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Oral Manifestations of Sjögren’s Syndrome
2 Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Correspondence: * corresponding author, biji-kurien{at}omrf.org
Sjögren’s syndrome is a common autoimmune rheumatic disease. The most common symptoms of Sjögren’s syndrome are extreme tiredness, along with dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Saliva plays an essential role in numerous functions of the mouth. Xerostomia can be caused by medications, chronic diseases like Sjögren’s syndrome, and medical treatments, such as radiation therapy and bone marrow transplant. Xerostomia can eventually lead to difficulty in swallowing, severe and progressive tooth decay, or oral infections. Despite having excellent oral hygiene, individuals with Sjögren’s syndrome have elevated levels of dental caries, along with the loss of many teeth, early in the disease. Sjögren’s syndrome alters the protein profile and brings about a change in the composition of saliva. There is an increase in the levels of lactoferrin, β2-microglobulin, sodium, lysozyme C, and cystatin C, and a decrease in salivary amylase and carbonic anhydrase. Up to 90% of individuals with Sjögren’s syndrome have antibodies targeting the Ro 60 and La autoantigens. Natural aging, regardless of Sjögren’s syndrome, is also another factor that brings about a significant change in the composition of saliva. The most prevailing cause of xerostomia in elderly persons is the use of anticholinergic medications. Currently, there is no cure for Sjögren’s syndrome, and treatment is mainly palliative.
Key Words: Sjögren’s syndrome • autoantibodies • dry mouth • dental caries
Sjögren’s syndrome has been described as a model for dental care in the 21st century (PC Fox et al., 1998). Dentists are often the first practitioners to detect the symptoms of Sjögren’s syndrome; their diagnosis and treatment are of critical importance (PC Fox et al., 1998). Sjögren’s syndrome is a common autoimmune rheumatic disease. The disease is second to rheumatoid arthritis, with about 1% (1:100) of the population affected. Sjögren’s syndrome is more commonly found in middle-aged women than in men, with a ratio of 9:1 (Hammi et al., 2005). The most common symptoms of Sjögren’s syndrome are extreme tiredness, dry eyes, and dry mouth. These latter two symptoms occur due to the reduction of flow in the salivary and lacrimal glands. Other symptoms associated with the disease include swelling of the salivary glands, sialorrhea, and tooth loss (Mignogna et al., 2005). Sjögren’s syndrome also has an impact on the peripheral and central nervous system, as well as affecting critical areas such as muscles, bone marrow, joints, kidneys, pancreas, and other organs (Alexander et al., 1986). When Sjögren’s syndrome appears alone, it is diagnosed as primary Sjögren’s syndrome. When it occurs alongside another autoimmune disease, like rheumatoid arthritis, systemic lupus erythematosus, and others, it is then diagnosed as secondary Sjögren’s syndrome. Along with Sjögren’s syndrome, individuals experience other diseases such as fibromyalgia, migraines, Raynaud’s phenomenon, and hypothyroidism (Hammi et al., 2005). Research also shows that systemic extraglandular manifestations, including lymphoma, appear in one-third of the individuals with primary Sjögren’s syndrome (Ryu et al., 2006).
The classification criteria introduced by Breiman et al.(1985) and the European preliminary criteria (Vitali et al., 1993) have been used commonly for research until recently. The European criteria rely upon any 4 out of 6 items, including eye and oral symptoms (e.g., ocular and mouth dryness), ocular and mouth signs (positive Schirmer test and sialoscintigraphy, for example), focal sialadenitis, and immunological parameters. The American-European Consensus Group classification criteria (American-European criteria) have been used since 2002 as a new "gold standard" (Vitali et al., 2002). The American-European criteria are based on the presence of 4/6 criteria (including the objective criteria, oral and ocular symptoms) when either anti-60 kD Ro or histopathology is tested positive (Table 1
Sjögren’s syndrome is primarily treated by alleviating the symptoms through the use of medications and therapies. This article specifically deals with the presence of dental caries and other oral problems associated with Sjögren’s syndrome.
