Download Cardiovascular autonomic nervous system

Q J Med 1999; 92:97–102
Cardiovascular autonomic nervous system dysfunction in
patients with rheumatoid arthritis and systemic lupus
erythematosus
W. LOUTHRENOO, P. RUTTANAUMPAWAN, A. ARAMRATTANA1
and W. SUKITAWUT
From the Division of Rheumatology, Department of Medicine, and 1Department of Family
Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Received 1 July 1998 and in revised form 3 December 1998
Summary
Although peripheral and central nervous system
involvement have been well recognized in patients
with rheumatoid arthritis (RA) and systemic lupus
erythematosus (SLE), autonomic nervous system
(ANS) involvement has rarely been studied, and has
shown conflicting results. We performed cardiovascular ANS assessment in 34 RA and 37 SLE patients,
using standard cardiovascular reflex tests. The
results in each patient were compared with ageand sex-matched healthy controls. Forty-seven percent of the RA patients and 19% of the SLE patients
had symptoms suggesting ANS dysfunction. The
heart rate variation in response to deep breathing
was significantly decreased in both the RA and SLE
patients ( p=0.001). This diminished heart rate
response showed no correlation with the disease
duration, the number of swollen joints, the Ritchie
articular index, ESR, or rheumatoid factor in the RA
group, or the disease duration, the SLEDAI score or
ESR in the SLE group. The clinical significance of
the diminished cardiovascular ANS response needs
to be investigated.
Introduction
Although involvement of the peripheral nervous
system (PNS) and central nervous system (CNS) in
rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) has been well described, autonomic
nervous system (ANS) involvement in RA and SLE
has rarely been described in standard textbooks of
rheumatology.1–3 The ANS can be assessed by several
tests including cardiovascular, sweating, pupillary
reflex and skin tests. However, cardiovascular reflex
tests have been most widely used as they are noninvasive, and results are easy to reproduce.
The purpose of this study was to evaluate cardiovascular ANS function in patients with RA and SLE,
and to correlate the ANS function with clinical
features. As the ANS function has been reported to
deteriorate with age,4 we used age- and sex-matched
healthy controls.
Methods
The patients studied were in- and out-patients with
RA and SLE at the Division of Rheumatology,
Department of Medicine, Faculty of Medicine,
Chiang Mai University. The diagnoses of RA and SLE
were made by using the criteria developed by the
American College of Rheumatology.5,6 Control subjects were selected from healthy hospital staff who
did not have symptoms of ANS dysfunction and
were not taking any medications. These controls had
never been studied before. All patients were checked
for symptoms and signs of possible ANS dysfunction,
including orthostatic hypotension (lightheadedness,
blurred vision, sensation of weakness and unsteadiness, fainting or syncope upon standing), perspiration, palpitation and Raynaud’s phenomenon. The
Address correspondence to Dr W. Louthrenoo, Associate Professor of Medicine, Division of Rheumatology, Department of
Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
© Association of Physicians 1999
98
W. Louthrenoo et al.
criterion for age matching was an age difference of
<3 years for each matched pair.
Patients were excluded from the study if they
(i) had <10 g/dl haemoglobin; (ii) were pregnant;
(iii) had diseases interfering with the autonomic
nervous system, including diabetes mellitus, renal
and liver diseases, Parkinson’s disease, porphyria
and amyloidosis; (iv) had cardiovascular diseases
including hypertension, ischaemic heart disease, congestive heart failure, valvular heart disease, cardiomyopathy and cardiac arrhythmia; or (v) had
neurological diseases including multiple sclerosis,
polyneuropathy or Guillain-Barré syndrome. Patients
taking drugs that interfered with the ANS including
antihypertensive, diuretic, adrenergic inhibitor, vasodilator, anti-arrhythmic, sedative, hypnotic and antiepileptic drugs were also excluded from the study.
