British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease.

Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams.

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell-Targeted Therapy in the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS).

OBJECTIVE: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints. METHODS: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing. RESULTS: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins  and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders  according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell-related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration. CONCLUSION: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification.

Topical betamethasone and systemic colchicine for treatment of recurrent aphthous stomatitis: a randomised clinical trial.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is painful oral ulceration frequently treated with topical steroids. There is limited published evidence for the efficacy of any treatment for RAS and there remains a need for longitudinal randomised clinical trials to evaluate and compare the effectiveness of different therapies in the management of RAS. The aim of the current project was to assess the efficacy of betamethasone mouthwash and colchicine tablets, individually and combined, for the treatment of RAS, and to establish the optimum treatment period necessary for a significant reduction in the disease severity. METHODOLOGY: A randomised, prospective, parallel-group clinical trial was conducted over one year, to compare the efficacy of three therapies in RAS. One hundred and six patients were randomized into three groups; 35 received betamethasone mouthwash, 35 had colchicine tablets and 36 received both therapies. The response was evaluated quantitatively every 3 months for 1 year, using the Ulcer Severity Score (USS). RESULTS: For all three treatment regimes, the mean USS decreased by about 30% in the first 3 months (p < 0.001). Further improvement was noted for up to 9 months. At the end of the study, the mean USS had improved by 50% from 34.9 ± 7.2 before treatment to 17.5 ± 8.9 after treatment (p < 0.001). Of included participants, 86% showed significant clinical improvement by the end of the study. There were no significant differences in outcomes between the three regimes (p < 0.05). CONCLUSIONS: This clinical trial has provided evidence for the efficacy of betamethasone mouthwash and for colchicine tablets in the treatment of RAS and has shown that at least six months of treatment may be required for optimum effect. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN3267716. Date of clinical trial registration: 15/04/2018.

Smell Dysfunction in Patients with Primary Sjögren's Syndrome: Impact on Quality of Life.

OBJECTIVES: Patients with primary Sjögren's syndrome (pSS) often report smell and taste disturbances. However, the correlation between smell impairment and mucosal dryness is not well understood. The objectives of this study were to investigate the following: (1) the prevalence of smell hypofunction in patients with SS; (2) the impact of smell hypofunction on their quality of life (QoL); (3) whether the patients' smell is correlated with xerostomia; and (4) whether the patients' smell is affected by taste hypofunction, disease duration, age, smoking or self-reported neuropathy. METHODOLOGY: An ethically approved cross-sectional study was conducted on 65 female patients with SS and 62 sex-matched healthy controls. Their smell was assessed using the University of Pennsylvania Smell Identification Test. Their taste acuity was assessed using the Taste Strips Test. A visual analogue scale was used for the self-assessment of smell and taste functions. Xerostomia was assessed by the salivary flow rate, clinical oral dryness score and the Xerostomia Inventory. The patients' QoL and mental health well-being were assessed using validated questionnaires. RESULTS: In the SS group, the patients' smell function was impaired in 27/65 patients compared with the controls (15/62, p < 0.05), and it did not correlate with the severity of xerostomia, taste acuity (r = 0.05, p = 0.6) or self-reported nasal dryness (r = -0.02, p = 0.7). In the patients' group, smell hypofunction was not correlated with disease duration (ß = 0.1, 95% CI = -0.07-0.1) or smoking (ß = -0.02, 95% CI = -8-7). Age was not correlated with the smell function in the patients' group (ß = -0.1, p = 0.5) but was correlated significantly with smell in the healthy participants' group (ß = -0.3, p = 0.02). Neuropathy affected 81.2% of the patients' group. Their QoL and mental health well-being were not affected by smell hypofunction. CONCLUSION: Smell hypofunction appears to be a clinical manifestation in patients with SS, but it does not seem to be associated with the severity of mucosal dryness or with taste disturbance.

High-throughput sequencing of IgH gene in minor salivary glands from Sjögren's syndrome patients reveals dynamic B cell recirculation between ectopic lymphoid structures.

