Types of Studies Reviewed. The author reviewed recent medical and dental studies that have advanced our understanding of the causes and treatment of SS. She particularly focused on studies addressing the diagnosis and treatment of the oral component of the disease.

Results. Sjögren’s syndrome is a widely underdiagnosed disease. A delay in the diagnosis of SS may have a significant physical, psychological and economic impact on the affected person. The pathogenesis of SS appears to involve a number of factors: immunological, genetic, hormonal and possibly infectious. Successful management of SS requires a multidisciplinary approach, and the dentist plays an essential role in the diagnosis and treatment of the disease.

Oral Implications. Impairment of salivary function in SS increases the risk of developing oral diseases. Effective management of oral health comprises enhancement of salivary output (cholinergic agonist drugs such as pilocarpine or cevimeline) and prevention and treatment of dental caries, oral candidiasis and allergic mucositis. Finally, periodic evaluation of various clinical and laboratory parameters is needed to monitor disease status.

	EPIDEMIOLOGY

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Sjögren’s syndrome is thought to be the most common autoimmune disease next to rheumatoid arthritis.⁴ It frequently is described as a disease of middle-aged and elderly women, although it has been reported in children and adolescents as well.⁵ It is encountered more often in women than in men (at a rate of 9:1).²

	DIVERSITY OF CLINICAL MANIFESTATIONS

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Clinically, SS may occur in two forms: primary and secondary. When the clinical manifestations are limited to the exocrine glands, the condition is considered primary SS. In the presence of another autoimmune disease, it is referred to as secondary SS. Some of the most common autoimmune diseases that may be associated with SS are rheumatoid arthritis, systemic lupus erythematosus and scleroderma. Both primary and secondary SS may be accompanied by a broad range of disorders (physical, psychological, hematologic or neurological).

Raynaud’s phenomenon, lymphadenopathy and peripheral neuropathies are among the frequent conditions associated with SS and may vary markedly in severity among patients.³ However, many SS symptoms are deceptively nonspecific, including fatigue, fibromyalgia and arthralgia. The most serious condition associated with SS is malignant lymphoma; the risk of developing lymphoma is up to 44 times higher for patients with primary SS than for age- and sex-matched controls.⁶

	PATHOGENESIS

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Histologically, SS is characterized by a lymphocytic infiltration of salivary and lacrimal glands. However, the reduction in salivary volume does not always correlate with the severity of dryness symptoms. Furthermore, even in patients with significant complaints of dryness, it is not unusual to find that only about 30 percent of the gland is infiltrated with inflammatory cells. These observations suggest that glandular infiltration cannot account fully for SS symptoms.⁷ Inflammatory cytokines have been implicated in the functional tissue injury associated with SS.⁸

Sjögren’s syndrome is considered an autoimmune disease, but our understanding of the pathogenesis of this disease is incomplete. The pathogenesis of SS appears to involve the complex interplay of a number of potential contributory factors. Immunological, neurological, genetic, viral and hormonal factors seem to interact to cause the disease.⁹

The lack of adequate understanding of the underlying cause of Sjögren’s syndrome and the broad spectrum of its clinical manifestations complicate a prompt diagnosis of the disease.

Up-regulation (increased activity) of the immune response, especially ß-cell activation, and elevated serum autoantibody levels suggest an autoimmune etiology for SS.³ One model for the pathogenesis of SS suggests a two-phase process, nonimmune and immune. In the nonimmune phase, a genetically based abnormality or an infection would trigger glandular epithelial cell death via accelerated apoptosis (programmed cell death). The byproducts of the dead cells would act as autoantigens, provoking an immune response. In the second phase, this immune-mediated inflammatory process would damage the target glands or other organs.¹⁰

Current research findings suggest that both neural and immune processes are involved in the pathogenesis of SS.¹¹ An immune-mediated neural pathogenesis for SS is supported by the fact that normal salivary function depends on neural input to the gland. Cholinergic efferent nerves that release acetylcholine induce tearing and salivation by stimulating muscarinic M₃ receptors of the lacrimal and salivary glands.⁷ Investigators have reported that immunoglobulin G from patients with primary SS could bind and activate M₃ receptors in lacrimal glands from rats.¹²

Sjögren’s syndrome is associated with the presence of specific human leukocyte antigens, and people who have a family history of SS are at increased risk of developing the disease. These observations suggest a possible genetic predisposition for SS.^13–16

The evidence for the involvement of specific viruses in SS is conflicting at present. Some of the viruses that have been implicated in the development of SS are cytomegalovirus, Epstein-Barr virus, hepatitis C virus, human T-cell leukemia/lymphoma virus-1 and human immunodeficiency virus, or HIV.^17–21 However, no direct correlation has been established between these viruses and SS.

