Assessment of SS-A and SS-B in parotid saliva of patients with Sjögren''s syndrome

Background: The purpose of this study was to compare the sensitivity of parotid saliva to that of serum in detecting anti‐SSA/Ro and anti‐SSB/La autoantibodies in patients with Sjögren's syndrome. Methods: Forty patients and 20 controls participated in the study; all patients met the 1993 European Community criteria for the diagnosis of Sjögren's syndrome. Healthy controls were age‐ and sex‐matched individuals with no signs or symptoms of Sjögren's syndrome. Serum and saliva samples were evaluated using AffiniTech SSA/Ro and SSB/La antibodies kits (AffiniTech, Ltd. Bentonville, AR, USA). The results were also compared with serological status of SS‐A and SS‐B as reported by an independent clinical laboratory. Results: Serum was significantly more sensitive than saliva in detecting SSA/Ro and SSB/La antibodies (P = 0.001). There was high agreement between the results with the AffiniTech kits and the independent laboratory (kappa = 0.80; P < 0.001). However, there was poor agreement between saliva and serum results (kappa = 0.174; P = 0.168). Conclusions: The overall results appear to support that serum analysis is effective method for evaluating the presence of SS‐A and SS‐B autoantibodies.     

Primary Sjögren syndrome in a 2-year-old patient: role of the dentist in diagnosis and dental management with a 6-year follow-up

International Journal of Paediatric Dentistry 2011; 21: 471–475 Background. Primary Sjögren syndrome is a rare autoimmune disease, especially in children, mainly affecting girls (77%), and usually diagnosed around 10 years of age. Diagnosis during childhood is difficult, especially because of the diversity of the clinical presentation and difficulty obtaining reliable history data, accounting for a higher frequency of underdiagnosed cases. Differential conditions should be considered, especially the ones that promote xerostomia, such as diabetes, ectodermal dysplasia, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, sarcoidosis, lymphoma, HIV and HTLV infection. Conditions associated with parotid enlargement should also be excluded, including juvenile recurrent parotitis (JRP), sialadenosis, sarcoidosis, lymphoma, infectious parotitis caused by streptococcal and staphylococcal infections, viral infections (paramyxovirus, Epstein–Barr virus, cytomegalovirus, and parvovirus), and diffuse infiltrative lymphocytosis syndrome (associated with HIV infection), and rare congenital conditions, such as polycystic parotid disease. Case report. A paediatric female patient was referred to our clinic for dental treatment complaining about dry mouth, oral discomfort, and dysphagia. The patient presented five of the required criteria to establish the diagnosis of pSS, including ocular symptoms, oral symptoms, evidence of keratoconjunctivitis sicca, focal sialadenitis confirmed by minor salivary gland biopsy, and evidence of major salivary gland involvement. Our patient did not have positive SS‐A and SS‐B autoantibodies. According to the literature, about 29% of individuals with pSS can present seronegativity for SS‐A (anti‐Ro) antibodies and about 33% can present seronegativity for SS‐B (anti‐La) antibodies. Conclusion. To the best of our knowledge, this is the youngest patient reported in the scientific English literature with pSS. Primary Sjögren syndrome has a wide clinical and immunologic spectrum and may progress with increased morbidity. Clinicians must be aware of the development of pSS in such an early age and exclude all possible differential findings to provide early diagnosis and treatment.     

