BALTIMORE—The autonomic nervous system is a marvel of coordinated physiology, but when things go awry, the resulting symptoms patients experience can be severe.
At the 20th Annual Advances in the Diagnosis and Treatment of the Rheumatic Diseases symposium at Johns Hopkins School of Medicine, Brit Adler, MD, assistant professor of medicine, Division of Rheumatology, Johns Hopkins School of Medicine, Baltimore, greatly expanded the cognitive horizons of the audience in her talk titled, Dysautonomia and POTS: What the Rheumatologist Should Know.
What Is POTS?
To begin her lecture, Dr. Adler explained that postural orthostatic tachycardia syndrome (POTS) was thought to affect between 500,000 and 3 million people in the U.S. before the COVID-19 pandemic.1 Currently, it’s believed this number may be much higher, although more research is needed.2
POTS is most commonly seen in young women, and symptoms can include fatigue, brain fog, headache, orthostatic intolerance, muscle pain and difficulty with exercise. Patients may be classified with POTS if they experience the following for at least six months:
- An increase in heart rate ≥30 beats per minute within 5–10 minutes of standing or upright tilt;
- The absence of orthostatic hypotension; and
- Lightheadedness, palpitations and tremulousness that occur with standing.3
Dr. Adler explained that the pathophysiology of POTS involves sympathetic vasomotor dysfunction leading to venous pooling on standing and exertional intolerance. Secondary sympathetic activation leads to tachycardia. Through these mechanisms, POTS is often associated with other symptoms of dysautonomia, including Raynaud’s phenomenon; urinary symptoms, such as loss of bladder control and difficulty voiding; and gastrointestinal symptoms, such as diarrhea or constipation.
The presence of hypertension in a patient does not rule out the possibility of their having POTS. Patients with hyperadrenergic POTS, which is thought to affect about 30–60% of all patients with POTS, typically demonstrate a systolic blood pressure increase of ≥10 mmHg during tilt along with tachycardia. This subtype of POTS is thought to result from elevated standing plasma norepinephrine levels in the hyperadrenergic state, which leads to an exaggerated sympathetic response with excessive orthostatic tachycardia. These patients typically experience such symptoms as palpitations, abdominal pain, nausea and hyperhidrosis, all of which are worsened with physical exertion and emotional stress.
Dr. Adler explained that POTS is a heterogeneous syndrome with a diverse set of potential etiologies and mechanisms. These include immune-mediated processes, such as infections (e.g., COVID-19, Lyme disease, Epstein-Barr virus), autoimmune conditions (e.g., Sjögren’s disease, systemic lupus erythematosus, Celiac disease) and vaccinations. Non-immune mediated processes may include Ehlers-Danlos and other hypermobility syndromes, concussions, genetic disorders and neurodegenerative diseases, such as multiple system atrophy. Other conditions, such as fibromyalgia, interstitial cystitis and mast cell activation syndrome, are connected to POTS because they all may result in small-fiber neuropathy.
Misunderstandings Surrounding POTS
Dr. Adler made note of a conundrum that exists in the medical community: POTS is reasonably common and clearly results in debilitating symptoms for patients, yet we know so little about the condition. How could this be?
Dr. Adler believes this is due, in part, to the tortured history of the condition. For years, POTS was thought to be due to deconditioning, and there was the belief that patients could exercise their way out of POTS. Patients with POTS also frequently encounter what Dr. Adler called medical gaslighting—a majority of patients with the condition are told their symptoms are all in their head or due to anxiety.
However, the COVID-19 pandemic forced medical providers to re-evaluate. In a study from Lee et al., more than half of nearly 300 patients with long COVID were found to experience orthostatic intolerance symptoms during National Aeronautics and Space Administration Lean Testing (NLT). Also, more than one in 10 study patients met criteria for either POTS or orthostatic hypotension.4
Diagnosis & Disease Management
It’s particularly important for rheumatologists to think about and help diagnose the condition because it can mimic symptoms sometimes associated with autoimmune disease, such as Raynaud’s, acrocyanosis, erythromelalgia and facial flushing in a malar distribution.
Once correctly identified, a range of treatments may be helpful in dealing with the vasomotor and sympathetic dysfunction seen in patients. Volume expansion and medications, such as midodrine, fludrocortisone and pyridostigmine can be beneficial.
Beta blockers serve to reduce compensatory tachycardia and can help some patients, although others may feel worse with this class of medication. When such medications are used, Dr. Adler recommends that clinicians employ non-selective beta blockers, such as propranolol over selective beta blockers like metoprolol. She also pointed out that ivabradine, which blocks the channel responsible for the cardiac pacemaker current and thereby lowers heart rate, is often better tolerated than beta blocker therapy.
Dr. Adler urged physicians to think about gastrointestinal (GI) symptoms in patients with POTS. Patients may experience issues from gastroparesis or rapid gastric emptying, as well as small bowel and colonic dysmotility. In patients with isolated upper GI tract dysmotility, treatments may include acid suppressants, dopamine-2 receptor antagonists and motilin agonists, such as erythromycin. If there is lower GI tract dysmotility, then bulking agents, osmotic and stimulant laxatives, secretagogues and somatostatin analogues may be beneficial. If there is global GI tract dysmotility, then mirtazapine, pyridostigmine and serotonin type 4 (5-HT4) receptor agonists may be of help.
Other common symptoms that should be addressed beyond the GI tract are sicca symptoms, hyper- or hypohidrosis, fatigue and chronic pain.
In terms of immunomodulation for POTS, the iSTAND study saw Vernino et al. perform a randomized controlled trial of intravenous immunoglobulin (IVIG) vs. intravenous albumin infusions—which ensured blinding and controlled for effects of volume expansion—in patients with POTS. This trial failed to find a statistically significant difference between the two groups with respect to Composite Autonomic Symptoms Score-31 (COMPASS-31) by week 2 after the final infusion.5 However, Dr. Adler noted that the patients were treated for only three months.
Current clinical trials in POTS are looking at IVIG, subcutaneous Ig and efgartigimod, which is a humanized IgG1 Fc fragment that reduces the levels of circulating IgG antibodies by binding to the neonatal Fc receptor, in treating patients with long COVID POTS.
In Sum
Dr. Adler’s lecture served to inform clinicians who may previously have had little knowledge on the subject.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- Safavi-Naeini P, Razavi M. Postural orthostatic tachycardia syndrome. Tex Heart Inst J. 2020 Feb 1;47(1):57–59.
- Blitshteyn S, Fedorowski A. The risks of POTS after COVID-19 vaccination and SARS-CoV-2 infection: More studies are needed. Nat Cardiovasc Res. 2022 Dec;1(12):1119–1120.
- Bryarly M, Phillips LT, Fu Q, et al. Postural orthostatic tachycardia syndrome: JACC focus seminar. J Am Coll Cardiol. 2019 Mar 19;73(10):1207–1228.
- Lee C, Greenwood DC, Master H, et al. Prevalence of orthostatic intolerance in long covid clinic patients and healthy volunteers: A multicenter study. J Med Virol. 2024 Mar;96(3):e29486.
- Vernino S, Hopkins S, Bryarly M, et al. Randomized controlled trial of intravenous immunoglobulin for autoimmune postural orthostatic tachycardia syndrome (iSTAND). Clin Auton Res. 2024 Feb;34(1):153–163.
