Protocols for Experimental Sjögren's Syndrome.

Salivary Gland Involvement in Chronic Graft-Versus-Host Disease: Prevalence, Clinical Significance, and Recommendations for Evaluation

Salivary function provides host protection, assists in the initiation of food and fluid intake, and enables communication through speech. Without adequate salivary output, oral and pharyngeal health declines along with a person’s quality of life. The complaint of a dry mouth (xerostomia) and the objective finding of salivary dysfunction are common occurrences in older individuals, producing transient and permanent oral and systemic problems. Salivary dysfunction, however, is not a normal consequence of growing older, and is due to systemic diseases, medications, and head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, head, and neck examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Therapies are designed to prevent the development of oral and pharyngeal sequelae of salivary hypofunction. Current xerostomia-based treatments include replacement therapies and gustatory, masticatory, and pharmacological stimulants. Healthcare professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventative and interventive techniques that will help preserve a person’s health, function, and quality of life.

Coexistence of Sarcoidosis and Sjögren's Syndrome: A Case-Report

P40 Dry eyes and a dry mouth: is it Sjögren’s syndrome?

Sjögren's Syndrome Accompanied by Prolactinoma: a case report and literature review.

Fibromyalgia syndrome (FMS) is a complex disorder that affects up to 5 % of the general population worldwide, more frequently in women. Sjogren’s syndrome (SS), the second most common autoimmune rheumatic disease results from immune lymphocytes that infiltrate the lacrimal and salivary glands. The distinction between FMS patients and primary SS remains difficult. Damages to the lacrimal and salivary glands and development of SS may accompany various autoimmune diseases. Apoptosis (programmed cell death) plays a fundamental role in the pathogenesis of SS. Annexins are a group of highly conserved proteins which exert several regulatory functions on cell biology and are involved in numerous cell processes including apoptosis. The aim of this study was to measure the level of serum Anti-Annexin V antibodies in FMS patients diagnosed according to the American College of Rheumatology criteria [1] and to study their significance in relation to associated SS diagnosed according to the revised version of classification criteria [2]. Fifty-six female patients with primary FMS (mean age 35.36±7.53 years) and 30 age and sex matched healthy subjects were included as controls (33.53±5.16 years) were included. Serum IgG anti-annexin V antibodies titre was assessed. The FMS patients had a mean Widespread Pain Index (WPI) of 8.98±2.93 and a symptom severity scale score (SSSS) of 8.27±2.21. Twenty seven patients gave symptoms of dry eyes or mouth of which only 12 (21.43 %) had SS. Anti-annexin V antibody level was significantly higher in FMS patients (19.96±10.29 AU/ml) compared to control (7.32±3.42 AU/ml); being higher in those with SS (29.87±10.44 AU/ml) compared to those without (17.25±8.53 AU/ml)(p 0.002) (Fig. 1). Furthermore, serum anti-Ro, anti-La and SSSS were significantly higher in those patients with SS (17.67±10.01 U/ml, 23.75± 11.14 U/ml, 9.67±1.83) compared to those without SS (7.14± 3.17 U/ml, 8.5±3.69 U/ml, 8.11±2.17) (p 0.004, 0.001, 0.02 respectively). In the FMS patients, anti-annexin V antibodies significantly correlated with SSSS (r 0.39, p 0.003) while there was a tendency to correlate with WPI (r 0.24, p 0.07). Apoptosis plays a fundamental role in the pathogenesis of SS [3]. Autoantibodies in SS directed against nuclear and cytoplasmic antigens may consequently activate the apoptotic process [4]. The role of apoptosis in FMS is not known. Anti-Annexin V antibodies are elevated in FMS with special attention to those with associated SS. In addition to the other T. A. Gheita (*) :H. A. Raafat Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt e-mail: gheitamer@hotmail.com