OBJECTIVES: B cells play a central role in Sjögren's syndrome (SS) whereby autoreactive B-cells populate ectopic germinal centres (GC) in SS salivary glands (SG) and undergo somatic hypermutation (SHM) and class-switch recombination of the immunoglobulin genes. However, the capacity of specific B cell clones to seed ectopic GC in different SG and undergo clonal diversification is unclear. To unravel the dynamics of B cell recirculation among minor SG biopsies, we investigated the immunoglobulin heavy chain (IgH) gene usage and the pattern of SHM using a high-throughput sequencing approach. METHODS: We generated ~166,000 reads longer than 350bp and detected 1631 clonotypes across eight samples from four different SS patients, all characterised by the presence of functional ectopic GC as demonstrated by the expression of activation-induced cytidine deaminase. RESULTS: A large number of shared clonotypes were observed among paired mSG biopsies from each patient but not across different patients. Lineage tree analysis revealed significant clonal expansion within the mSG with the identification of shared dominant B cell clones suggestive of extensive recirculation across different SG. Several shared clonotypes with high proliferating capacity displayed IgH-VH gene usage common in autoreactive B cells, including VH1-69, which is typical of rheumatoid factor+ B cells representing potential lymphoma precursors. CONCLUSIONS: The complex dynamic recirculation of B cells that we observed within ectopic GC responses linked with their ability to independently proliferate, undergo ongoing SHM and Ig class-switching within individual glands may explain the difficulty in achieving consistent eradication of ectopic GCs following B cell depleting agents reported in different studies.

The impact of SjÓ§gren's syndrome on the quality of sexual life of female patients in the UK: a controlled analysis.

Mucosal dryness and dyspareunia are symptoms that may significantly affect women with primary SjÓ§gren syndrome (pSS). We investigated whether vaginal dryness is correlated with sexual function, and the impact may have on the quality of life (QoL) and mental health well-being in pSS patients. Ethically approved comparative cross-sectional study was designed to assess sexual function using the Female Sexual Function Index (FSFI) in 65 pSS female patients vs 62 sex-matched controls. The effect of vaginal dryness and fatigue on sexual function was investigated. Vaginal dryness was correlated with oral dryness estimated by salivary flow rate and the Clinical Oral Dryness Score to investigate whether genital dryness is indicative of general mucosal dryness in pSS. Validated questionnaires were used to investigate the effect of sexual function on QoL and mental health well-being. The number of sexually active pSS participants was significantly less than in the control group (28/65 vs 42/62, p < 0.05). The sexual function was significantly impaired in the pSS group (mean FSFI = 19 vs 28.3, p < 0.05). There was no significant association between self-reported vaginal dryness and oral dryness or sexual function. The open-ended questions showed that the most troublesome symptom reported by pSS patients was oral dryness (43%, n = 28/65) followed by fatigue (31%, n = 20/65). Sexual dysfunction had a negative impact on QoL and the mental health well-being of pSS patients in all aspects, especially on the quality of social life (ß = 0.7, p = 0.02). Addressing sexual dysfunction can potentially improve the QoL of pSS patients significantly, especially their social well-being.

NKp30 Receptor Upregulation in Salivary Glands of Sjögren's Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands.

Reversal of Root Caries with Casein Phosphopeptide-Amorphous Calcium Phosphate and Fluoride Varnish in Xerostomia.

Different formulas of topical fluoride have been used to manage root carious lesions. This clinical trial aimed to investigate the efficacy of a dental varnish containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and fluoride compared with fluoride alone in reversing/arresting root caries in xerostomic patients over 1 year. A total of 80 patients (age range 45-92 years) with primary root caries (n = 184 root carious lesions) and unstimulated salivary flow rate of <0.2 mL/min were randomly allocated to receive either dental varnish containing CPP-ACP and 5% fluoride (group 1: MI varnish; GC, Japan) (n = 41, 83 lesions), or dental varnish with 5% fluoride alone (group 2: NUPRO White; Dentsply, USA) (n = 39, 101 lesions). Clinical assessments with Severity Index (SI) for root caries, DIAGNOdent measurements, and varnish application were carried out at baseline, 3, 6, and 12 months. Standard oral hygiene instructions with 1,450 ppm fluoride toothpastes were provided for both groups. After 3 months, 63.9% (n = 46) of root caries in group 1 became hard (SI: 0) compared with 39.3% (n = 35) in group 2 (p < 0.01). After 6 and 12 months, the differences in SI were insignificant (group 1, n = 60, 83.3%) (group 2, n = 66, 74.2%) (p = 0.36), and (group 1, n = 60, 89.6%) (group 2, n = 67, 81.7%, n = 1 soft, 1.2%) (p = 0.29), respectively. In both groups, noncavitated leathery lesions were more likely to become hard when compared to the cavitated root caries. A significant decrease in plaque index, surface roughness, lesion dimension, and DIAGNOdent readings with a significant increase in lesion distance from the gingival margin was reported in both groups (p < 0.05). This study has provided evidence that fluoride dental varnish either with or without calcium and phosphate has the potential to arrest/reverse root caries, especially noncavitated lesions for patients with xerostomia.

