In this study we demonstrated evidence, obtained from both self-reported symptoms and objective cardiovascular reflex testing, of mild autonomic dysfunction in pSS. From the cardiovascular reflex testing, there was evidence of multiple autonomic disturbances in pSS relating to decreased HRV, decreased blood pressure variability and an increased heart rate (tachycardia), which were most evident in response to postural change. There was a strong trend toward an association between decreased HRV and increased severity of the secretomotor, orthostatic, bladder, gastroparesis and constipation self-reported symptom cluster 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. Of note, we [21
] and others [23
] previously reported increased bladder symptoms in pSS patients; furthermore, a high frequency of both delayed gastric emptying and decreased bladder detrusor muscle tone has also been observed in pSS patients [24
Previous studies addressing cardiovascular autonomic function in pSS have yielded conflicting results, although a pattern is emerging. Two studies using 24-hour Holter monitoring [4
], which reflects tonic balance, both reported negative results. In contrast, a number of studies of provoked cardiovascular responses or short-term HRV [6
] identified abnormalities in pSS, although not all of these were controlled studies or used appropriate age-adjusted criteria for interpretation of abnormal test results. Four controlled studies [8
] found abnormalities in either the 30/15 ratio or blood pressure response to postural challenge, as we also observed, and two controlled studies [6
] identified reduced HRV/blood pressure variability in pSS patients by using spectral analysis. Our observation of a relative tachycardia in pSS patients has not previously been reported. Four studies [8
] also reported a decreased breathing E/I ratio in pSS patients, which we did not observe. However, this test is also influenced by breathing tidal volume, which may have differed between study participants and potentially confounded the results. Similar to other studies [10
], we did not observe an association between cardiovascular reflex test scores and objective measures of sicca in pSS patients, but this is the first study to both examine and report an association between objective measures of sicca and self-reported autonomic symptoms in pSS patients.
Potential mechanisms of autonomic dysfunction in SS include T-cell infiltration and destruction of ganglions and nerves [28
], cytokine-induced inhibition of neuropeptide secretion from nerve endings [29
], immune complex-mediated inflammation (although few pSS patients in this study exhibited cryoglobulins and/or low C3 or C4, which might indicate immune complex deposition), and pathogenic autoantibodies targeting receptors relevant for autonomic functioning [30
]. IgG autoantibodies, which inhibit the function of type 3 muscarinic receptors (M3Rs), have been described in pSS patients [3
]. Importantly, these autoantibodies inhibit salivary secretion [32
], bladder detrusor muscle contraction [3
], and colon contractions [33
. Evidence that lower urinary tract symptoms in pSS are autoantibody mediated comes from passive transfer of SS immunoglobulin or rabbit anti-M3R to mice, which produces the phenotype of overactive bladder [2
]. Furthermore, neutralization of anti-M3R autoantibodies by intravenous immunoglobulin led to improvement in bladder and bowel autonomic symptoms in patients with autoimmune diseases [34
]. Therefore, pathogenic M3R autoantibodies are strongly implicated in the pathophysiology of the cluster of secretomotor, bladder, gastroparesis, constipation and orthostatic autonomic symptoms in pSS patients observed in the present study.
Pathogenic M3R autoantibodies may also potentially influence cardiovascular autonomic responses. Although the M2R subtype is the numerically and functionally predominant muscarinic receptor in the heart, recent studies have provided compelling and solid evidence in support of the important roles of M3R in regulating and maintaining cardiac function and heart disease [35
]. Furthermore, given the close structural similarity between the M2R and M3R, it is likely that the autoantibodies may be cross-reactive.
Muscarinic receptor-mediated cardiac parasympathetic activity is essential for regulating heart rate [35
] and HRV [36
]. Furthermore, vasodilatory responses to cholinergic stimuli are diminished in M3R knockout mice [37
] and in pSS patients [38
], which may – at least in part – underpin the reduced blood pressure variability observed in the present study. Cardiovascular reflex tests are traditionally interpreted as an indication of parasympathetic or sympathetic function, but our results are better interpreted as multiple autonomic disturbances in pSS relating to decreased HRV, decreased blood pressure variability and increased heart rate, which are likely to reflect a disturbance of parasympathetic/sympathetic balance.