dysfunction, sleep disorder, and reflex syncope. The autonomic symptom domains of the ASP consist of questions that evaluate the presence, severity, distribution, frequency, and progression of various autonomic symptoms. The domain scores are weighted according to their clinical relevance and can be added to calculate a total ASP score that measures the total impact of AD symptoms.

Objective signs and subjective symptoms of AD correlate poorly in pSS patients [9, 15]. These discrepancies could be due to differences in mechanisms behind objective signs and subjective symptoms of AD. Furthermore, cardiovascular ARTs do not necessarily reflect autonomic nervous function in other parts of the ANS, and end-organ damage may obscure possible associations between objective and subjective AD. For these reasons, it seems reasonable to assess subjective AD symptoms as well as objective signs, as permitted by the ASP.

22.4Parasympathetic and Sympathetic Disorders

In previous studies on cardiovascular AD, both the parasympathetic and the sympathetic nervous systems have been reported to be affected in pSS patients (Table 22.1). Since many symptoms of pSS mimic several AD symptoms [54], AD may not only be a feature of the disease but may also contribute to the various classical symptoms of the disease. For example, involvement of the parasympathetic nervous system and interference with the parasympathetic nervous transmission pathways may contribute to secretomotor dysfunction, bladder symptoms, and disturbed gastrointestinal motility in pSS. The sympathetic nervous system involvement may contribute to orthostatic intolerance, impaired sweating, and vasomotor dysfunction [52]. Fatigue in pSS may also relate to certain features of AD [9, 14, 54].

22.4.1Secretomotor Disorder

Exocrine gland inflammation and dysfunction are hallmarks of pSS. In the past, the exocrine dysfunction of pSS has been ascribed principally to the presence of inflammation and its consequent destruction of the exocrine glands. As noted, however, the observed discrepancy between exocrine gland destruction and exocrine dysfunction requires other mechanisms to explain the exocrine insufficiency in pSS [16, 17]. The exocrine glands are innervated by both parasympathetic and sympathetic nerves. The liquid part of secretion appears to be modulated primarily by parasympathetic input, whereas protein secretion is principally under sympathetic control. However, the two parts of the ANS work synergistically in the exocrine glands.

Before secretion, the salivary gland blood flow is increased due to the release of nitric oxide and vasointestinal peptide from parasympathetic nerve endings. Otherwise, the main signal for secretion is acetylcholine (ACh), which is also released by parasympathetic nerve endings. ACh binds to the G-protein-coupled M3R on the acinar cells in the exocrine glands. The activated G protein stimulates phospholipase

C to generate inositol 1, 4, 5-trisphosphate (IP3), which in its turn causes a release of Ca2+ ions from intracellular Ca2+ storages. The increment of intracellular Ca2+ activates apical membrane Clchannels and basolateral K+ channels, causing an efflux of Cland K+ ions. The efflux of Clions to the apical lumen also causes a similar movement of Na+ ions in order to maintain electrochemical neutrality, resulting in an osmotic effect that brings water into the lumen, a process further facilitated by the presence of aquaporins in the acinar and myoepithelial cells.

Apart from the parasympathetic pathways, sympathetic pathways also affect the glandular cells. These act via noradrenaline and adrenaline, activating mainly the adenylate cyclase pathway, and also NPY. The sympathetic pathways play a role in modulating protein secretion in particular, but also liquid secretion to some extent. In addition to the secretory effects of autonomic nerve signals, there are also trophic effects as illustrated by the atrophy seen in a salivary gland deprived of parasympathetic signals. Following the production of primary saliva, its composition is modulated by the salivary ductal cells during its passage through the salivary gland ducts.