Urban legends series: Sjögren’s syndrome

Oral Diseases (2012) 19 , 46–58 Sjögren’s syndrome (SjS) is one of the most common autoimmune rheumatic diseases, clinically characterized by xerostomia and keratoconjunctivitis sicca. We investigated the following controversial topics: (i) Do we have reliable ways of assessing saliva production? (ii) How important are the quantity and quality of saliva? (iii) Are only anti‐SSA/Ro and anti‐SSB/La relevant for the diagnosis of SjS? (iv) Are the American‐European Consensus criteria (AECC) the best way to diagnose SjS? Results from literature searches suggested the following: (i) Despite the fact that numerous tests are available to assess salivation rates, direct comparisons among them are scarce with little evidence to suggest one best test. (ii) Recent developments highlight the importance of investigating the composition of saliva. However, more research is needed to standardize the methods of analysis and collection and refine the quality of the accumulating data. (iii) In addition to anti‐Ro/La autoantibodies, anti α‐fodrin IgA and anti‐MR3 autoantibodies seem to be promising diagnostic markers of SjS, but more studies are warranted to test their sensitivity and specificity. (iv) AECC are classification, not diagnostic criteria. Moreover, recent innovations have not been incorporated into these criteria. Consequently, treatment directed to patients diagnosed using the AECC might exclude a significant proportion of patients with SjS.     

Salivary autoantibodies in HIV-associated salivary gland disease

A subset of HIV-positive patients develops salivary gland disease (HIV-SGD), characterized by salivary gland enlargement and/or decreased salivary flow. While clinical symptoms are similar to Sjögren's syndrome (SS). patients with HIV-SGD lack circulating anti-SS-A/Ro and anti-SS-B La. Occasionally, SS patients lacking circulating anti-SS-A/Ro and anti-SS-B'La have these antibodies in their saliva. Salivas from II patients with HIV-SGD, 13 HIV+ patients without HIV-SGD, 14 HIV-negative men controls, and 11 patients with SS were screened for autoantibodies. Five HIV-SGD salivas had antibodies recognizing the cytoplasm of a salivary cell line. No HIV 4- controls showed reactivity. Ten of 11 SS patients had salivary autoantibodies, and one HIV-negative control was positive for them. Salivary anti-SS-A/Ro was present in 8/11 SS patients, and 7 also contained anti-SS-B/La. No HIV-SGD salivary samples had these specific autoantibodies. These findings suggest that while glandular polyclonal expansion occurs in both HIV-SGD and SS, different autoantibodies are produced.     

IgG4‐related sialadenitis and Sjögren's syndrome

IgG4‐related disease (IgG4‐RD) has emerged as a new entity in the last decade. It comprises numerous conditions previously thought to be unrelated. Macroscopically, these diseases cause diffuse organ swelling and formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with increased IgG4+ plasma cells and storiform fibrosis. Despite rapid progress within the last years, our knowledge on these conditions is still fragmented. To date, more than forty organs have been reported to be included in IgG4‐RD, and salivary gland involvement is amongst the most common organs affected [IgG4‐related sialadenitis (IgG4‐RS)]. Interestingly, IgG4‐RS shares commonalities with Sjögren's syndrome (SS), like glandular enlargement, sicca symptoms, arthralgias, hypergammaglobulinemia, hypocomplementemia, and circulating antinuclear antibodies. Nonetheless, they differ in that the incidence of anti‐Ro and anti‐La reactivity is not frequently found in patients with IgG4‐RS, their salivary glands are infiltrated by a large number of IgG4+ plasma cells and IgG4‐RS symptoms respond promptly to steroids. The aim of this review was to describe the clinical, serological, histopathological and pathophysiological aspects of IgG4‐RS in the context of IgG4‐RD and highlight the differences between IgG4‐RS and SS.     

Loss of PKCδ results in characteristics of Sjögren's syndrome including salivary gland dysfunction

Oral Diseases (2011) 17 , 601–609 Objectives: Chronic infiltration of lymphocytes into the salivary and lacrimal glands of patients with Sjögren’s Syndrome (SS) leads to destruction of acinar cells and loss of exocrine function. Protein kinase C‐delta (PKCδ) is known to play a critical role in B‐cell maintenance. Mice in which the PKCδ gene has been disrupted have a loss of B‐cell tolerance, multiple organ lymphocytic infiltration, and altered apoptosis. To determine whether PKCδ contributes to the pathogenesis of SS, we quantified changes in indicators of SS in PKCδ?/? mice as a function of age. Salivary gland histology, function, the presence of autoantibodies, and cytokine expression were examined. Materials and methods: Submandibular glands were examined for the presence of lymphocytic infiltrates, and the type of infiltrating lymphocyte and cytokine deposition was evaluated by immunohistochemistry. Serum samples were tested by autoantibody screening, which was graded by its staining pattern and intensity. Salivary gland function was determined by saliva collection at various ages. Results: PKCδ?/? mice have reduced salivary gland function, B220+ B‐cell infiltration, anti‐nuclear antibody production, and elevated IFN‐γ in the salivary glands as compared to PKCδ+//+ littermates. Conclusions: PKCδ?/? mice have exocrine gland tissue damage indicative of a SS–like phenotype.     