Biological Therapy in Primary Sjögren's Syndrome: Effect on Salivary Gland Function and Inflammation.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease. It is the second most common rheumatic autoimmune disorder, affecting 0.7% of European Americans and up to 1% of people globally. pSS is characterized by the impaired secretory function of exocrine glands, including salivary and lachrymal glands. A lymphocytic infiltration of these organs leads to the common and debilitating symptoms of oral and ocular dryness, majorly affecting the quality of life of these patients. Currently, no disease-modifying drug has been approved for the treatment of pSS, with therapies largely aimed at relieving symptoms of dry mouth and dry eyes. In particular, management of oral dryness still represents a major unmet clinical need in pSS and a significant burden for patients with this condition. Recently, several randomized clinical trials in pSS with biological therapies targeting specific mechanistic pathways implicated in the disease pathogenesis, including B-cell hyperactivity, T-cell co-stimulation and the aberrant role of cytokines, have been completed with mixed results. In this review, we summarize evidence from recent clinical trials investigating biological therapy in pSS, specifically highlighting efficacy, or lack thereof, in modulating local inflammation and improving salivary gland function.

What's new in ocular and oral aspects of Sjögren's syndrome and do new treatments work?

Primary SS (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands leading to glandular dysfunction, resulting in dryness of the eyes, mouth and other mucosal surfaces. Systemic manifestations also occur in the majority of patients. There has been increasing interest in recent years, with a number of publications regarding the classification criteria, diagnostic tools, disease activity, damage, impact and potential treatments. This article reviews recent advances in the diagnosis and treatment of ocular and oral involvement in pSS. Recent stand-out developments include measurement of tear osmolarity as a marker in dry eye disease diagnosis, new devices measuring tear constituents and meibomian gland structure and treatment of its dysfunction. Lip biopsy is still valuable despite emerging evidence of non-invasive diagnostic techniques, notably salivary gland ultrasound.

The management of Sjögren's syndrome: British Society for Rheumatology guideline scope.

The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol [1]. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Advanced imaging for quantification of abnormalities in the salivary glands of patients with primary Sjögren's syndrome.

OBJECTIVES: To assess non-invasive imaging for detection and quantification of gland structure, inflammation and function in patients with primary Sjogren's syndrome (pSS) using PET-CT with 11C-Methionine (11C-MET; radiolabelled amino acid), and 18F-fluorodeoxyglucose (18F-FDG; glucose uptake marker), to assess protein synthesis and inflammation, respectively; multiparametric MRI evaluated salivary gland structural and physiological changes. METHODS: In this imaging/clinical/histology comparative study (GSK study 203818; NCT02899377) patients with pSS and age- and sex-matched healthy volunteers underwent MRI of the salivary glands and 11C-MET PET-CT. Patients also underwent 18F-FDG PET-CT and labial salivary gland biopsies. Clinical and biomarker assessments were performed. Primary endpoints were semi-quantitative parameters of 11C-MET and 18F-FDG uptake in submandibular and parotid salivary glands and quantitative MRI measures of structure and inflammation. Clinical and minor salivary gland histological parameter correlations were explored. RESULTS: Twelve patients with pSS and 13 healthy volunteers were included. Lower 11C-MET uptake in parotid, submandibular and lacrimal glands, lower submandibular gland volume, higher MRI fat fraction, and lower pure diffusion in parotid and submandibular glands were observed in patients vs healthy volunteer, consistent with reduced synthetic function. Disease duration correlated positively with fat fraction and negatively with 11C-MET and 18F-FDG uptake, consistent with impaired function, inflammation and fatty replacement over time. Lacrimal gland 11C-MET uptake positively correlated with tear flow in patients, and parotid gland 18F-FDG uptake positively correlated with salivary gland CD20+ B-cell infiltration. CONCLUSION: Molecular imaging and MRI may be useful tools to non-invasively assess loss of glandular function, increased glandular inflammation and fat accumulation in pSS.

