Autonomic dysfunction involving the gastrointestinal and the urinary tracts in primary Sjögren’s syndrome

L. Kovács1, M. Papós2, R. Takács3, R. Róka2, Z. Csenke4, A. Kovács1, T. Várkonyi3, L. Pajor5, L. Pávics2, G. Pokorny1

Department of Rheumatology1, Department of Nuclear Medicine2, 1st Department of Internal Medicine3 and Department of Urology5, University of Szeged, Faculty of Medicine, Szeged; Division of Urology, Municipial Clinic, Szeged, Hungary4

Abstract Objective Antibodies reacting with the m3 subtype muscarinic acetylcholine receptor appear to be an important patho- genic factor in primary Sjögren’s syndrome (pSS). As this receptor subtype is functionally important in the gastrointestinal and urinary tracts, and very little is known about the function in these organs in pSS patients, the occurrence and clinical significance of an autonomic nervous system dysfunction involving the gastrointestinal and urinary tracts were investigated.

Methods Data on clinical symptoms attributable to an autonomic dysfunction were collected from 51 pSS patients. Gastric emptying scintigraphy and urodynamic studies were performed on 30 and 16 patients, respectively, and the results were correlated with patient characteristics and with the presence of autonomic nervous system symptoms.

Results Gastric emptying was abnormally slow in 21 of the 30 examined patients (70%). Urodynamic findings compatible with a decreased detrusor muscle tone or contractility were found in 9 of the 16 patients tested (56%). Various symptoms of an autonomic nervous system dysfunction were reported by 2-16% of the patients.

Conclusion Signs of an autonomic nervous system dysfunction involving the gastrointestinal and the urinary systems can be observed in the majority of pSS patients. This high occurrence is rarely associated with clinically significant symptoms. The authors presume a role of autoantibodies reacting with the m3 muscarinic acetylcholine receptor in the elicitation of the autonomic dysfunction.

Key words Primary Sjögren’s syndrome, anti-muscarinic acetylcholine receptor antibodies, gastric emptying scintigraphy, urodynamic studies, autonomic dysfunction.

Clinical and Experimental Rheumatology 2003; 21: 697-703. Autonomic dysfunction in Sjögren’s syndrome / L. Kovács et al.

László Kovács, Assistant Professor; Introduction autonomic dysfunction can be detected Miklós Papós, Associate Professor; Primary Sjögren’s syndrome (pSS) is a in the GI and the urinary tracts. Róbert Takács, Resident; Richárd Róka, systemic charac- Resident; Zoltán Csenke, Head Physician; terised by a lymphocytic infiltration Patients and methods Attila Kovács, Assistant Professor; Tamás Várkonyi, Assis-tant Professor; and a subsequent functional impair- Study patients László Pajor, Professor; László Pávics, ment of various exocrine glands. There From among the cohort of pSS patients Professor; Gyula Pokorny, Professor. is increasing evidence that, in addition followed up at the Department of The work was supported by National to the structural damage to the involved Rheumatology at the University of Scientific Research Fund of Hungary grant glands caused by a lymphocytic infil- Szeged, all those who did not have dia- OTKA038303 and Health Care Scientific tration, decreased stimulation by the betes mellitus, chronic renal failure or Council of the Ministry of Health Care of autonomic nervous