TACI-Fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice

Oral Diseases (2012) 18 , 365–374 Objective: Patients with Sjögren’s syndrome (SS) show aberrant expression of the B cell‐related mediators, B cell‐activating factor (BAFF), and a proliferation‐inducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS. Material and Methods: A recombinant serotype 2 adeno‐associated virus (rAAV2) encoding TACI‐Fc was constructed, and its efficacy was tested in the SGs of non‐obese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines. Results: AAV2‐TACI‐Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD⁺ cells and CD138⁺ cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2‐TACI‐Fc‐treated mice. Salivary flow was unaffected. Conclusion: Although local expression of soluble TACI‐Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI‐Fc can provide a satisfying treatment for the clinical symptoms of patients.     

Oral diseases associated with hepatitis C virus infection. Part 1. sialadenitis and salivary glands lymphoma

Morbidity associated with hepatitis C virus (HCV) infection is due not only to the sequelae of chronic liver disease, but also to a variety of extraheaptic manifestations (EHM). Some of the most frequently reported EHM of HCV infection involves the oral region predominantly or exclusively and they are the topics of this 2‐part review. The current part 1 discusses the evidences on the association of salivary glands disorders with HCV. HCV‐ infected patients may frequently have histological signs of Sjögren‐like sialadenitis with mild or even absent clinical symptoms. However, the pathogenetic role of HCV in Sjogren Syndrome (SS) development and the characteristics distinguishing classic SS from HCV‐related sialadenitis are still an issue. It is unclear if the virus may cause a disease mimicking primary SS or if HCV is directly responsible for the development of SS in a specific subset of patients. Notably, some patients may present a triple association between HCV, SS‐like sialadenitis and salivary gland lymphoma and the virus may be involved in the lymphomagenesis. The risk of having a salivary gland lymphoma is particularly high in patients with mixed cryoglobulinemia. Little attention has been paid to the effects of anti‐HCV treatment on sialadenitis or lymphoma development.     

Cholinergic autoantibodies from primary Sjögren’s syndrome modulate submandibular gland Na+/K+‐ATPase activity via prostaglandin E2 and cyclic AMP

Passafaro D, Reina S, Sterin‐Borda L, Borda E. Cholinergic autoantibodies from primary Sjögren’s syndrome modulate submandibular gland Na ⁺ /K ⁺ ‐ATPase activity via prostaglandin E ₂ and cyclic AMP. Eur J Oral Sci 2010; 118: 131–138. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci We demonstrate that patients with primary Sjögren’s syndrome (pSS) produce functional IgG autoantibodies that interact with the glandular M₃ muscarinic acetylcholine receptors (mAChRs). These autoantibodies act as a partial muscarinic agonist, increasing prostaglandin E₂ (PGE₂) and cyclic AMP production through modifying Na⁺/K⁺‐ATPase activity, but also interfere with the secretory effect of the parasympathetic neurotransmitter. The IgG from patients with pSS has two effects on the submandibular gland. On the one hand, it may act as an inducer of the proinflammatory molecule (PGE₂) that, in turn, inhibits Na⁺/K⁺‐ATPase activity. On the other hand, it plays a role in the pathogenesis of dry mouth, abolishing the Na⁺/K⁺‐ATPase inhibition and the net K⁺ efflux stimulation of the salivary gland in response to the authentic agonist pilocarpine, decreasing salivary fluid production.     

Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting the exocrine glands, primarily the salivary and lacrimal glands. It has been suggested that exogenous agents may trigger SS in genetically predisposed individuals. However, at present, the etiology of SS is far from being understood, and no direct evidence for any of these triggers has been presented. The salivary and lacrimal glands from patients with SS harbor unique and highly selected T‐ and B‐cell populations. Disturbance in glandular cell apoptosis may be one possible explanation for the sicca symptoms in SS. However, discrepancies between glandular destruction and salivary flow give rise to processes causing glandular dysfunction preceding or triggering glandular cell destruction. Recent reports suggested autoantibodies inhibiting neuronal innervation of acinar cells and defective water transport to be implicated in salivary secretion deficiency observed in SS. Several types of autoantibodies have been suggested to contribute to the pathogenesis of SS. However, how the tolerance to these structures is broken down is unknown at present. Studies on B‐cell activating factor indicated that diminished apoptosis and disturbed B‐cell maturation could be responsible for the occurrence of autoreactive B‐cells and B‐cell hyperreactivity. B‐cell activation may also provide a basis for lymphoma development observed in up to 5% of the patients with SS.     

Sialochemical markers of salivary gland involvement with Sjögren''s syndrome secondary to rheumatoid arthritis and primary biliary cirrhosis

Abstract: Sjögren’s syndrome is an autoimmune condition affecting the lacrimal and salivary glands and can be associated with rheumatoid arthritis and primary biliary cirrhosis. Parotid salivas collected from patients and normal controls were analysed for lactoferrin, IgA and beta₂‐microglobulin (measured by ELISA), and cystatin (measured by a enzyme inhibition assay). Output data provided less variable means, whilst expressing results as a proportion of the total protein provided greater specificity as markers for Sjögren’s syndrome. Levels of specificity for IgA, lactoferrin and beta₂‐microglobulin were all high (100, 95 and 100%, respectively). Sensitivity levels of these markers (but not cystatin) tended to be similar for Sjögren’s syndrome secondary to primary biliary cirrhosis (IgA, 25%; lactoferrin, 63%; and beta₂‐microglobulin, 50%), compared to Sjögren’s syndrome secondary to connective tissue diseases such as rheumatoid arthritis (IgA, 50%; lactoferrin, 86%; and beta₂‐microglobulin; 38%).     

Comparison of salivary calmodulin binding proteins in Sjögren''s syndrome and healthy individuals

Background: Reduction in salivary secretion is the hallmark of Sjögren's syndrome (SS). Calmodulin (CaM) and calmodulin binding proteins (CaMBPs) play a key role in the secretory process of saliva. Recent studies have suggested that SS‐B, an autoantibody associated with SS, is a CaMBP. This finding suggests that CaMBP may contribute to the loss of saliva in SS. To better understand the role(s) of these proteins in SS, the purpose of this study was to compare salivary CaMBPs in Sjögren's patients and controls. Methods: Saliva samples were collected from 20 patients and 20 age‐, race‐, and gender‐matched controls. CaM overlay was used to identify CaMBPs in saliva of patients and controls. Results: Higher number of salivary CaMBPs was observed among patients than controls. Conclusions: The increased number of salivary CaMBPs in SS may suggest a potential role for these proteins in the pathogenesis of the disease.     

Are the B cells cast with the leading part in the Sjogren's syndrome scenario?

The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti‐SSA/Ro, and anti‐SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2‐plus‐Bm2′ cells to early Bm5‐plus‐late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B‐cell‐activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B‐cell survival and hence implicated in the pathogenesis of autoimmunity. In practice, B cells have turned quite attractive as a target for biotherapy. For example, treatment with anti‐CD20 Ab has afforded some benefits in this disease, while BAFF blockers are still on the way, but should expand our armamentarium for treating SS. With such B‐cell‐directed biotherapies in mind, we delineate herein the distinguishing traits of B lymphocytes in SS.     