Cardiovascular ANS function assessment was performed by one of us, PR, using the standard technique
described by Ewing et al.7 Two tests, the heart rate
response to deep breathing and the immediate heart
rate response to standing (or the R-R ratio), were
performed to measure heart rate changes, reflecting
the parasympathetic nerve function. The other two
tests, the systolic blood pressure response to standing
and the diastolic blood pressure response to sustained
handgrip, were done to measure changes in blood
pressure, reflecting the sympathetic nerve function.
All patients and controls were confirmed to have a
normal sinus rhythm, without evidence of a conduction defect in a standard electrocardiograph (ECG).
The tests were performed under standardized conditions, in the morning, after a period of relaxation.
Tobacco, alcohol and medications were not allowed
before the tests.
RA activity was determined by using the number
of swollen joints, the joint tenderness scores determined by the Ritchie articular index, the rheumatoid
factor (RF) determined by the latex agglutination test
and erythrocyte sedimentation rate (ESR). An RF titre
of 1580 or more was considered significant. The
activity of SLE was determined by ESR and the
SLEDAI score.8 The SLEDAI score was modified in
this study, as the DNA binding assay was not
available at our hospital, and its score was not
counted as part of our SLEDAI score. Thus our
maximum modified SLEDAI score was 103.
Statistical analysis
Test values are reported as means±SD. Student’s t
test for paired samples was used to compare these
means. Wilcoxon matched-pairs signed-ranks test
was used for non-parametric values. Regression analysis was used to find the correlation between the
cardiovascular ANS function test and disease activity
or dosage of medication. A p value <0.05 was
considered statistically significant. Statistical analysis
used the SPSS for Windows program, release 7.0.
Results
Thirty-four RA and 37 SLE patients were included in
this study. The characteristics of these patients are
given in Table 1. Nineteen RA patients (55.8%)
had positive RF (1580). Their mean number of
swollen joints, the Ritchie articular index and
the ESR were 15.50±10.46, 11.59±6.08, and
35.22±18.27 mm/h, respectively. None had rheumatoid vasculitis or peripheral neuropathy. All RA
patients were taking non-steroidal anti-inflammatory
drugs and disease-modifying anti-rheumatic drugs at
the standard dosage.
The mean modified SLEDAI score and ESR in SLE
patients were 4.65±5.77, and 27.65±11.67 mm/h,
respectively. A past history of vasculitis, CNS lupus
and peripheral neuropathy was documented in 12,
six and two patients, respectively. Among the patients
with CNS lupus, there were seizures in three, organic
brain syndrome in one, transverse myelitis in one
and aseptic meningitis in one. Two patients who had
peripheral neuropathy had had mononeuritis multiplex. At the time of the study, four patients had
cutaneous vasculitis and one had a residual ulnar
neuropathy from her previous neuropathy. Antinuclear antibody test, using the indirect immunofluorescent method, was positive in 31 and was negative
in six cases.
There were 62 healthy controls (50 females and
12 males). Each RA and SLE patient was matched
for age with these controls, and for sex where
possible. The mean±SD ages of the control groups
for RA and SLE were 47.0±10.6 and 30.3±7.9
years, respectively ( p>0.05); the percentages of sexmatched control patients in the RA and SLE groups
were 76% and 81%, respectively. Results of the
cardiovascular ANS function assessment in RA and
SLE patients and their age- and sex-matched controls
are shown in Table 2. The heart rate response to
deep breathing was significantly diminished in both
RA and SLE groups when compared with controls
( p=0.001). There was no correlation between the
diminished heart rate response to deep breathing
and number of swollen joints, the Ritchie articular
index or ESR or RF titre in RA patients, nor to the
modified SLEDAI score or ESR in SLE patients. There
was no significant correlation between the extent to
which the systolic blood pressure fell and the orthostatic hypotension symptoms, nor between the heart
rate variation in response to deep breathing or the
R-R ratio and palpitation in both RA and SLE groups.