Saliva plays an essential role in the numerous functions of the mouth, such as protecting and preserving the oral cavity. It is composed of proteins, glycoproteins, enzymes, electrolytes, and small organic molecules in a secretion that is capable of maintaining oral homeostasis. Ninety percent of saliva produced is secreted by the acinar cells of three types of salivary glands: parotid, sublingual, and submandibular. The parotid glands secrete a thin, serous substance that has watery characteristics, and which contains a large quantity of antibacterial proteins and other components that help in remineralizing the teeth (Tabak and Kuska, 2004). The sublingual glands secrete a viscous fluid containing mucin, which plays a major role in lubricating the throat and mouth, while a mixture of serous and mucinous saliva is produced by the submandibular gland. Minor salivary glands are located throughout the buccal mucosa and palate, and account for the remainder of the secretory output (Astor et al., 1999). The palatal gland (minor salivary gland) has the lowest flow rate of all the glands. The palate and the upper lip are the mucosal regions that are covered with the least amount of saliva. The palate contains a few minor salivary glands and is an area subject to high evaporation (Dawes, 1987; Marton et al., 2006). A healthy adult produces about 1.5 L of saliva every 24 hrs, or 0.4 mL of saliva per min (Astor et al., 1999). Saliva also provides an excretory route for mercury, lead, and thiocyanate (Geiszt et al., 2003; Hsu and Dickinson, 2006). The salivary array of proteins includes lysozyme (antibacterial), proline-rich proteins (instrumental in enamel pellicle formation and enamel surface mineralization), statherin (helps keep saliva supersaturated in calcium and phosphate to bring about enamel mineralization and possibly inhibits calculus formation), histatins (antifungal peptides), and mucins (Hsu and Dickinson, 2006). Saliva is secreted when there is a cholinergic stimulation upon the muscarinic receptors in the salivary glands.
Xerostomia, the primary symptom of Sjögren’s syndrome, can affect the oral mucosa. Xerostomia occurs only when the rate of salivary flow is reduced to less than 50%. Signs of xerostomia include dry and cracked lips, oral mucosal sores, and tongue depapillation (Mavragani et al., 2006). Older adults frequently complain of xerostomia (Thomson et al., 1999; Ship, 2002). It was thought earlier that salivary function declined as one became older. However, it is now accepted that salivary output from the major salivary glands does not significantly decrease clinically (Vissink et al., 1996; Ship, 2002). The decrease in salivary flow due to Sjögren’s syndrome can cause xerostomia or dry mouth in individuals. Dry mouth can be caused by many drugs now sold over the counter (like anti-histamines), by prescription pharmacological agents, by chronic diseases like Sjögren’s syndrome, and by medical treatments, which include radiation therapy and bone marrow transplant (Ship, 2002). Swelling of salivary glands can also occur alongside dry mouth. About 25–66% of persons with Sjögren’s syndrome had enlarged parotid or submandibular glands (Ryu et al., 2006). Xerostomia secondary to Sjögren’s syndrome alters the protein content of saliva, and this includes a decrease in secretory IgA. This decrease weakens the antibacterial defense system against caries (Astor et al., 1999). Dental procedure sites for fillings, bridges, and crowns can cause the accumulation of microbes, which can cause a shift in the oral microflora and make it difficult for a person to maintain proper oral hygiene (Pedersen et al., 2005). Healthy people have a parotid salivary flow rate of 0.672 mL/min/gland, while those with Sjögren’s syndrome have parotid salivary flow rates of 0.291 to 0.360 mL/min/gland. This can eventually lead to difficulty in swallowing, severe and progressive tooth decay, or oral infections. Using a micro-moisture meter device (Periotron, Harco Ltd, Winnipeg, MB, Canada), Shern et al.(1990) measured the palatal salivary flow rate. These investigators found it to be 0.74 µL cm–2 –min (unstimulated flow rate) and that this flow rate was unaffected by a single application of a gustatory (citric acid) stimulant. Marton et al.(2006) studied the palatal salivary flow rate in 49 people with Sjögren’s syndrome and 43 healthy control individuals and found no difference in flow between the healthy persons and the control individuals. They found that the subjective feeling of xerostomia in Sjögren’s syndrome is due to the reduction in the volume of the whole saliva, and not of the viscous palatal saliva. The maintenance of pH in the oral cavity is highly important. When the pH in the oral cavity is stable, there is a decrease in the amount of demineralization that takes place. The pH and buffer capacity in the parotid saliva of individuals with Sjögren’s syndrome are much lower when compared with those in normal control individuals. The buffer systems responsible for the human saliva-buffering capacity include bicarbonate, phosphate, and protein. Even a minor drop in pH can result in dental caries or damage to the teeth by erosion (Pedersen et al., 2005). Sjögren’s syndrome may present in a variety of ways, mostly related to poor salivary and lacrimal gland function. Signs and symptoms of salivary gland swelling, early tooth loss, and sialorrhea have led to the presentation and diagnosis of Sjögren’s syndrome (Mignogna et al., 2005). Extra-oral findings could include cracked and dry lips that are frequently colonized with Candida species (angular cheilitis). Intra-oral findings can range from the subtle to the obvious. The tongue becomes desiccated, sticky, and furrowed. There is decreased or no pooling of saliva at the floor of the mouth (at Wharton’s duct).