Finally, the fact that SS occurs more often in women than in men suggests a possible role for the sex hormones in the pathogenesis of the disease.²²

	DIAGNOSTIC CRITERIA

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The lack of adequate understanding of the underlying cause of SS and the broad spectrum of its clinical manifestations complicate a prompt diagnosis of the disease. Several sets of criteria have been proposed to facilitate the diagnosis of SS. Each set requires fulfillment of specific clinical and laboratory tests.^23–26

Most of the published criteria place considerable emphasis on salivary gland biopsy for the diagnosis of SS. The European Community, or EC, criteria are among the most inclusive. The EC criteria require evaluation of oral signs and symptoms, ocular signs and symptoms, histopathology (salivary gland biopsy) and serum auto-antibodies such as rheumatoid factor, or RF; antinuclear antibody, or ANA; anti-Ro, or anti–-SS-A, antibody; and anti-La or anti–SS-B antibody (box, "European Community Criteria for the Diagnosis of Sjögren’s Syndrome"). Using the EC criteria, the diagnosis of SS requires fulfillment of four of the six criteria. A proposed modification would require, for the diagnosis of SS, the presence of either focal sialadenitis on salivary gland biopsy or antibody among the four criteria that are met.²⁴

	EVALUATION FOR SJÖGREN’S SYNDROME

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Patient history. Patients may complain of xerostomia, difficulty chewing and swallowing, burning mouth, changes in taste or difficulty wearing dental prostheses.^27–30 Difficulty in speaking and intolerance of certain foods and beverages are common symptoms of xerostomia.

Because of the subjective nature of xerostomic symptoms, it is important to recognize that patients with SS may be unaware of such symptoms or may not consider them significant. In a 1994 study of more than 600 patients, 15 percent of patients with primary SS and 26 percent of patients with secondary SS did not complain of xerostomia.³¹

Physical examination. Salivary gland enlargement occurs in one-fourth to two-thirds of patients with primary SS.³² When salivary gland enlargement is present, the affected area usually is not tender to palpation.³³ In some cases, however, the diminished salivary flow allows oral bacteria to migrate into the salivary glands and cause recurrent sialadenitis. In such cases, the salivary glands may become tender to palpation. Although SS affects all of the salivary glands, it is not uncommon for recurrent sialadenitis to be limited to one or two salivary glands (Figure 1). Therefore, in cases of recurrent sialadenitis, it may be advisable to investigate for possible SS before considering surgical intervention.

View larger version (111K): [in this window] [in a new window]   Figure 1. Parotid gland swelling and recurrent parotitis in a patient with Sjögren’s syndrome.

Finally, patients with SS are at higher risk of experiencing recurrent atrophic candidiasis, which often is associated with burning mouth (Figure 2).^34,35 The diagnosis of candidiasis can be verified by an "oral yeast" culture.³⁴

View larger version (90K): [in this window] [in a new window]   Figure 2. Smooth erythematous tongue: oral candidiasis.

The biopsy specimen (involving five to seven minor salivary glands) is examined under a light microscope for the presence of inflammatory cell infiltration. The histopathologic findings are graded on a scale according to the number of inflammatory foci per 4 square millimeters, or mm²; a cluster of 50 or more lymphocytes is termed a focus. A finding of at least one focus per 4 mm² is consistent with the diagnosis of SS, provided other diagnostic criteria are satisfied.^23,24

Other diagnostic tests for the oral component of SS include sialometry (measurement of salivary output), salivary electrophoresis, contrast sialography, sequential salivary gland scintigraphy and ultrasonography.

Collection of saliva for sialometry is a painless and simple procedure. Since a wide range of salivary flow rates exists among healthy adults, flow rate measurements alone are inadequate for assessing patients who may have SS.³⁷

Studies from several laboratories, including the author’s, have shown that the electrophoretic profile of salivary proteins of SS patients differs from that of healthy subjects.³⁸ Salivary electrophoresis is a simple and economical procedure with high specificity and sensitivity in the diagnosis of SS.³⁸ This procedure is not available for commercial use at the present time. Commercial availability of this test will facilitate the diagnosis of SS and help reduce its cost.

