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Rheumatology Advance Access published online on April 14, 2008
Rheumatology, doi:10.1093/rheumatology/ken107
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Autonomic nervous symptoms in primary Sjögren's; syndrome

T. Mandl1, V. Granberg2, J. Apelqvist2, P. Wollmer3, R. Manthorpe4 and L. T. H. Jacobsson1

1Department of Rheumatology, 2Department of Endocrinology, 3Department of Clinical Physiology, Malmö University Hospital and 4Sjögren's Syndrome Research Centre, Malmö, Sweden.

Correspondence to: T. Mandl, Department of Rheumatology, Ing 25 plan 2, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: thomas.mandl{at}med.lu.se


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Objective signs of autonomic dysfunction (AD) have been reported in patients with primary SS (pSS) while the presence of associated symptoms has not been systematically studied. Therefore, the aims of this study were (i) to assess the presence and severity of various AD symptoms in pSS patients and (ii) to relate AD symptoms to other clinical features of pSS.

Methods. Thirty-eight pSS patients and 200 population-based controls were studied for presence and severity of AD symptoms using the Autonomic Symptom Profile (ASP), a validated self-completed questionnaire evaluating various AD symptoms. In addition, patients were investigated by three different objective autonomic nervous function tests.

Results. pSS patients scored significantly higher in the parasympathetic [secretomotor disorder, urinary disorder, gastroparesis (females only) and pupillomotor disorder] as well as sympathetic (orthostatic intolerance and vasomotor disorder) ASP domains compared with controls. Consequently, the standardized ASP total score was significantly increased in pSS patients [1.77 (0.57, 3.15) vs – 0.21 (–0.82, 0.72); P = 0.00] and 45% of pSS patients had an ASP total score ≥2 S.D. Furthermore, the autonomic nervous function tests showed signs of objective parasympathetic and sympathetic dysfunction as well. However, the ASP domain and total scores showed limited associations with the objective autonomic nervous function test parameters as well as clinical and serological factors of pSS.

Conclusions. pSS patients showed subjective and objective signs of both a parasympathetic and a sympathetic dysfunction. However, AD symptoms showed limited associations with objective autonomic nervous function as well as other clinical features of the disease.

KEY WORDS: Autonomic symptoms, Primary Sjögren's; syndrome, Cardiovascular, Nervous, Physiology


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
Primary Sjögren's; syndrome (pSS) is an autoimmune disease not only affecting the exocrine glands always but also affecting various non-exocrine organs, including the nervous system, frequently. Several studies report signs of peripheral neuropathy in pSS [1–6] and the autonomic nervous system (ANS), according to case reports and case series, may also be involved in the disease manifested by various autonomic dysfunction (AD) symptoms [6–11]. In pSS, the degree of exocrine gland destruction and function often correlate poorly [12, 13]. Since exocrine secretion is modulated by the ANS, impaired secretion could partly be due to interference with nervous signals to the exocrine glands [12, 14]. In previous studies, using autonomic reflex tests, parasympathetic and sympathetic dysfunction in pSS has been demonstrated [15–18] while studies measuring heart rate variability and baroreflex sensitivity have yielded contradictory results [18–21]. The observed AD in pSS has been ascribed to various immunological factors [6, 22–27]. Since immunological mechanisms have been proposed to affect autonomic function and the recent American–European Consensus Criteria (AECC) [28] in comparison with older criteria [29, 30] include pSS patients with at least some evidence of autoimmunity, an increased prevalence of ANS involvement would be expected in pSS patients diagnosed according to the AECC. Whilst objective signs of AD in pSS have been studied in several previous studies [15–21] and although only three of these applied the AECC [15, 18, 20], its subjective correlates have not been systematically studied.

The aims of this study were to evaluate AD symptoms in pSS patients using the Autonomic Symptom Profile (ASP), a validated and self-completed questionnaire assessing AD symptoms [31, 32], and to study associations between AD symptoms and clinical and serological features of pSS.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Statistics
 Results
 Discussion
 Acknowledgements
 References
 
Patients
Thirty-eight patients [median age 56 (range 25–61) yrs, 35 females], with pSS according to the AECC were recruited from the outpatient clinic at the Department of Rheumatology, Malmö University Hospital.