A significant correlation between the diminished
heart rate response to deep breathing and the dosage
99
Cardiovascular autonomic dysfunction in RA and SLE
Table 1 Characteristics of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients
Sex (F5M)
Age (years)
Duration (years)
Medication: n (dosage)
Prednisolone (mg/day)
Chloroquine (mg/day)
Methotrexate (mg/week)
Cyclophosphamide (mg/day)
ANS symptoms
Orthostatic hypotension
Palpitation
Raynaud’s symptom
Perspiration
RA
(n=34)
SLE
(n=37)
3054
47.2±10.5
5.1±3.6
3453
30.4±8.1
3.1±2.2
9 (4.45±1.10)
20 (168.45±61.17)
11 (4.55±1.51)
–
35 (17.03±13.59)
21 (202.33±71.10)
–
13 (50.00±17.68)
16
12
5
4
7
7
5
5
Data are either numbers, or means±SD.
Table 2 Results of cardiovascular autonomic assessment in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)
Parameter
RA patients
(n=34)
RA controls
(n=34)
HRmax (beats/min)
HRmin (beats/min)
HRvar (beats/min)
R-R15 (mm)
R-R30 (mm)
R-R ratio
BPs baseline (mmHg)
BPs stimulated (mmHg)
BPs decrease
BPd baseline (mmHg)
BPd stimulated (mmHg)
BPd increase
91.59±15.80
77.38±16.06
14.20±7.57
16.19±2.23
16.19±2.51
1.08±0.11
125.06±16.71
114.65±17.70
10.41±11.48
76.65±12.39
87.00±11.49
10.35±6.55
84.91±12.00
65.38±11.16
19.52±6.83
17.59±3.57
18.27±3.01
1.05±0.12
118.44±14.00
110.85±13.41
7.58±9.22
76.21±7.91
84.91±8.22
8.70±3.92
p
0.001
0.21
0.30
0.25
SLE patients
(n=37)
SLE controls
(n=37)
100.57±15.46
81.19±15.51
19.37±7.93
14.43±2.83
14.76±2.68
1.02±0.08
124.32±14.99
113.78±13.04
10.54±8.97
78.60±10.40
91.94±12.34
13.35±8.57
90.95±11.80
64.43±9.92
26.51±8.22
17.03±2.77
18.05±2.47
1.07±0.12
115.32±13.04
109.16±12.81
6.16±7.89
75.24±9.66
84.70±10.15
9.45±9.00
p
0.001
0.18
0.06
0.06
Values are means±SD. HRmax, maximum heart rate during deep breathing; HRmin, minimum heart rate during deep
breathing; HRvar, the difference between HRmax and HRmin; R-R 15, R-R interval at 15th heart beat after standing; R-R
30, R-R interval at 30th heart beat after standing; R-R ratio, the ratio of R-R 30 to R-R 15; BPs baseline, systolic blood
pressure while supine; BPs stimulated, lowest systolic blood pressure while standing; BPs decrease, BPs baseline—BPs
stimulated; BPd baseline, diastolic blood pressure before handgrip; BPd stimulated, highest diastolic blood pressure during
handgrip exercise; BPd increase, BPd stimulated−BPd baseline.
of chloroquine used in RA patients was observed
( p<0.05), but this correlation disappeared on multiple regression analysis.
Discussion
In this study, we used non-invasive cardiovascular
reflex tests to evaluate cardiovascular ANS function.
The heart rate response to deep breathing was found
to be significantly diminished in both RA and SLE
groups compared to their age- and sex-matched
healthy controls. This diminished heart rate response
showed no correlation to the duration of the disease,
the disease activity, or the dosage of the medication
used in both RA and SLE. Unfortunately, we did not
study the correlation between the presence of ANS
dysfunction and the degree of articular destruction
in our RA patients. Forty-seven percent of our RA
and 19% of our SLE patients had symptoms suggesting ANS dysfunction. The high incidence of ANS
dysfunction symptoms seen in our RA patients might
have been related to their advanced age group. In
this study, control subjects were recruited from
healthy hospital staff. They were in general healthconscious. Thus, they might not represent the population from which the patients were drawn. As the
controls had no symptoms of ANS dysfunction, it is
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W. Louthrenoo et al.
not known whether the ANS dysfunction symptoms
seen in both our RA and SLE patients are more
common than those of the general population.
