Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study

•Individuals at risk of developing RA show autonomic dysfunction similar to established RA patients.•Autonomic dysfunction is a predictor of development of arthritis in subjects at risk of RA, suggesting a role in its etiopathogenesis.The autonomous nervous system is a neurological control system that acts largely unconsciously and regulates a variety of bodily functions. We found that dysfunction of this system may precede and predict the development of rheumatoid arthritis (RA), a chronic inflammatory disease with great unmet need. These findings provide important insights into the changes in the nervous system contributing to the development of this condition. They also open up the perspective of potential measures aimed at prevention of RA by restoring the balance in the nervous system before arthritis develops, which would have major implications for patients as well as society.

BackgroundHeart rate variability (HRV) is a validated method to establish autonomic nervous system (ANS) activity. Rheumatoid arthritis (RA) is accompanied by ANS imbalance. We hypothesized that ANS dysfunction may precede the development of RA, which would suggest that it plays a role in its etiopathogenesis.MethodsFirst, we assessed HRV parameters in supine (resting) and upright (active) position in healthy subjects (HS, n = 20), individuals at risk of developing arthritis (AR subjects, n = 50) and RA patients (RA, n = 20). Next, we measured resting heart rate (RHR), a parasympathetic HRV parameter, in an independent prospective cohort of AR subjects (n = 45). We also evaluated expression levels of the parasympathetic nicotinic acetylcholine receptor type 7 (α7nAChR) on circulating monocytes.FindingsBoth AR subjects (68 beats per minute (bpm), interquartile range (IQR) 68–73) and RA patients (68 bpm, IQR 62–76) had a significantly higher RHR compared to HS (60 bpm, IQR 56–63). RHR was significantly higher at baseline in individuals who subsequently developed arthritis. Expression levels of α7nAChR were lower in AR subjects with RHR ≥ 70 bpm compared to those with RHR < 70 bpm, consistent with reduced activity of the parasympathetic cholinergic anti-inflammatory pathway.InterpretationThese data support the notion that autonomic dysfunction precedes the development of RA.