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Cleveland Clinic Journal of MedicineUnexplained Pathology is Not Always Autoimmune

Does our understanding of the autoimmune hypothesis in POTS need a rigorous re-examination to prevent premature therapeutic interventions?

The following content critically examines the prevailing inclination among clinicians to attribute complex syndromes with unclear etiology, such as postural orthostatic tachycardia syndrome (POTS), to autoimmunity. It calls for caution against unconsidered immunosuppressive or immunomodulatory therapies for POTS without clear, substantiated evidence.

Key Points:

  • POTS is a clinically defined positional intolerance syndrome, the pathophysiology of which remains unclear.
  • The symptomatology of POTS often coincides with that of autoimmune disorders like systemic lupus erythematosus (SLE), leading to presumptions of an autoimmune cause.
  • A diagnosis of autoimmunity is often fueled by the discovery of low-level autoantibodies such as antinuclear antibody (ANA) or SSA antibody. However, this is not a definitive indicator, as approximately 20% of young women show positive, low-titer ANA tests without autoimmune disease.
  • Autoimmune disorders and syndromes like POTS share symptoms, but these are not disease-defining.
  • There’s no reproducible evidence of a pathogenic antibody, lab abnormality, or inflammatory sign to confirm an autoimmune etiology in patients with POTS.

Additional Points:

  • Many symptoms in question are also common in patients diagnosed with conditions like fibromyalgia or after acute illnesses such as Lyme disease or COVID-19.
  • Despite our advanced understanding of many autoimmune diseases and targeted therapies, we still do not fully understand the pathogenesis of POTS and its frequent link with major stressors earlier in life.


  • Though patients with POTS and autoimmune diseases share some symptoms, the presence of these symptoms doesn’t definitively denote autoimmunity in POTS.
  • Autoantibodies, if detected, do not prove causation, and there is no current convincing data that warrants the institution of immunosuppressive or immunomodulatory therapy in POTS patients.

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Did You Know?
According to recent studies, about 1 to 3 million Americans are estimated to be affected by POTS, yet its etiology and pathophysiology remain enigmatic.

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