Eight patients were ≥60 yrs of age (60 yrs, n = 3, 61 yrs, n = 5). None of the patients had any comorbidity or was currently on any medication (anti-cholinergic drugs, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or pilocarpine) known to affect autonomic nervous function. All patients completed the ASP. In addition, the patients had previously been studied by three different objective autonomic nervous function tests i.e. the deep-breathing test, the orthostatic test and the finger skin blood flow test, the results of which have been previously reported [15]. One patient could not perform the finger skin blood flow test due to pain during cold provocation and two patients could not be investigated by the tilt table test due to feeling of panic, when being strapped to the tilt table. Further characteristics of the patients are presented in Table 1.


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  		TABLE 1. Characteristics of the patients with pSS and ASP controls

 
Controls
Two hundred controls [median age 45 (range 20–69) yrs, 100 females] were randomly selected from the Swedish general population registry and were required to be living in the City of Malmö or its surroundings. To ensure a balanced sex- and age-distribution, equal numbers of male and female controls were selected in each 10-yr stratum. The controls were asked via mail if they would like to participate in the study. If the subject was willing to participate and had no disease (diabetes mellitus, RA orSS) or medication (anti-hypertensives, cardiovascular medication or anti-depressants) affecting autonomic nervous function, then the questionnaire was filled out and sent back by post. A ticket to the cinema was sent back to each subject returning a fully completed questionnaire. If no answer was received within 4 weeks, then a reminding letter was sent and if that was not answered either, a new control of the same age and gender was selected, until 200 controls were included. Further characteristics of the controls are presented in Table 1.

Autonomic nervous function tests
The pSS patients had, as previously reported [15], been studied regarding autonomic nervous function by three autonomic nervous function tests—the deep-breathing test, the orthostatic test and the finger skin blood flow test. The time difference between the completion of the autonomic nervous function tests and the ASP was median 17 [interquartile range (IQR) 10, 24] months.

Deep-breathing test
This test measured the heart rate variation, monitored by ECG, during deep-breathing. An expiration/inspiration (E/I) ratio was calculated as the mean of the longest R–R intervals, i.e. inter beat intervals, during expirations divided by the mean of the shortest R–R intervals during inspirations [33]. According to previous studies, the E/I-ratio mainly reflects parasympathetic nervous function [33, 34].

Orthostatic test
This test measured the heart rate, monitored by ECG and blood pressure reaction to tilt, the latter manually measured by a trained nurse before as well as every minute after tilt. A mean of the R–R intervals before tilt (A) was calculated and the shortest R–R interval during the first minute after tilting (B) was determined. From these values, an acceleration index (AI), defined as [(A–B)/A x 100], was calculated [35, 36]. The AI seems to be influenced mainly by the parasympathetic [37] but also to some degree by the sympathetic nervous system [38, 39]. The systolic and diastolic blood pressures before tilt (SBPrest and DBPrest) as well as the lowest systolic and diastolic blood pressures during the first 8 min after tilt (lSBP and lDBP) were determined. From these, orthostatic systolic and diastolic blood pressure-ratios were calculated [lSBP-ratio = lSBP/SBPrest] and [lDBP-ratio = lDBP/DBPrest]. According to previous studies, the orthostatic blood pressure response is considered reflecting sympathetic nervous function [40].

Finger skin blood flow test
This test measured the reflex vasoconstriction to contralateral cold provocation. The subject's finger skin blood flow was monitored by a laser doppler imaging (LDI) instrument, at first during a 40°C heating procedure, and subsequently during immersion of the contralateral hand and forearm into a 15°C water bath. By dividing the lowest finger skin blood flow value during the first minute of contralateral cooling (LDIc) by the mean of the two last measurements of finger skin blood flow at rest, before the cooling procedure, (LDIh) a vasoconstriction (VAC) index could be calculated (VAC-index = LDIc/LDIh). According to previous studies, this reflects the sympathetic nervous function in the skin [41].

Since autonomic function tends to deteriorate with increasing age, the autonomic nervous function variables were age corrected and expressed as z-scores by comparison with three control groups, namely 56 controls for the E/I-ratio and AI consisting of healthy subjects [median age 40 yrs (range 16–59 yrs), 22 females] all of whom had passed a health examination without signs of cardiovascular disease, respiratory disorders or diabetes mellitus [42], 80 controls for the VAC-index consisting of healthy subjects [median age 43 yrs (range 19–81 yrs), 37 females] all of whom were non-smokers, had no history of vascular disease and were not on any medication [41] and 238 controls for the lSBP and lDBP-ratios consisting of healthy non-diabetic individuals [median age 60 yrs (range 16–96 yrs), 106 women] previously described in detail [43]. Since gender does not seem to affect significantly the autonomic variables measured in this study [41, 42], sex was not matched for. All autonomic nervous function tests were performed in the morning under standard conditions, i.e. the temperature conditions were kept stable and the patients were not allowed to eat, drink coffee or smoke later than 2 h prior to testing.

