Elevated serum fibrinogen levels in Chinese patients with minor recurrent aphthous stomatitis: An observational study.

Fibrinogen is a protein that reflects systemic inflammation and regulates the immune response to disease. However, there is a scarcity of data on fibrinogen in recurrent aphthous stomatitis (RAS). We aimed to test the hypothesis that fibrinogen is involved in the aetiology of RAS. Between November 2016 and November 2018, we included 109 minor RAS patients and 29 age- and sex-matched controls in a single-center, observational study. Their clinical history and ulcer manifestations led to the diagnosis of minor RAS. The ulcer severity score (USS) was used to assess disease severity, and fibrinogen was also collected. We conducted three analyses: Analysis 1 (comparison of fibrinogen levels between patients and controls), Analysis 2 (comparison of fibrinogen levels between high and low USS patients) and Analysis 3 (comparison of fibrinogen levels between before and after anti-inflammatory treatment in patients). The fibrinogen levels in the 109 minor RAS patients were statistically higher than in the 29 controls (mean [SD], 2.6 [0.5] vs. 2.3 [0.3]; Student's t-test, p < 0.001). However, there were no significant differences in fibrinogen levels among the 43 patients with high USS and the 39 patients with low USS (mean [SD], 2.7 [0.5] vs. 2.6 [0.4]; Student's t-test, p = 0.278). Furthermore, fibrinogen levels were significantly higher before anti-inflammatory treatment in comparison to those after anti-inflammatory treatment in the 35 paired patients (mean [SD], 2.6 [0.4] vs. 2.5 [0.4]; Student's t-test, p = 0.026). Interestingly, fibrinogen levels were significantly higher in the 35 paired patients after anti-inflammatory treatment compared to the 29 control subjects (mean [SD], 2.5 [0.4] vs. 2.3 [0.3]; Student's t-test, p = 0.026]. Fibrinogen may play a role in the aetiology of RAS and may be a drug target for RAS treatment. Clinicians should be alert that high serum fibrinogen levels might be associated with the risk of RAS.

Cardiovascular diseases, risk factors, and ulcer relapse in older adults with aphthous stomatitis.

OBJECTIVES: To test the hypothesis that cardiovascular diseases and risk factors are associated with ulcer relapse in after-retirement patients with recurrent aphthous stomatitis. SUBJECTS AND METHODS: This retrospective cohort study analyzed the data of 40 minor recurrent aphthous stomatitis patients aged 55-75 years, admitted to Oral Medicine Clinic at one university hospital in China between 2016 and 2018. The diagnosis of minor recurrent aphthous stomatitis was made based on the history and manifestation of oral ulcers. The ulcer relapse was evaluated after a 5-week anti-inflammatory treatment, and the history of systemic diseases was collected. cardiovascular disease/metabolic risk referred to the presence of any cardiovascular diseases and metabolic cardiovascular disease risks. Associations among cardiovascular diseases, risk factors, and ulcer relapse were evaluated. RESULTS: The mean age of 40 patients with minor recurrent aphthous stomatitis was 62.4 years (SD 5.1), and 60% were women. The ulcer relapse rate was 37.5% (95% CI, 0.242-0.530). The proportion of cardiovascular disease/metabolic risk was higher in the relapse group than in the no-relapse group after 5-week anti-inflammatory treatment (Fisher's exact test, p = 0.041). CONCLUSIONS: According to this single-center experience, older patients with cardiovascular disease/metabolic risk may be more prone to oral ulcer recurrence. Nevertheless, larger prospective studies are needed to confirm our findings.

Dynamic salivary cytokine profile of recurrent aphthous stomatitis patients in thalidomide maintenance treatment.

