23.1Introduction

SjšgrenÕs syndrome (SS) is an autoimmune disease which shows exocrinopathies characterized by lymphocytic inÞltration into the salivary and lacrimal glands, resulting in dry mouth and dry eyes [1]. The management of xerostomia (dry mouth) has included using air humidiÞers, rinsing the mouth with water or mouthwash, and the application of a salivary substitute. Recently, the usefulness of a reservoir bite guard [2] and an

I. Saito ( )

Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama, Japan

e-mail: saito-i@tsurumi-u.ac.jp

intraoral lubricating device [3Ð5] was reported to deliver a saliva substitute to the oral cavity for the hyposalivation patients. Additionally, a large number of systemic agents have been proposed as secretagogues but only a few have shown consistent salivary-enhancing properties in well-designed, controlled trials [6]. There are three secretagogues (cevimeline hydrochloride hydrate (cevimeline), pilocarpine hydrochloride, and anetholtrithion) suitable for alleviation of dry mouth in SjšgrenÕs syndrome patients in Japan. Cevimeline is the most prevalent secretagogue now.

Cevimeline, which is an agonist of muscarinic type 1 and 3 receptors [7], has shown clinical efÞcacy in increasing saliva production and improving the subjective perception of oral dryness in

SjšgrenÕs syndrome patients [8, 9]. SjšgrenÕs syndrome leads to the loss of salivary acinar cells and secretagogues are expected to enhance salivation from the remaining functional acinar cells. It can thus be hypothesized that the greater the salivary gland tissue damage, the less the cevimeline effect. However, to the best of our knowledge the correlation between the severity of SjšgrenÕs syndrome and the effectiveness of cevimeline has not been reported. In addition, IgG from patients with primary SjšgrenÕs syndrome reduced the carbachol-evoked increase in calcium ions (Ca2+) in both mouse and human acinar cells showing that IgG from patients with primary SjšgrenÕs syndrome contains autoantibodies capable of damaging saliva production [10]. The study suggests the involvement of autoantibodies to the receptors in the response to cevimeline in patients with SjšgrenÕs syndrome. Therefore, the clinical effect of cevimeline to enhance salivary secretion would be inßuenced multifactorially and little is known as to which clinical or immunological factors can predict the effect. If the efÞcacy of cevimeline can be predicted from the Þndings of diagnostic clinical examinations before treatment, it would be useful in arriving at the prognosis in patients with SjšgrenÕs syndrome. The relationship between the effect of cevimeline and clinical Þndings in combination with immunological features in patients with SjšgrenÕs syndrome will be discussed as one of the topics in this chapter.

Xerostomia is deÞned as a subjective complaint of oral dryness [11] and is caused by the hyposalivation and/or hyperevaporation of saliva. Hyposalivation occurs due to various causes such as SjšgrenÕs syndrome, radiation therapy to the head and neck, the use of medications, and diabetes mellitus [11]. Hyperevaporation is mainly caused by mouth opening or mouth breathing, which often occurs during the night without an apparent decrease in the salivary ßow. Hyperevaporation occurs even in the SjšgrenÕs syndrome patients. Recently, we applied a simple mouth guard for sleep-related xerostomia [12] and as the mouth guard is expected to alleviate xerostomia in patients with SjšgrenÕs syndrome, we will also discuss this as another topic.

23.2Japanese Criteria for Diagnosis of Sjögren’s Syndrome

The Committee on SjšgrenÕs Syndrome of the Ministry of Health and Welfare of Japan proposed the revised diagnostic criteria for SjšgrenÕs syndrome in 1999. The criteria are composed of four examinations: histopathology, oral, ocular, and serological examinations [13] and do not include subjective evaluation of the symptoms (Table 23.1). Although the revised Japanese criterion is widely used in Japan as the diagnostic guideline, clinicians often refer to the SjšgrenÕs syndrome criteria proposed by the AmericanÐEuropean Consensus Group to make a diagnosis [14].

In 2002, Tsurumi University Dental Hospital opened a Dry Mouth Clinic. Of the 2,269 cases attended to at this clinic with the complaint of a dry mouth sensation, 159 (7.0%) were diagnosed with SjšgrenÕs syndrome (Fig. 23.1). As for the distribution according to age of these SjšgrenÕs syndrome patients, 59 patients were 60Ð69 years old and 33 patients were 50Ð59 years old. These results demonstrated that the causes of dry mouth were various, and that SjogrenÕs syndrome existed in only less than 10% of the dry mouth cases, thus the importance of examinations for the diagnosis was emphasized.

23.3Efficacy Prediction of Cevimeline in Patients with Sjögren’s Syndrome

Thirty consecutive Japanese female primary SS patients with a mean age of 62.3 ± 11.2 (range 22Ð78 years) treated with cevimeline for their dry mouth at the Tsurumi University Dental Hospital Dry Mouth Clinic were enrolled in this study. The diagnosis of SS was based on the revised diagnostic criteria for SjšgrenÕs syndrome by the Committee on SjšgrenÕs syndrome of the Ministry of Health and Welfare of Japan and the SS criteria proposed by the AmericanÐEuropean Consensus Group [14].

Fig. 23.1 Cause of dry mouth. Of the 2,269 cases seen at Tsurumi University Dental Hospital Dry Mouth Clinic during November 2002ÐApril 2007, 159 (7.0%) were diagnosed with SjšgrenÕs syndrome

Whole stimulated sialometry (WSS) was determined by measuring a volume of stimulated whole saliva, which was stimulated by chewing a piece of gum (Free zone gum, Lotte Co., Ltd, Tokyo, Japan). WSS was compared between the pre-treatment and post-treatment points (4 weeks after cevimeline administration).

Our study on parotid sialography showed that SjšgrenÕs syndrome patients with sialectasis were less sensitive to cevimeline than those without sialectasis [15]. In addition, those patients with severe periductal lymphocyte inÞltration in the minor salivary gland demonstrated a lower efÞcacy of cevimeline than those with slight lymphocyte inÞltration.

Figure 23.2a shows the pre-treatment and post-treatment WSS in groups classiÞed according to the sialography Þndings. In both the Stage 0 and the Stage IÐIV groups, post-treatment WSS demonstrated a signiÞcant increase compared

with the pre-treatment values (P = 0.008 and P = 0.015, respectively).

The magnitude of the increase in WSS after cevimeline treatment in the Stage 0 group was signiÞcantly higher than that in the Stage IÐIV