system of the glands any other disease that may cause an Hungary grant ETT214/2001 plays an important role in the elicita- autonomic neuropathy, and who were Please address correspondence to: tion of the exocrine dysfunction (1). We younger than 75 years, were asked to László Kovács, MD, Department of have found that pSS patients demon- complete a questionnaire relating to Rheumatology, Faculty of Medicine, strate an impaired microvascular re- symptoms which may potentially be University of Szeged, Kossuth Lsgt. 42, 6724 Szeged, Hungary. sponse to cholinergic stimuli as com- caused by an autonomic dysfunction. E-mail: [email protected] pared with healthy individuals (2). The Fifty-one patients (48 women) satisfied Received on February 10, 2003; accepted presence of antibodies reacting with th e the above-mentioned criteria (average in revised form on July 1, 2003. rodent and human muscarinic acetyl- age: 53 [range 31-71] years, and aver- © Copyright CLINICAL AND EXPERIMEN- choline receptor subtype 3 (m3AchR), age time since the appearance of the TAL RHEUMATOLOGY 2003. the predominant receptor subtype in first symptom of pSS: 14 [range 2-31] the lachrymal and salivary glands, has years). An answer was considered posi- been demonstrated in pSS patients (3- tive when no other medical condition 5). potentially attributable to the elicitation The m3AchR is also the functionally of the symptom was present in the dominant acetylcholine-receptor in the given patient. All of them fulfilled the gastrointestinal (GI) and the genito-uri- American-European classification cri- nary (GU) tracts (6,7), where it medi- teria for pSS (16). For the clinical tests, ates contraction of the parietal smooth further exclusion criteria were defined, muscles and relaxation of the sphincter as discussed later; the numbers of muscles (7). An impairment of these patients participating in the individual mechanisms, most commonly as a con- clinical examinations was therefore sequence of an autonomic neuropathy, smaller. The protocol was accepted by leads to significant morbidity as evi- the Medical Ethics Committee of the denced in patients with melli- University of Szeged. tus (8). Although a cardiovascular auto- nomic neuropathy has been described Examination of gastric emptying in pSS (9-15), data are scarce or lack- The gastrointestinal autonomic nervous ing as concerns autonomic neuropathy function was examined by assessment involving other organs, including the of the gastric motility with gastric emp- GI and the GU tracts. tying scintigraphy. The examination With regard to the emerging impor- was performed in the morning after an tance of anti-m3AchR autoantibodies overnight fast. The patients ingested a in pSS, and the fact that very little is radiolabelled meal (2 hard-boiled eggs known about the autonomic function in labelled with 20 MBq 9 9 mTc - h u m a n the GI and the urinary systems in this serum albumin macroaggregate + one disease, we designed a clinical study bread roll and 200 ml water). A dynam- among pSS patients to examine the ic scintigraphic study was performed autonomic nervous system function in about the gastric region. Digital images these organ systems. We hypothesised were taken at a frequency of 1 minute/ that anti-m3AchR antibodies bind to frame for 2 hours. As a parameter of receptors not only located in the sali- gastric emptying, the emptying half-

