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.

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.

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.

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.

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.

The global changing pattern of the oral manifestations of HIV.

The significance of the oral manifestations of HIV has been widely recognised since the start of the epidemic. It is estimated that more than 38 million people are living with HIV currently, with more than a third presenting with oral manifestations. Access to optimum clinical management and effective treatment in resource-rich countries has led to a remarkable decrease in some of the oral manifestations in the HIV population but this is not mirrored in developing countries, where most HIV-positive patients reside. In this paper, a review of the literature since the start of the HIV infection in different parts of the world is presented to highlight the current significance of the oral conditions in this population. Oral candidiasis was repeatedly reported as the most encountered oral manifestation of HIV in different countries, including in studies on groups on anti-retroviral therapy. Over time salivary gland disease was reported less in developed countries but was encountered more in developing countries. There is evidence to show that the prevalence of oral warts increased with the establishment of anti-retroviral therapy. A review of the worldwide prevalence of HIV-related oral conditions indicates that except for oral hairy leucoplakia, the prevalence of all other nine commonly reported oral conditions remained the same or increased over time. Oral opportunistic infections in HIV-infected patients are an ongoing clinical burden mainly in developing countries. Maintaining research in the subject and improving access to HIV treatment will help address the oral health inequalities around the world.

Impaired Interleukin-27-Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome.

OBJECTIVE: Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin-27 (IL-27) is a key regulator of adaptive immunity and limits Th17 cell-driven pathology. We undertook this study to elucidate the role of IL-27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS. METHODS: ELS formation was induced in wild-type and Il27ra-/- mice via salivary gland (SG) cannulation of a replication-deficient adenovirus in the presence or absence of IL-17A neutralization. In SG biopsy samples, IL-27-producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL-27 levels were determined by gene expression and enzyme-linked immunosorbent assay. The in vitro effect of IL-27 on T cells was assessed using fluorescence-activated cell sorting and cytokine release. RESULTS: In experimental sialadenitis, Il27ra-/- mice had larger and more hyperactive ELS (focus score; P < 0.001), increased autoimmunity, and an expanded Th17 response (P < 0.001), compared to wild-type mice. IL-17 blockade in Il27ra-/- mice suppressed the aberrant ELS response (B and T cell reduction against control; P < 0.01). SS patients displayed increased circulating IL-27 levels (P < 0.01), and in SG biopsy samples, IL-27 was expressed by DC-LAMP+ dendritic cells in association with CD3+ T cells. Remarkably, in SS T cells (but not in T cells from patients with rheumatoid arthritis or healthy controls), IL-27-mediated suppression of IL-17 secretion was severely impaired and associated with an aberrant interferon-γ release upon IL-27 stimulation. CONCLUSION: Our data indicate that the physiologic ability of IL-27 to limit the magnitude and function of ELS through control of Th17 cell expansion is severely impaired in SS patients, highlighting a defective immunoregulatory checkpoint in this condition.

Is the taste acuity affected by oral dryness in primary Sjögren's syndrome patients?

OBJECTIVES: Taste disturbance is a symptom of primary Sjögren's syndrome (pSS) of unknown aetiology. This study's objectives were (a) to compare taste function in pSS vs. healthy subjects; (b) to establish whether there is an association between the taste acuity and oral dryness and/or the neurosensory threshold; and (c) to assess the impact of taste dysfunction on the quality of life (QoL). METHODOLOGY: This study was conducted on 65 pSS females and 62 healthy volunteers. The gustatory function was tested with taste strips test. Visual analogue scale was used for self-assessment of taste function. The electrogustometer was used to assess the neurosensory threshold. The oral dryness was assessed by the Clinical Oral Dryness Score, salivary flow rate and Xerostomia Inventory. The general and oral health-related QoL and mental health well-being were assessed using validated questionnaires. RESULTS: The pSS group had significantly impaired taste function, but this was not correlated with oral dryness. There was an association between taste acuity and the neurosensory threshold (ß = -0.5, 95% CI = -0.2 to -0.1). The QoL was not impacted by taste dysfunction (p > .5). CONCLUSION: The results suggest that taste impairment in pSS is associated with neurosensory dysfunction and is unlikely to be due to oral dryness.

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren's syndrome: results of the TRACTISS randomised double-blind multicentre substudy.

OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI -2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results.