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Keywords:

  • Sjögren’s syndrome;
  • aetiology;
  • pathogenesis;
  • diagnosis;
  • dental management

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. References

Sjögren’s syndrome is a chronic autoimmune disease that affects many individuals within the community. Despite this, its exact aetiology and pathogenesis is still unclear. Sjögren’s syndrome affects many organ systems in the body. However, for dental practitioners it is important to recognize the many oral and dental manifestations that are associated with the syndrome. In addition to these oral manifestations, this review will discuss the systemic manifestations of Sjögren’s syndrome as well as the current understanding of factors that have a role in its aetiology and pathogenesis. Furthermore, this review will highlight the difficulties and complexities that are inherent in the diagnosis of Sjögren’s syndrome and the important role that dental practitioners can play in the management of its oral manifestations. The effective management of oral manifestations and minimization of oral disease in patients with Sjögren’s syndrome can result in improved quality of life for these patients.


Abbreviations and acronyms:
HCV

hepatitis C virus

HIV

human immundodeficiency virus

HLA

human leukocyte antigen

IFN

interferon

MHC

major histocompatibility complex

SS

Sjögren’s syndrome

TNF

tumour necrosis factor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. References

Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration and subsequent destruction of the exocrine glands,1–3 including those found in the nose, ears, skin, vagina, respiratory and gastrointestinal systems.4 Clinically, involvement of the salivary and lacrimal glands leads to salivary gland hypofunction and keratoconjunctivitis sicca.1,2 Accordingly, the syndrome has many dental implications that are important for dentists to be aware of. In addition, dental practitioners also need to recognize the systemic nature of the disease and refer patients for specialist medical management when appropriate. Patients are classified as having either primary or secondary SS according to the presence of other concurrently occurring autoimmune diseases. Primary SS does not occur in association with other systemic autoimmune disease.5 However, secondary SS does occur in association with another autoimmune disease, most commonly rheumatoid arthritis. Other associated conditions include lupus erythematosus and scleroderma,2 which also have important oral manifestations.

Epidemiology

SS is estimated to affect 1–3% of the general population.6 Whilst all ages can be affected, it is generally seen in menopausal women in the fourth and fifth decades of life.7,8 SS is more prevalent in women than men, with a ratio of 9:1.1 The symptoms of SS are often vague and may, in some cases, be mistakenly attributed to other diseases and/or medications that are being taken by the patient. Misdiagnosis of the condition is therefore common and it is estimated that approximately half of all sufferers are currently undiagnosed.9 Early onset SS (onset less than 35 years of age) has been associated with more severe signs and symptoms.4 Interestingly, approximately one-third of patients with some form of autoimmune disorder concurrently suffer from SS.1,10

Aetiology, risk factors and pathogenesis

The aetiology of SS is controversial, however it is well established that it is multifactorial.3 Although not completely understood, there is thought to be a series of four events that occur in all SS patients: (1) initiation by an exogenous factor; (2) disruption of salivary gland epithelial cells; (3) T lymphocyte migration and lymphocytic infiltration of exogenous glands; (4) B lymphocyte hyper-reactivity and production of rheumatoid factor and antibodies to Ro(SS-A) and La(SS-B).11

Risk factors

Genetic predisposition

A genetic predisposition to SS has been suggested because of multiple reports of two or more members of the same family developing the syndrome.8 A family history of the disease puts people at an increased risk of developing SS compared to the general population.2 This is also supported by the development of SS in twins.12 It has been suggested that a genetic susceptibility is required for the development of autoantibodies which are found in SS4 and this may be associated with a link between polymorphic major histocompatibility complex (MHC) genes and the development of autoimmune diseases.8 This area needs further exploration before a definitive link can be found.