In Sjögren’s syndrome, the saliva loses its ability to buffer, lubricate, and perform antimicrobial duties. This leads to an increase in mucosal friability and oral infection. The dental caries present is usually root and incisal caries (Mavragani et al., 2006). In individuals with Sjögren’s syndrome, there is an increase in dental caries, appearing as destruction around the necks of the teeth and even on the labial and incisal surfaces (Newbrun, 1996). However, Sjögren’s syndrome does not appear to contribute to periodontitis. Dental plaque, consisting of more than 500 species of bacteria in a mature state, is a complex biofilm of microbes that adheres to the surfaces of teeth and provides a reservoir for oral microbial pathogens (Paster et al., 2001; Matsumoto et al., 2004). Streptococci account for approximately 20% of the total number of oral bacteria (Marsh, 1999), and they are predominantly the first colonizers of freshly cleaned enamel surface. These bacteria are also the primary causative agents of biofilm formation and dental caries. S. sanguis and S. mitis are early colonizers of the salivary pellicle, while S. mutans become established later on. These bacteria bind strongly to salivary proteins and glycoproteins, and this is important in biofilm development (Van Houte et al., 1970; Liljemark and Gibbons, 1972). The bacteria normally are dislodged and expelled from the tooth surfaces and oral cavity by the mechanical forces of salivary flow and tongue movement (Daniels and Fox, 1992; Bergdahl and Bergdahl, 2000). Sjögren’s syndrome increases a person’s likelihood of contracting opportunistic infections and the proliferation of cariogenic microorganisms (Astor et al., 1999). Persons with primary Sjögren’s syndrome have been reported to have lower numbers of periopathogenic microorganisms and higher numbers of cariogenic and acidophilic microorganisms in comparison with those found in control individuals (Pedersen et al., 2005). A comprehensive study, carried out with interviews and clinical oral examinations of 53 persons with primary Sjögren’s syndrome and 53 age-matched control individuals, found that those with primary Sjögren’s syndrome had more teeth extracted, more trouble with their teeth in their lifetime, and higher dental expenses compared with the control group. The number of decayed, missing, or filled teeth was higher in both the younger and older groups of persons with primary Sjögren’s syndrome compared with the normal control individuals. The young persons had, on average, 7 teeth missing, compared with 2 missing in the control individuals. Those with primary Sjögren’s syndrome had more frequent dental visits compared with control individuals (Christensen et al., 2001). Even with excellent oral hygiene, individuals with Sjögren’s syndrome have elevated levels of dental caries, along with the loss of many teeth early in the disease. Pedersen et al.(2005) reported that persons who brushed their teeth with toothpaste containing fluoride and visited their dentist more frequently still had higher numbers of missing, filled, and decayed teeth, along with a higher gingival index. An animal model of salivary flow dysfunction (mutation of the E2f1 gene) was found to be more susceptible to recolonization with oral streptococci compared with control mice. The E2f1 gene (a member of the E2F transcription factor family) has been suggested to affect the susceptibility for oral film formation by streptococci in humans with dry mouth (Matsumoto et al., 2004).
The decreased buffering capacity, salivary output, and the immunocompromised state in persons with Sjögren’s syndrome are associated with the increased occurrence of candidal infections. Frequency of candidiasis is decreased by the host’s T-cell-mediated delayed-type hypersensitivity to C. albicans. The unique ability of C. albicans to colonize, penetrate, and damage the tissue of the host depends on the weakness of the host’s immune system and the virulence of the fungus. The factors contributing to its virulence are adhesins, dimorphism, integrins, secretion of hydrolytic enzymes, and phenotype switching (Ship et al., 2007). Fungal infection in the form of candidiasis can be exhibited as, e.g., erythematous mucosal lesions, denture-associated stomatitis, and tongue fissuration (Mavragani et al., 2006). Oral candidiasis is one of the most common oral infections. In 1980, an inverse relationship between salivary flow rates and the level of Candida infection was described (Tapper-Jones et al., 1980). Also, persons with Sjögren’s syndrome have been reported to have Candida albicans more frequently than the general population (MacFarlane and Mason, 1974; Radfar et al., 2003). A recent study found that a low stimulated flow rate of saliva (and not a low unstimulated flow rate) was associated with Candida carriage (Radfar et al., 2003). New and recurrent dental caries is the second most frequent infection. Denture-supporting mucosal tissues become fragile and susceptible to traumatic lesions (Cannon and Chaffin, 1999; Ship, 2002). Thus, dentures are ill-fitted and poorly tolerated in individuals with Sjögren’s syndrome. Swollen major salivary glands are common in Sjögren’s syndrome. It is therefore important to rule out malignancy when the salivary glands and lymph nodes are persistently enlarged. There is a 44-fold increase in the frequency of B-cell lymphoma in those with Sjögren’s syndrome, and these are commonly non-Hodgin’s lymphomas of mucosa associated lymphoid tissues (Kassan et al., 1978; Ship, 2002).
