mast Cell Activation Syndrome (MCAS). Mast cells are immune cells that release potent chemical mediators, including histamine and tryptase, causing localized inflammatory symptoms. Researchers are increasingly using changes in tryptase levels during symptom flares to correlate mast cell activity with clinical features in EDS. The chronic release of these mediators can drive symptoms like flushing, itching, gastrointestinal distress, and widespread pain.
Pathophysiology: The Link Between Connective Tissue and Immune Response
The mechanism linking a primary structural defect to chronic inflammation involves a dual pathway: mechanical stress and immune cell dysregulation. The inherent fragility of the connective tissue means that daily activities and normal movement cause constant micro-trauma to ligaments, tendons, and fascia. This persistent tissue damage releases cellular debris and fragments of the extracellular matrix (ECM).
These fragments act as damage-associated molecular patterns (DAMPs), which are danger signals initiating a localized, non-infectious immune response called sterile inflammation. This cycle of continuous micro-injury and incomplete repair creates a state of low-grade inflammation that sustains chronic pain and fatigue. The body’s attempt to heal unstable tissue may involve dysregulated immune responses, evidenced by the altered expression of components of the complement system in hEDS patients. This suggests innate immune dysfunction is a central feature, challenging the traditional view of the condition as purely structural.
The second major pathway involves mast cells embedded throughout the unstable connective tissue. Mechanical irritation from hypermobility and tissue laxity physically destabilizes these mast cells. This agitation triggers the cells to degranulate, releasing inflammatory contents like histamine and various cytokines into the surrounding environment. The resulting surge of chemical mediators drives a chronic inflammatory cycle, explaining the frequent comorbidity of MCAS with EDS.
Clinical Implications and Management Strategies
The knowledge that EDS involves a measurable inflammatory component has direct clinical implications for diagnosis and monitoring. Since traditional inflammatory markers like CRP are often unhelpful, clinicians rely heavily on a detailed clinical examination and patient history for diagnosis, especially for hEDS which lacks a specific genetic test. The identification of specific biomarkers, such as altered complement proteins or ECM fragments, offers hope for future objective diagnostic and monitoring strategies.
Management increasingly focuses on addressing the inflammatory and immune components of the disorder. Controlling mast cell activation is a primary management strategy, often achieved through a combination of medications. This typically involves using both H1-receptor blockers (e.g., cetirizine) and H2-receptor blockers (e.g., famotidine) to block histamine’s effects. Mast cell stabilizers are also employed to prevent the cells from releasing their inflammatory contents.
Targeted dietary changes can help reduce the inflammatory burden. An anti-inflammatory diet minimizing processed sugars and potential triggers like gluten or dairy is often recommended. Due to the high prevalence of MCAS, some patients find relief by following a low-histamine diet. Supportive care, such as gentle strengthening physical therapy and pain management techniques, remains central to stabilizing the structurally compromised body.