Viral initiating factor

Animal models using mice found that cytomegalovirus infection led to the development of SS-like symptoms and it has been subsequently suggested that this may occur in humans as well.4,12 Other viruses potentially involved in the aetiology of SS are Epstein-Barr virus, hepatitis C virus (HCV) and human T-cell Leukaemia virus-1.4,12 It is hypothesized that viruses can promote autoantibody production through molecular mimicry,8 resulting in cross-reactivity of immune reagents with host antigens. The amino-acid sequence and structural similarities between foreign and self-peptides (molecules from dissimilar genes) allows an immune response directed against the virus to concurrently elicit a tissue-specific immune response via the creation of cytotoxic cross-reactive lymphocytes and antibodies which result in cell and tissue destruction.13 This results in the development of autoimmunity and the process can then progress without the initiating virus being present chronically. It has been shown that HCV induces similar symptoms to SS and this has led to its inclusion in the list of “exclusion criteria” developed by the American-European Consensus Group.12 Therefore, HCV may not actually cause SS, but may just display similar signs and symptoms. In some patients, the human immunodeficiency virus (HIV) has been associated with inflammation and damage to the salivary glands,2 leading to Sjögren’s-like symptoms such as xerostomia and reduced salivary flow.

Sex hormones

The high percentage of females with SS compared to males suggests that the immune regulatory properties of sex hormones are involved in its development.14 The ratio of androgen to oestrogen modulates the cellular immune response which is involved in the destruction of exocrine glands.15 Oestrogen is an immune stimulator that has a role in lymphocyte growth, differentiation, proliferation, antigen presentation, cytokine production, antibody production, cell survival and apoptosis.15 Oestrogen has been shown to stimulate B-cell dependent response in diseases leading to increased antibody production.15 Oestrogen declines during menopause and this is the time when women are most susceptible to developing SS, suggesting that either oestrogen decline or the difference in the oestrogen:androgen ratio is involved with disease onset.15

Prolactin is a pro-inflammatory hormone that stimulates oestrogen activity and, when at a high level, inhibits oestrogen production.15 Prolactin is an immune stimulator and is involved in T cell proliferation, induction of interleukin-2 receptor expression, support of interferon-gamma production and stimulation of antibody production.15 As cytokines released from T cells attract immune cells to the salivary gland ductal epithelium and acinar cells, and prolactin is involved with modulating their release, this suggests that the oestrogen-prolactin relationship may affect immune response and hence be involved in Sjögren’s development.15 Murine testing has demonstrated that prolactin accelerates the disease process and that oestrogen alone (i.e., not in the presence of prolactin) becomes immunosuppressive and inhibits interleukin-2 production, further supporting the theory that prolactin and its subsequent effects on the immune system are involved in the development of SS.15 In a study by Taiym et al.,15 patients with SS were shown to have higher levels of prolactin and oestrogen. Higher levels of oestrogen may be involved with the development and proliferation of Ro/SSA and La/SSB antibodies involved in SS.15

Pathogenesis

Autoantibodies

Autoantibodies are found in the serum of both primary and secondary SS patients. Most common are Ro/SSA and La/SSB autoantibodies which are found in the serum of 60–70% of patients with primary SS.1,3 The presence of these autoantibodies have been linked with an earlier onset of disease, increased disease severity, longer duration of disease, recurrent parotid gland enlargement and extraglandular manifestations.4,6,8 Therefore, it may be possible to use the presence of these autoantibodies as a predictor of disease severity in newly diagnosed patients. Patients with younger onset SS demonstrated higher serum levels of Ro/SSA and La/SSB antibodies and higher rheumatoid factor. This was associated with more severe clinical symptoms in the younger onset group of patients.7

Chronic lymphocytic infiltration and subsequent damage of salivary gland acini

A characteristic histological feature in Sjögren’s syndrome is the focal lymphocytic infiltration of the salivary glands.1,16 Diagnostically, this focal infiltrate is classified as a “focus score”, with “one focus” defined as a collection of 50 or more lymphocytes within 4 mm2 of tissue. Over time, exocrine glands display acinar atrophy, ductal hyperplasia and replacement of acinar cells with fibrosis and/or fatty infiltration which results in these areas of the gland being non-functional.4,8 The lymphocytic infiltrate contains T cells and B cells at a ratio of 4:18,17 as well as plasma cells.8 The T cells produce interleukins, tumour necrosis factors (TNF) and interferon (IFN). TNF may increase the antigen presenting nature of epithelial cells, and along with interleukin-1, may inhibit the release of acetylcholine from cholinergic efferent nerves, therefore affecting exocrine gland secretion.18,19 IFN may induce apoptosis of the salivary gland epithelial cells.9 This suggests a mechanism for gland destruction as the ductal cells undergo apoptosis.9 The acinar and ductal epithelial cells have also been implicated in the autoimmune destruction as they attract immune cells by producing pro-inflammatory cytokines and chemokines.1 The B cells then produce immunoglobulins with autoantibody activity.8

