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SWEAT RESPONSES (SYMPATHETIC INVOLVEMENT)
In 1965 Bennett undertook a study to determine the presence, extent and location of autonomic nerve involvement in adult subjects with RA. He studied 18 RA patients with peripheral neuropathy, 8 patients with uncomplicated RA and 13 non-RA subjects. The thermo-regulatory sweating response to warm water immersion and the local sweating response to intradermal injection of acetyl choline and faradic stimulation were tested. In the Control Group (CG), areas of deficient sweating were small and symmetrical. In the uncomplicated RA group 6 of the 8 patients showed sweat responses similar to the CG, with 2 patients showing larger areas of sweat loss. In the RA group with peripheral neuropathy there was sweat loss in areas corresponding to those of cutaneous sensory impairment. It was concluded that clinical sensory neuropathy in RA is usually accompanied by an autonomic neuropathy of postganglionic type(52). Kalliomaki et al performed axon reflex sweating tests in 100 RA patients and 100 non-RA patients with mental disorders. The number of patients reacting negatively to the test was significantly higher (p<0.01) in the RA group. These findings were only found in the female patients and the authors wrote that their observations suggested impaired axon reflex sweating (i.e. sympathetic involvement) in females suffering from RA(53).
CARDIOVASCULAR REFLEX TESTS (CRT)
Ewing described a test battery to evaluate cardiac autonomic function(54-56). This battery tested the parasympathetic nerve function as follows: i. Heart rate response to Valsalva manoeuvre ii. Heart rate variation during deep breathing iii. Immediate heart rate response to standing and the sympathetic nerve function: i. Blood pressure response to standing ii. Blood pressure response to sustained handgrip. These measurements were adopted by some authors to test for autonomic dysfunction in RA patients(57-59) while other used shorter or modified versions(60-68). In 1979 Edmonds published his findings of autonomic neuropathy in RA. They investigated the cardiovascular reflexes, only using the tests described for parasympathetic nerve function. The conclusion was that significantly more patients with RA had abnormal autonomic function when compared to the control groups. They also felt that these abnormal cardiovascular reflexes could not be ascribed by other cardiac abnormalities found in RA patients (like pericarditis) and that autonomic neuropathy on its own might be a complicating factor leading to increased morbidity and mortality in RA(62). Leden in 1983 assessed autonomic nerve function in RA of varying severity by means of deep breathing and an orthostatic test. Irrespective of disease severity all RA patients had increased resting heart rates. Only patients with severe RA showed significant abnormal responses to orthostatic stress, suggesting autonomic neuropathy(63). Observing only parasymphatic nerve function, Piha could not show abnormalities in the cardiovascular reflexes of RA patients comparing 34 of them to 76 diabetes patients and 67 healthy controls. They suggested that the elevated resting heart rate in RA patients could be due to physical deconditioning and concluded that their data indicated that the parasympathetic pathway mediating cardiovascular reflexes via the vagus nerve is intact in RA(67). Toussirot also only reported on parasympathetic involvement. A significant difference was found for Valsalva manoeuvre comparing RA patients to healthy subjects (p<0.01), but there was no correlation with inflammatory markers, presence of RF, disease duration or degree of joint destruction(68). Bekkelund in 1996 compared RA subjects (n 43) to controls (n 61). They used 4 of the 5 tests described by Ewing, including: i. Heart rate response to Valsalva manoeuvre ii. Heart rate variation during deep breathing iii. Immediate heart rate response to standing iv. Blood pressure response to standing. Cardiovascular reflexes were equal in the 2 