Sjögren’s syndrome alters the protein profile and brings about changes in the composition of saliva. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and two-dimensional gel electrophoresis have been used in screening and profiling the proteins present in Sjögren’s syndrome (Ryu et al., 2006). There was an increase in the amounts of lactoferrin and β2-microglobulin in those with Sjögren’s syndrome (Tabak et al., 1978; Ryu et al., 2006). Increased levels of β2-microglobulin in the saliva are related to the inflammatory activity in the salivary gland (Ryu et al., 2006). These studies also detected an increase in lysozyme C and cystatin C and a decrease in salivary amylase and carbonic anhydrase in the salivary protein profile (Ryu et al., 2006). The acinar cells in the salivary glands produce primary saliva, which passes through the salivary duct and becomes modified, finally being secreted into the oral cavity as a hypotonic solution. Various laboratory markers, like the concentration of sodium and chloride, can be used to determine the progression of primary Sjögren’s syndrome (Pedersen et al., 2005). However, in comparisons of the concentrations of the other electrolytes (potassium, total calcium, and total phosphate) with the organic components (total protein and amylase activity), no statistically significant differences could be found between the two groups. There is no difference between the statherin and acidic proline-rich proteins, which reflect the secretions of selected parotid proteins between those with primary Sjögren’s syndrome and healthy control individuals (Pedersen et al., 2005). The concentration of total protein in saliva in primary and secondary Sjögren’s syndrome is increased considerably, due to the decreased amount of salivary liquid volume. The infiltration of the salivary glands with lymphocytes could be another reason for the increased total salivary protein levels (Hammi et al., 2005).
The hallmark indication of Sjögren’s syndrome is the lymphocytic infiltration in the salivary and lacrimal glands. The infiltrations have been examined through immunohistochemical staining of the salivary glands with biotinylated recombinant 60-kDa Ro and 48-kDa La antigen. The staining showed the presence of anti-Ro and anti-La B-cells in the infiltrates (Tengner et al., 1998). Approximately 20% of the infiltrates are B-cells, while the majority of the cells are CD4-positive T-cells. A study utilizing B-cell Elispot was used to determine the number of cells producing anti-60-kDa Ro. These cells were present in salivary glands of people with primary Sjögren’s syndrome and also correlated with the antibody titers in the peripheral blood (Halse et al., 1999). Two-thirds of the focal lymphocytic infiltrations from the labial and palatal salivary glands in healthy individuals were B-cells. Approximately one-fourth of the cells from the same focal lymphocytic infiltrations were CD4-positive T-cells. The CD4-positive cells were more ubiquitous than CD8 T-cells. Plasma cells from the focal lymphocytic infiltrations play an important role in the pathogenesis of Sjögren’s syndrome. When the secretion rate of immunoglobulins was compared with those of rheumatic arthritis and systemic lupus erythematosus, Sjögren’s syndrome had an increased rate of secretion for immunoglobulins. The IgM and IgG levels were also higher in those with Sjögren’s syndrome when compared with others with normal labial salivary glands (Yarom et al., 2007).
One of the main diagnostic tools for persons with Sjögren’s syndrome is the presence of circulatory autoantibodies to 60-kDa Ro (SS-A) (Harley and Scofield, 1991; Farris et al., 1996) and La (SS-B) (Hendrick et al., 1981). Sjögren’s syndrome can cause the activation of B-lymphocytes in the salivary and lacrimal glands. Autoantibodies to the Ro and La antigens occur in about 60–70% of affected individuals. The anti-60-kDa Ro autoantibodies react with the 60-kDa protein, while anti-La autoantibodies react with the 48-kDa protein. Antibodies targeting the 52-kDa Ro autoantigen are also present (Scofield et al., 1999). In comparison, those with primary Sjögren’s syndrome who had autoantibodies to the Ro and La antigens had high levels of IgG in their serum, while those with no autoantibodies had lower levels of IgG (Hammi et al., 2005). About 71% of persons with primary Sjögren’s syndrome had serum IgG anti-Ro antibodies, and 67% had anti-La antibodies (Hammi et al., 2005). Studies are now suggesting that the levels of anti-60-kDa Ro and anti-La are correlated with several features of disease, including earlier onset, longer duration, and recurrent parotid gland enlargement, as well as extraglandular manifestations (Hammi et al., 2005). Anti-centromere antibodies have been shown to be associated with Sjögren’s syndrome (Takada et al., 2006). These antibodies target centromere-associated proteins that include the constitutive proteins CENP-A, CENP-B, CENP-C, CENP-D, CENP-G, and CENP-H and the facultative proteins CENP-E and CENP-F (Skibbens and Hieter, 1998; Sugata et al., 1999; Hsu et al., 2006). One study investigated the relationship between a person’s sicca-related autoantibodies type and changes in salivary production rate (SPR; measured by the Saxon test or the chewing gum test). The authors found that SPR did not decrease with age in normal female control individuals. However, SPR was found to decrease significantly with age in the groups with sicca-related autoantibodies. The decrease in SPR was largest in persons with only anti-centromere antibodies or anti-Ro 60, compared with those with anti-Ro 60 and anti-La antibodies together (Takada et al., 2006).