Autoantibodies to muscarinic M3 receptors

It was recently shown that there are autoantibodies to lacrimal and salivary gland muscarinic M3 acetylcholine receptors produced in SS. This prevents the synapse between the efferent nerves and the gland cells resulting in decreased saliva production.18 Studies have shown that despite decreasing saliva production, patients can still sense the discomfort in their mouth; this implies that afferent nerve fibres are still intact. Histological examination of affected glands has demonstrated that only 50–60% of the gland parenchymal tissues are destroyed by cell apoptosis. This led Fox and Stern18 to the conclusion that the remaining gland must be inactive via “paralysis” of either the release of neurotransmitters from cholinergic nerve fibres or post-signalling response of the glandular cells. Considering that drugs such as pilocarpine act via mimicking the action of acetylcholine, and the glandular cells are able to respond to this by increasing saliva flow, it can be assumed that the “paralysis” is through the release of neurotransmitters from cholinergic nerve fibres. If the dysfunction lay in the post-signalling response of the glandular cells, then these drugs would have no effect.

Up-regulated expression of human leukocyte antigen molecules

Jonsson et al.8 suggested that the up-regulated expression of human leukocyte antigen (HLA) molecules by the epithelial cells in the salivary glands in SS patients is involved with antigen-presentation, leading to exocrine glandular destruction by CD4+  T cells. It is also suggested that this leads to increased cytokine production and stimulation of B cell proliferation and differentiation which hence increases the immune response. Epithelial cells produce cytokines: IL-1β, IL-6 and TNF. HLA molecules are also involved with the activation of cytotoxic T cells that induce cell apoptosis when presented with antigen.8

B cell hyperreactivity

B cell activating factor and a proliferation-inducing ligand are increased in patients with SS. It has been shown that the levels of these correlate with the focus score seen in the salivary gland biopsy,3 supporting the notion that B cells play a role in the pathogenesis of SS. Furthermore, hyperreactivity of B cells has been found in patients with SS. Kassan et al.9 discussed the finding that B and T cell activation leads these cells to “invade and destroy” target organs.

Diagnosis

The diagnosis of SS is not straightforward as many of the symptoms are subjective and vague and can be dismissed initially as other conditions or effect of medications (Table 1).3 The difficulty in diagnosis means that the estimated interval between initial symptoms and diagnosis of the disease is approximately 6 to 10 years.4,14 The common vague symptoms that patients initially present with are arthralgia, fatigue and extraglandular complications.20

Table 1.   Differential diagnosis of Sjögren’s syndrome3
Drug therapyAnticholinergic drugs
Past treatmentsPast head and neck radiation treatment
Systemic diseaseSarcoidosis
Hep C
HIV/AIDS
Graft-versus-host disease
Pre-existing lymphoma
Rheumatoid arthritis
Systemic lupus erythematosus
Scleroderma
Primary biliary cirrhosis
Diabetes mellitus
Cytomegalovirus and other herpes viruses
Ectodermal dysplasia

The current method of diagnosis is a set of criteria that need to be satisfied and it has been established that the expert clinician’s assessment is currently the “gold standard” for diagnosis of SS.4 The American-European Diagnostic Criteria were revised in 2002 and altered to allow a higher sensitivity and specificity of testing. The criteria differ in that there are two objective criteria, one of which must be satisfied, to make a diagnosis of primary SS. These two obligatory objective criteria are IV and VI (Table 2).2,10 A classification of SS can be made when: (a) four of the six criteria are present, one of which is IV or VI; or (b) presence of any three of the four objective criteria, III, IV, V or VI.2,10