vary and the lachrymal glands, but also time (t1/ 2 ), i.e. the time until the radioac- in other organs where the m3AchR su b - tivity in the stomach had decreased to type predominates, and thereby cause an half the initial value, was determined. autonomic dysfunction. Our aim was to Two of the 51 patients had a condition attempt to clarify whether signs of an that may influence gastric emptying

698 Autonomic dysfunction in Sjögren’s syndrome / L. Kovács et al.

(previous surgical polypectomy and Table I. The occurrences of the most important organ manifestations and serological para- pernicious anaemia, respectively), and meters in the 51 pSS patients enrolled in the study.A labial biopsy was performed in 35 of they were therefore considered ineligi- the 51 patients. ble for this examination. Of the remain- Organ involvement/laboratory abnormality No. (%) ing patients, 30 consecutive subjects (27 women) participated in this exami- Articular involvement* 42 (82) nation. The patients did not have any Raynaud’s phenomenon 20 (39) sign of an organic upper gastrointesti- Purpura 11 (22) nal disease; moreover, gastroscopic Renal involvement** 11 (22) examinations on 23 of the patients did Pulmonary fibrosis 3 (6) not reveal such abnormalities either. Non-Hodgkin’s lymphoma 3 (6) The use of prokinetics or other drugs Antinuclear antibody positivity 35 (69) which influence the autonomic nervous Anti-SSA 42 (82) system or smooth muscle contractility Anti-SSB 26 (51) was suspended at least 3 days before Minor salivary gland focus score ³ 1 30 (86) the examination. During the validation process for this procedure, the cut-off *Articular involvement: arthralgia not due to degenerative joint disease, or arthritis. **Renal involvement: renal tubular acidosis or biopsy-proven tubulointerstitial nephritis. value for an abnormal t1/2 was deter- mined as the average + 1 SD of the t1/ 2 values for 7 healthy individuals (6 and were excluded from the urodynam- The correlation of the t1/2 values with women) with an average age similar to ic examinations. The administration of the patient parameters was examined that of the pSS patients. Thus, a t1/2 va l u e drugs influencing the autonomic ner- with linear regression analysis or with >74 minutes was considered abnormal. vous system or the function of the blad- Pearson’s correlation test. The relation- der was suspended an appropriate peri- ships between the urodynamic vari- Urodynamic examinations od before the measurements. Six pa- ables and the various patient data were For assessment of the autonomic neural tients refused to participate; of the re- analysed with Spearman’s rank correla- ef fects on the urinary tract, standard uro- maining patients, 16 women took part tion test. dynamic examinations were perform- in the urodynamic examinations. The ed. Uroflow measurements and cysto- groups of patients who participated in Results metric examinations were carried out either the gastric or the urological Patient characteristics and symptoms in a manner completely identical to the examinations and of those who did not Clinical characteristics of the 51 pa- routine diagnostic examinations. A n take part were similar as regards the tients are presented in Table I. T h e overall evaluation of all the clinical demographic, clinical and immunoser- number of patients who experienced data and the urodynamic charts was ological characteristics and the fre- the particular symptoms potentially made following the international guide- quencies of complaints possibly attrib- attributable to an autonomic dysfunc- lines for diagnostic urodynamic exami- utable to an autonomic neuropathy. tion are demonstrated in Table II. nations (17). As an autonomic nervous system dysfunction leads to an altered Sensory nerve function assessment Gastric emptying scintigraphy detrusor muscle tone or contractility, The somatic sensory nerve function The gastric emptying was significantly the following parameters were consid- was assessed by examination of the slower in the pSS patients than in the ered for the purposes of statistical vibration perception threshold. A cali- healthy controls. The average (±SD) analysis: maximum cystometric blad- brated vibrameter was placed on the t1/2 of gastric emptying was 94 ± 35.9 der capacity (normal: 320-590 ml), medial malleolus, and the patients’per- peak detrusor pressure (i.e. the differ- ception of the vibration was examined Table II. The numbers of pSS patients ence of the peak intravesical pressure and graded on a scale 0-8 (7-8: normal; complaining of symptoms possibly attrib- and the intra-abdominal pressure; nor- 6: borderline; < 6: abnormal). utable to an autonomic dysfunction. The mal: 35-60 cmH2O), and the maximum total number of patients tested was 51. urinary flow rate (normal: 15-36 ml/ Statistical methods Complaint No. of pts. sec). The normal values we applied are The t1 / 2 values exhibited a normal, standard values established for adult while the urodynamic variables a non- Postprandial fullness 6 females (17). Urological or gynaecolo- normal distribution. The mean or the / after eating 1 gical examinations, routine laboratory median values were compared via an Bloating 4 urinary tests, and abdominal and pelvic independent samples t-test or a Mann- 3 ultrasonographic examinations reveal- Whitney U-test between the patient and Urge incontinence 4 ed that 8 patients have an organic dis- control groups. The frequencies of the Stress incontinence 8 ease (3 men had bilateral prostate hy- various abnormalities in the two groups Difficulty in starting voiding 1 pertrophy and 5 women had cystocele), were compared by means of a c 2 test.

