The seropositive POTS patients were an average of 29 years old, compared with an average age of 20 years old for those who were negative (p=.012). Sixty percent of patients who were seropositive had complications from autoimmune diseases compared to 8 percent in the seronegative group (p< 0.001).
Researchers acknowledged that the majority of seropositive patients did not have high levels of the antibodies.
“Therefore, elevated expression of antibodies to gAChR subunits may contribute to secondary autoimmune responses to antiganglionic neuron damage in seropositive patients,” they wrote. “Anti-gAChR antibodies may impair autonomic ganglionic synaptic transmission, and antibodies that interfere with ganglionic transmission may contribute to dysautonomia in patients with POTS.”
Dr. Nakane said that other antibodies — to adrenergic receptors, muscarinic AChR, or other targets — could play a role in at least some of the 61 percent of patients who were seronegative.
In the researchers' planned nationwide study, he said, they'll look at gAChR antibodies and treatment outcomes for each subcategory of POTS — neuropathic, hyper-adrenergic, volume dysregulating, and physical reconditioning.
A Mayo Clinic case series of 152 patients in 2007 found that one in seven patients tested positive for gAChR antibodies. Other studies since then have found elevated levels of autoantibodies to adrenergic receptors and muscarinic receptors. In 2015, a study of 100 consecutive patients with POTS found that 25 percent were positive for antinuclear antibodies and 31 percent had some type of marker of autoimmunity, both of which were significantly higher than the rate in general population.
Svetlana Blitshteyn, MD, director of the Dysautonomia Clinic and clinical assistant professor of neurology at the University of Buffalo School of Medicine and Biomedical Sciences, said that findings on gAChR antibodies in POTS have been tinged with controversy, with some researchers speculating that it may not play a meaningful role.
These findings help bring the gAChR antibodies rightfully back into prominence, she said. “In the past decade, there has been a greater research interest in POTS and autoimmunity because there is evidence of autoimmunity found in a substantial subset of patients with POTS. The Japanese study reaffirms this concept,” Dr. Blitshteyn said. “It's good to bring attention back to gAChR antibody that should be looked at further and not dismissed.”
She said it's a “good target antibody,” in part because it's already known to play a role in autoimmune autonomic ganglionopathy (AAG), in which gAChR antibodies are found at higher levels.
“While POTS is not AAG, there are certain key features that go in parallel, such as orthostatic intolerance, dysregulation of blood pressure, heart rate, digestive system, and perspiration control. So, while they're not the same disorder, gAChR antibodies could potentially play a role in POTS.”
She noted that the antibodies in this study were found to be more prevalent than in previous studies, and that it could be because a different assay — the luciferase immunoprecipitation system, or LIPS — was used. In the United States, a radioimmunoassay is typically used, and does not test for the beta4 subunit, as LIPS does.
“It's going to be important for this study to be replicated in the United States, using both radioimmunoassay and LIPS assays, and to see if we can have the same results as the study from Japan,” she said. “The two assays differ, and it would be good to know if they correlate and whether their assay, LIPS, is a good methodology for us to utilize.”
Dr. Blitshteyn said a better understanding of the etiology of POTS could lead to better treatment, which is badly needed. Current treatment is mainly non-pharmacologic, often with liberal fluid and salt intake and an exercise program, and off-label pharmacologic therapy, such as vasoconstrictors and beta blockers. But these typically aren't very effective, and the pharmacologic options bring side effects.
“The treatment options for POTS have always been suboptimal, but we always go with the non-pharmacologic and pharmacologic approach,” Dr. Blitshteyn said. “For some patients, it will help them feel better and improve their functional status. But in my experience, for the majority of patients, the existing therapies are not effective enough to result in significant and meaningful improvement or recovery.”
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