Table 2.   Revised International Classification Criteria for Sjögren’s syndrome2,10
Criteria
IOcular symptoms: at least one of the following
 1. Daily dry eyes for >3 months
 2. Persistent sensation of sand or gravel
 3. Use of tear substitutes >3 times daily
IIOral symptoms: at least one of the following
 1. Dry mouth daily >3 months
 2. Recurrent salivary gland swellings
 3. Use of liquid to aid in swallowing food
IIIOcular signs: at least one of the following
 1. Schirmer’s I test (≤5 mm in 5 min)
 2. Rose Bengal score (≥4)
IVHistopathology: focal lymphocytic sialoadenitis with focus score ≥1 per 4 mm2 of tissue
VSalivary gland involvement: at least one of the following
 1. Unstimulated salivary flow ≤1.5 ml/15 min
 2. Abnormal parotid sialography
 3. Abnormal salivary scintigraphy
VIAutoantibodies: presence of Ro(SSA) or La(SSB) or both, in serum

Exclusion criteria have been stipulated which prevent a diagnosis of SS being made. These criteria are based on the fact that the signs and symptoms of these conditions are so similar to SS that a definitive diagnosis cannot be made. These criteria are: past head and neck radiation treatment, hepatitis C infection, HIV/AIDS, pre-existing lymphoma, sarcoidosis, graft-versus-host disease and the use of anticholinergic drugs.10

Methods of diagnosis of the four objective criteria (Table 3)2,3,10,14,21,23

Table 3.   Diagnostic tests for Sjögren’s syndrome2,3,10,14,21,23
Testing for opthalmic involvement
 Schirmer’s I test: quantitative measure of tear production over a specific period of time
 Rose Bengal eye stain: reveals breaks in the corneal-epithelial surface to evaluate ocular surface irritation
 Patient history of opthalmic symptoms
Testing for oral involvement
 Salivary sialometry: low salivary flow is defined as less than 1.5 ml of saliva per 15 minutes
 Labial minor salivary gland biopsy: showing lymphocytic sialoadenitis with a focus score of ≥1 per 4 mm2 of tissue
 Examination for salivary gland enlargement: parotid and/or submandibular
 Patient history of oral symptoms
Systemic tests
 Presence of Ro/SSA and La/SSB autoantibodies in patients serum
 Presence of rheumatoid factor in patients serum

Criteria III: ophthalmic involvement may be tested objectively by the use of the Schirmer’s I test which is a quantitative measurement of tear production over a specific period of time.2 This test has the advantage of being simple and cost-effective but has been shown to be difficult to reproduce accurately in mild cases of keratoconjunctivitis sicca. As the severity of keratoconjunctivitis sicca increases, the Schirmer’s I test concurrently increases in reproducibility. The Rose Bengal eye stain, which stains the conjunctival surface to reveal any breaks in the corneal-epithelial surface,21 may be used in conjunction with the Schirmer’s I test to aid in diagnosis. The Schirmer’s I test may be performed with or without anaesthesia, but testing without anaesthetic has a lower specificity.19

Criteria IV: a histopathological examination of minor salivary glands showing focal lymphocytic sialadenitis (lymphocytic infiltration of the salivary glands) with a focus score of ≥1 within 4 mm2 of tissue satisfies this criteria.10 As indicated in previous sections, a focus is considered to be a cluster of 50 or more lymphocytes. The sensitivity and specificity for the biopsy are 82.4% and 86.2%, respectively.4 However, a recent study by Stewart et al.16 suggested that the labial minor salivary gland biopsy can be misdiagnosed. The study compared oral and surgical pathologists and found “agreement to be uniformly poor for judgments of diagnostic status, focus scores and histological characteristics of biopsy specimens”.16 The authors suggested that there needs to be improved consistency of histological interpretations, and this may include altering the criteria and methodology.16

