What antibodies should be tested in patients with Postural Orthostatic Tachycardia Syndrome (POTS)?

Antibody Testing in Postural Orthostatic Tachycardia Syndrome (POTS)

In patients with POTS, autoantibody testing should be targeted to those presenting with clinical manifestations suggesting autoimmune involvement, with specific focus on adrenergic receptor autoantibodies and angiotensin II type 1 receptor autoantibodies. 1, 2

Recommended Antibody Testing in POTS

Primary Antibody Tests

• G-protein coupled receptor autoantibodies:
  • Alpha-1 adrenergic receptor autoantibodies 2, 3, 4
  • Beta-1 adrenergic receptor autoantibodies 2, 3
  • Beta-2 adrenergic receptor autoantibodies 2, 3
  • Muscarinic acetylcholine M4 receptor autoantibodies 4
  • Angiotensin II type 1 receptor autoantibodies 5

When to Consider Testing

• Patients with refractory symptoms despite standard management
• History of preceding viral illness or infection (including post-COVID-19) 2
• Presence of other autoimmune disorders or family history of autoimmunity 2
• Patients with concurrent hypermobile Ehlers-Danlos syndrome (hEDS) 1, 2
• Patients with symptoms suggesting mast cell activation syndrome (MCAS) 1, 2

Clinical Context for Testing

Autoimmune Associations

• Up to 89% of POTS patients may have elevated alpha-1 adrenergic receptor autoantibodies 4
• Approximately 53% may have elevated muscarinic acetylcholine M4 receptor autoantibodies 4
• Significantly higher levels of angiotensin II type 1 receptor autoantibodies have been found in POTS patients compared to controls 5

Testing Considerations

• Autoantibody testing should be performed in experienced laboratories 1
• Concentration levels should be reported, not just presence/absence of antibodies 1
• Consider referral to specialized centers for proper interpretation of results 1

Important Caveats

• Conflicting evidence: Some studies show no significant difference in autoantibody concentrations between POTS patients and healthy controls using standard ELISA methodology 6
• Interpretation challenges: The clinical significance of detected autoantibodies remains under investigation
• Limited standardization: Testing methods vary between laboratories, affecting result reliability
• Universal testing not recommended: The American Gastroenterological Association advises against universal testing for all POTS patients 1

Additional Testing Considerations

For patients with suspected MCAS and POTS:

• Serum tryptase levels at baseline and during symptom flares (1-4 hours after) 1, 2
• Increases of 20% above baseline plus 2 ng/mL are necessary to demonstrate evidence of mast cell activation 1

For patients with suspected hEDS and POTS:

• Consider Beighton score assessment for joint hypermobility 1
• Apply 2017 diagnostic criteria for hEDS if screening is positive 1

By focusing antibody testing on patients with clinical features suggesting autoimmune involvement, clinicians can better identify potential underlying mechanisms while avoiding unnecessary testing in all POTS patients.