What causes the overlap of symptoms between Systemic Lupus Erythematosus (SLE), Mast Cell Activation Syndrome (MCAS), autonomic dysfunction, and Hypermobile Ehlers-Danlos Syndrome (hEDS)?

From the Guidelines

The overlap of symptoms between Systemic Lupus Erythematosus (SLE), Mast Cell Activation Syndrome (MCAS), autonomic dysfunction, and Hypermobile Ehlers-Danlos Syndrome (hEDS) is primarily due to shared inflammatory pathways and connective tissue abnormalities, as evidenced by recent studies 1. These conditions frequently co-occur because they share underlying mechanisms involving immune dysregulation and tissue integrity issues.

Key Mechanisms

• In SLE, autoimmune activity causes widespread inflammation affecting multiple organ systems.
• MCAS involves inappropriate mast cell activation, releasing inflammatory mediators like histamine that cause allergy-like symptoms throughout the body.
• Autonomic dysfunction often results from inflammation affecting the autonomic nervous system, disrupting involuntary bodily functions.
• In hEDS, genetic collagen defects create connective tissue fragility that affects blood vessels, skin, and joint stability, which can trigger secondary inflammatory responses.

Overlapping Symptoms

The common thread is that connective tissue abnormalities can trigger mast cell activation, which releases inflammatory mediators that may exacerbate autoimmune responses and disrupt autonomic function. This creates overlapping symptoms like:

• Fatigue
• Pain
• Gastrointestinal issues
• Cardiovascular abnormalities

Diagnosis and Management

Diagnosis typically requires comprehensive evaluation by specialists familiar with these conditions, often including rheumatologists, immunologists, geneticists, and autonomic specialists, as no single test can definitively diagnose all these conditions simultaneously 1. A thorough workup for each condition and treatment according to evidence-based medical standards is essential, even with a precise diagnosis of MCAS or other conditions 1. Recent studies suggest that patients with long COVID may also experience similar overlapping symptoms, highlighting the need for further research into the relationship between these conditions 1.

From the Research

Overlapping Symptoms

The overlap of symptoms between Systemic Lupus Erythematosus (SLE), Mast Cell Activation Syndrome (MCAS), autonomic dysfunction, and Hypermobile Ehlers-Danlos Syndrome (hEDS) can be attributed to several factors. Some key points to consider include:

• Chronic inflammation and immune-mediated responses play a significant role in the development of these conditions 2, 3.
• Aberrant mast cell activation has been shown to contribute to the disruption of connective tissue integrity, leading to symptoms associated with hEDS and MCAS 2, 4.
• The co-occurrence of MCAS, postural tachycardia syndrome (POTS), and hEDS is well-documented, with studies suggesting a significant relationship between these conditions 5.
• Autonomic dysfunction, such as POTS, can also contribute to the overlap of symptoms between these conditions 5, 3.

Shared Pathophysiology

The shared pathophysiology between hEDS, MCAS, and other conditions like long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an area of ongoing research. Key findings include:

• Hypermobility spectrum disorders (HSD) and hEDS are often comorbid with conditions like ME/CFS, fibromyalgia, and POTS 3.
• Mast cell activation and degranulation may contribute to hyperinflammation and damage to connective tissue, leading to hypermobility and other symptoms 3, 4.
• The relationship between MCAS and hEDS is complex, with some studies suggesting that certain variants of MCAS may drive hEDS 4.

Clinical Implications

The overlap of symptoms between these conditions has significant implications for clinical diagnosis and treatment. Some key points to consider include:

• A multidisciplinary approach is required for the treatment of patients with hEDS and other related conditions 2.
• Screening for hypermobility and other related conditions is essential for individuals experiencing symptoms like fatigue, musculoskeletal pain, and dysautonomia 3.
• Pharmacological treatments should be symptom-focused and geared to a patient's presentation, with non-pharmacological interventions like paced exercise, massage, and meditation also providing benefits 3.