Natural aging, regardless of Sjögren’s syndrome, brings about a significant change in the composition of saliva. In elderly people, the amount of ptyalin decreases and mucin increases, causing the saliva to become thicker and more viscous. The most prevailing cause of xerostomia in elderly persons is the use of medication, especially anticholinergic medications. The production of saliva is maintained by cholinergic innervations and, thus, is decreased by the use of anti-cholinergic drugs. Diuretics can also decrease salivary flow. This dryness can affect the process of chewing and swallowing, and the ability of the dentures to stay in the mouth. In elderly persons, xerostomia is present along with depression, mucositis, oral and dental infections, dysphagia, speech disorders, and digestive problems. Other agents that cause xerostomia are alpha-adrenergic agents, and antihypertensive agents (beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors) (Russell and Reisine, 1998; Ship, 2002; Amarasena and Bowman, 2007). Finally, dry mouth in elderly persons can also be caused by radiation therapy. Dental problems can also arise in xerostomia from uncommon causes. Parotid and submandibular salivary gland aplasia or agenesis is a rare factor for dental destruction. A case report describes a 19-year-old man suffering from decreased salivary volume and an unusual pattern of tooth destruction that could be described as "chipping" that was clinically traced to a complete lack of the 4 major salivary glands (Mandel, 2006).
The exact mechanism of autoimmunity in Sjögren’s syndrome is unknown, and several processes are thought to be involved. Even though there is a close overlap, the etiology is apparently different from that of SLE, and appears to involve genetic, immunological, hormonal, and viral components. Currently, there is no evidence of either a specific trigger or the presence of specific genes that can delineate the establishment of Sjögren’s syndrome. However, there is strong evidence involving Sjögren’s autoimmunity with reduced neural stimulation of salivary glands. Histological analysis of lacrimal and salivary glands shows large, persistent mononuclear cell infiltrates (so-called foci; mainly T-cells, with fewer B-cells) inside the glandular tissue. The mechanisms that lead from lymphocytic infiltration to diminished saliva excretion, however, are not clear. Acinar epithelial atrophy and progressing fibrosis are observed within glands of persons with Sjögren’s syndrome. However, it should be noted that several research groups have found anomalies between the extent of destroyed glandular tissue and salivary flow in some persons with Sjögren’s syndrome. In spite of chronic symptoms of serious oral dryness, as seen by a 80–90% decrease in salivary flow compared with that in normal individuals, the acinar and ductal structures do not appear to be destroyed to such an extent. Therefore, pathological processes that affect saliva production and secretion can also contribute to the sicca symptoms in Sjögren’s syndrome. Examples of such processes include autoantibodies that inhibit neuronal innervation, aquaporins, cytokines, and matrix metalloproteinases (Delaleu et al., 2005). The B- and T-lymphocytes that infiltrate the salivary gland interfere with glandular function in a variety of ways, including: (a) cell-mediated destruction of glandular elements; (b) secretion of cytokines, leading to activation of pathways bearing the types 1 and 2 interferon ’signature’; (c) production of autoantibodies that interfere with muscarinic receptors; and (d) secretion of metalloproteinases that interfere with efficient glandular functions by interfering with the interaction of the glandular cell with its extracellular matrix. Sjögren’s syndrome is generally considered a T-cell-mediated disease. Mechanisms of etiopathogenesis underlying Sjögren’s syndrome range from disturbances in apoptosis (Bolstad and Jonsson, 1998, 2002) to autoantibodies directed against Ro and La ribonucleoproteins or cholinergic muscarinic receptors in salivary and lacrimal glands in genetically predisposed individuals. Even though this is not unambiguous, other mechanisms relate salivary and tear flow decrement to aberrant glandular aquaporin-5 water channel proteins (Beroukas et al., 2001; Bolstad and Jonsson, 2002). Of possibly greater importance is the recently described selective down-regulation of aquaporin-1 expression in myoepithelial cells in salivary glands in primary Sjögren’s syndrome (Beroukas et al., 2002). There have been few studies concerning the heritability of Sjögren’s syndrome. The relative genetic risk is not known. Large twin studies in Sjögren’s syndrome are lacking, and therefore the twin concordance rate cannot be estimated. There are only a few case reports describing twins with primary Sjögren’s syndrome (Scofield et al., 1997; Bolstad et al., 2000; Bolstad and Jonsson, 2002). The release of acetylcholine from the parasympathetic nerves initiates the stimulus-secretion coupling in the acinar cells of the salivary gland (Petersen, 1992). The release of acetylcholine is brought about by an increase in the intracellular calcium level (Ambudkar, 2000) that ends in the activation of the calcium-dependent K+ and Cl– channels (Park et al., 2001). Disruption of any of these steps of the signal transduction pathways will bring about a decrease of fluid secretion (Li et al., 2004). Muscarinic M3 receptors (M3Rs) bring about parasympathetic neurotransmission to salivary and lacrimal glands, the gastrointestinal tract, urinary bladder, and blood