The diagnosis of Sjogren’s syndrome depends on the interaction of several subjective and objective parameters, which are obtained by means of clinical and laboratory investigation. Apart from the subjective findings (xerostomia e xeroftalmia), blood tests and the objective evaluation of the salivary and lacrimal gland function are part of the diagnostic routine of thesyndrome. Biopsy of minor salivary glands from the lower lip has been used as an important diagnostic criteria for diagnosis of the syndrome, but the quality of the specimens and the subjective interpretation of the histological parameters by the pathologists can limit its usefulness. Focal lymphocytic infiltrate on the salivary glands has been considered an important histological marker for diagnosis. The aim of the present study is to report three cases diagnosed as Sjogren’s syndrome with the aid of the histological features observed in the affected salivary glands. The three patients were submitted to biopsy of minor salivary glands from the lower lip due to oral symptoms and clinical alterations leading to the suspicion of Sjogren’s syndrome. In all three specimens the presence of numerous focal lymphocytic infiltrates was the histological feature that lead to final diagnosis compatible with the syndrome. There were no complications associated with the surgical procedures and the postoperative period and tissue repairing were within normal limits. Biopsies of labial minor salivary glands are useful in diagnosing Sjogren’s syndrome and the early indication of this surgical procedure seems important to demonstrate the glandular lymphocytic infiltrate. The precise interpretation of the histological features turn them reproductible and adequate technical steps, correct specimen preservation and criterious histological analysis is essential for diagnosis of the Sjogren’s syndrome.

Sjögren syndrome and fibromyalgia after radioiodine therapy in cancer thyroid patients

Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjögren’s Syndrome Immunopathogenesis

Sjögren's disease (SjD), which is also known as Sjögren's syndrome (SS), is a chronic autoimmune disease characterized by dysfunction of exocrine glands, such as the salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Mice in which the SATB1 gene is conditionally deleted in hematopoietic cells (SATB1cKO mice) develop SS as early as 4 weeks of age; however, the etiology of the disease remains to be elucidated. Here, we found that the frequency of abnormally appearing CD4+CD8+ double positive (DP) T cells in the periphery of SATB1cKO mice was higher in the salivary glands than that in the spleen, suggesting a possible involvement of DP T cells in the pathogenesis of SS in SATB1cKO mice. To investigate the nature of DP T cells, we established DP T cell hybridomas by fusing T cells from the cervical lymph nodes of SATB1cKO mice with the BW5147 thymoma cell line. Among six DP hybridoma clones, the TCRβ gene from five clones exhibited a fetal or immature phenotype. In addition, four out of five clones exhibited upregulated transcription of IL-2 in the salivary glands of T/B cell-deficient RAG2-/- mice, suggesting that autoreactive T cells were enriched in the DP T cell population of SATB1cKO mice. These results suggest that unusual DP T cells in SATB1cKO mice may be involved in autoimmune pathogenesis in SATB1cKO mice.

IntroductionCurrent diagnostic criteria for Sjogren’s syndrome developed by the American College of Rheumatology include the presence of antinuclear antibodies, rheumatoid factor, anti-Ro or anti-La autoantibodies. The purpose of this report is to describe two patients with biopsy-proven Sjogren’s syndrome lacking these autoantibodies but identified by antibodies to salivary gland protein 1. Diagnosis was delayed until salivary gland tumors developed in these patients because of the lack of the classic autoantibodies. This report emphasizes the existence of patients with primary Sjogren’s syndrome who lack autoantibodies anti-Ro or anti-La and may therefore be misdiagnosed. Antibodies to salivary gland protein 1 identify some of these patients.Case presentationTwo patients are described and were seen in the autoimmune disease clinics of the State University of New York (SUNY) at the Buffalo School of Medicine. In both patients, chronic dry mouth and dry eye had been dismissed as idiopathic because test results for autoantibodies anti-Ro and anti-La were negative. Both patients had swelling of major salivary glands that prompted biopsies. Biopsies of major salivary glands from both cases demonstrated salivary gland tumors and existence of inflammation consistent with Sjogren’s syndrome. Serologic testing revealed antibodies to salivary gland protein 1.ConclusionsPatients presenting with classic clinical symptoms of dry mouth and eyes do not always show the current serologic markers of Sjogren’s syndrome, anti-Ro and anti-La. In these cases, investigation for antibodies to salivary gland protein 1 is of importance to make the diagnosis of Sjogren’s syndrome. Early diagnosis of Sjogren’s syndrome is necessary for improved management as well as for vigilance regarding potential complications, such as salivary gland tumors as were seen in the described cases.