groups, contradicting some of the other reports. They suggested that the high variability in the assessments of ANS between studies may be due to non-standardised test procedures as well as the choice of the statistical test used(60). Maule et al in their study using CRT wanted to assess autonomic nervous function in a group of patients with Systemic Lupus Erythmathosus (SLE), RA and a matched healthy population. At the same time they assessed for the presence of circulating autoantibodies directed against sympathetic and parasympathetic nervous structures. Similar to Toussirot, they did not find any correlation between autonomic dysfunction and disease duration. They did however confirm autonomic nervous function impairment in connective tissue disease and this was significantly associated with the presence of autoantibodies to autonomic nervous structures(65). Like Maule, Louthrenoo included SLE, RA and healthy controls, and they correlated ANS function as measured by CRT, to clinical features. 47% of the RA patients had symptoms suggesting ANS dysfunction. They confirmed Maule and Toussirot’s findings that there was no correlation between ANS dysfunction and disease duration, or raised ESR(64). Sandhu used 5 tests as described by Ewing to investigate autonomic cardiovascular reflexes in RA patients with reference to age, presence of RF and disease duration. The RA group comprised of 62 and the healthy CG of 41 subjects. Compared to the CG the RA group had significantly lower values for the following: i. Heart rate response to Valsalva manoeuvre ii. Heart rate variation during deep breathing iii. Immediate heart rate response to standing iv. Blood pressure response to sustained handgrip. When age was taken into account the group <60 years of age showed significant differences for the same measurements as for the whole group compared to the CG. The group >60 years of age showed a significant difference only for the blood pressure response to sustained handgrip. Contrary to previous authors’ findings, Sandhu reported a positive correlation for ANS impairment and presence of RF as well as disease duration(57). A further study was performed by Stojanovich, who evaluated cardiovascular ANS function in patients with SLE, RA, Sjögren syndrome, scleroderma and Polymyalgia Rheumatica (PMR). They correlated the ANS function to clinical features. They reported that in all tests higher percentages of the different patient groups demonstrated abnormal results compared to the controls (p <0.05). No correlation was found between ANS dysfunction and disease duration, clinical manifestations or disease activity(58). Bidikar investigated sympathetic nervous system involvement in RA. 50 RA patients were compared to 50 healthy controls. Compared to the controls the RA patients had a significant higher resting HR and blood pressure (BP). Significant differences were also shown for the sympathetic autonomic function tests between the two groups(61).
FOUR TASKS INDICATING AUTONOMIC FUNCTION
Geenen et al investigated the responsiveness of the ANS in RA of recent onset. The two groups (RA 21; CG 20) were subjected to 4 tasks presented in a fixed order: film watching and mild physical exercise to assess the parasympathetic system; and cognitive discrimination and the Stroop test for sympathetic activation. The patients showed normal responses to film watching and mild physical exercise, but diminished responses to cognitive discrimination and the Stroop test. According to them this implies normal parasympathetic activity but diminished sympathetic activity. They concluded that already in early disease there is evidence for diminished autonomic responsiveness, while baseline ANS levels may only deteriorate in the course of the disease. Their patients (recent onset disease) had normal resting heart rate, but they commented on the hypothesis of Piha that elevated heart rate levels might be due to physical deconditioning and that this may be a reversible phenomenon that can be rectified by exercise(69).
