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.

Needs-led human resource planning for Sierra Leone in support of oral health.

BACKGROUND: In Sierra Leone (SL), a low-income country in West Africa, dental care is very limited, largely private, and with services focused in the capital Freetown. There is no formal dental education. Ten dentists supported by a similar number of dental care professionals (DCPs) serve a population of over 7.5 million people. The objective of this research was to estimate needs-led requirements for dental care and human resources for oral health to inform capacity building, based on a national survey of oral health in SL. METHODS: A dedicated operational research (OR) decision tool was constructed in Microsoft Excel to support this project. First, total treatment needs were estimated from our national epidemiological survey data for three key ages (6, 12 and 15 years), collected using the 'International Caries Classification and Management System (ICCMS)' tool. Second, oral health needs were extrapolated to whole population levels for each year-group, based on census demographic data. Third, full time equivalent (FTE) workforce capacity needs were estimated for mid-level providers in the form of Dental Therapists (DTs) and non-dental personnel based on current oral disease management approaches and clinical timings for treatment procedures. Fourth, informed by an expert panel, three oral disease management scenarios were explored for the national population: (1) Conventional care (CC): comprising oral health promotion (including prevention), restorations and tooth extraction; (2) Surgical and Preventive care (S5&6P and S6P): comprising oral health promotion (inc. prevention) and tooth extraction (D5 and D6 together, & at D6 level only); and (3) Prevention only (P): consisting of oral health promotion (inc. prevention). Fifth, the findings were extrapolated to the whole population based on demography, assuming similar levels of treatment need. RESULTS: To meet the needs of a single year-group of childrens' needs, an average of 163 DTs (range: 133-188) would be required to deliver Conventional care (CC); 39 DTs (range: 30-45) to deliver basic Surgical and Preventive care (S6P); 54 DTs for more extended Surgical and Preventive care (S5&6P) (range 38-68); and 27 DTs (range: 25-32) to deliver Prevention only (P). When scaled up to the total population, an estimated 6,147 DTs (range: 5,565-6,870) would be required to deliver Conventional care (CC); 1,413 DTs (range: 1255-1438 DTs) to deliver basic Surgical and Preventive care (S6P); 2,000 DTs (range 1590-2236) for more extended Surgical and Preventive care (S5&6P) (range 1590-2236); and 1,028 DTs to deliver Prevention only (P) (range: 1016-1046). Furthermore, if oral health promotion activities, including individualised prevention, could be delivered by non-dental personnel, then the remaining surgical care could be delivered by 385 DTs (range: 251-488) for the S6P scenario which was deemed as the minimum basic baseline service involving extracting all teeth with extensive caries into dentine. More realistically, 972 DTs (range: 586-1179) would be needed for the S5&6P scenario in which all teeth with distinctive and extensive caries into dentine are extracted. CONCLUSION: The study demonstrates the huge dental workforce needs required to deliver even minimal oral health care to the Sierra Leone population. The gap between the current workforce and the oral health needs of the population is stark and requires urgent action. The study also demonstrates the potential for contemporary epidemiological tools to predict dental treatment needs and inform workforce capacity building in a low-income country, exploring a range of solutions involving mid-level providers and non-dental personnel.

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.

Global inequalities in HIV infection.

HIV infection continues to be one of the world's greatest pandemics, affecting nearly every country on the globe. By September 2018, it is estimated that 38 million people were living with HIV, 30 million people are aware of their status, and 23 million people are taking anti-retroviral therapy (8 million in 2010). Thus, currently 8 million people living with HIV are not aware that they are HIV-positive and 15 million persons are not being treated. There are nearly 15 million orphans (aged 0-17). There is widespread inequality both in the prevalence of HIV infection and in the access to therapy. However, although the number of people living with HIV continues to increase, the number of new infections shows a steady decrease over the last 9 years and in 2018 was 1.7 million. Deaths from AIDS in 2018 also decreased to 750,000 from 1.2 million in 2010. The world prevalence of HIV is about 0.23% but is over 0.3% in South-East Asia, Latin America, North America and Eastern Europe and with particularly high prevalence in the Caribbean (1.1%) and sub-Saharan Africa (5.5%). It is approximately 0.5% in Indonesia. There were approximately 5,000 new HIV infections (adults and children) a day during 2018. About 61% were in sub-Saharan Africa, nearly 50% were in females and 500 were in children. HIV therapy seems to have had a global impact, with AIDS-related deaths decreasing by 33% since 2010, and new infections decreasing by 16%. Nevertheless, the majority of the world's HIV is in low and middle resource countries and social determinants are strongly related. Many people living with HIV or at risk for HIV still do not have access to prevention, care and treatment, and there is still no cure.