Criteria V: salivary gland hypofunction is one of the first symptoms of SS but is often overlooked as it can be caused by many other concurrent factors such as anticholinergic drugs, systemic disease, psychological and physiological changes.22 Low salivary flow can be detected using salivary sialometry, the measurement of salivary flow,2 and this is highly reproducible.20 The threshold for low salivary flow is less than 1.5 ml produced in 15 minutes.10,23 Patients with SS show less unstimulated salivary flow than healthy adults. In a study by Pederson et al.,23 25% of patients with Sjögren’s syndrome had no measurable salivary flow. Patients may also have more complaints about dysphagia and dysgeusia than unaffected adults23 and show altered properties of secretions that are thicker, more opaque and more viscous.17 Xerostomia is a subjective symptom of SS and hence is considered in many studies to be a relatively unreliable indicator, although Pederson et al.23 demonstrated that Sjögren’s patients who had a complaint of xerostomia did demonstrate lower unstimulated salivary flow rates than those who did not. This indicates that even though xerostomia is a subjective symptom, it may be relatively reliable and should be considered in diagnosis. This is supported by its inclusion in the American-European Diagnostic Criteria. Medications may alter the unstimulated salivary production in some patients, however stimulated salivary flow is not affected to the same extent,4 and therefore may be more reliable for sialometry. Some patients show enlargement of the parotid and/or submandibular salivary glands, with the incidence being 20–30%,3 and recurrent salivary gland enlargement may be used to aid in diagnosis. It is detectable either visually or on palpation, but taking an adequate patient history is required.22

Criteria VI: the presence of Ro/SSA or La/SSB autoantibodies in the patient’s serum. The low to moderate prevalence of these autoantibodies, 13–88% for Ro/SSA and 48–73% for La/SSB, supports the American-European criteria that mandates either histopathological or autoantibody evidence to be present, and not both. If Ro/SSA and La/SSB are considered with rheumatoid factor, also found in serum, 80–90% of patients with SS display these three factors concurrently.14 This means that it could be considered that testing for these three markers together in serum may give a higher sensitivity. These autoantibodies have previously been located in saliva, but in a recent study by Hammi et al.6 it was shown that the sensitivity of identifying these in saliva was much lower than for serum, which indicates that serum testing should be used to detect these antibodies. The reasoning for the criteria method of classification is again demonstrated as it has been shown that some healthy patients without SS have tested positive to the autoantibodies Ro/SSA and La/SSB.24 Therefore, it is important that patients meet other criteria before a diagnosis is made.

Al-Hashimi et al.25 demonstrated that the three symptoms that together had the highest predictive value for disease were: (a) dry mouth; (b) sore mouth; and (c) dry eyes. Together, they correctly identified 93% of cases of SS and 97.7% of healthy individuals. If these are put together with the histopathology test from a labial salivary gland biopsy and/or the presence of Ro/SSA or La/SSB autoantibodies in serum, then it is expected that the sensitivity and specificity would be very high. It was shown that meeting this combination of criteria had the most favourable sensitivity and specificity, 89.5% and 95.2%, respectively. Although these were quite high, Vitali et al.10 noted a shortcoming in this method of classification: “that patients with true primary SS, but without any subjective symptoms, might easily be misclassified”. This demonstrates that although the sensitivity and specificity are acceptable, the risk of misdiagnosis is still quite high, and highlights the need for a more definitive set of tests and criteria to classify these patients.

Associated pathology and complications

SS systemic disease affects many other body systems and can elicit many varied systemic symptoms. It is associated with many disorders such as Raynaud’s phenomenon, lymphadenopathy, peripheral neuropathies – but the severity varies between patients.2