OBJECTIVE: To dynamically compare the longitudinal (time axis) and transverse (between groups) differences of the salivary cytokines during thalidomide maintenance treatment of recurrent aphthous stomatitis. METHODS: A randomized, controlled, clinical trial was performed. After the initial prednisone treatment, thalidomide (50 mg/d vs. 25 mg/d) was used as a maintenance drug for 4 or 8 weeks. The salivary IL-4, 5, 6, 10, TNF-α, and IFN-γ were dynamically detected with a cytometric bead array. RESULTS: Overall, the level of six elevated salivary cytokines after prednisone treatment was significantly downregulated, remained low during thalidomide maintenance, and rebounded at recurrence. The effect of 50 mg/d thalidomide on the salivary cytokines was not superior to 25 mg/d medication. The relapse-free period following drug withdrawal was the longest in the subgroup using 25 mg/d thalidomide for 8 weeks. The order of magnitude of IL-6 was the most obvious, and at week 8, only the level of IL-6 in the group (25 mg/d thalidomide for 8 weeks) continued to decline compared with the other groups. CONCLUSION: Thalidomide maintenance treatment can effectively sustain low levels of salivary IL-4, 5, 6, 10, TNF-α, and IFN-γ of recurrent aphthous stomatitis patients. IL-6 displayed a good correlation with the disease and is expected to become an index for diagnosis and follow-up. CLINICAL RELEVANCE: Low-dose long-term thalidomide maintenance treatment was supported for recurrent aphthous stomatitis. TRIAL REGISTRATION: Trial registration number of ChiCTR-IPR-16009759 at http://www.chictr.org/index.aspx .

Hematological parameters in patients with recurrent Aphthous Stomatitis: a systematic review and meta-analysis.

OBJECTIVES: Recurrent Aphthous Stomatitis (RAS) known as recurrent aphthous ulcer is a common and painful ulcerations in oral cavity. It has been suggested that hematological parameters seems to be considered as an etiologic factor. So, this meta-analysis and systematic review was aimed to examine the relationship between RAS and hematological parameters. METHODS: Relevant studies were found using online international databases including Scopus, Science direct, Web of science (ISI), PubMed, and Google Scholar search engine between 2000 and October 2023. The quality of all papers was determined by NOS checklist. Heterogeneity between the results of primary studies was evaluated with I-square index and publication bias was performed by Egger's test and funnel plots. Also, sensitivity analysis was done to check the effect of each of the primary studies on the overall estimate. Also, the statistical analyses were done using Stata software Ver. 11. RESULTS: By combining the results of primary studies, the standardized mean difference (SMD) of vitamin B12, ferritin, folic acid, hemoglobin, iron and zinc indices with a 95% confidence interval (CI) between the case (patients with RAS) and control (Healthy) groups were estimated -0.52(-0.89, -0.14), -0.20(-0.51, 0.11), -0.42(-0.95, 0.11), -0.58(-0.90, -0.27), 0.01(-0.12, 0.15), -0.33(-0.81, 0.14) respectively. The patients with vitamin B12, ferritin, folic acid, and iron deficiencies and reduced hemoglobin (Hb) level reported 2.93(2.28, 3.78), 2.50(1.48, 4.22), 1.51(0.53, 4.29), 1.46(0.70, 3.03), and 2.14(1.38, 3.32), times more susceptible to develop RAS than healthy individuals. CONCLUSION: The results of the meta-analysis indicated that the SMD of vitamin B12 serum and Hb levels in the case group was 52%. Our result have also showed that the odds ratio of vitamin B12, ferritin deficiencies, and decreased Hb level in case group was 2.93, 2.50, and 2.14 times more than healthy group.