vessels. By inhibiting cholinergic neurotransmission at post-synaptic M3Rs, autoantibodies directed against M3Rs are thought to play a part in inducing sicca symptoms and autonomic dysfunction in persons with primary and secondary Sjögren’s syndrome and scleroderma. Functional autoantibodies against G-protein-coupled M3R have been reported in those with Sjögren’s syndrome, based on radioligand-binding studies and functional assays. These functional human autoantibodies against muscarinic M3 receptors have been shown to inhibit cholinergic neurotransmission at the post-synaptic level and mediate parasympathetic dysfunction, including sicca symptoms in Sjögren’s syndrome (Cavill et al., 2004). Experimentally raised anti-muscarinic M3 receptor antibodies, directed at a peptide sequence representing a dominant functional epitope at the carboxy terminus of the second extracellular loop of M3R, were shown to share the functional properties of autoantibodies in those with Sjögren’s syndrome (Cavill et al., 2004). Li et al.(2004) studied the role of these anti-M3R antibodies in the development of Sjögren’s syndrome. In this study, purified IgG was obtained from the sera of 11 persons with Sjögren’s syndrome, and the inhibitory effects of these antibodies on the M3R of the salivary gland were determined by RT-PCR, microspectrofluorimetry, immunocytochemistry, and immunoblot analysis. Carbochol stimulation induced a [Ca2+] transient in fura-2-loaded human salivary gland (HSG) cells. Pre-treatment of the cells with 0.5 mg/mL of Sjögren’s syndrome IgG for 12 or 24 hrs reduced the magnitude of the carbachol-induced [Ca2+] transient (CICT). There was a 62–45% decrease in the magnitude of CICT when the cells were pre-treated with Sjögren’s syndrome IgG. Salivary gland dysfunction preceded lymphocytic infiltration of the salivary gland in an animal model of Sjögren’s syndrome (Robinson et al., 1998). Antibody production was found to correlate with abnormal glandular function, thus suggesting that antibodies are essential for this dysfunction in this animal model. Antibodies to muscarinic acetylcholine receptors have been shown in sera of persons with primary Sjögren’s syndrome, as well as in experimental models (Bacman et al., 2001). One study (Berra et al., 2002) investigated the role of ELISA-tested salivary IgA from persons with primary Sjögren’s syndrome or secondary Sjögren’s syndrome in binding membrane parotid gland cellular antigens and a synthetic peptide corresponding to the second extracellular loop of human M3 muscarinic acetyl choline receptors. While these antibodies were found to bind these antigens, salivary IgA from women without dry mouth failed to bind. Berra et al.(2002) suggested that these antibodies are important in the pathophysiology of the development of dry mouth in those with primary Sjögren’s syndrome. A water-channel protein, aquaporin, is involved in the rapid water transport across cell membranes, and this protein plays a putative role in salivary secretion. Reduced levels of aquaporin-5 at the apical membrane of the acinar cells in the salivary and lacrimal glands have been shown to decrease the flow of saliva and tears in persons with Sjögren’s syndrome (Steinfeld and Delporte, 2002). Aquaporin-5 trafficking from the cytoplasm to the apical membrane by muscarinic receptor stimulation has been shown in the salivary gland (Ishikawa et al., 2000). Certain disturbances of the immune system play a central role in the etiopathogenesis of Sjögren’s syndrome. (i.e., B-cell hyperreactivity and enhanced levels of B-cell-activating factor/B-lymphocyte stimulator). B-cells have been shown to play a pivotal role in the etiopathogenesis of primary Sjögren’s syndrome. Elevated levels of B-cell activating factor (also known as B-lymphocyte stimulator) (a member of the TNF superfamily that regulates B-lymphocyte proliferation, maturation, and survival) (Mackay and Browning, 2002) have been demonstrated in rheumatic illnesses such as primary Sjögren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis (Szodoray et al., 2003). Interestingly, the highest levels of B-cell-activating factor have been found in persons with primary Sjögren’s syndrome (Hansen et al., 2005). Expression of BAFF/BLyS locally by infiltrating T-cells and macrophages may trigger B-cell hyperactivation and (auto)antibody production and help in the progression of the entire autoimmune process (Hansen et al., 2005; Mackay et al., 2005). In addition, cytokines are believed to play a major role in primary Sjögren’s syndrome pathogenesis by initiating and promoting many cellular and humoral autoimmune processes (Szodoray et al., 2003, 2004; Hansen et al., 2005; Jonsson et al., 2006). More importantly, cytokines involved in T-helper type-1-driven immune responses may be important in the pathogenesis of primary Sjögren’s syndrome as well as other autoimmune diseases (Bombardieri et al., 2004; Eriksson et al., 2004; Hansen et al., 2005). Elevated plasma levels of interleukin-18, for example, have been found to correlate with IgG1 levels in persons with primary Sjögren’s syndrome (and anti-SSA/Ro and anti-SSB/La levels in these individuals) or rheumatoid arthritis (Bombardieri et al., 2004; Eriksson et al., 2004). In addition, interleukin-18 appears to be involved in local glandular inflammatory pathways in primary Sjögren’s syndrome (Bombardieri et al., 2004). Increased levels of interleukin-10 in the saliva have also been found to correlate with severity of primary Sjögren’s syndrome, similar to circulating plasma interleukin-10 levels (Bertorello et al., 2004).