PRE-EJECTION PERIOD AND RESPIRATORY SINUS ARRHYTHMIA
In 2004 Dekkers published results on autonomic nervous system involvement in recent onset RA. Subjects with RA (n 25) were compared to healthy controls (n 28). The pre- ejection period (reflecting sympathetic nerve activity) and respiratory sinus arrhythmia (reflecting para-sympathetic nerve activity) were measured. The findings were in agreement with those of Geenen with abnormal sympathetic nervous system activity but normal parasympathetic nervous system activity in RA of recent onset. They did comment however that the environment was not standardized and this could have influenced the sympathetic nervous system activity(70). SYMPATHETIC SKIN RESPONSE AND RR-INTERVAL VARIATION In 1993 Tan decided to investigate autonomic function in RA patients with methods previously described by Shahani(71,72). Sympathetic skin response (SSR) is an indicator of sympathetic nervous system function and RR-interval variation (RRIV) tests vagal function. Both tests were normal in the healthy CG (n=30). The RA group (n=30) had abnormal SSR’s in 6 patients and abnormal RRIV’s in 8 patients. Only 5 patients had complaints of clinical dysautonomia, leading to their conclusion that ANS dysfunction is frequent in RA patients even in the absence of clinical dysautonomia(73). Gozke took this a step further and examined RA patients without clinical dysautonomia. Using the same methods as Tan et al they could not prove sympathetic involvement, but in 50% of RA cases the RRIV values were decreased (74). 2.3.6 PUPILLOGRAPHY By using an infrared light reflection method, one can measure both parasympathetic function (constriction latency and latency of maximum constriction velocity) and sympathetic function (dilatation latency). Barendregt used this method to study autonomic dysfunction in 18 RA patients with ocular dryness, 18 RA patients without ocular dryness and 33 healthy controls. Constriction latency and maximum constriction velocity latency were prolonged in RA patients with ocular dryness compared to the other two groups (p <0.05). Dilation latency did not differ between the three groups, neither was any correlation found between pupillography and age, disease duration or DAS score(75). Schwemmer et al used a combination of pupillography and cardiovascular reflex tests to assess the prevalence and the characteristics of autonomic dysfunction in RA. This was followed by a longitudinal study to investigate if disturbed autonomic function is linked to higher mortality. Autonomic dysfunction was demonstrated in 60% of patients, with the prevalence for pupillary autonomic dysfunction (PAD) 15 out of 30 (50%) and for cardiac autonomic dysfunction (CAD) 6 out of 30 (20%). During the longitudinal study (8 years observation), 4 out of 30 patients died. The non-survivors did not differ at baseline with regards to age, gender, disease duration, swollen joint count, tender joint count, Visual Analogue Scale (VAS) for pain, Physician’s Global Assessment, or medicine from survivors. Both CAD and PAD were…
Chapter One: Introduction :
- 1.1 Rheumatoid Arthritis background
- 1.2 Morbidity and mortality in Rheumatoid Arthritis
- 1.3 Autonomic dysfunction in RA
- 1.4 Exercise as intervention
- 1.5 Relevance of the study: role of exercise
- 1.6 Research questions
- 1.7 Study aims and objectives
- 1.7.1 PHASE
- 1.7.2 PHASE
- 1.7.2.1 Objective
- 1.7.2.2 Objective
- 1.7.2.3 Objective
- 1.7.2.4 Objective
- 1.8 Hypotheses
- 1.8.1 PHASE one
- 1.8.2 PHASE two
- 1.9 Possible limitations of the study
- Bibliography
- Chapter Two: Literature Review
- 2.1 Pathogenesis and etiology
- 2.1.1 Role of immunity
- 2.1.2 Gender (Hormonal)
- 2.1.3 Tobacco
- 2.1.4 Infection
- 2.1.5 Genetic
- 2.2 Clinical features
- 2.2.1 Prevalence and incidence
- 2.2.2 Patterns of onset
- 2.2.2.1 Insidious onset
- 2.2.2.2 Acute onset
- 2.2.2.3 Intermediate onset
- 2.2.2.4 Unusual patterns (variants) of disease
- 2.2.2.4.1 Palindromic
- 2.2.2.4.2 Rheumatoid Nodulosis
- 2.2.2.4.3 Arthritis Robustus
- 2.2.2.4.4 RA and paralysis