Primary and secondary Sjögren’s syndrome in children – a comparative study

Sjögren’s syndrome is a chronic inflammatory systemic autoimmune disease mainly affecting the exocrine and, particularly, the salivary and lacrimal glands. The condition usually occurs in adults. In 1994, the criteria for this syndrome were redefined in a multicenter European study. In children, Sjögren’s syndrome is a rare and probably underdiagnosed disease. To date, Sjögren’s syndrome in children has only been described in case reports and in the comparative presentation of various study results. So far, no study of a comparative classification into primary and secondary Sjögren’s syndrome has been carried out in a patient population of any size. Sjögren’s syndrome should be considered in the differential diagnosis of children with recurrent parotitis, keratoconjunctivitis sicca, or pronounced and early tooth decay associated with xerostomia. In this study of 23 children and adolescents under the age of 16 with the clinical symptoms and laboratory findings of Sjögren’s syndrome, we differentiate between primary and secondary Sjögren’s syndrome. The value of the individual methods of assessing the oral and the ophthalmological components and the manifestation of the underlying rheumatic condition are discussed on the basis of the EULAR criteria. The EULAR diagnostic criteria are of limited applicability in children because reliable anamnestic data are frequently lacking. Another problem in diagnosing Sjögren’s syndrome is the short-term detection of serological alterations and clinical symptoms. Even if young patients do not completely fulfill the required criteria, Sjögren’s syndrome can be assumed or confirmed in the presence of positive testing for oral and ocular manifestations and recurrent salivary gland enlargement.     

B cell dysregulation in primary Sjögren’s syndrome: A review

Primary Sjögren’s syndrome is a chronic autoimmune disorder of unknown etiology and is characterized by progressive focal lymphocytic infiltration of the lacrimal and salivary glands. Comparison of B cell subsets from the peripheral blood and salivary glands of patients with primary Sjögren’s syndrome and those from healthy individuals shows dysregulation and derangement of B cell subsets in both peripheral circulation and in inflamed glandular tissues. This dysregulation is expressed as a decrease in the percentage of CD27+ memory B cells in peripheral blood and an increase in the CD27+ memory B cells in the affected glands. Further, the overall percentage of long-lived autoantibodies-producing plasma cells within the affected glands is increased. In the last two decades, several studies have shown growing evidences that B cells play multiple roles in primary Sjögren’s syndrome pathophysiology, and that dysregulation of these cells may actually play a central role in the disease development.     

A comparison of salivary gland hypofunction in primary and secondary Sjögren's syndrome

OBJECTIVE: A commonly held view by clinicians is that the salivary gland hypofunction associated with primary Sjögren's syndrome (SS‐1) is more severe than that associated with secondary Sjögren's syndrome (SS‐2). This study aimed to determine if this view could be substantiated, when applied to a large sample group. METHOD: Unstimulated and paraffin wax‐stimulated whole salivary flow rates were retrospectively compared for age and gender matched, patients diagnosed with SS‐1 or SS‐2 according to the preliminary European criteria. The patients had attended the Xerostomia Clinic, in the Oral Medicine Department, at the Liverpool University Dental Hospital. RESULTS: Sixty‐seven patients with SS‐1 (average age 57.1 years) were matched with 67 patients with SS‐2 (average age 57.6 years), according to gender and age, within 5 years. The mean unstimulated whole salivary flow rates (±s.d.) for patients with SS‐1 and SS‐2 were 0.11 (±0.15) and 0.12 (±0.18) mL min^?1 respectively. The mean paraffin wax stimulated, whole salivary flow rates (±s.d.) for patients with SS‐1 and SS‐22 were 0.45 (±0.02) and 0.47 (±0.49) mL/min^?1 respectively. No significant differences, in either stimulated (P= 0.54) or unstimulated (P= 0.60) whole salivary flow rates were found between individuals with SS‐1 or SS‐2. CONCLUSION: The severity of salivary gland hypofunction does not appear to be related to the clinical variant of Sjögren's syndrome.     