Contrast sialography is a radiographic test that allows visualization of salivary gland and duct architecture. It involves slow injection of a contrast medium into Stensen’s duct. Sialograms are graded on a scale of 1, representing punctate sialactasia, to 4, representing end-stage disease.^39,40

Scintigraphy is a method for the evaluation of salivary gland function.^41,42 Scintigraphy uses the sequential measurement of uptake and excretion of technetium-99m pertechnetate.⁴³ The drawbacks of salivary scintigraphy are that it does not permit visualization of ductal structures and that it is not specific for SS.

Ultrasonographic imaging of the parotid gland is a simple and noninvasive procedure and could be useful for the evaluation of salivary involvement in SS.⁴⁴

Ophthalmic involvement. Patients with SS typically complain of a dry, sandy, gritty feeling in their eyes or "friction," burning or itchiness of the eyes. The eyes may be sensitive to air drafts and light. Most patients have a history of using tear substitutes.

Diagnostic tests for the ocular component of SS include Schirmer’s test for quantitative measurement of tear production; tear break-up time; the rose bengal test to evaluate ocular surface irritation; and measurement of tear lactoferrin.

Systemic involvement is fairly common among SS patients. It is important to obtain a thorough hematologic workup and complete urinalysis to properly evaluate the patient’s overall health (box, "Routine Laboratory Tests for Sjögren’s Syndrome"). Some of the frequent serologic findings are elevated serum immunoglobulin levels,⁴⁵ abnormal liver enzyme levels, abnormal blood cell count (leukopenia, lymphocytosis or thrombocytopenia), and detectable levels of autoantibodies, particularly ANA, RF, anti-Ro/anti–SS-A and anti-La/anti–SS-B.

Xerostomia is a common clinical complaint and cannot by itself convey a diagnosis.

	THE ROLE OF SALIVA IN ORAL HEALTH

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Because saliva performs several protective functions in the oral cavity, a disruption of normal salivary flow has a wide range of detrimental consequences for oral health. Saliva helps prevent dental caries by promoting dental remineralization and by maintaining a physiological oral pH level. ²⁹ Saliva provides a supersaturated environment with respect to calcium and phosphate, thereby helping to prevent demineralization of teeth and to retard calculus formation. Salivary glycoproteins, particularly mucins, maintain the coating and lubrication of the oral mucosa, facilitating speech, mastication and swallowing.²⁹ Saliva also facilitates taste perception, which is crucial to the enjoyment of food and affects nutritional status.^29,55 It is worth keeping in mind, too, that the effectiveness of sublingually administered medications (for example, nitroglycerin) may be reduced in patients with xerostomia.

Several salivary proteins possess antimicrobial functions. Salivary enzymes such as lysozymes and lactoperoxidase, as well as secretory immunoglobulin A and histidine-rich peptides (histatins), help to control oral infections.^29,55–58

One of the key roles of saliva in the oral cavity is formation of the salivary pellicle.⁵⁹ The salivary pellicle is a tissue coat or a "blanket" that covers the mucosal surfaces and teeth. This tissue coat provides a physical barrier for the underlying structures and acts as a lubricant to facilitate oral functions. When the salivary secretion is diminished, the oral cavity is deprived of this protection. Consequently, the oral mucosa becomes vulnerable to various physical, chemical and microbial insults. Lack of the salivary pellicle subjects patients with SS to mucosal allergies (sometimes called "contact mucositis") to various foods, beverages, dental hygiene products and dental materials^60,61 (Figure 3).

View larger version (71K): [in this window] [in a new window]   Figure 3. Intraoral contact mucositis: mucosal sloughing of the cheeks and tongue.

View larger version (97K): [in this window] [in a new window]   Figure 4. Traumatic ulcers: scarring and ulceration of the lateral border of the tongue due to biting.

	TREATMENT OF THE ORAL COMPONENT OF SJÖGREN’S SYNDROME

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Dental clinicians are well-placed to identify patients with this often-overlooked disease. Their contribution to its treatment also is essential, since optimal management of SS requires a multi-disciplinary approach. The dentist, primary care physician, ophthalmologist and rheumatologist all should be involved.

All treatment of the oral component of SS should be tailored to the individual patient’s needs and depends on the severity of the salivary dysfunction.