Characterization of immune landscape and development of a novel N7-methylguanine-related gene signature to aid therapy in recurrent aphthous stomatitis.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is the most common inflammatory disease of the oral mucosa resulting in an impaired life quality and even leading to tumors in susceptible populations. N7-Methylguanine (m7G) plays a vital role in various cellular activities but has not yet been investigated in RAS. We aimed at picturing the immune landscape and constructing an m7G-related gene signature, and investigating candidate drugs and gene-disease association to aid therapy for RAS. METHODS: For our study, m7G-related differentially expressed genes (DEGs) were screened. We outlined the immune microenvironment and studied the correlations between the m7G-related DEGs and immune cells/pathways. We performed functional enrichment analyses and constructed the protein-protein interaction (PPI) and multifactor regulatory network in RAS. The m7G-related hub genes were extracted to formulate the corresponding m7G predictive signature. RESULTS: We obtained 11 m7G-related DEGs and studied a comprehensive immune infiltration landscape, which indicated several immune markers as possible immunotherapeutic targets. The PPI and multifactor regulatory network was constructed and 4 hub genes (DDX58, IFI27, IFIT5, and PML) were identified, followed by validation of the corresponding m7G predictive signature for RAS. GO and KEGG analyses revealed the participation of JAK-STAT and several immune-related pathways. Finally, we suggested candidate drugs and gene-disease associations for potential RAS medical interventions. CONCLUSIONS: The present study pictured a comprehensive immune infiltration landscape and suggested that m7G played a vital role in RAS through immune-related pathways. This study provided new insight for the future investigation of the mechanisms and therapeutic strategies for RAS.

Gene polymorphisms and serum levels of mannose-binding lectin in Czech patients with recurrent aphthous stomatitis: A case-control study.

BACKGROUND: Recurrent aphthous stomatitis is one of the most prevalent oral mucosal immunological diseases. A recent case-control study in the Egyptian population suggested that single nucleotide polymorphism Gly54Asp (rs1800450) of the mannose-binding lectin 2 gene might affect the mannose-binding lectin serum level and recurrent aphthous stomatitis development. The aim of this study was to determine the distribution of six functional mannose-binding lectin 2 gene polymorphisms and analyse their role in recurrent aphthous stomatitis susceptibility in the Czech population. METHODS: The study included 227 subjects; 137 healthy people and 90 patients with recurrent aphthous stomatitis. Six mannose-binding lectin 2 gene polymorphisms (rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, rs1800451) were analysed by the SNaPshot assay method, mannose-binding lectin serum levels were determined by enzyme-linked immunosorbent assay (ELISA) method in a subgroup of subjects (N = 87). RESULTS: No significant differences in mean of mannose-binding lectin serum levels between healthy controls and patients with recurrent aphthous stomatitis were observed (383 ng/ml ± 249 standard deviation (SD) vs. 316 ng/ml ± 177 SD in remission phase vs. 343 ng/ml ± 254 SD in active phase; p > 0.05), also the allele and genotype frequencies of the studied mannose-binding lectin 2 polymorphisms did not differ significantly between the two groups (p > 0.05, odds ratio (OR): 0.75-1.23). Moreover, the distribution of mannose-binding lectin 2 haplotypes and haplogenotypes was similar in the healthy subjects and patients with recurrent aphthous stomatitis (p > 0.05, OR: 0.75-1.23). CONCLUSIONS: This study did not confirm the previously reported association of the mannose-binding lectin 2 Gly54Asp gene variant and low mannose-binding lectin serum level as the risk factors for susceptibility to recurrent aphthous stomatitis. In addition, no significant relationships between mannose-binding lectin 2 functional haplotypes or haplogenotypes and recurrent aphthous stomatitis were observed.

Coeliac disease and its implications on the oral health of children: A systematic review.

AIM: Apart from various typical gastrointestinal symptoms, coeliac disease may have its clinical manifestations in the oral cavity which is the entrance of the gastrointestinal tract. METHODS: A systematic review of literature was performed using the following databases: Medline, Scopus, EBSCOhost and Cochrane Library for Systematic Review. INCLUSION CRITERIA: observational or experimental original studies published in English with full text available between January 2000 and December 2022, regarding children and adolescents under the age of 20. Risk of bias was determined with the use of Risk Of Bias In Non-randomised Studies of Exposure. RESULTS: Thirty-four studies were included in the review. The analysis confirmed a higher prevalence of numerous oral manifestations in coeliac disease concerning both hard and soft tissues. Our study found the prevalence of dental enamel defects to be at the level of 17.9%-83.5% (P value <0.047) and recurrent aphthous stomatitis of 8.3%-69% (P value <0.039). CONCLUSION: Oral manifestations may precede gastrointestinal symptoms. Patients presenting such manifestations should be screened for coeliac disease. The cooperation of gastroenterologists and dentists could lead to an increased detectability of coeliac disease.

