Table 23.2 Results of multiple regression analysis to examine factors inßuencing the objective variable of post-treatment whole stimulated sialometry

WSS whole stimulated sialometry, Lip biopsy labial minor salivary gland biopsy, SS-B anti-La/SS-B antibodies.

of the evaluation site (parotid gland versus minor salivary gland). These results are congruent with those reported by Saito et al. [19].

The increment rate of WSS after cevimeline treatment in the Grade 0Ð2 group was signiÞcantly higher than that in the Grade 3 and 4 group (P = 0.002) (Fig. 23.3b).

Similar Þndings [20] were reported by the use of pilocarpine, a cholinergic parasympathomimetic agent, which has shown efÞcacy in treating dry mouth symptoms in SjšgrenÕs syndrome patients [21, 22]. Rosas et al. [20] reported that SjšgrenÕs syndrome patients with a pilocarpine-stimulated salivary ßow less than 1.5 mL had a higher prevalence of positive anti-Ro/SS-A, anti-La/SS-B, parotid scintigraphy class III or IV, and positive salivary gland biopsy compared to those with a pilocarpine-stimulated ßow over 1.5 mL. Our Þndings that the effect of cevimeline is inßuenced by the severity of SS concur with those reported by Rosas et al. [20].

Interestingly, the response to cevimeline was quite different between the Grade 0Ð2 and the Grade 3 and 4 groups. This implies the existence of soluble factors interfering with cevimeline in the Grade 3 and 4 group. When considering the higher prevalence of autoantibodies to La/SS-B in the Grade 3 and 4 group compared to the Grade 0Ð2 group, local production of autoantibodies or cytokines might lead to dysfunction of the residual glandular tissues. The prevalence of anti-La/SS-B antibodies in the Grade 3 and 4 group was signiÞcantly higher than that in the Grade 0Ð2 group (P = 0.022).

Multiple regression was employed to examine the relative contributions of sialography stage,

grade of lip biopsy, and titer of anti-La/SS-B antibody to the post-treatment WSS. Results showed that post-treatment WSS was predicted by the model (R2 = 0.880): Post-treatment WSS = 5.784 + (0.847 × pre-treatment WSS) − (0.869 × grade of lip biopsy) − (0.867 × stage of sialography) − (0.001 × anti-La/SS-B antibody), and that the stage classiÞcation of sialography (P = 0.004) and the histological grade of the labial minor salivary gland biopsy (P = 0.003) were signiÞcantly associated with the post-treatment WSS (Table 23.2).

Our preliminary results demonstrated the relationship between the effect of cevimeline on saliva secretion and the degree of salivary gland destruction evaluated by sialography and histopathological Þndings in the labial minor salivary glands. These diagnostic approaches could provide useful prognostic information on the efÞcacy of cevimeline in SS patients. However, this study is a preliminary open-label trial without placebo-treated patients from a practical standpoint, which is limited by its relatively small sample size and the lack of blinding of patients and outcome assessors. Therefore, to verify the results in the present study, a placebo-controlled, double-blind randomized trial should be done in the next step.

23.4The Application of a Bite Guard

Sleep-related xerostomia is a sensation of dry mouth associated with a report of either mouth and/or throat discomfort that induces awakenings for water intake [23, 24]. The prevalence of

self-reported dry mouth complaints during sleep in a survey of Swedish pensioners was estimated to be 13.7% for men and 24.1% for women [25]. However, the etiology of sleep-related xerostomia has not been revealed. The secretory response to mastication is associated with the stimulation of periodontal mechanoreceptors of the teeth and taste receptors, which usually occur during food intake in the daytime [26]. During the night, salivary secretion diminishes dramatically, even in healthy subjects [27, 28].

We applied a simple mouth guard for the sleep-related xerostomia [12]. The device, fabricated with a soft material, is often used as a sports mouth guard or as a night guard for the treatment of nighttime bruxism. The 1.5-mm-thick ethylene vinyl acetate sheet (Sof-Tray Sheets, Ultradent Products, Inc., South Jordan, UT, USA) was heated and aspirated to secure the model using a vacuum-forming system (Dental Sta-Vac Model; Buffalo Dental Manufacturing, Syosset,

NY, USA). The night guard covered the dental arch and the hard palate and did not possess a reservoir for retaining the saliva substitute (Fig. 23.4a).