Sjögren's syndrome (SS) is a chronic systemic autoimmune inflammatory disease. In addition to its destructive effects upon salivary and lacrimal glands, causing xerostomia and keratoconjunctivitis sicca, upward of 30% of patients develop systemic involvement, including a 5%-10% lifetime risk of non-Hodgkin lymphoma. Correct diagnosis of SS is crucial in order to optimally manage patients with respect to management of oral and ocular disease, detection and treatment of extra-glandular disease, and monitoring for lymphoma. Confirmation of primary SS (pSS) is contingent upon objective measures of dysfunction of salivary or lacrimal glands, in addition to evidence of autoimmunity, comprising either serum anti-Ro/SSA antibodies, or salivary gland histopathology demonstrating focal sialadenitis. The process to diagnose pSS mirrors published research classification criteria, recently revised following large collaborative efforts. This multistep process may be seen as arduous, and diagnostic accuracy can be compromised by the omission of objective tests for glandular dysfunction, resulting in misdiagnosis of undifferentiated connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis, fibromyalgia, or menopausal symptoms. Conversely, patients with non-autoimmune sicca syndrome may receive a clinical diagnosis of pSS, and unnecessarily labelled for life as having an autoimmune disease. There is a need therefore for a readily available, accurate and reliable test to aid in the diagnosis of pSS, and to supplant the need for other tests such as salivary collection and salivary gland biopsy. With the advent of clinical trials of biologics and kinase inhibitors in pSS, a safe and reliable test for longitudinal evaluation of salivary gland function and architecture is also paramount. In 2002 the American-European Consensus Group (AECG) published the most widely used classification criteria for SS,1 refined and most likely to be superseded by the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for pSS.2 Whereas the AECG criteria included abnormal sialography, salivary scintigraphy, or unstimulated whole saliva production as evidence of salivary gland dysfunction, sialography and scintigraphy are absent from the latest ACR/EULAR criteria. Although sialography is considered the most reliable imaging method, major limitations include its invasiveness, radiation exposure, potential for complications including sialadenitis, and contraindication in patients with infection, inflammation or allergy to iodine. Major salivary gland scintigraphy is sensitive for the diagnosis of pSS; however, specificity is poor, and it is not widely available. Magnetic resonance imaging offers good sensitivity and specificity to detect structural abnormalities in pSS, but access to this modality is limited and expensive. Major salivary gland ultrasound (SGUS) has emerged as a promising tool for the diagnosis, prognosis, and monitoring of response to treatment in patients with pSS. It is inexpensive, readily available, non-invasive, non-irradiating, rapidly performed, repeatable, and convenient for patients. Literature in this area is in its infancy, and studies conducted to date scoring parenchymal changes on B-mode images such as echogenicity, heterogeneity, border features, or vascularization have shown wide variability in sensitivity and specificity. A recent meta-analysis assessing the diagnostic properties of SGUS in pSS reported a pooled sensitivity of 69% and specificity 92%.3 This meta-analysis noted great clinical and methodological heterogeneity between studies, which hampered interpretation of pooled outcomes and influenced results reported within the various studies. This heterogeneity included the use of differing classification criteria, different resolutions of the US transducers used, absence of a standardized scanning method, lack of standardized definitions of US gland pathologies, use of different scoring systems for parenchymal changes, subjectivity in the assessment of US images, and inadequate demonstration of intra- and inter-observer reliability. The EULAR US-pSS Study Group assessed the validity of SGUS compared with parotid and labial gland biopsy outcome in 103 consecutive patients with clinically suspected pSS, and found high rates of agreement between SGUS, scored according to the Hocevar scoring system,4 and parotid (83%) and labial (79%) gland biopsies. Compared with AECG classification, SGUS demonstrated absolute agreement in 82%, with a sensitivity of 71% and specificity 92%. Compared with ACR/EULAR classification, absolute agreement was seen in 86%, with a sensitivity of 67% and specificity 94%. The combination of positive SGUS and the presence of anti-Ro/SSA antibodies highly predicted classification of pSS,5 raising the possibility of forgoing labial biopsy in this population. The SGUS Outcome Measures in Rheumatology task force group, composed of international clinicians and experienced sonographers, aims to develop a standardized scanning method using standardized definitions of gland pathology. A consensual Delphi process about definitions and scoring using B-mode SGUS showed good to excellent intra- and inter-operator reliabilities between 18 sonographers.6 A new US technique under investigation for the diagnosis of pSS is elastography, where ultrasound is used to investigate the elasticity of soft tissues. The principle underlying this method is that tissue compression produces strain (displacement) within the tissue, which is less pronounced in harder than in softer tissues. Real time 'sono' elastography (RTS) has been used in oncology to discriminate between hard and soft nodules, and more recently in rheumatology for the assessment of skin involvement in systemic sclerosis, rheumatoid nodules and tophi. RTS of the major SGs was prospectively investigated in 45 patients with pSS according to AECG criteria, 24 individuals with sicca complaints, and 11 healthy controls.7 In patients with an inconclusive B-mode SGUS, RTS provided a sensitive (66.7%) and specific (85.7%) classification of patients and sicca controls. Increased signal in SG of pSS patients may reflect increased tissue rigidity due to lymphocytic infiltration, hyperplasia of ductal epithelial cells, and fibrosis, although histopathologic confirmation is lacking. Cindil et al8 studied 58 patients with pSS by AECG criteria and 25 healthy controls by B-mode US and elastography using a semi-quantitative strain ratio method. They also found statistically significant differences between the groups in parotid glands (sensitivity 83% specificity 88%) and submandibular glands (sensitivity 83% and specificity 92%), with pSS SG again being stiffer. Notably, this technology is dependent on the operator applying repetitive similar pressure with the ultrasound probe, and reproducibility is poor. Soft tissue elasticity can also be measured using acoustic radiation force impulse (ARFI) US, where local tissue displacement by a brief acoustic radiation induces the emission and propagation of shear waves, which are then digitally recorded. Shear wave velocity (SWV) is measured in meters per second and increases with tissue stiffness. The advantage of the ARFI technique is that the strength of acoustic radiation does not require external compression, and acoustic radiation of short duration generates tissue displacement; however, results can vary with differing applied pressure of the US probe, thus accuracy and reproducibility are strongly operator-dependent. Strategies to avoid error, particularly in serial assessments, include the use of the same machine, transducer settings and frequency, and taking multiple measures with minimal pressure. Parotids are more diffusely fatty than submandibular glands, especially in older patients, highlighting the importance of scoring glands separately, and controlling for age in comparative studies. The deep parotid lobe is often more affected than the superficial lobe; thus tissue plane standardization is essential and should be documented, particularly for follow up and where variant anatomy has been encountered. Care is needed to avoid taking values from planes containing intra-glandular parotid lymph nodes and vessels. ARFI elastometry was performed in 10 patients with pSS according to ACR criteria and 15 healthy controls.9 In parotid glands the mean SWV was significantly higher in the pSS group, whereas mean SWG values for the submandibular glands were not significantly different between patients and controls. Zhang et al10 evaluated SG stiffness using quantitative ARFI imaging, including Virtual Touch tissue quantification (VTQ) and Virtual Touch tissue imaging quantification (VTIQ). VTQ was used to calculate the SWV, providing an objective numerical evaluation of the tissue stiffness, whereas VTIQ, a 2D shear wave imaging displaying a color-coded image, was used to enable the detection of SWV in multiple locations. Twenty-one patients with pSS according to the AECG criteria and 11 healthy controls were included. Parotid gland VTQ values were significantly higher in the pSS group than controls, and VTIQ values for both the parotid and submandibular glands were also significantly higher in pSS. Turnaoglu et al11 studied 25 patients with pSS by AECG criteria and 25 healthy controls by ARFI and reported that SWV values of both the parotid and submandibular glands were significantly higher in patients with pSS, even in early stages of disease. In this issue of the journal, Pia et al12 studied patients with SS classified by AECG criteria (pSS n = 30, secondary SS n = 13), patients with sicca symptoms not meeting SS criteria (n = 18), and healthy controls (n = 29), to assess the utility of ARFI VTQ in the diagnosis of SS. Their results were consistent with the two most recent reports cited above: in patients with SS, parotid and submandibular gland SWV were significantly higher than in control subjects, with average parotid gland sensitivity 67% and specificity 53%, and submandibular gland sensitivity 68% and specificity 50%. These results may underestimate the utility of this technique in pSS, given that patients with pSS and sSS were grouped together in the analysis, and previous studies have shown increased severity of US parameters in pSS. Indeed, within the text of this paper, the authors report that rigidity of the salivary glands was higher in pSS vs sSS; however, the data were not shown. It would also have been of interest to know the underlying diagnoses of patients with sSS in this study. With respect to the requirements for classification by AECG criteria, there was some confusion within the Materials and Methods section, with the statement that the patient must fulfill 4 histopathological or autoantibody criteria to reach SS classification. For classification as pSS, patients must: fulfill 4 of 6 criteria, including at least one of the histopathological or autoantibody criteria; or fulfill 3 of the 4 objective criteria; or be classified via use of a classification tree procedure, which is mainly intended for clinical-epidemiological surveys. For classification as sSS, patients need to fulfill a subjective criterion, and at least 2 objective criteria, which need not include histopathology; the autoantibody criterion does not apply. There is clearly an unmet need to simplify the diagnosis of SS, and to monitor response to therapy. Increased confidence in pSS diagnosis will lead to a deeper understanding of the scope of this disease, and will facilitate both observational research and clinical trials in the development of targeted therapies. Major salivary gland elastography, performed simultaneously with B-mode ultrasound using the same equipment, holds promise as an adjunct in the diagnosis of SS. Ongoing efforts to standardize and validate methodologies and reliability, will be central to this aim.