Cardiovascular ANS assessment in RA has been
studied by several investigators, and there have been
conflicting results because of the way in which
controls were selected and the criteria used to
determine ANS dysfunction. Tests measuring heart
rate variation have been most commonly employed,
and these have usually given abnormal results.
Edmonds et al.9 demonstrated abnormalities in parasympathetic cardiovascular reflexes in nine of their
27 RA patients (33%). Four of nine patients with
abnormal tests had symptoms suggesting ANS dysfunction. However, more than 50% of their patients
with abnormal tests had evidence of peripheral
neuropathy. Tan et al.10 also found abnormal heart
rate response to deep breathing in eight of their 30
RA patients (27%). Five of these eight had had
clinical symptoms of dysautonomia. Nine patients
had evidence of peripheral neuropathy, of whom
five had clinical symptoms of dysautonomia. Leden
et al.11 studied 17 RA patients and found an increase
in resting heart rate in all patients, and an abnormal
heart rate response to standing in all seven patients
who had severe RA. An increase in resting heart rate
in RA was confirmed by Piha et al.12 but they found
no abnormalities in parasympathetic cardiovascular
reflex tests. This increased heart rate was independent
of severity of the disease, pain and ESR. They
concluded that the increase in resting heart rate
might have been related to vascular inflammation,
accelerated atherosclerosis and poor physical condition. Parasympathetic cardiovascular ANS dysfunction was confirmed by Toussirot et al.13 who
demonstrated that 60% of their 50 RA patients had
ANS dysfunction, defined by abnormal results on
two of the three cardiovascular reflex tests. However,
ANS dysfunction showed no correlation with the
duration of the disease, inflammatory syndrome, RF
titre or articular destruction. Approximately 50% of
their patients had severe disease and showed some
degree of articular destruction. Geenen et al.14 found
diminished ANS function in RA patients who had
had the disease for <1 year. This diminished ANS
function was related to severity of pain and might
have been related to the pathophysiological mechanisms in RA. In contrast to previous studies, Bekkelund
et al.15 found no cardiovascular ANS abnormality in
their 43 RA patients, who had no ANS symptoms.
An abnormal cardiovascular ANS function in SLE
has also been found in several studies. Gledhill
et al.16 found that 13 of their 14 SLE patients (93%)
without autonomic symptoms had cardiovascular
ANS dysfunction. However, 12 of these patients had
evidence of peripheral neuropathy. The reason for
the high incidence of autonomic neuropathy in their
study is not clear. Liote et al.17 found that 88% of
their 17 SLE patients with mild disease activity had
at least one abnormal cardiovascular reflex test. Both
the standing heart rate ratio and the fall in standing
systolic blood pressure were abnormal, reflecting
abnormalities in both the parasympathetic and the
sympathetic nervous system. In contrast to Gledhill’s
study,16 no relationship between autonomic neuropathy and peripheral neuropathy was found. Straub
et al.18 found that three of their 31 SLE patients
(9.7%) had cardiovascular ANS dysfunction defined
by abnormal results in two of the five cardiovascular
reflex tests. The systolic blood pressure response to
standing was abnormal in 29%. A significant correlation between disease activity and the number of
abnormal cardiovascular reflex tests was observed.
Recently Lagana et al.19 and Laversuch et al.20 used
24-h ECG monitoring in addition to the standard
cardiovascular reflex tests to evaluate cardiovascular
ANS function and showed that a significant
decreased heart rate variability occurred in SLE
patients, especially at night when the parasympathetic nerve function is prominent, when compared
with controls. Twenty-two percent of Laversuch’s,20
but none of Lagana’s19 patients had symptoms of
dysautonomia. The diminished heart rate variability
showed no correlation with the disease duration, the
disease activity or serology. In contrast to the above
studies, Omdal et al.21 found no abnormality in the
cardiovascular ANS function in their 34 SLE patients
when using age- and sex-matched controls.