ASP
The ASP is a self-completed questionnaire assessing autonomic nervous symptoms which in its original English version has been validated in patients with autonomic neuropathies of different aetiologies [31] and used in patients with diabetes [32]. Recently, the questionnaire was also translated into Swedish and validated in patients with type I diabetes (Mandl et al., unpublished data). Both the English and Swedish versions of the ASP were considered valid.

The ASP consists of questions evaluating nine domains of autonomic symptoms i.e. orthostatic intolerance, secretomotor dysfunction, male sexual dysfunction, urinary dysfunction, gastrointestinal dysfunction (divided into three subdomains namely gastroparesis, diarrhoea and constipation), pupillomotor dysfunction, vasomotor dysfunction, sleep disorder and reflex syncope. In addition, 12 interspersed questions addressing psychosomatic and understatement tendencies are included. The autonomic symptom domains consists of questions evaluating presence, severity, distribution, frequency and progression of various autonomic symptoms and the separate answers are scored according to their predictability for disease. In addition, domain scores are weighted according to their clinical relevance.

Consequently, the weighted maximum domain scores are as follows: orthostatic intolerance, 40; secretomotor dysfunction, 20; male sexual dysfunction, 30; urinary dysfunction, 20; gastroparesis, 10; diarrhoea, 20; constipation, 10; pupillomotor dysfunction, 5; vasomotor dysfunction, 10; sleep disorder, 15 and reflex syncope, 20. By adding the autonomic domain scores, an ASP total score is calculated with a maximum score of 200 for males and 170 for females, lower for females due to the lack of questions addressing female sexual dysfunction. Furthermore, the psychosomatic and understatement domains are given a maximum score of 10 each and are presented separately. Since some of the ASP domain scores are affected by age, gender, height and weight, several of the ASP scores were age, gender, height and weight standardized in comparison with the 200 controls and expressed as z-scores. Due to a preponderance of zero values in the gastroparesis and reflex syncope domains among controls, although with some gender differences, these domains were expressed as gender stratified raw scores. Similarly, the psychosomatic and underestimation domains were also expressed as gender-stratified raw scores.


   Statistics
Top
 Abstract
 Introduction
 Materials and methods
 Statistics
Results
 Discussion
 Acknowledgements
 References
 
Due to a skewed distribution of the ASP scores as well as for the autonomic nervous function parameters, the Mann–Whitney U-test was used for group comparisons and the Spearman rank correlation test for correlations. Fisher's exact test was used for discrete variables. Values were presented as median (IQR) or percentages with pathological results. P-values <0.05 were considered statistically significant.

Ethics
The study was approved by the ethics committee at Lund University (LU814-04). All participants gave written informed consent.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
Discussion
 Acknowledgements
 References
 
The pSS patients, as previously reported [15], were found to have a decreased E/I-ratio and an increased VAC-index compared with controls reflecting a parasympathetic and a sympathetic dysfunction, respectively. Furthermore, the lSBP- and lDBP-ratios were decreased in pSS patients compared with controls, also indicating a sympathetic dysfunction (Table 2).


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  		TABLE 2. Autonomic nervous function test results in the 38 patients with pSS and autonomic nervous function controls, representing a subgroup of pSS patients previously evaluated for objective AD as formerly reported [15]

 
As expected, pSS patients scored higher compared with controls in the secretomotor and pupillomotor domains, but also in other parasympathetic domains, i.e. urinary disorder, and gastroparesis (females only) domains. In addition, pSS patients scored higher in the sympathetic domains, i.e. orthostatic intolerance and vasomotor disorder domains. Consequently, the ASP total score was significantly increased in pSS patients compared with controls (Table 3) and 45% (17/38) of the pSS patients had a standardized ASP total score ≥2 S.D. indicating a pathological autonomic symptomatology.


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  		TABLE 3. Comparisons of the ASP domain scores in 38 patients with pSS and 200 controls

 
The female pSS patients also scored significantly higher in the psychosomatic domain, reflecting psychosomatic tendencies. However, two questions on psychosomatic symptoms from the original questionnaire addressed presence of swallowing difficulties and experience that all food tastes the same, symptoms which cannot necessarily be regarded as psychosomatic symptoms in hyposalivating pSS patients. If these two questions were omitted from the psychosomatic domain and an adjusted psychosomatic index was calculated and re-weighted with a maximum score of ten, then the difference between female pSS patients and female controls was no longer significant (Table 3). Even if patients and controls with an adjusted psychosomatic score >0 were omitted, pSS patients still scored significantly higher in the orthostatic intolerance, gastroparesis (females only), secretomotor, pupillomotor and vasomotor disorder domains as well as in the ASP total score. Moreover, several ASP domain scores correlated with each other as well as with the ASP total score (Table 4).