The relationship between Helicobacter pylori infection and recurrent aphthous stomatitis: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis was designed to provide new insights into the relationship between Helicobacter pylori (H. pylori) infection and recurrent aphthous stomatitis (RAS). MATERIALS AND METHODS: We included and evaluated studies on H. pylori infection and RAS from PubMed, EMBASE, Cochrane Library, and Web of Science databases published up to January 31, 2023. The characteristics of these studies were collected, and the quality was evaluated by Newcastle-Ottawa Scale (NOS). The random effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI). To further explore the sources of heterogeneity, meta-regression analysis and subgroup analyses were performed. Funnel plot, Egger's test, and Begg's test were used to assess publication bias. RESULTS: In total, fifteen case-control studies with 1137 individuals (601 cases and 536 controls) were included. The H. pylori was found to be significantly associated with RAS (OR: 1.83 95% CI: 1.41-2.37, P = 0.001). In the subgroup analyses, studies that used PCR (OR: 2.03 95% CI: 1.31-3.15) or UBT (OR: 1.83 95% CI: 1.13-2.96) yielded a significant positive association, while a non-significant association (OR: 1.12 95% CI: 0.61-2.08) was found from studies that used ELISA method. Sensitivity analyses showed that the results were robust. No significant publication bias was found. CONCLUSIONS: The current evidence does not rule out an association between H. pylori and RAS. The effect of H. pylori on RAS varies in detection methods and sources of sample. Large samples, multiple clinical studies, and improved methods are still needed to determine the exact effect of H. pylori on RAS. CLINICAL SIGNIFICANCE: H. pylori infection may be a risk factor for the pathogenesis of RAS.

The effect of sage (Salvizan gel) compared to triamcinolone acetonide on the treatment of recurrent aphthous stomatitis: a double-blinded randomized clinical trial.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is one of the most common lesions of the oral mucosa. Herbal medicine can be used for the treatment of this disease. The present study aimed to compare the effects of topical application of Sage (Salvizan) and triamcinolone acetonide gels on RAS. METHODS: This double-blind clinical study recruited sixty patients with minor aphthous ulcers. Half of the patients were treated with Salvizan gel, and the other half were treated with oral triamcinolone acetonide gel. The effect of Salvizan topical gel was evaluated and compared with that of oral triamcinolone acetonide gel. Factors such as Pain recovery time, wound healing time, and pain level was evaluated. Data were analyzed by SPSS version 22 using independent t-test, paired t-test, repeated measures ANOVA, and survival analysis, including Kaplan-Meier and Cox regression. RESULTS: The mean duration of pain recovery was 1.5 days for Salvizan and 2.5 days for triamcinolone acetonide (p < 0.001). Moreover, the duration of wound healing was 3.3 days for Salvizan and 6 days for triamcinolone acetonide (p < 0.001). Patients' satisfaction from factors such as taste and smell had no significant difference between the two groups. CONCLUSION: The results of this study showed that Salvizan gel is very effective in the treatment of RAS. It was significantly better than triamcinolone acetonide in the pain recovery and wound healing. These promising results favor herbal treatments and show that they can be used more commonly for treating diseases such as RAS. TRIAL REGISTRATION: This study was approved by the ethics committee of Isfahan University of Medical Sciences (IR.MUI. RESEARCH: REC.1399.834) on 17/03/2021. It was also registered in the Iranian Registry of Clinical Trials (IRCT20100202003251N7).

Salivary proteins offer insights into keratinocyte death during aphthous stomatitis. A case-crossover study.