The participants in the preliminary study complained of nocturnal oral dryness, but they showed normal salivation during the examination at the clinic. No factors that cause nocturnal hyposalivation, such as medication side effects, could be identiÞed. The patients did not show any signs in their oral cavity. Fourteen patients (7 males, 7 females; mean age 66.5 ± 9.2, ranging from 55 to 93 years) were allocated to the treatment group, while 14 patients (7 males, 7 females; mean age 73.1 ± 10.0, ranging from 54 to 78 years) were allocated to the control group. The control group used a mouth rinse three times daily (daytime and before going to bed). There were no signiÞcant differences between the groups in terms of age, WRS (whole resting saliva ßow), and WSS by the MannÐWhitney test at the pre-treatment period.

Fig. 23.5 Comparison of the improvement in general impression between treatment and control groups. The general impression was scaled using Þve levels: 3, extremely improved; 2, improved; 1, improved a little; 0, unchanged; −1, deteriorated (MannÐWhitney test)

Table 23.3 Comparison of VAS between the treatment and control groups

The Wilcoxon signed-rank test was used to compare the visual analog scale (VAS) between pre-treatment and post-treatment periods.

Following completion of the 2-week treatment, substantial improvement was reported by the treatment group (Fig. 23.5). In the results of the general impression, the treatment group showed that 10 of the 14 patients (71%) showed improvement in their symptoms, but 4 expressed that their symptoms were unchanged. No patients experienced an aggravation or worsening of symptoms. As for the results of the visual analog scale (VAS), the sensation of dryness was improved in the treatment group except in two cases. The post-treatment VAS value signiÞcantly decreased compared with that of the pre-treatment period in sensation of oral dryness, thirstiness, and burning sensation of the tongue in the treatment group (Table 23.3).

A hypothesis was proposed that unconscious episodes of rhythmic masticatory muscle activity play an important role in lubricating the oral cavity [23, 24] and that the night guard could help to regulate appropriate rhythmic muscle activity. Alternatively, secretion was accelerated by mechanical stimulation to the oral

mucosa. Stimulation of the fauces is known to lead to an increase in salivation [29], therefore the night guard possibly stimulates the oral mucosa mechanically, which may thus induce saliva secretion.

A second possible mechanism for nocturnal xerostomia improvement with the night guard is maintenance of saliva volume in the oral cavity. It was suggested that patients recognized the sensation of dryness when there was not enough saliva to cover the various oral surfaces, especially the palate [30]. In addition, the resting ßow rates from the palatal salivary gland less than 6.0 L/cm2 cause patients to suffer from a dry mouth [31]. Due to the ability of the night guard to cover the palate, enough saliva volume on the palate could be maintained between the palate and the night guard, resulting in a decreased sensation of dryness.

A third possible factor for symptom improvement could be that the night guard decreases vaporization of saliva from the oral cavity, which is dependent upon how long the mouth is open.

Mouth breathing occurs due to malocclusion, nasal congestion, and enlarged adenoids.

We concluded that the application of a night guard is therefore suggested to be a useful and simple method for the management of nocturnal xerostomia. If the mouth guard possesses the functions of an increase of salivary secretion, the maintenance of saliva volume in the oral cavity, and a decrease of saliva vaporization, the device could also be useful for SjšgrenÕs syndrome patients. The device can be used not only during the night but also during the day time. Furthermore, patients can use the device to maintain the lubricants (Fig. 23.4b).

23.5Immunological Treatment for Primary Sjögren’s Syndrome

Immunological management will be one of the options for patients who could neither expect the effect of secretagogues nor moisturizing agents using the bite guard. However, no trial concerning immunological treatment of primary SjšgrenÕs syndrome such as interferon-α [32, 33] and antiCD20 antibody [34, 35] has been conducted so far. Even systemic administration of corticosteroid to the primary SjšgrenÕs syndrome patients has not been accepted by all clinicians in Japan, and thus the corticosteroid irrigation of the parotid gland has been an alternative option [36].

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