To analyse the frequency of some extrahepatic manifestations of chronic hepatitis C virus (HCV) infection in northern European patients, including a postulated association between HCV and primary Sjögren's syndrome (SS). Cohort study. Department of Medicine, Malmö University Hospital, Sweden. Twenty-one patients with HCV infection and 53 with primary SS (according to the Copenhagen criteria). Cryoglobulins were analysed in all patients, while patients with primary SS were investigated with regard to markers of HCV infection, and HCV patients with objective tests of SS (Schirmer-1 test, break-up time, van Bijsterveld score, sialometry, labial salivary gland biopsy) and antibodies against nuclear antigens, smooth muscle (SMA) and mitochondria (AMA). HCV antigens in small salivary glands from lower lip biopsies were detected by immunohistochemical analysis. Only one of the SS patients had detectable cryoprecipitates, while another was HCV-positive. None of the 21 HCV patients had cryoprecipitates. A total of 14/21 (67%) patients with HCV infection had at least one abnormal objective test suggestive of xerostomia or keratoconjunctivitis sicca, while eight (38%) had objective evidence of both eye and salivary gland involvement. HCV antigens were not detected in affected glands. Only two patients had clinical symptoms of SS, and two fulfilled the Copenhagen criteria for SS. None of the HCV-positive patients had detectable antibodies against SS-A, SS-B, RNP, Jo-1, PCNA or Scl-70, and the frequency of ANA/SMA/AMA was low. While involvement of salivary and lacrimal glands was common in Swedish patients with HCV infection, cryoglobulinaemia was not observed. The pathogenetic mechanism responsible for glandular inflammation appears to be different from that in primary SS. HCV infection does not seem to be an aetiological factor for primary SS in this population. These observations suggest that viral, genetic or possibly environmental factors may be responsible for the reported high frequencies of systemic complications associated with chronic hepatitis C infection in southern Europe.