699 Autonomic dysfunction in Sjögren’s syndrome / L. Kovács et al. minutes in the patients and 59.6 ± 16.7 Correlations between test results nary tract autonomic dysfunction in minutes in the controls (p<0.05). 21/30 and patient characteristics pSS patients. The methods applied are pSS patients (70%) yielded an abnor- Neither the gastric emptying t1/2, nor accepted methods for the assessment of mal gastric emptying t1/2; moreover, in the 3 urodynamic parameters showed a autonomic neuropathy; however, as 9 of them, a markedly elevated t1 / 2 correlation with the results of the sen- anti-acetylcholine-receptor autoanti- (more than 120 minutes) was observed. sory nerve function test, the disease bodies are a special feature in pSS, and Representative images of normal gas- duration, the presence of any extraglan- these antibodies may also influence the tric emptying of a healthy control sub- dular manifestation or immunoserolog- innervation mechanism, we preferred ject and prolonged gastric emptying of ical positivity or the stimulated saliva use of the term “autonomic dysfunc- a pSS patient are shown in Figure 1. production measured with the Saxon tion” to “autonomic neuropathy”. Sev- test (18). In all of the patients who had eral case reports have described occa- Urodynamic examinations symptoms of autonomic dysfunction sional pSS patients with signs of an In the 16 examined pSS patients, we and underwent the urodynamic exami- autonomic neuropathy such as ortho- detected an abnormally high bladder nations, abnormal test results were static hypotension, , capacity in 9 patients (56%) and an obtained: the patient who experienced segmental anhydrosis or Adie’s tonic abnormally low capacity in 1 patient occasional difficulties in starting the pupil (19-21). In recent years, a number (mean: 553 ml, SD: 152 ml). The peak voiding was found to have both an of controlled clinical trials have been detrusor pressure was lower than nor- abnormally high bladder capacity and published in connection with cardio- mal in 6 patients (38%), while a de- decreased peak detrusor muscle con- vascular autonomic neuropathy in pSS creased maximum uroflow value was tractions. A further 4 patients with (9-15). However, to our knowledge, found in 5 (31%). At least 1 of the latter stress incontinence and one patient only one article mentions gastric motil- 2 tests was abnormal in 9 patients; thus with urge incontinence demonstrated ity in pSS (22), and no clinical trial has 56% of the patients exhibited some results compatible with a decreased been published on the urogenital in- sign of a decreased detrusor muscle detrusor contractility. However, the sta- volvement. c o n t r a c t i l i t y. On the other hand, for tistical analysis failed to reveal a corre- In patients with diabetes mellitus, each of the above parameters, one pa- lation between the presence of symp- examination of the gastric emptying is tient demonstrated an abnormally high toms and the test results on either organ an accepted method of indication of value (different patients in the two system. gastrointestinal autonomic neuropathy tests). Examples of cystometric charts (23). The parasympathetic influence demonstrating normal conditions, an Discussion predominates in the regulation of the abnormally high bladder capacity, and In this cross-sectional clinical trial, we upper motility, a decreased peak detrusor muscle pres- investigated the prevalence, severity including the stomach (24). A loss of sure are presented in Figure 2. and clinical correlates of GI and uri- vagal tone, resulting in the inhibition of

Fig, 1. (a) Radionuclide gastric emptying study in a healthy control subject (gastric emptying t1/2 = 39 minutes); and (b) study of prolonged gastric emptying in a pSS patient (t1/2 = 171 minutes). The graphs show the radioactivity (cpm) recorded in the region of the stomach as a function of time (min).

700 Autonomic dysfunction in Sjögren’s syndrome / L. Kovács et al.

Fig, 2. Cystometric charts of 3 pSS patients. (A) normal conditions; (B) increased cystometric bladder capacity; (C) decreased detrusor muscle contractile pressure. The charts show pressure values (cmH2O) during the examination registered using an intravesical (P1) and an intra-abdominal (P3) manometer, and the detrusor muscle contractile pressure, which was calculated as P1-P3. The was filled with sterile isotonic distilled water at an average rate of 70 ml/min. Sta: start of the filling; Fs: time of the first sensation of the need for voiding; Pea: peak pressure values during voiding; Sto: pressure values at the timepoint when voiding was intentionally interrupted by the patient.