The most serious and well-established complication of SS is the increased incidence of malignant lymphoma (lymphoproliferative disease). This has been shown to be 44 times higher than the general population in some studies.25 A recent study has demonstrated that certain patients with SS are at higher risk of developing lymphoproliferative disease and are subsequently at a higher risk of mortality than general patients with the syndrome. This group of patients shows certain risk factors upon disease diagnosis that may predict the risk of developing lymphoma. Patients with one of: (a) parotid enlargement; (b) palpable purpura; (c) low C4 (complement) levels; or (d) mixed monoclonal cryoglobulinemia at the time of diagnosis, display a nine times increased risk of developing lymphoproliferative disease.26,27 It was demonstrated that only one out of five patients (20%) showed any of these adverse risk factors on diagnosis, and the authors therefore suggested that the four out of five patients without these risk factors could be assured of a benign clinical course and no risk of mortality higher than that of the general population.27 It was noted by the authors that the patients had a limited follow-up period, on average six years, which suggests that the longer term merits of these results have not been fully investigated. The study also noted that patients who died from lymphoproliferative disease also showed cryoglobulins in their blood, but currently no definitive conclusion can be drawn as to the role in disease or mortality of this particular molecule. This is an area that needs to be investigated further as there may be some predictive value of mortality associated with the level of cryoglobulins in the blood of patients with SS. The presence of clonal expansion of B cells in salivary glands has been shown to increase the risk of developing a lymphoma and it has been suggested that patients displaying this feature should be monitored more closely than others. Another feature of lymphoma development in SS is the decrease in immunoglobulin levels and a decrease in the serum levels of autoantibodies.8

Other exocrine symptoms that may be experienced by patients with SS include: dryness of the nose, skin and vagina. Patients also suffer recurrent sinusitis, chronic cough from dryness of the trachea, recurrent oral candidiasis resulting from salivary gland hypofunction, indigestion and constipation.4 Chronic keratoconjunctivitis sicca causes an irregular surface of the cornea which leads to deteriorating vision and increased risk of recurrent infections.20

SS may also have extraglandular symptoms. The joints, liver, kidneys and the central nervous system can be affected (Table 4).25 A study has shown that 45% of patients with SS also had associated thyroid dysfunction. This is further supported by a study suggesting that the prevalence of SS is 10 times higher in patients with autoimmune thyroiditis.25 Although more research needs to be done to confirm this, it is important to note and make sure all Sjögren’s patients are monitored for any thyroid problems.6

Table 4.   Symptoms associated with extraglandular manifestations of Sjögren’s syndrome26
MalaisePeripheral neuropathyPrimary biliary cirrhosis
FatigueAutoimmune thyroiditisGI symptoms
FibromyalgiaRenal tubular acidosisRespiratory diseases
FeverMyositisPsychosis
ArthralgiaChronic hepatitisLymphadenopathy
SynovitisPurpuraSplenomegaly
Raynaud’s phenomenon VasculitisLymphoma

Skin involvement mainly manifests in the form of vasculitis and cutaneous purpura. Lesions found in SS are described as being clinically identical to lesions found in patients with systemic lupus erythematosus, which highlights the difficulty of differentiating SS from other autoimmune and associated diseases. The exocrine glands of the skin are affected by the lymphocytic infiltration and hence patients present with dry skin in about 55% of cases.9

Respiratory disease may occur early in the course of SS but these diseases often have a long, chronic clinical course.5 Cough is the most common symptom and this is usually indicative of a dry trachea as the exocrine gland secretions have been adversely affected.9

Raynaud’s phenomenon is a vascular condition where there is fluctuating vasoconstriction of the blood vessels in the extremities such as fingers and toes1 and is seen in approximately 13% of patients with SS, but is also commonly associated with scleroderma. This suggests that SS and scleroderma need to both be considered when this phenomenon occurs and care taken to explore all differential diagnoses.1

Glomerulonephritis is seen commonly in SS, with one study showing a prevalence of 55%.26 It is, therefore, a serious complication of SS as it can lead to an increased risk of mortality. Glomerulonephritis has also been shown to have a statistically significant correlation with the development of lymphoma and this supports the suggestion that certain patients develop multiple serious complications whilst others do not develop any.26

Subclinical muscle inflammation is seen in approximately 50% of SS patients5 and arthralgia is seen in approximately 53% of patients.9 This highlights a common area where physicians may confuse SS with rheumatoid arthritis.9