Various factors disturbing these signal transduction pathways may thus result in a decreased or altered exocrine gland secretion as well as dryness. Although AD thus may explain part of the secretomotor dysfunction seen in pSS, AD and exocrine dysfunction are generally poorly associated [2]. This could have several explanations. First, ANS function usually is evaluated by cardiovascular tests, which do not necessarily mirror exocrine ANS function. Second, anti-M3R antibodies may give rise to an exocrine AD that cannot be detected sufficiently by cardiovascular ANS function tests. And finally, end-organ damage may obscure possible associations, especially in late disease.

In analogy to what is seen in other exocrine glands, interference with nerve signalling to the sweat glands may result in a decreased and altered secretion from these and contribute to the xerosis of the skin. As is true for other exocrine glands, it is difficult to differentiate the effects of AD from end-organ damage in the sweat glands.

22.4.2Urinary Disorder

The effects of AD on the bladder may explain the increased prevalence of urinary dysfunction symptoms, which appear to be overrepresented in pSS patients [9, 15]. Because M3R is found in the bladder and is important in eliciting bladder contraction, the putative anti-M3R antibodies have also been suggested as causatives of the pSS-related bladder symptoms. When studying objective signs of AD in the bladder, 56% of pSS patients were reported to show signs of decreased detrusor muscle tone and contractility [41]. An association with the anti-M3R antibodies has been proposed. Conversely, irritable bladder, which is also overrepresented in pSS patients, has also been suggested to be associated with anti-M3R antibodies [42, 55]. Although these results are contradictory, a hypothesis states that the anti-M3R antibodies, after a period of blockade of cholinergic transmission, may induce a cholinergic hyperresponsiveness with upregulation of the M3R, which in its turn may explain the bladder irritability seen in some pSS patients [42, 55].

22.4.3Gastrointestinal Disorder

Dysphagia is a recognized feature in pSS and may be attributed both to lack of saliva, esophageal dysmotility, and esophageal webs. Because both exocrine secretion and esophageal motility are modulated by the ANS, dysphagia could partly be due to AD. Also constipation has been reported in pSS [16] and impaired gastric emptying has been found in 70% of pSS patients, studied by gastric emptying scintigraphy [41]. Such findings are all consistent with involvement of the enteric ANS or the putative anti-M3R antibodies, since the M3R are involved in gastrointestinal motility as well as secretion [41].

22.4.4Pupillomotor Disorder

Adie’s syndrome has been found in association with sensory neuropathy in pSS [27]. A ganglionitis affecting the ciliary and dorsal root ganglia was suggested to be the causative. Since the main parasympathetic receptor of the iris is again the M3R, it is possible that such symptoms could also be attributable to the anti-M3R antibodies.

22.4.5Orthostatic Intolerance

Both objective signs of orthostatic blood pressure drops and subjective symptoms of orthostatic intolerance are encountered commonly in pSS [15, 26]. However, the objective signs of postural hypotension and subjective symptoms of lightheadedness usually correlate poorly with each other [15, 26]. Both orthostatic systolic and diastolic hypotension in pSS have been demonstrated in several studies [2, 13, 14]. Diastolic hypotension has been shown to progress during follow-up [14]. Orthostatic hypotension is generally considered a sign of sympathetic dysfunction [25]. The pathogenesis behind these finding thus seems to fit well with theories of inflammation that involves sympathetic ganglia or nerves [22] or cytokines that interfere with neurotransmission [24]. Because the anti-M3R antibodies can affect blood vessel tone and possibly blood pressure, an influence of these antibodies on the orthostatic blood pressure reaction cannot be excluded.

The subjective symptoms of orthostatic intolerance are very common in pSS patients [15], but their pathogenesis is complex and incompletely understood. Symptoms of orthostatic intolerance may be related to orthostatic hypotension, but the correlation of orthostatic intolerance is usually with an increased heart rate during orthostatic challenge rather than orthostatic hypotension. The pathogenesis of these symptoms is considered multifactorial and predisposing factors include: excessive venous pooling, impairment of renal sympathetic innervation, decreased plasma volume, sympathetic overactivity, beta-adrenergic hypersensitivity, and a reduced vagal cardioinhibitory reflex [52].