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  		TABLE 4. Correlations between the age-, gender-, height- and weight-standardized ASP domain scores in the 38 patients with pSS

 
When correlating the objective autonomic nervous function test parameters with the ASP scores, significant correlations were only found between the VAC-score and the sleep disorder domain score (r's = 0.42; P = 0.01) as well as between the lSBP-ratio and the constipation domain score (r's = –0.43; P = 0.01). Even when ASP domains possibly reflecting end-organ damage/exocrine destruction as well as autonomic function, i.e. the secretomotor and pupillomotor disorder domains, were omitted and a new standardized ASP total score was calculated, this adjusted ASP total score did not correlate with the objective autonomic nervous function test parameters. Furthermore, when comparing pSS patients with abnormal (≥2 S.D.) and normal (<2 S.D.) scores in the orthostatic intolerance, urinary disorder, vasomotor disorder, secretomotor disorder, pupillomotor disorder and total score domains as well as the gastroparesis domain in female patients (abnormal >0), respectively, no significant differences in the objective autonomic indices were found. However, when comparing pSS patients with abnormal (≤2 S.D.; n = 3) and normal (>2 S.D.; n = 33) lSBP-ratios, the former had significantly increased scores in the orthostatic intolerance [median 2.86 (IQR 2.29, 3.43) vs 1.00 (–0.63, 1.84); P = 0.01], constipation [2.72 (2.56, 4.23) vs –0.47 (–0.56, 1.05); P = 0.03], vasomotor disorder [3.98 (2.37, 4.04) vs –0.26 (–0.50, 2.92); P = 0.02], pupillomotor disorder [3.25 (3.06, 3.69) vs 1.44 (–0.18, 2.65); P = 0.02] domains, the ASP total score [4.26 (3.52, 6.55) vs 1.65 (0.39, 2.47); P = 0.00] as well as a non-significant tendencies towards increased scores in the urinary disorder [2.13 (1.89, 8.32) vs 0.08 (–0.70, 1.93); P = 0.07] and gastroparesis (females only) [1.50 (1.50, 5.00) vs 0.00 (0.00, 1.50); P = 0.06] domains.

ASP scores were not affected by disease duration, or presence of anti-SS-A and B-antibodies or non-exocrine symptoms (as defined in Table 1), respectively. However, when comparing patients with and without RP, there was, as expected, a significantly higher score in the vasomotor [2.92 (1.70, 3.22) vs –0.32 (–0.50, 2.42); P = 0.04] but also in the constipation [1.05 (–0.50, 5.80) vs –0.53 (–0.57, 0.95); P = 0.03] domains and a non-significant tendency towards a lower score in the orthostatic intolerance domain [0.31 (–0.91, 1.46) vs 1.55 (–0.10, 2.80); P = 0.09] among the former. When comparing patients with and without symptoms of peripheral neuropathy the former scored significantly higher in the sleep disorder domain [1.26 (0.10, 2.15) vs –0.42 (–0.83, 0.80); P = 0.05], while no significant differences were found in the remaining ASP domains. Finally, the prevalence of current smokers did not significantly differ between pSS patients and controls (13 vs 24%; P = NS) and the ASP domain scores were not found to significantly differ between smoking and non-smoking pSS patients.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
 Discussion
Acknowledgements
 References
 
In this first larger cohort study systematically studying subjective AD symptoms in pSS, patients were found to have various subjective and objective signs equivalent of parasympathetic and sympathetic dysfunction. However, AD symptoms showed limited associations with objective AD signs and other clinical features of pSS.

