title: Autonomic function and rheumatoid arthritis: a systematic review.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is a chronic inflammatory condition with increased all-cause and cardiovascular mortality. Accumulating evidence indicates that the immune and autonomic nervous systems (ANS) are major contributors to the pathogenesis of cardiovascular disease. We performed the first systematic literature review to determine the prevalence and nature of ANS dysfunction in RA and whether there is a causal relationship between inflammation and ANS function.
  
  
  METHODS
  Electronic databases (MEDLINE, Central and Cochrane Library) were searched for studies of RA patients where autonomic function was assessed.
  
  
  RESULTS
  A total of 40 studies were included. ANS function was assessed by clinical cardiovascular reflex tests (CCTs) (n = 18), heart rate variability (HRV) (n = 15), catecholamines (n = 5), biomarkers of sympathetic activity (n = 5), sympathetic skin responses (n = 5), cardiac baroreflex sensitivity (cBRS) (n = 2) and pupillary light reflexes (n = 2). A prevalence of ~60% (median, range: 20-86%) of ANS dysfunction (defined by abnormal CCTs) in RA was reported in 9 small studies. Overall, 73% of studies (n = 27/37) reported at least one of the following abnormalities in ANS function: parasympathetic dysfunction (n = 20/26, 77%), sympathetic dysfunction (n = 16/30, 53%) or reduced cBRS (n = 1/2, 50%). An association between increased inflammation and ANS dysfunction was found (n = 7/19, 37%), although causal relationships could not be elucidated from the studies available to date.
  
  
  CONCLUSIONS
  ANS dysfunction is prevalent in ~60% of RA patients. The main pattern of dysfunction is impairment of cardiovascular reflexes and altered HRV, indicative of reduced cardiac parasympathetic (strong evidence) activity and elevated cardiac sympathetic activity (limited evidence). The literature to date is underpowered to determine causal relationships between inflammation and ANS dysfunction in RA.
authors.affiliation: College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2 TT, UK. Electronic address: adlan.ahmed@gmail.com.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Adlan
authors.affiliation: University of Birmingham Centre of Cardiovascular Sciences, City Hospital, Birmingham, UK.
authors.forename: Gregory Y H
authors.initials: GY
authors.lastname: Lip
authors.affiliation: School of Physiology and Pharmacology, Bristol CardioVascular Medical Sciences Building, University of Bristol, Bristol, UK.
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
authors.affiliation: Department of Rheumatology, Dudley Group NHS Foundation Trust, Russells Hall Hospital, Dudley, West Midlands, UK.
authors.forename: George D
authors.initials: GD
authors.lastname: Kitas
authors.affiliation: College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2 TT, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Fisher
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D001341:Autonomic Nervous System / Q000503:physiopathology*; D001342:Autonomic Nervous System Diseases / Q000453:epidemiology* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007107:Immune System / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015995:Prevalence
keywords: Autonomic; Autonomic balance; Autonomic function; Cardiovascular; Cardiovascular risk; Cytokine; Heart rate variability; Inflammation; Nervous; Physiology; Rheumatoid arthritis; Sympathetic nerve activity; Systematic review