Sjögren's disease (SjD) is a systemic autoimmune disorder primarily affecting the exocrine glands and characterized by dry mouth and dry eye, the presence of anti-SSA and/or anti-SSB autoantibodies in blood serum, and chronic lymphocytic infiltration of salivary and lacrimal glands (i.e., sialadenitis and dacryoadenitis, respectively). In addition to reduced quality of life, SjD patients experience severe oral health complications and are at increased risk of developing B cell lymphoma. Because current SjD treatments primarily focus on oral and ocular symptom management, identifying initiating factors and mechanisms of disease progression may offer new therapeutic insights for SjD. The interleukin-14α transgenic (IL-14αTG) mouse model of SjD recapitulates many aspects of human SjD, including progressive sialadenitis, loss of salivary gland function, and development of B cell lymphoma. We utilized immunofluorescence, flow cytometry, bulk RNA sequencing and spatial transcriptomic analyses to identify immune cell subpopulations and differentially expressed genes (DEGs) in submandibular glands of IL-14αTG Sjögren's-like mice and age-matched C57BL/6 mouse controls. We further compared the gene ontology of DEGs in IL-14αTG mice to DEGs identified in minor salivary gland biopsies from SjD patients and healthy volunteers. Results demonstrated significantly increased sialadenitis in IL-14αTG compared to C57BL/6 mice that correlated with an increased proportion of marginal zone B cells infiltrating the submandibular gland. Whole transcriptome analyses showed substantial overlap in enriched DEG ontology between IL-14αTG mouse submandibular gland and SjD patient minor salivary gland, compared to C57BL/6 mice and healthy human volunteer controls, respectively. Lastly, we spatially resolved DEG expression and localization within IL-14αTG salivary glands, marking the first publication of a spatial transcriptomic dataset from submandibular glands in a SjD mouse model.