The diminished heart rate response to deep breathing in RA and SLE seen in this study is in line with
previous studies. However, many of the previous
studies had some limitations, such as selection of
controls and statistical analyses. Although the ages
of patients were matched to those of controls, they
compared means of the group rather than the agematched pairs used by Laversuch et al.,20 Omdal
et al.,21 Stein et al.,22 and our study. Moreover, some
studies used the standard-age reference values as
controls. As the ANS has been shown to deteriorate
with age,4 it is crucial to correct for age, and if
possible for sex, to strengthen results of the statistical analysis.
Although 26% of our RA and 95% of our SLE
patients took low doses of corticosteroids, the diminished heart rate response to deep breathing seen in
our patients showed no correlation with the dosage
of prednisolone used. This diminished heart rate
variability has been previously demonstrated to be
independent of the use of corticosteroids.22 Most of
our SLE patients had mild disease activity, with an
average modified SLEDAI score of 4.65, similar to
those of Loite et al.,17 Laversuch et al.,20 and Stein
et al.22 Patients with more severe disease tended to
have renal involvement, be anaemic, have high
Cardiovascular autonomic dysfunction in RA and SLE
blood pressure or to have conditions or be taking
drugs which were excluded from our study. It might
be of interest to study the cardiovascular ANS
function in the more severe SLE patients.
There have been substantial advances in the
assessment of autonomic function, particularly of
the cardiovascular system.23 However, the Ewing
approach, which has been used to assess ANS
function in clinical research for many years remains
satisfactory.7,9,15,17,20,21 A 24-h ECG record has been
recently used to evaluate heart rate variability in
combination with the standard cardiovascular reflex
tests as it is more sensitive in detecting the parasympathetic nervous system dysfunction, but an analysis
of the time and frequency domain for an evaluation
of the heart rate variation from a 24-h ECG recording
is mathematically complex and perhaps cannot be
done at a general hospital. Moreover, there is a good
correlation between the high frequency 24-h heart
rate variability, which is influenced by the parasympathetic nervous system, and the heart rate variation
in response to deep breathing.20
Note the fall in the systolic blood pressure, at a
mean of 10 mmHg in RA and SLE groups versus 8
and 6 mmHg, respectively, in the controls. The large
standard deviation indicates that there were great
variations, implying that our subjects were heterogeneous. The fall in systolic blood pressure showed no
correlation with the orthostatic hypotension symptoms in both groups. However, there is no agreement
for the normal range for the postural change, and a
decrease of as much as 25 mmHg can be normal.24
At the time of study, none of our RA patients had
vasculitis or numbness that was suggestive of sensory
neuropathy. Four lupus patients had cutaneous vasculitis and one had residual sensory and motor ulnar
neuropathy. As we did not do a peripheral nerve
conduction study, it is difficult to rule out the
absence of peripheral neuropathy in these patients.
Peripheral neuropathy, especially sensory, can affect
responses in some of the tests, in particular cold
stimulation. However, this test was not used in
our study.
The pathogenesis of the ANS dysfunction in
patients with RA and SLE is not clearly understood.
Vasculitis of the vasa nervorum and secondary amyloidosis has been proposed.13 The pathogenesis may
have an immune component. This is supported by
improvement of acute autonomic neuropathy after
treatment with immunosuppressive drugs in a patient
with SLE.25 The presence of circulating autoantibodies against nerve growth factor, cervical
ganglia and the vagus nerve has been recently
demonstrated in RA and SLE patients who had
cardiovascular ANS dysfunction.26,27 The significance
of these auto-antibodies in the pathogenesis of ANS
dysfunction remains to be determined.
101
In summary, cardiovascular ANS dysfunction, particularly the parasympathetic nervous system, occurs
in RA and SLE. It is usually not evident unless one
specifically tests for it, by using the standard cardiovascular reflex tests, before overt symptoms of ANS
dysfunction occur. The significance of asymptomatic
cardiovascular ANS dysfunction in clinical practice
remains to be investigated. One should be cautious
in prescribing drugs that have effects on the cardiovascular ANS in patients with RA and SLE with
possible autonomic dysfunction.
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