Gastric involvement has been demonstrated in 55% of patients with SS.25

The incidence of psychological disorders and depression are high in patients with SS.25 This may be related to the downturn in quality of life elicited by the symptoms of the disease. Xerostomia has a severe impact as patients find eating, speaking, swallowing and sleeping difficult. Patients with oral removable prostheses may have difficulty retaining dentures. The development of oral ulcers and mucosal inflammation is common. The incidence of debilitating fatigue in approximately 50% of patients, may also contribute to the depression commonly seen in patients with SS, particularly the elderly.9 Patients often struggle with social withdrawal, economic burden and poor nutrition as a result of difficulty eating.4

Oral complications

SS has been proven to be a progressive disease as patients have shown deteriorating lacrimal and salivary secretions over time.26 Skopouli et al.26 showed that the rate of dry mouth increased from 41% of patients at initial diagnosis to 84% 10 years after diagnosis.

Decreased salivary flow has many effects on the oral cavity. Saliva is protective of enamel by its supersaturation with calcium and phosphate ions, and less saliva predisposes patients to caries especially on smooth surfaces which are usually the most protected.2 Saliva contains antimicrobial proteins and immunoglobulins that help to limit the adherence and growth of plaque bacteria.4 This was supported by Pederson et al.23 in a study that concluded that patients with a labial salivary gland biopsy focus score of one or more (as per the American-European Classification Criteria) or the presence of Ro/SSA and La/SSB antibodies in serum, had a significantly higher DMFT/DMFS score than patients without these two factors.

In SS the gingiva and mucosa of the oral cavity are not protected by salivary mucins, leading to less lubrication of the tissues. This can cause signs such as oral mucosal inflammation, mucosal sloughing, erythematous mucosa and traumatic ulcers (Fig 1).2 Pederson et al.23 also demonstrated that patients with a labial biopsy focus score of one or more, or the presence of Ro/SSA and La/SSB antibodies in their serum, had a higher frequency of mucosal changes including atrophic and dry mucosal membranes. Patients may demonstrate depapillation of the tongue in advanced disease cases (Fig 2).9 The decrease in saliva flow can lead to an inflammatory response in the gingiva, manifesting as oedema, inflammation or recession as a result of poor oral lubrication and less clearance of plaque and food particles by saliva.9 Patients with dentures may have difficulty retaining them and there also may be discomfort associated with wearing the denture as a result of reduced saliva flow.9

image

Figure 1.  Erythematous mucosa in a patient with Sjögren’s syndrome.

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image

Figure 2.  Depapillation of the tongue in a patient with Sjögren’s syndrome.

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Saliva contains protective molecules such as immunoglobulins and lysozymes. As saliva flow decreases, patients are increasingly susceptible to opportunistic infections such as candida as these protective molecules decrease. Candida infections often present as atrophic or erythematous candidiasis and is associated with burning mouth described by approximately one-third of patients with SS (Fig 1).2,3,22 The prevalence of Candida albicans is >68% in patients with SS whereas the prevalence in the normal population ranges from 23 to 68%. Radfar et al.29 showed an association between candida and decreased stimulated salivary flow rate.

Management and future treatment options

Effective dental management of patients with SS by a general dental practitioner is vital to treat oral symptoms and prevent the oral disease which is prevalent in these patients. An individualized treatment regime is important to best manage patient’s oral problems. Al-Hashimi2 suggests a dental regime for patients diagnosed with SS to help prevent dental disease from flourishing and to manage the current symptoms (Table 5)2,3,8,18 (Table 6).2,8 As patients are at a higher caries risk (Fig 3) they need to be seen more regularly for examinations and given preventive treatment such as home fluoride regimes to follow2 and they also need to maintain excellent oral hygiene that should be regularly reinforced by the dental practitioner.8 Patients should be advised to drink water regularly to: (a) help lubricate the oral tissues; (b) increase saliva flow where possible; and (c) aid in balancing the oral pH to lower caries risk. Artificial saliva substitutes may be used to enhance oral comfort and aid in tissue lubrication.8

Table 5.   Management of salivary deficit2,3,8,18
Regular sipping of water
Artificial saliva substitutes
Sugar-free chewing gum
Avoidance of anticholinergic drugs if possible
Pharmacological treatments (not yet available in Australia) including pilocarpine and cevimeline
Table 6.   Prevention of oral disease in Sjögren’s syndrome patients2,8
Regular examinations and recalls
Professional topical fluoride applications
Home fluoride regimes tailored to individual patient
Monitoring and reinforcement of oral hygiene instruction
Regular water intake
Sugar-free chewing gum
image

Figure 3.  Smooth surface caries resulting from salivary gland hypofunction.