HIV in Indonesia and in neighbouring countries and its social impact.

HIV incidence is still increasing in parts of Indonesia and in several Asian Countries. New cases of HIV in Indonesia have risen from 7,000 per year in 2006 to 48,000 per year in 2017. In spite of this increase, the number of newly diagnosed cases of AIDS has decreased from a peak of over 12,000 in 2013 to a little over 9,000 in 2017. The mean prevalence of HIV in Indonesia is 0.41% but there is a ten-fold difference in the prevalence in different regions with the highest in Papua (5%). Women represent over 35% of new infections per year and of the total (640,000) in Indonesia. Over 50% of HIV diagnoses are made when patients already have AIDS. Stigma and discrimination are still strong barriers in prevention and treatment but also there are considerable challenges in access to appropriate anti-retroviral therapy. There is a need for further investment in HIV Programs in Indonesia so that prevention can be enhanced, and diagnosis made at an earlier stage. Health Professionals including dentists should be readily willing to provide joint prevention efforts and care to people at risk and with HIV and other infectious diseases to help meet the WHO aims of 2030. Public health programmes are needed to make certain that the general public is aware of HIV testing and the role of dental healthcare workers in facilitating this, thereby further normalising attitudes to people living with HIV.

The impact of the world Workshops on oral health and disease in HIV and AIDS (1988-2020).

The first World Workshop on Oral AIDS was held in San Diego in 1988, organized by John and Deborah Greenspan who saw the need and advantages of getting together all those health workers globally who were interested in oral aspects of HIV with a common purpose of advancing the field collectively and collaboratively. Since that time and over the following 30 years, World Workshops on oral HIV have been held every four years or so. The aims of the first and all subsequent Workshops were to bring together clinicians and non-clinical scientists who have an interest in the oral manifestations of HIV disease, to share worldwide perspectives, knowledge and understanding of oral health and disease in HIV infection, to agree on global definitions and classifications of oral diseases and to identify research needs taking account of the worldwide perspectives and opportunities. Thus, there have been clinical science, social science and basic science aspects of each World Workshop. The Workshops have achieved their aims and have had impact in all three fields, leading to robust research agendas, changes in national HIV policies and international collaborations. They have led to policy declarations of access to oral care as a basic human right for both HIV-positive and HIV-negative individuals and advancing the rights of all HIV-positive healthcare workers to perform clinical practice.

Predictive value of ultrasound scoring in relation to clinical and histological parameters in xerostomia patients.

BACKGROUND: Salivary gland dysfunction is one of the main clinical features of Sjögren's syndrome (SS), manifested by xerostomia with subsequent complications and well-established effects on the person's quality of life. OBJECTIVES: To determine firstly whether selected tests of salivary gland function and structure, unstimulated whole salivary flow rate (UWSFR), parotid flow rate (PFR), clinical oral dryness score (CODS) and ultrasound score (USS), can discriminate SS from non-SS sicca patients and secondly whether these tests can differentiate between patients in different subgroups of SS. METHOD: Unstimulated whole salivary flow rate, PFR, CODS and USS were determined in 244 patients comprised of SS patients (n = 118), SS patients at higher risk of lymphoma (n = 30) or with lymphoma (n = 26), and non-SS sicca disease controls (n = 70). RESULTS: All assessments showed a significant difference between the overall SS group and the disease control group, attributed mainly to the lymphoma subgroups of SS (p < 0.0001 for all parameters). There was a significant correlation (Spearman r = 0.7, p value <0.0001) and 87.3% agreement between USS and the histology focus scores of 119 patients. CONCLUSION: The results suggest that salivary gland tests including USS can aid in differentiating between SS and non-SS dry mouth, especially the subgroups of SS with lymphoma or at higher risk of developing lymphoma.

Salivary S100A8/A9 in Sjögren's syndrome accompanied by lymphoma.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that affects the exocrine glands. The absence of early diagnostic markers contributes to delays in its diagnosis. Identification of changes in the protein profile of saliva is considered one of the promising strategies for the discovery of new biomarkers for SS. OBJECTIVE: To identify salivary protein biomarkers with potential for use in discriminating between different lymphoma risk subgroups of SS. METHOD: Parotid and whole mouth saliva samples were collected from patients with SS, including those in subgroups at higher risk of developing or with confirmed lymphoma, non-SS sicca disease controls and healthy subjects. An initial proteomics analysis by mass spectrometry (LCMSMS) identified S100A8/A9 as a biomarker and was followed by validation with an enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant differences were found in levels of S100A8/A9 in parotid saliva but not whole mouth saliva between patients with SS compared with healthy and disease control subjects (P = 0.001 and 0.031, respectively). Subgroups of patients with SS based on lymphoma risk showed significant differences in salivary levels of S100A8/A9. CONCLUSION: The results suggest that salivary levels of S100A8/A9 can aid in differentiating between SS, disease control and healthy control subjects, especially the subgroups of SS with lymphoma or at higher risk of lymphoma.

