title: Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study.
abstract: BACKGROUND
  Heart 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.
  
  
  METHODS
  First, 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.
  
  
  RESULTS
  Both AR subjects (68 beats per minute (bpm), interquartile range (IQR) 68-73) and RA patients (68bpm, IQR 62-76) had a significantly higher RHR compared to HS (60bpm, 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 ≥70bpm compared to those with RHR <70bpm, consistent with reduced activity of the parasympathetic cholinergic anti-inflammatory pathway.
  
  
  CONCLUSIONS
  These data support the notion that autonomic dysfunction precedes the development of RA.
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: Koopman
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M W
authors.initials: MW
authors.lastname: Tang
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Vermeij
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: de Hair
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: I Y
authors.initials: IY
authors.lastname: Choi
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Vervoordeldonk
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: D M
authors.initials: DM
authors.lastname: Gerlag
authors.affiliation: Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Karemaker
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: p.p.tak@amc.uva.nl.
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000503:physiopathology*; D001342:Autonomic Nervous System Diseases / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000097:blood*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Autonomic nervous system; Heart rate; Heart rate variability; Norepinephrine; Preclinical; RA