Prevention and treatment of dental caries. Dentists and dental hygienists must work closely with SS patients to manage the increased frequency of dental caries. Patients with SS require frequent dental visits with regular fluoride treatment. Daily use of a prescription fluoride is highly recommended. Because of the increased mucosal sensitivity, the use of gentle toothpastes with mild flavors is recommended.

Treatment of oral candidiasis. Recurrent oral candidiasis can be treated with topical anti-fungal medications. Sugar-free nystatin solution can be used as a rinse and expectorated to avoid potential systemic side effects. Angular cheilitis can be treated with nystatin or clotrimazole cream. Removable prostheses should be treated separately by soaking in nystatin or chlorhexidine. Adequate treatment of oral candidiasis will improve oral discomfort significantly.

Enhancement of salivary output. Restoring salivary output is a key to ensuring ultimate oral health. Increasing salivary output could minimize oral infections, mucosal irritation and allergies. Stimulation of salivary output can be achieved by either physiological or pharmacological means.

Physiological stimulation. Physiological stimulation can be accomplished by gustatory and masticatory stimuli, such as sugar-free candies and chewing gum. The use of sugar-containing products should be minimized because of their potential cariogenicity. The use of lemon drops and citrus candies also should be minimized, because of their potential demineralizing effect on the teeth.

Pharmacological stimulation. For pharmacological stimulation, two cholinergic agonist drugs, pilocarpine and cevimeline, have been approved by the U.S. Food and Drug Administration for treatment of dry mouth associated with SS. Pilocarpine has been shown to stimulate salivary secretion and relieve symptoms of xerostomia in SS.⁶² The recommended dosage is 5 milligrams four times per day.⁶² Pilocarpine is contraindicated for patients with narrow-angle glaucoma, iritis and uncontrolled asthma. The most common side effect of pilocarpine is increased sweating.⁶²

Cevimeline is a new cholinergic agonist that has been shown to improve the symptoms of xerostomia in patients with SS.⁶³ It binds selectively to muscarinic M₃ receptors in salivary glands⁶⁴ (also J. Baumgold, Ph.D., and S.L. Max, Ph.D., Daiichi Pharmaceutical Corp., Montvale, N.J., unpublished data, April 1997) and has a longer half-life than pilocarpine.^7,65 In comparison with pilocarpine, cevimeline exhibits a greater time for receptor occupancy, which may make its action both longer-lasting and more gradual and thus may minimize some of the side effects experienced with pilocarpine.⁷

The recommended dosage for cevimeline is 30 mg three times per day. The most common side effect of cevimeline is increased sweating.⁶³ Cevimeline is contraindicated for patients with uncontrolled asthma, acute iritis or narrow-angle glaucoma.⁶³

Selective use of saliva substitutes. The benefit obtained from use of saliva substitutes is limited and of brief duration, but these preparations may be helpful for patients with oral ulceration or denuded epithelium. Patients with removable dental prostheses also may benefit from the use of saliva substitutes. The use of removable prostheses as reservoirs for artificial saliva has been advocated, but in the author’s experience this practice has proved unsuccessful. A number of over-the-counter saliva substitutes are available in the United States.

Hydration. Finally, maintaining reasonably high levels of hydration is helpful to reduce oral dryness. However, excessive water intake, especially of distilled water, should be discouraged; the author’s clinical observations suggest that it could potentially promote loss of electrolytes and precipitate electrolyte imbalance.

Monitoring of salivary output and disease progression. It is important to appreciate that SS is a multisystem disorder. Periodic routine evaluation of the affected organs is important for proper treatment and management of the disease. Periodic evaluation of salivary output and various blood parameters is highly recommended for monitoring the disease. Establishing frequent interaction and communication among the patient’s dentist, ophthalmologist, rheumatologist and primary care physician is a key to optimal patient care.

	CONCLUSION

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SS is a common and underdiagnosed inflammatory disease of the exocrine glands with a significant impact on oral health. Dental practitioners are likely to be the first health care providers to encounter the early signs of SS. Therefore, they should be familiar with the manifestations of the disease and be prepared to take an active role in the diagnosis, management and treatment of the oral complications of SS.

View larger version (114K): [in this window] [in a new window]   Dr. Al-Hashimi is the director, Salivary Dysfunction Clinic, Baylor College of Dentistry, Department of Periodontology, 3302 Gaston Ave., Dallas, Texas 75246, e-mail "alhashim{at}ont.com". Address reprint requests to Dr. Al-Hashimi.