AD is a complication of many chronic diseases [35, 44–49] and may result in several debilitating symptoms [50]. Objective signs of AD have previously been demonstrated in pSS patients [15–19, 21] including the present group of patients [15] and various immunological mechanisms behind AD in pSS, namely anti-muscarine-3 (M3)-receptor antibodies [22–24], cytokines interfering with nervous signalling [25, 26, 51] and inflammation of autonomic nerves or ganglia [6, 27], have been proposed. Considering that exocrine gland destruction in pSS is often much less pronounced than the decreased exocrine function, other mechanisms beside exocrine gland destruction have to be accountable for exocrine impairment in pSS. Since autonomic nervous signalling to the exocrine glands is a prerequisite for secretion, a disturbance in these signalling pathways in pSS, as suggested already in the early 1990s, by Konttinen and co-workers [52], could explain the discrepancy between exocrine gland morphology and function in pSS. Although, several case reports and case series report on AD signs and symptoms, e.g. orthostatic hypotension [6–9], urinary symptoms [9, 10], Adie's syndrome [6, 11] and constipation [6] in association with pSS, the subjective correlates of AD in pSS have not previously been systematically studied.

The strengths of this study were the use of the nowadays widespread AECC [28] for pSS, the exclusion of patients on medications interfering with autonomic function as well as a large population-based control group for the ASP, allowing for standardization with regards to age, gender, height and weight. One of the possible concerns, is the fact that the ASP has not been validated specifically in pSS patients, although the original English version of the ASP has been validated in patients with symptomatic AD due to different aetiologies [31] and the Swedish version in patients with type I diabetes (Mandl et al., unpublished data). However, if the anti-M3-receptor antibodies, as suggested, play a central role in pSS-related AD, a validation of the ASP in pSS patients should include analysis of these antibodies. Another possible concern with this study is the risk that some of the ASP domains, e.g. the secretomotor and pupillomotor disorder domains, could evaluate end-organ damage rather than AD in pSS patients. Finally, since several correlation analyses were performed when performing correlations between the ASP domains and the objective autonomic nervous function tests, there is a risk that some significant correlations could be due to multiple comparisons.

In this study, we found an increased frequency of both symptoms and objective signs related to a parasympathetic and sympathetic dysfunction, although they showed limited associations. This lack of association, however, could well be due to end-organ damage, obscuring a possible association between objective and subjective AD. Other possible explanations could be variable concentrations of the putative anti-M3-receptor antibodies in various tissues; the inability of the objective autonomic nervous function tests to measure the physiological effects of anti-M3 receptor antibodies, which might still result in various symptoms; the sometimes few stepped ASP domain score scales; insufficient power in the present study to address this issue, as well as the time lap between subjective and objective tests.

Although the increased secretomotor and pupillomotor disorder domain scores in pSS were expected and could be due to exocrine gland destruction, i.e. end-organ damage, the increased scores in the urinary disorder and gastroparesis (females only) as well as the decreased E/I-ratio imply a parasympathetic dysfunction in pSS. Moreover, the increased scores in the orthostatic intolerance and vasomotor disorder domains in pSS patients, the increased VAC-index and decreased orthostatic blood pressure response imply a sympathetic dysfunction as well. Due to the excess of AD symptoms in pSS patients, 45% of these had an ASP total score ≥2 S.D., indicating a pathological AD symptomatology. We also found a tendency that female pSS patients scored higher in the psychosomatic domain, which however, became statistically non-significant when for pSS patients inappropriate psychosomatic questions were omitted. Furthermore, omitting subjects with adjusted psychosomatic scores above zero did not change most statistical differences in ASP scores between patients and controls. It is thus unlikely that the increased ASP scores in pSS patients reflect an overall increased tendency to report symptoms. Presence of orthostatic symptoms correlated with sleep disorder, pupillary and vasomotor symptoms implying a common cause for such symptoms. Although secretomotor symptoms, as expected, are common in pSS patients such symptoms only correlated with sleep disorder symptoms and not with the majority of the other AD symptoms, implying that other mechanisms beside AD, e.g. end-organ damage in patients with long disease duration, may be accountable for the secretomotor dysfunction in pSS. For that reason, future studies should investigate the presence of objective and subjective AD signs as well as anti-M3-receptor antibodies in pSS patients with shorter disease duration, to establish if an association between these entities is more apparent in the disease before exocrine destruction has occurred. Finally, AD symptoms were also found to associate poorly with the presence of different diagnostic autoantibodies as well as with other non-exocrine symptoms.

In conclusion, pSS patients were found to have various subjective and objective signs of parasympathetic and sympathetic dysfunction. Generally, however, AD symptoms showed limited associations with objective AD signs as well as other clinical features of pSS.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
 Discussion
 Acknowledgements
References
 
We would like to thank Jan-Åke Nilsson for statistical support.

Funding: The study was supported by grants from the Swedish Rheumatism Association.

Disclosure statement: The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 21 November 2007; revised version accepted 13 February 2008.
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