- 2.2.3 Classification
- 2.2.4 Constitutional symptoms
- 2.2.5 Joint involvement
- 2.2.6 Extra-articular manifestations
- 2.2.6.1 Musculoskeletal involvement
- 2.2.6.2 Cardiac involvement
- 2.2.6.2.1 Conventional cardiovascular risk factors
- 2.2.6.2.2 Accelerated atherosclerosis
- 2.2.6.2.3 Conduction disorders and arrhythmias
- 2.3 Autonomic dysfunction in RA
- 2.3.1 Sweat responses (sympathetic involvement)
- 2.3.2 Cardiovascular reflex tests
- 2.3.3 Four tasks indicating autonomic function
- 2.3.4 Pre-ejection period and respiratory sinus arrhythmia
- 2.3.5 Sympathetic skin response and RR interval variation
- 2.3.6 Pupillography
- 2.3.7 Heart rate variability
- 2.3.8 Heart rate turbulence
- 2.3.9 Summary of literature on autonomic dysfunction in RA
- 2.4 Role of exercise
- 2.5 Assessment of disease activity
- 2.6 Conclusion
- Bibliography
- Chapter Three: Methodology
- 3.1 Hypotheses
- 3.1.1 PHASE
- 3.1.2 PHASE
- 3.2 Study aims and objectives
- 3.2.1 PHASE 1 Aim
- 3.2.2 PHASE 2 Aim
- 3.2.2.1 Objective
- 3.2.2.2 Objective
- 3.2.2.3 Objective
- 3.2.2.4 Objective
- 3.3 Study design
- 3.4 Setting
- 3.5 Patient / Research object selection
- 3.5.1 Healthy Control Group (PHASE 1 of the study)
- 3.5.2 Rheumatoid Group (PHASE 1 and 2 of the study)
- 3.6 Equipment
- 3.7 Measurements
- 3.7.1 Height
- 3.7.2 Body mass
- 3.7.3 Heart rate
- 3.7.4 Blood pressure
- 3.7.5 Heart rate variability
- 3.7.5.1 Method of Heart rate variability data sampling
- 3.7.5.2 Heart rate variability quantification
- 3.7.5.2.1 Time domain
- 3.7.5.2.2 Frequency domain
- 3.7.5.2.3 Poincaré plots
- 3.7.6 Disease Activity Score (DAS28)
- 3.7.6.1 Tender joint count
- 3.7.6.2 Swollen joint count
- 3.7.6.3 Patient global assessment
- 3.7.6.4 Physician global assessment
- 3.7.6.5 C-reactive protein
- 3.7.7 Quality of life
- 3.7.8 Visual Analogue Scale
- 3.7.9 Functional capacity
- 3.7.9.1 Flexibility
- 3.7.9.1.1 Wrist flexion
- 3.7.9.1.2 Wrist extension
- 3.7.9.1.3 Knee flexion
- 3.7.9.1.4 Knee extension
- 3.7.9.1.5 Hip flexion
- 3.7.9.1.6 Hip extension
- 3.7.9.1.7 Lateral flexion
- 3.7.1.9.8 Back scratch test
- 3.7.1.9.9 Chair sit and reach test
- 3.7.9.2 Strength
- 3.7.9.2.1 Hand grip strength
- 3.7.9.2.2 Leg strength test
- 3.7.9.2.3 Arm curl test
- 3.7.9.2.4 Sit to stand test
- 3.7.10 Aerobic capacity
- 3.8 Data analysis
- 3.9 Ethical considerations
- 3.9.1 Ethical approval
- 3.9.2 Consent
- 3.9.3 Confidentiality
- Bibliography
- Chapter Four: Results
- 4.1 PHASE one: Healthy Control Group versus Rheumatoid Arthritis Group
- 4.1.1 Demographic background
- 4.1.2 Heart rate variability
- 4.1.2.1 Variables in the supine (resting) position
- 4.1.2.2 Variables in the standing (stress) position
- 4.1.2.3 Heart rate and heart rate response
- 4.1.2.4 Postural change
- 4.2 PHASE two: Rheumatoid Arthritis Exercise Group versus Rheumatoid
- Arthritis Control Group
- 4.2.1 Demographic background
- 4.2.2 Heart rate variability
- 4.2.2(A) Descriptive statistics
- 4.2.2(B) Assessment for initial bias between the twO groups
- 4.2.2(C) Within group analysis
- 4.2.2(D) Differences between the two groups at study completion
- 4.2.3 Disease Activity Score28, Health Assessment Questionnaire and Visual Analogue Scale
- 4.2.3(A) Descriptive statistics
- 4.2.3(B) Assessment for initial bias between the two groups
- 4.2.3(C) Within group analysis
- 4.2.3(D) Differences between the two groups at study completion
- 4.2.4 Functional parameters
- 4.2.4(A) Descriptive statistics
- 4.2.4(B) Assessment for initial bias between the two groups
- 4.2.4(C) Within group analysis
- 4.2.4(D) Differences between the two groups at study completion
- Bibliography
- Chapter Five: Discussion
- 5.1 Cardiac autonomic function between healthy participants and rheumatoid arthritis patients
- 5.2 Effect of exercise on cardiac autonomic function, disease activity and functional parameters in rheumatoid arthritis
- 5.2.1 Autonomic nervous system (HRV)
- 5.2.2 Disease outcome
- 5.2.3 Functional parameters
- 5.3 Conclusion
- 5.3.1 Added value
- 5.3.2 Limitations of the study
- Bibliography