The use of digital image analysis in the histological assessment of Sjögren's syndrome salivary glands improves inter-rater agreement and facilitates multicentre data harmonisation.

OBJECTIVES: To assess whether the use of digital image analysis (DIA) in primary Sjögren's syndrome (pSS) for the calculation of the total area of the salivary gland (SG), focus score (FS) and SG area occupied by the inflammatory infiltrate (area fraction, AF), was able to generate reproducible readings among different raters, reducing disagreement. METHODS: Haematoxylin and Eosin digital slides from pSS and non-specific chronic sialadenitis (NSCS) patients were analysed blindly by 4 independent raters among 3 centres. Using an open-source software (QuPath) raters were asked to provide the total area of the gland i) using a grid-based method and ii) a software-based area-calculation tool, iii) the number of inflammatory foci and iv) the total area of the inflammatory infiltrate. Collected data was used to calculate the inter-rater agreement. RESULTS: For the calculation of the total SG area, DIA generated higher agreement among raters than grid-based calculation (inter-class correlation coefficient ICC=0.85 vs 0.98). Agreement for calculated total area of the inflammatory infiltrate (ICC=0.94) and for AF (ICC=0.94) was higher than infiltrates count number (ICC=0.54) and FS (ICC=0.56). AF achieved a 30% improvement over the FS at generating consensus among raters when used as a diagnostic cut-off. CONCLUSIONS: A digital approach achieved a far superior inter-rater agreement when calculating the total area compared to a grid-based approach. The calculation of AF proved superior to FS in correctly classifying pSS vs NSCS biopsies. We suggest that digitally calculated AF should be used alongside FS for large multi-centre studies to improve data harmonisation.

Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma.

OBJECTIVES: To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren's syndrome (SS) patients. METHODS: Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production. RESULTS: Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α). CONCLUSIONS: Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

HIV Teaching: A dental curriculum which fosters knowledge and attitude.

HIV TEACHING: A dental curriculum which fosters knowledge and attitude. OBJECTIVES: A pilot study to explore dental students views of current HIV related teaching and to assess the impact of this teaching on the students' self-perceived confidence in delivering dental care to HIV patients. METHODS: A short cross-sectional survey was conducted to gather the views of students on both objectives. Data was collected using an online self-administered questionnaire. Descriptive data analysis was conducted and used to present the data. Additionally, a one to one interview was performed with a past dental student for a thematic analysis. RESULTS: The HIV teaching at this dental school uses different learning approaches involving didactic, reflective, and participatory methods to address the knowledge, attitudinal and skills objectives. A didactic and experiential problem-based approach using role-play with simulated patients with feedback, and discussion is utilised. Preliminary results show dental students perceive the course to be valuable and there is a general improvement in confidence in their knowledge and ability to communicate with HIV-positive patients. CONCLUSIONS: This evaluation suggests the course format and content are appropriate in providing education and training for dental students and supports the value of teaching HIV to undergraduate students.

Oral health and HIV: What dental students need to know.

INTRODUCTION: Dentists have an important role in reducing new HIV infections by early diagnosis and need to know how to treat patients with HIV and understand universal cross-infection control. In many parts of the world, healthcare professionals struggle to provide care because of barriers including stigma and cultural attitudes. AIM: To investigate the effectiveness of a brief educational intervention in understanding/changing the views of dental school deans regarding the quality of the oral health and HIV/AIDS teaching and their willingness to undertake a curriculum review if appropriate. METHODS: Questionnaires before and after interactive presentation to the deans of 30 Indonesian dental schools and discussion. RESULTS: Only six of 30 dental school deans believed that their HIV undergraduate dental student teaching was inadequate before the intervention, but 29 of 30 deans recognised the need to review their curriculum after the intervention. Whilst the majority (24/30) felt that their HIV teaching was adequate, good or excellent, the majority also thought that their students would find it difficult to treat patients with HIV. CONCLUSION: The brief educational intervention was effective in improving the understanding/changing the views of dental school deans regarding the quality of HIV/AIDS teaching and learning at their own institution and engaging a willingness to undertake curriculum review.