IGF-1 and insulin receptor expression in the minor salivary gland tissues of Sjögren's syndrome and mucoceles--immunohistochemical study

OBJECTIVE: To investigate the expression of IGF‐1 receptors and insulin receptors on the minor salivary gland (MSG) tissues of patients diagnosed with Sjögren's syndrome (SS) and normal salivary gland tissue surrounding mucoceles. SUBJECTS AND METHODS: Five MSG tissue sections from SS and seven from mucocele patients were stained immunohistochemically using antibody to IGF‐1 receptor and insulin receptor in a horse radish peroxidase and DAB system. RESULTS: The expression of the insulin receptor was increased in the SS sections compared with controls, while the insulin‐like growth factor‐1 receptor was more intensely expressed in the controls. CONCLUSION: The presence of differential expression of receptors for IGF and insulin might suggest a possible role of these growth factors in the pathogenesis of SS.     

Effects of gustatory stimulants of salivary secretion on salivary pH and flow in patients with Sjögren’s syndrome: a randomized controlled trial

J Oral Pathol Med (2011) 40 : 785–792 Objectives: To compare salivary pH changes and stimulation efficacy of two different gustatory stimulants of salivary secretion (GSSS) in patients with primary Sjögren syndrome. Setting: Portuguese Institute for Rheumatological Diseases. Design: Double‐blind randomized controlled trial. Subjects: Eighty patients were randomized to two intervention groups. Sample size was calculated using an alpha error of 0.05 and a beta of 0.20. Materials and methods: Participants were randomly assigned to receive a new GSSS containing a weaker malic acid, fluoride and xylitol or a traditionally citric acid‐based one. Saliva collection was obtained by established methods at different times. The salivary pH of the samples was determined with a pH meter and a microelectrode. Main outcome measures: Salivary pH variations and counts of subjects with pH below 4.5 for over 1 min and stimulated salivary flow were the main outcome measures. Results: Both GSSS significantly stimulated salivary output without significant differences between the two groups. The new gustatory stimulant of salivary secretion presented an absolute risk reduction of 52.78% [33.42–72.13 (95% CI)] when compared with the traditional one. Conclusions: In Xerostomic Primary Sjögren syndrome patients, gustatory stimulants of salivary secretion based on acid mail only with fluoride and xylitol present similar salivary stimulation capacity when compared to citric acid‐based ones, besides significantly reducing the number of salivary pH drops below 4.5. This could be related to a diminished risk for dental erosion and should be confirmed with further studies.     

Resting and stimulated whole salivary flow rates in Sjögren's syndrome patients over time: a diagnostic aid for subsidized dental care?

The aim of the present study was to evaluate Swedish and Norwegian criteria currently applied in the assessment of eligibility for subsidized dental care of Sjögren's syndrome (SS) patients. These criteria are partly based on a single salivary test showing a resting whole salivary secretion rate of ≤0.1 mL/min. Thirty secondary Sjögren (SSS) patients (29 F and 1 M) participated for the duration of the study, in which resting (RWS) and stimulated (SWS) whole salivary flow rates were collected in the morning and afternoon, over 3 consecutive weeks, once per week, as well as at different times over a 5-year period. Twenty patients presented levels of RWS flow rates of ≤0.1 mL/min on one or more occasions over a 3-week period, while 8 of these also exceeded, on one or more occasions, the cut-off level of 0.1 mL/min, indicating that salivary flow rates varied over time. Six patients showed consistently low secretion rates of RWS as well as of SWS, estimated as ≤0.1 mL/min and ≤0.7 mL/min, respectively. Based on the results, salivary tests that are to be used as a diagnostic aid for SS diagnosis, and thus as a basis for inclusion within the subsidy net for dental care, must be taken on several occasions in order to more accurately give information about salivary gland function. In line with this, current regulations governing the eligibility of SS patients within subsidized dental care programs should be reviewed.