BACKGROUND: The death of oral keratinocytes is a crucial step in the emergence of recurrent aphthous stomatitis (RAS, also known as aphthae or aphthous ulcers). Since there are no experimental models available to research aphthous ulcers, little is understood about this process. We hypothesize that saliva can be a data bank of information that offers insights on epithelial damage. METHODS: In this case-crossover study, we assessed the salivary proteome of patients with RAS (n = 36) in the presence and absence of ulcers using discovery proteomics and bioinformatics. Additionally, we contrasted these patterns with those of healthy individuals (n = 31) who had no prior aphthous ulceration. RESULTS: Salivary proteome showed that during the ulcerative phase, controlled cell death was downregulated. Due to its ability to distinguish between individuals with and without ulcers, the ATF6B protein raises the possibility that endoplasmic reticulum (ER) stress is responsible for the damage that leads to the death of oral keratinocytes. The high abundance of TRAP1 and ERN1 matches with this biological discovery. The type of death is immunogenic, according to the functional data found in a cell death database. CONCLUSION: We identified a cellular process that can lead to the death of oral keratinocytes in the etiopathogenesis process of RAS. Future studies should be conducted to identify what is responsible for the increase in ER stress signaling that would lead to an anti-cell death response.

Total Salivary Antioxidant and Serum Antioxidant Levels in Recurrent Aphthous Stomatitis: A Case-Control Study.

BACKGROUND: Recurrent Aphthous Stomatitis (RAS) is an inflammatory lesion of the oral mucous lining, accounting for 5 to 25% of the chronic oral lesions. Studies have suggested that RAS patients have increased oxidative stress (OS) and impaired antioxidant capacity, and non-invasive screening using saliva assessment of oxidative stress and antioxidant capacity may be beneficial in RAS. OBJECTIVES: This study determined total salivary antioxidant concentration and compared it to the total serum antioxidant levels in patients with RAS and controls. METHODS: This was a case-control study of subjects with RAS and without RAS. Unstimulated mid-morning saliva was collected using the spitting method, and venous blood was collected into a plastic vacutainer. Saliva and blood samples were assayed for total oxidative stress (TOS), total antioxidant capacity (TAC), ferric reducing antioxidant power (FRAP) and glutathione. RESULTS: A total of 46 subjects, 23 with RAS and 23 healthy controls, participated in the study. Twenty-five (54.35%) were males, and 21(45.65) were females aged 17 to 73 years. We identified an increase in salivary and serum TOS (10.06 ± 7.49, 8.26 ± 2.18/ 15.00 ± 8.92, 9.36 ± 3.55µmol/L) and OSI while the TAC (16.85 ± 1.97, 17.07 ± 2.36/17.07 ± 2.36, 2.97 ± 0.29mM/L) and significantly GSH (0.02 ± 0.02, 0.10 ± 0.02/0.10 ± 0.02/0.19 ± 0.11 µmol/ml) were decreased in serum and saliva of the RAS group compared to controls respectively. In addition, there were positive correlations between salivary and serum levels of FRAP r=0.588, p= 0.003 and glutathione r=0.703, p<0.001 in RAS subjects and controls. CONCLUSION: Oxidative stress is associated with RAS, and saliva can be used as a biological marker for glutathione and FRAP.