The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome.

OBJECTIVE: To determine whether the Sjögren's syndrome B (SSB)-positive/Sjögren's syndrome A (SSA)-negative antibody profile is associated with key phenotypic features of SS. METHODS: Among registrants in the Sjögren's International Collaborative Clinical Alliance (SICCA) with possible or established SS, we compared anti-SSA/anti-SSB reactivity profiles against concurrent phenotypic features. We fitted logistic regression models to explore the association between anti-SSA/anti-SSB reactivity profile and each key SS phenotypic feature, controlling for potential confounders. RESULTS: Among 3297 participants, 2061 (63%) had negative anti-SSA/anti-SSB, 1162 (35%) had anti-SSA with or without anti-SSB, and 74 (2%) anti-SSB alone. Key SS phenotypic features were more prevalent and had measures indicative of greater disease activity in those participants with anti-SSA, either alone or with anti-SSB, than in those with anti-SSB alone or negative SSA/SSB serology. These between-group differences were highly significant and not explained by confounding by age, race/ethnicity or gender. Participants with anti-SSB alone were comparable to those with negative SSA/SSB serology in their association with these key phenotypic features. Among SICCA participants classified with SS on the basis of the American-European Consensus Group or American College of Rheumatology criteria, only 2% required the anti-SSB-alone test result to meet these criteria. CONCLUSIONS: The presence of anti-SSB, without anti-SSA antibodies, had no significant association with SS phenotypic features, relative to seronegative participants. The solitary presence of anti-SSB antibodies does not provide any more support than negative serology for the diagnosis of SS. This serological profile should thus be interpreted cautiously in clinical practice and potentially eliminated from future classification criteria.

Fifteen-minute consultation: a structured approach to the management of recurrent oral ulceration in a child.

OBJECTIVE: To present a structured approach for an outpatient consultation of a child with recurrent mouth ulcers. METHOD: Review of literature and description of approach followed in our unit. CONCLUSIONS: The literature emphasises the need to consider local and systemic causes for oral ulceration in a child. Focused history and examination are key in establishing the cause and in order to ensure appropriate management.

A novel human IgA monoclonal antibody protects against tuberculosis.

Abs have been shown to be protective in passive immunotherapy of tuberculous infection using mouse experimental models. In this study, we report on the properties of a novel human IgA1, constructed using a single-chain variable fragment clone (2E9), selected from an Ab phage library. The purified Ab monomer revealed high binding affinities for the mycobacterial α-crystallin Ag and for the human FcαRI (CD89) IgA receptor. Intranasal inoculations with 2E9IgA1 and recombinant mouse IFN-γ significantly inhibited pulmonary H37Rv infection in mice transgenic for human CD89 but not in CD89-negative littermate controls, suggesting that binding to CD89 was necessary for the IgA-imparted passive protection. 2E9IgA1 added to human whole-blood or monocyte cultures inhibited luciferase-tagged H37Rv infection although not for all tested blood donors. Inhibition by 2E9IgA1 was synergistic with human rIFN-γ in cultures of purified human monocytes but not in whole-blood cultures. The demonstration of the mandatory role of FcαRI (CD89) for human IgA-mediated protection is important for understanding of the mechanisms involved and also for translation of this approach toward development of passive immunotherapy of tuberculosis.

Clinical assessment of disease severity in recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases in many parts of the world. However, there is very limited published clinical evidence for the therapies used in this condition. This could be partly due to the difficulty in evaluating the efficacy of oral ulcer treatment objectively. In this paper, we present a method for assessing and monitoring the severity of oral ulcers before and after treatment. METHODS: Six ulcer characteristics, number, size, duration, ulcer-free period, site and pain, were used to generate an ulcer severity score (USS). The scores for 223 RAS patients were determined, and 79 were scored again after 3-month therapy with topical betamethasone. RESULTS: The scores for the minor RAS group were between 18 and 43 (mean 29.2 ± 5.3). The mean score in the major ulcers group (range: 28-60, mean 39.9 ± 6.1) was significantly greater than in the minor group (P < 0.001). The herpetiform recurrent ulcers score range was wide (range: 18-57, mean 36.6 ± 8.4). The mean severity score decreased significantly after treatment (P < 0.001). CONCLUSIONS: The USS was indicative of the disease activity in recurrent oral ulceration. It helped in assessing the efficacy of therapy, as the change in the numerical score reflected the change in ulcer severity in response to treatment. This tool may well prove to be of value in clinical management, research and in clinical trials.

Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants.

OBJECTIVE: To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögren's syndrome (SS). METHODS: The database of the Sjögren's International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features. RESULTS: LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS. CONCLUSION: Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity.

Experience with anti-TNF-α therapy for orofacial granulomatosis.

BACKGROUND: Orofacial granulomatosis (OFG) can be challenging to treat and experience with anti-TNF-α therapy is limited. We report our experience with infliximab (IFX) and adalimumab (ADA) for OFG in 14 patients, the largest reported series to date. METHODS: A review of patients receiving induction and maintenance IFX for OFG +/- Crohn's disease (CD) for active oral disease failing other therapies was performed. Clinical response defined by global physician assessment, aided by oral disease activity scores, was assessed at 2 months, 1 and 2 years. ADA was considered for patients failing IFX. Adverse events were recorded. Predictors of need for anti-TNF-α therapy were determined by comparison with OFG patients not requiring anti-TNF-α from our overall OFG database (n = 207). RESULTS: Fourteen patients (9 men) were treated with IFX [OFG only (n = 7), OFG with CD (n = 7)]. Nine patients received concomitant immunosuppression. Median duration of treatment was 18 months. Shortterm response was achieved in 10/14 (71%) patients. Eight of 14 (57%) and 4/12 (33%) patients remained responsive at 1 and 2 years, respectively. Two patients who failed IFX responded to ADA. Factors predicting need for anti-TNF-α therapy were oral sulcal involvement, intestinal CD and a raised C-reactive protein (CRP). Oral sulcal involvement predicted response at 1 and 2 years. Intestinal CD did not predict response. The only significant adverse event was an IFX infusion reaction. CONCLUSION: IFX provided good short-term response for most OFG patients; however, a significant proportion lost response long term. Adverse events were uncommon. Patients failing IFX may respond to ADA.

Implications in the quantification of SARS-CoV2 copies in concurrent nasopharyngeal swabs, whole mouth fluid and respiratory droplets.

OBJECTIVE: Association of SARS-CoV2 burden in the aerodigestive tract with the disease is sparsely understood. We propose to elucidate the implications of SARS-CoV2 copies in concurrent nasopharyngeal swab (NPS), whole mouth fluid (WMF) and respiratory droplet (RD) samples on disease pathogenesis/transmission. METHODS: SARS-CoV2 copies quantified by RT-PCR in concurrent NPS, WMF and RD samples from 80 suspected COVID-19 patients were analysed with demographics, immune response and disease severity. RESULTS: Among the 55/80 (69 %) NPS-positive patients, SARS-CoV2 was detected in 44/55 (80 %) WMF (concordance with NPS-84 %; p = 0.02) and 17/55 (31 %) RD samples. SARS-CoV2 copies were similar in NPS (median:8.74 × 10^5) and WMF (median:3.07 × 10^4), but lower in RD (median:3.60 × 10^2). The 25-75 % interquartile range of SARS-CoV2 copies in the NPS was significantly higher in patients who shed the virus in WMF (p = 0.0001) and RD (p = 0.01). Multivariate analyses showed that hospitalized patients shed significantly higher virus copies in the WMF (p = 0.01). Hospitalized patients with more severe disease (p = 0.03) and higher IL-6 values (p = 0.001) shed more SARS-CoV2 virus in the RD. CONCLUSIONS: WMF may be used reliably as a surrogate for diagnosis. High copy numbers in the NPS probably imply early disease onset, while in the WMF and RD may imply more severe disease and increased inflammation.

Protein and mucin retention on oral mucosal surfaces in dry mouth patients.

Oral homeostasis depends largely on proteins and mucins present in saliva that coat all oral surfaces. The present study compared the protein composition of residual fluid on mucosal surfaces in subjects with normal salivary flow with that of patients with dry mouth caused by salivary hypofunction. Samples of residual mucosal fluid were collected using paper strips and then analysed by protein electrophoresis and immunoblotting. In both patients and controls, residual fluids on mucosal surfaces (except the anterior tongue in control subjects) had higher protein concentrations than unstimulated whole-mouth saliva. High-molecular-weight mucin (MUC5B) was present in greater amounts on the anterior tongue than on other surfaces in control subjects. In dry mouth patients who were unable to provide a measurable saliva sample, MUC5B was often still present on all mucosal surfaces but in reduced amounts on the anterior tongue. The membrane-bound mucin, MUC1, was prominent on buccal and labial surfaces in patients and controls. Statherin was still present on surfaces that were dried to remove salivary fluid, suggesting that it may be adsorbed as a protein pellicle. It is concluded that oral mucosal surfaces in dry mouth patients can retain MUC5B and other salivary proteins, although the functional integrity of these proteins is uncertain.