Heart Rate Variability to Predict Treatment Response in Patients with RA

“Such high positive predictive value, negative predictive value, and relative risk support the claim that the ANS plays an important role in therapeutic response and may be useful in stratifying patient outcomes and identifying their need for adjunctive ANS optimization,” Dr. Holman says.

The next step in research, he says, is offering adjunctive treatment to raise the low parasympathetic score to a higher number “so that we can transform a nonresponder to an anti-TNF treatment to a responder.” He is scheduled to present an update on his research at the 2015 ACR/ARHP Annual Meeting in November, where he will present data highlighting the benefit of using adjunctive autonomic therapies with etanercept in 66 patients with RA. He will also be leading a study group on autonomic neuroregulation of RA during the meeting.

According to Kevin Tracey, MD, president and CEO of The Feinstein Institute for Medical Research and professor of molecular medicine and neurosurgery at Hofstra North Shore—LIJ School of Medicine in New York, this avenue of research is “provocative and potentially very important. Right now, we have these important TNF drugs that are very expensive, and some have black box warnings, and you would not want to give them to a patient unnecessarily. So the ability to make a simple test in a patient, a heart rate variability test, and say that a patient has a 90% chance of not responding to the drug is very important,” he says.

Inflammation Pathway

Several researchers have investigated the ANS as a pathway involved in inflammation. Elenkov and Wilder’s review article in Pharmacological Reviews described the sympathetic nerve as an “integrative interface between two supersystems—the brain and the immune system” (see Rheuminations, p. 10). Because the fields of neuroscience and immunology developed independently, an understanding of how these two systems interact had been relatively unknown or understood, the authors say.

Dr. Tracey

Dr. Tracey has focused on how the nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. This inflammatory reflex is a neurophysiological mechanism that regulates the body’s immune system. More than 100 research articles have examined how activating this reflex could reduce inflammation through blockade of TNF production and other mechanisms.

He explained in a recent Scientific American article that when the inflammatory reflex does not function well, cytokines can lead to complications, such as RA.⁴ At SetPoint Medical, a biomedical technology company focused on the field of bioelectronics, which Dr. Tracey co-founded and where he now serves as a consultant, researchers are working on neuromodulation therapies for RA, a field called bioelectronics. They are testing the efficacy of stimulating the vagus nerve via an implantable microregulator, thus activating the inflammatory reflex and curtailing inflammation. Their pilot study with the implantable vagus nerve stimulation device was presented at the 2012 ACR/ARHP Annual Meeting.⁵

HRV: An Inflammatory Marker?

HRV as a potential inflammatory marker has been explored in previous research over the past several decades. A review article by Adlan et al in 2014 in Seminars in Arthritis and Rheumatism reported on evidence showing that ANS dysfunction is a feature of RA, although it is not universal in all patients with RA.⁶ This ANS dysfunction, they said, is characterized by low heart rate variability (HRV), reduced parasympathetic activity and elevated sympathetic activity.