Mild autonomic dysfunction in primary Sjögren's syndrome: a controlled study

Abstract

Introduction: The aim of this study was to compare cardiovascular autonomic nervous system function in patients with primary Sjögren's syndrome (pSS) with that in control individuals, and to correlate the findings with autonomic symptoms and the presence of exocrine secretory dysfunction.

Methods: Twenty-seven female patients with pSS and 25 control individuals completed the COMPASS (Composite Autonomic Symptom Scale) self-reported autonomic symptom questionnaire. Beat-to-beat heart rate and blood pressure data in response to five standard cardiovascular reflex tests were digitally recorded using a noninvasive finger pressure cuff and heart rate variability was analyzed by Fourier spectral analysis. Analysis was performed by analysis of variance (ANOVA), multivariate ANOVA and repeated measures ANOVA, as indicated. Factor analysis was utilized to detect relationships between positive autonomic symptoms in pSS patients.

Results: Multiple, mild autonomic disturbances were observed in pSS patients relating to decreased heart rate variability, decreased blood pressure variability and increased heart rate, which were most evident in response to postural change. There was a strong trend toward an association between decreased heart rate variability and increased severity of the secretomotor, orthostatic, bladder, gastroparesis and constipation self-reported autonomic symptom cluster identified in pSS patients. This symptom cluster was also associated with fatigue and reduced unstimulated salivary flow, and therefore may be an important component of the clinical spectrum of this disease.

Conclusion: There was evidence of mild autonomic dysfunction in pSS as measured with both cardiovascular reflex testing and self-reported symptoms. Pathogenic autoantibodies targeting M3 muscarinic receptors remain a strong candidate for the underlying pathophysiology, but practical assays for the detection of this autoantibody remain elusive.

Figure 1

Factor analysis of COMPASS autonomic symptom scale scores within pSS patients. (a) Scatterplot of rotated (varimax normalized) COMPASS subscale factor loadings for factor 1 (24% of total variance) and factor 2 (15% of total variance), both with appreciable loadings for the secretomotor subscale. Factor 1 had the highest loadings for secretomotor, orthostatic, gastroparesis, constipation and bladder subscales, which is indicative of a substantial clustering of these symptoms within patients who have primary Sjögren's syndrome (pSS). The highest loadings for factor 2 were observed with both the secretomotor and pupillomotor subscales. (b) Scatterplot of the COMPASS factor 1 scores for each pSS patient by results of the contemporaneous 15-minute unstimulated salivary flow test. The horizontal bars represent mean scores for each group. Factor 1 scores were significantly higher in patients with this objective measure of dryness (P = 0.025), whereas factor 2 scores were not (P = 0.40; data not shown). Scatterplot of the COMPASS factor 1 scores for each pSS patient by the FACIT-F scores. Factor 1 scores were significantly correlated with fatigue scores (P = 0.035), whereas factor 2 scores were not (P = 0.18; data not shown). COMPASS, Composite Autonomic Symptom Scale; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue.

Figure 2

Abnormal HRV responses after postural change in pSS patients. All analyses were performed by repeated measures analysis of variance. (a) Brachial systolic blood pressure (SBP). The initial SBP response to standing was normal in patients who have primary Sjögren's syndrome (pSS). However, between 2 and 5 minutes after standing, there was a relative decline in SBP in pSS patients and a relative increase in control individuals (P = 0.015). (b) RR intervals. There was a relative tachycardia in pSS patients. This was most pronounced during standing (P = 0.039). (c) The proportion of successive RR intervals differing by more than 50 ms (pNN50) was lower in pSS patients than in control individuals over both postural positions (P = 0.025). (d) SBP power. The normal response to standing is an increase in SBP power, most evident in the low frequency (0.04 to 0.15 Hz) domain. This was significantly attenuated in pSS patients (P = 0.01). (e) RR power. Parasympathetic withdrawal upon standing results in a decrease in heart rate variability (HRV). In the low frequency (LF) domain, this is counterbalanced by an increase associated with increased LF blood pressure variability (see panel c). The net result of a normal response to standing is very little change in LF HRV and a substantial decrease in high frequency HRV. In control individuals, there was minimal change in LF HRV in response to standing, consistent with a normal response. However, in pSS there was a substantial decrease in LF HRV upon standing, and therefore standing LF HRV was significantly lower in pSS patients (P = 0.024).

Figure 3

Factor analysis of abnormal postural change cardiovascular autonomic indices within pSS patients. RR intervals, low frequency RR power (HRV_LF), proportion of successive RR intervals differing by more than 50 ms (pNN50), change in systolic blood pressure on standing (ΔSBP), low frequency systolic blood pressure power (BPV_LF) and the 30/15 ratio were all decreased in patients who have primary Sjögren's syndrome (pSS) relative to control individuals on standing. (a) Three-dimensional scatterplot of rotated (varimax normalized) factor loadings. Factor 1 had the highest loadings for HRV_LF, pNN50 and the 30/15 RR ratio. Factor 2 had the highest loadings for ΔSBP and BPV_LF. Factor 3 had the highest loading for RR intervals during standing. (b) Scatterplot of the HRV factor 1 scores for each pSS patient by the presence of Raynaud's phenomenon. The horizontal bars represent mean scores for each group. Factor 1 scores were significantly lower (more abnormal) in patients without Raynaud's (P = 0.025). (c) Scatterplot of the HRV factor 1 scores (y-axis) versus COMPASS factor 1 scores (x-axis) for each pSS patient. There was a negative correlation that did not quite reach statistical significance (P = 0.08).