701 Autonomic dysfunction in Sjögren’s syndrome / L. Kovács et al. gastric emptying, is characteristic of an in the upper GI tract attributable to a autonomic dysfunction in pSS patients autonomic neuropathy in diabetes mel- parasympathetic autonomic dysfunc- remains an open question. A reasonable litus (8). With gastric emptying scintig- tion can be detected in a great propor- explanation can be the role of an auto- raphy, severely delayed gastric empty- tion of pSS patients. However, we note nomic neuropathy, similarly as in sev- ing was observed in many diabetic that we failed to reveal a correlation eral other chronic diseases. In diabetes patients (23, 25). In this study, we between the abnormalities of the gas- mellitus, the autonomic neuropathy determined the t1/2 cut-off value of nor- tric and the oesophageal motility mea- usually, but not necessarily correlates mal gastric emptying in healthy sub- sured in 6 patients who participated in with the degree of somatic neuropathy jects to be 74 minutes. This figure is in both trials (data not shown). (31), and also with the disease duration the same range as obtained in other To the best of our knowledge, this is the (32). Moreover, a correlation can usu- published studies with conditions simi- first report on a systematic search for ally be observed between the severity lar to those in this trial (26,27). Our signs of an autonomic dysfunction in- of the autonomic neuropathy in differ- results indicate that the gastric empty- volving the urinary bladder in pSS ent organ systems in the same patient ing is prolonged in 70% of pSS pa- patients, despite some reports of uri- (33). In this study, we examined the tients, and a considerable proportion of nary retention in patients with this dis- vibration perception, which correlates these patients exhibit a markedly de- ease. However, animal experiments well with the overall status of the creased gastric motility. As org a n i c have revealed that serum from pSS peripheral nervous system (34). In our changes that may influence the gastric patients has an inhibitory effect on iso- pSS patients, correlations similar to emptying were not detected in the pa- lated rabbit urinary bladder smooth those in diabetic patients could not be tients, this abnormality is most proba- muscle contractions, this effect being detected, and the present test results did bly a consequence of an impaired para- mediated by anti-m3AchR antibodies not exhibit a correlation with those of sympathetic activity. Data on gastric (29). The normal function of the uri- examinations on the cardiovascular emptying in pSS patients have been re- nary bladder is mainly under the con- autonomic function (unpublished ob- ported in only one study, aimed at an trol of the parasympathetic nervous servations). It is of note that an auto- evaluation of the oesophageal involve- system, which facilitates the contrac- nomic dysfunction, albeit highly preva- ment in scleroderma and pSS (22). tion of the detrusor muscle and the lent, appears to be less severe in pSS Similarly to us, the authors found that relaxation of the internal sphinchter. patients than in diabetics. T h e r e f o r e , the gastric emptying was slower in the The loss of parasympathetic stimuli more precise and detailed neurological pSS patients than in the controls. It is due to sacral plexus injury or diabetic examinations may be necessary to re- of note that pSS patients rarely had autonomic neuropathy leads to urinary veal subtle abnormalities in the periph- complaints of an impaired gastric emp- retention, bladder atonia or flaccidity eral somatic and autonomic nerves. tying, and even the 8 patients in our (30). In this study, the most frequent A further potential explanation of an study who had complaints of postpran- complaint concerning the urinary blad- autonomic dysfunction can be the dial fullness had merely mild symp- der was consistent with a mild stress- interference of antirecepor antibodies toms which they reported only upon incontinence, which is usually a conse- with the autonomic innervation pro- direct questioning. Nevertheless, the quence of factors other than an auto- cess. Since similarly as for the salivary exact clinical significance of gastric nomic dysfunction in women of similar and the lachrymal glands, the function- symptoms can be assessed only by age to that in this study group. Howev- ally predominant muscarinic receptor means of longitudinal studies. e r, the difficulty in starting voiding, subtype in the GI and the GU tracts is P r e v i o u s l y, we have investigated the mentioned by one patient, may be also the m3 subtype, our findings are in oesophageal motor function in pSS explained by a parasympathetic dys- favour of the hypothesis that anti- patients (28). In that study, the predom- function, as an obstructive disorder had m3AchR antibodies also bind to recep- inant abnormality appeared to be a been excluded. Similarly to the results tors located in organs other than the ex- decreased oesophageal body peristaltic on the GI system, asymptomatic chan- ocrine glands. This concept is strongly v e l o c i t y. We concluded that both a ges, i.e. an increased bladder capacity, supported by the recent finding that the diminished salivary function and a decreased detrusor pressure and a immunoglobulin G fraction purified oesophageal motor abnormalities are decreased maximal uroflow were de- from the sera of pSS patients specifi- factors in the development of swallow- tected in approximately half of the cally inhibited the m3-muscarinic ing difficulties in pSS patients. As the patients. As obstructive changes or r e c e p t o r-mediated contractions of the oesophageal body muscles are partly other organic pelvic diseases were ex- mouse colon (35). This interaction may innervated via the parasympathetic ner- cluded, these results are consistent with contribute to the elicitation of the vous system, we suggested a choliner- a decreased detrusor muscle tone and extraglandular manifestations of pSS. gic autonomic dysfunction as one c o n t r a c t i l i t y, and, similarly as with Nevertheless, to obtain direct evidence, potential explanation of an impaired flaccid neurogenic bladder, a decreased further examinations of the fine anti- oesophageal motor function. T h e s e parasympathetic influence can be sus- genic and organ specificities and of the findings are in keeping with the present pected (30). physiological actions of anti-mAchR results and suggest that abnormalities The precise mechanisms leading to antibodies are necessary.

702 Autonomic dysfunction in Sjögren’s syndrome / L. Kovács et al.

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