Even though interferon (INF)-
Currently, there is no cure for Sjögren’s syndrome, nor is there any treatment that will reduce or restore the damage done to the glands. Treatment is usually symptomatic and supportive, and includes the use of moisturizing mouthwashes, chewing gums, and salivary substitutes. Both pilocarpine and cevimeline are well-documented muscarinic agonists, used in treatment of xerostomia. They are especially effective in increasing salivary flow, along with improving the symptoms of dry mouth. Cevimeline hydrochloride (a muscarinic M1 and M3 receptor agonist), which has a greater specificity for M3 receptors than does pilocarpine, has been approved for the treatment of xerostomia in those with Sjögren’s syndrome in the USA (Fox, 2002). Even though cimeveline has been effective in several randomized, placebo-controlled studies, the side-effects associated with its use may limit its use clinically (Fife et al., 2002). Side-effects include urinary frequency, excessive sweating, flushing, and headache (Mavragani et al., 2006). One study has evaluated the efficacy of a hydrogel polymer buccal insert as a controlled-release delivery vehicle for pilocarpine (Gibson et al., 2007). The authors found that the insert delivered more than 85% of a 5-mg dose of pilocarpine hydrochloride with minimal side-effects. Thanou-Stavraki and James (2008) suggest that the pilocarpine-stimulated salivary flow is linked to the excretory capacity of salivary glands. Sialography, in those with primary Sjögren’s syndrome, can show the correlations between sialometry and the extent of gland destruction (Thanou-Stavraki and James, 2008).
Other systemic therapies for the stimulation of salivary gland function include bromhexine, anetholetrithione, and TNF-alpha blockers. Interferon (IFN)- Oral candidiasis can be treated with topical antifungal treatment and then followed by systemic antifungal agents for intermittent episodes. Nystatin (cream or oral suspension) and pastille (lozenge) are given for treatment, followed by azole for systemic treatment. Persons with dentures are discouraged from wearing dentures overnight and are encouraged to clean the dentures with 2% chlorhexidine. Individuals with a hyperplastic variation of Candida infection are advised to undergo a biopsy, because there is an increased risk of malignant transformation (Mavragani et al., 2006).
B-cells play a vital role in the pathogenesis of many autoimmune diseases as well as certain lymphomas and leukemias. Antibodies that are antagonistic to B-cells are thus gaining an increasing role in the management of these diseases. Epratuzumab, the first antagonistic antibody to the B-cell marker CD22, appears to function, in contrast to CD20 antibodies, more by modulation of B-cells than by their high depletion in circulation (Goldenberg, 2006). It functions as a humanized IgG1 monoclonal antibody against the CD22 antigen and down-regulates the B-cell receptor (Steinfeld et al., 2006). Epratuzumab was originally developed for treating non-Hodgkin’s lymphoma and has now been found to be effective, with a very good safety profile, in systemic lupus erythematosus and primary Sjögren’s syndrome (Goldenberg, 2006). Epratuzumab, in an open-label phase I/II study, showed promising results in the treatment of primary Sjögren’s syndrome. The study consisted of 16 Caucasian individuals, two of whom discontinued due to complications (Table 2
Another drug on which more research is being conducted is rituximab (Table 4  ). Rituximab, known for its tolerance and short-term efficacy, is an anti-CD20 antibody, which is effective in persons with various autoimmune diseases. It targets B-cells, suggesting that it may play a role in the etiopathogenesis of Sjögren’s syndrome (Ramos-Casals and Brito-Zerón, 2007). Rituximab is also frequently used as therapy for B-cell non-Hodgkin’s lymphomas and can be combined with chemotherapy (Thanou-Stavraki and James, 2008).