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Candidiasis should be managed with topical anti-fungal treatments.30 Patients are advised to avoid anticholinergic drugs if possible as these can exacerbate xerostomia and keratoconjunctivitis sicca symptoms by further decreasing flow of tears and saliva.1 Regular professional fluoride applications as well as at-home fluoride therapy should be employed to aid in caries prevention.2

Systemic muscarinic agonists are drugs currently approved for use in the United States for management of the symptoms associated with SS but are not yet in use in Australia. They have proven to be effective in increasing salivary flow from exocrine glands. These agonists stimulate the M1 and M3 receptors in salivary and lacrimal glands. Pilocarpine and cevimeline are drugs currently being used and have shown subjective and objective improvement in both saliva and tear flow rates.5

Pilocarpine mimics acetylcholine and acts as a messenger between cholinergic neural cells and glandular acinar cells18 and may prevent apoptosis.9 It was reported that the effect of pilocarpine lasts for approximately two to three hours when taken orally. Another study found that using a pilocarpine mouthwash increased salivary flow for 75 minutes.3 The mouthwash is considered a better option as it is a topical application and its absorption systemically is much reduced from the oral form. This then reduces the possible systemic side effects such as increased motility of the gastrointestinal tract and increased smooth muscle tone.3 However, the action of pilocarpine relies on there being residual unaffected portions of the exocrine glands, therefore it is most effective in the early stages of disease when fibrosis of the acinar cells has just begun.

Cevimeline is a newer drug that is an acetylcholine analogue stimulating muscarinic M3 receptors on lacrimal and salivary glands. Studies show that cevimeline improves subjective xerostomia and objective hyposalivation and is given three times daily as an oral tablet.3 This drug has been shown to bind for a longer duration to M3 receptors as it has a greater affinity,2 and therefore may have a more prolonged and chronic clinical effect. This may also aid in the reduction of adverse side effects2 associated with both cevimeline and pilocarpine which include sweating, urinary frequency, nausea, rhinitis and diarrhoea.4 Cevimeline has been shown to have decreased binding to M2 receptors in heart and lung tissue compared to pilocarpine which decreases the stimulation of cardiac tissue.19

Pharmacological intervention in SS is not appropriate for all patients as it may interfere with other medications that a patient is taking or it may interact with a systemic illness. In these patients symptomatic relief is very important such as oral lubricating gels and saliva substitutes that aid in oral function.4

As SS is an autoimmune disease, some studies have shown the use of corticosteroids to be effective in improving symptoms as well as histological features of the disease. Ramos-Casals5 demonstrated that corticosteroids, such as prednisolone, used in high doses have decrease serum anti-Ro/SSA and anti-La/SSB antibodies, as well as IgG, IgM and IgA. Conversely, Fox, Datiles and Atkinson31 showed that there was no improvement histologically or functionally in salivary and lacrimal glands from the use of prednisone. Fox and Stern18 suggested that the long-term side effects associated with this treatment far outweighed the benefits.

It should be noted that there is a spontaneous improvement in symptoms in approximately 12% of patients, indicating that not all disease is progressive.20

SS is a complex multifactorial disease that, as well as having significant oral manifestations, also has potentially serious systemic complications. Together, these features significantly affect the quality of life of patients. Early diagnosis is imperative so that oral complications can be minimized and appropriate management is instituted both medically and dentally. Appropriate management of these patients with SS requires a cooperative approach between all health professionals involved in the patient’s care. As such, dentists and other members of the dental team need to be fully aware of the clinical signs and symptoms as well as management of these patients.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. References