Sjögren's syndrome (SS) is a chronic and progressive multisystem autoimmune disease typically managed by rheumatologists. Diagnostic delays are common, due in large part to the non-specific and variable nature of SS symptoms and the slow progression of disease. The hallmark characteristics of SS are dry eye and dry mouth, but there are a broad range of other possible symptoms such as joint and muscle pain, skin rashes, chronic dry cough, vaginal dryness, extremity numbness or tingling, and disabling fatigue. Given that dry eye and dry mouth are typically the earliest presenting complaints, eye care clinicians and dental professionals are often the first point of medical contact and can provide critical collaboration with rheumatologists to facilitate both timely diagnosis and ongoing care of patients with SS. Current diagnostic criteria advocated by the American College of Rheumatology are predicated on the presence of signs/symptoms suggestive of SS along with at least two objective factors such as traditional biomarker positivity, salivary gland biopsy findings, and/or presence of keratoconjunctivitis sicca. Traditional biomarkers for SS include the autoantibodies anti-Sjögren's syndrome-related antigen A (SS-A/Ro), anti-Sjögren's syndrome-related antigen B (SS-B/La), antinuclear antibody (ANA) titers, and rheumatoid factor (RF). While diagnostically useful, these biomarkers have low specificity for SS and are not always positive, especially in early cases of SS. Several newly-identified biomarkers for SS include autoantibodies to proteins specific to the salivary and lacrimal glands [SP-1 (salivary gland protein-1), PSP (parotid secretory protein), CA-6 (carbonic anhydrase VI)]. Data suggest that these novel biomarkers may appear earlier in the course of disease and are often identified in cases that test negative to traditional biomarkers. The Sjö® test is a commercially available diagnostic panel that incorporates testing for traditional SS biomarkers (anti-SS-A/Ro, anti-SS-B/La, ANA, and RF), as well as three novel, proprietary early biomarkers (antibodies to SP-1, PSP, and CA-6) which provide greater sensitivity and specificity than traditional biomarker testing alone. Timely diagnosis of SS requires appropriate clinical vigilance for potential SS symptoms, referral and collaborative communication among rheumatology, ophthalmology, and oral care professions, and proactive differential work-up that includes both physical and laboratory evaluations.