Individuals with primary Sjögren’s syndrome and associated lymphoma were given rituximab in an uncontrolled open-label rituximab trial that was conducted with 15 persons with primary Sjögren’s syndrome (seven of whom had MALT-type lymphoma). The drug proved to be efficient in the remission of lymphoma, along with improvement in the salivary and lacrimal gland function in those individuals with previously reduced gland function. Notably, salivary gland can also become a location for shelter from rituximab, due to signals from the microenvironment of the gland, inhibiting the pro-apoptotic effect of the drug (Thanou-Stavraki and James, 2008). Although 3 different trials were conducted that showed some improvement of sicca features, a larger controlled study should be conducted to evaluate the efficiency of rituximab (Ramos-Casals and Brito-Zerón, 2007). Side-effects were not observed, and considerable regression in the parotid swelling and improvement in the symptoms of dry mouth and eyes was evident. There were still detectable levels of anti-Ro and anti-La after treatment with rituximab. Recent trials with rituximab showed significant improvement in the general symptoms and an increase in salivary function (Touma et al., 2006). A recent study has suggested cevimeline as a treatment for the control and prevention of oral infection. The study was conducted to observe cevimeline’s effect on the concentrations and secretion rates of IgA, lysozyme, alpha-amylase, and squamous cell carcinoma antigen in human saliva. Cevimeline at a dose of 30 mg was given to 14 healthy women and 12 women with Sjögren’s syndrome, with saliva collection performed after 90 min. The results demonstrated that both groups showed an increase in salivary flow rate and amylase concentration and no significant change in the lysozyme and IgA concentrations. There was also a significant decrease in the SCC antigen concentration in the control group and no change in the Sjögren’s syndrome group. There was an increase in the amylase and IgA secretion rates in both the control and Sjögren’s syndrome groups. There was a significant increase in the lysozyme secretion rate in the control group and in the SCC secretion rate of lysozyme in the Sjögren’s syndrome group (Suzuki et al., 2005). Local therapies targeted to the oral cavity may be of use. Electrical stimulation of the tongue and hard palate with a battery device has been shown to be useful in stimulating salivary flow in some persons with Sjögren’s syndrome with residual salivary flow, but not in those with low or no salivary flow (Steller et al., 1988). Studies have also shown that oral administration of interferon-alpha lozenges (150 IU 3 times a day) for persons with primary Sjögren’s syndrome was well-tolerated and resulted in improved saliva production, offering relief to symptoms of xerostomia and xerophthalmia (Khurshudian, 2003). In addition, several pseudo-pharmaceutical products and herbal supplements are available (Ship, 2002). In animal studies, green tea polyphenols can reduce the amount of lymphocytic infiltration of the submandibular glands, and epigallocatechin-3-gallate can also protect the acinar cells from TNF-alpha-induced cytotoxicity. However, it is unknown whether the results can be translated to humans (Hsu et al., 2007). Each person with Sjögren’s syndrome should receive personalized, individual care. Dental caries can be prevented by increasing host resistance and decreasing the amount of cariogenic organisms found in the oral cavity (Newbrun, 1996). One of the methods for preventing dental caries includes control of plaque by the practice of meticulous oral hygiene, which will decrease the number of micro-organisms found on the surfaces of the teeth. A complementary method of prevention is the topical application of fluoride to the surfaces of the teeth. The fluoride strengthens the tooth enamel, which makes the tooth more resistant to tooth decay. A small cavity can be stopped and even reversed by the remineralization process enhanced by fluoride (Pedersen et al., 2005). A 60-kDa Ro-peptide-immunized animal model of Sjögren’s syndrome (Scofield et al., 2005) provides an avenue for therapeutic manipulation studies. One study found the amelioration of Sjögren’s syndrome-like conditions in these mice by oral feeding of either 60 kDa Ro or a peptide sequence from this antigen (Kurien et al., 2005).
At the dental office, a wide variety of individuals with salivary gland disorders is observed. One such condition is Sjögren’s syndrome, a common autoimmune rheumatic disease. Xerostomia from Sjögren’s syndrome causes a spectrum of oral problems, including dental caries, candidal infection, and inflammation of the oral mucosa. Swollen sublingual and parotid glands, as well as lymphocytic infiltrates, are a hallmark of Sjögren’s syndrome. Even though the exact etiology of Sjögren’s syndrome is unknown, it is thought to be brought about by a variety of factors. The diagnosis and treatment of Sjögren’s syndrome are a problem for dentists. The change in salivary flow and salivary composition (minerals and protein) in Sjögren’s syndrome predisposes to dental caries (in spite of excellent dental care), loss of taste, and fungal and bacterial infections. Xerostomia is a difficult condition to treat. Good hydration, optimal hygiene, and prophylaxis of candidosis are the treatment options. Oral cholinergic stimulators have been proven to be the main drug with demonstrated beneficial effects, if contraindications do not exist. Management of those with Sjögren’s syndrome encompasses necessary treatment for oral and craniofacial problems in addition to the teeth and periodontium, and may therefore serve as a model for the future scope of the practice of dental care.
Received for publication April 13, 2007. Revision received November 20, 2007. Accepted for publication November 29, 2007.
Journal of Dental Research, Vol. 87, No. 4,
308-318 (2008) This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
is not elevated in the sera of those with Sjögren’s syndrome, an activated type 1 interferon system has been described recently in their salivary glands (