CONTEXTE: La stomatite aphteuse récurrente (SAR) est une lésion inflammatoire de la muqueuse buccale qui représente 5 à 25 % des lésions buccales chroniques. Des études ont suggéré que les patients atteints de stomatite aphteuse récurrente présentent un stress oxydatif (SO) accru et une capacité antioxydante altérée, et qu'un dépistage non invasif utilisant l'évaluation salivaire du stress oxydatif et de la capacité antioxydante pourrait être bénéfique dans la stomatite aphteuse récurrente. OBJECTIFS: Cette étude a déterminé la concentration totale d'antioxydants dans la salive et l'a comparée aux niveaux totaux d'antioxydants dans le sérum chez des patients atteints de SRA et chez des témoins. MÉTHODES: Il s'agit d'une étude cas-témoins portant sur des sujets atteints ou non du syndrome respiratoire aigu sévère. De la salive non stimulée a été recueillie en milieu de matinée par la méthode du crachat, et du sang veineux a été prélevé dans un vacutainer en plastique. Les échantillons de salive et de sang ont été analysés pour déterminer le stress oxydatif total (TOS), la capacité antioxydante totale (TAC), le pouvoir antioxydant réducteur ferrique (FRAP) et le glutathion. RÉSULTATS: Au total, 46 sujets, 23 atteints de SRA et 23 témoins sains, ont participé à l'étude. Vingt-cinq (54,35 %) étaient des hommes et 21 (45,65) des femmes âgés de 17 à 73 ans. Nous avons identifié une augmentation des TOS salivaires et sériques (10.06 ± 7.49, 8.26 ± 2.18/ 15.00 ± 8.92, 9.36 ± 3.55µmol/L) et de l'OSI tandis que le TAC (16.85 ± 1.97, 17.07 ± 2.36/17.07 ± 2.36, 2. 97 ± 0.29mM/L) et significativement le GSH (0.02 ± 0.02, 0.10 ± 0.02/0.10 ± 0.02/0.19 ± 0.11 µmol/ml) ont été diminués dans le sérum et la salive du groupe RAS par rapport aux contrôles respectivement. En outre, il y avait des corrélations positives entre les niveaux salivaires et sériques de FRAP r=0,588, p= 0,003 et de glutathion r=0,703, p<0,001 chez les sujets RAS et les témoins. CONCLUSION: Le stress oxydatif est associé au SAPR et la salive peut être utilisée comme marqueur biologique pour le glutathion et la FRAP. Mots clés: Stomatite aphteuse récurrente, Antioxydants, Salive, Stress oxydatif.

Role of genetic polymorphisms in recurrent aphthous stomatitis: A systematic review and meta-analysis.

Recurrent aphthous stomatitis (RAS) is one of the most common oral ulcerative diseases with unknown etiology. Identifying the genetic markers can improve medical care and prevention of RAS. Genetics variants inflammatory agents are associated with the risk of RAS. Thus, this meta-analysis aimed to investigate the genetic polymorphisms in RAS. Electronic literature search was carried out on Scopus, PubMed, and Web of Science (WOS). The references of relevant reviews were also manually checked. The observational studies till the end of 2020 were included. Odds ratio (OR) was estimated by fixed and random effect model. Seventeen polymorphisms in 23 studies were included in analysis. Pooled analysis performed for 12 polymorphisms (IL-2+166, IL-2-330, IL-4-590, IL-4 RA1902, IL-6-597, TNF-α-308, NLRP3(rs4612666, rs10754558), MMP2- rs2285053, MMP9- rs11697325, MMP9- rs3918242, MMP9- rs17576, IL-1a-889, IL-10-819, and IL-12+1188). The meta-analyses carried out for six polymorphisms (IL-1ß-511, IL-1ß+3954, IL-6-174, IL-10-592, IL-10-1082, and serotonin transporter). There were following significant results for IL-10, 819 in allelic:1.46(1.04-2.05) and homozygote: 1.61(1.08-2.39) models, serotonin Transporter in allelic:0.53(0.40-0.71), recessive:0.56(0.35-0.90), dominant:0.35(0.22-0.57) and homozygote:0.30(0.17-0.54) models. IL-1ß-511 in dominant 0.69(0.50-0.95) and overdominant 0.73(0.55-0.96) models, IL-1ß+3954 in allelic 1.25(1.05-1.50), homozygote 1.67(1.05-2.63) and dominant 1.26(1.01-1.57) models, IL-6-174 in dominant 2.24(1.36-3.67), IL-10-592 in homozygote 0.41(0.23-0.72) and dominant 0.55(0.33-0.93), IL-10-1082 in allelic 1.19(1.01-1.39) and dominant 1.29(1.02-1.64). In conclusion, serotonin transporter(L/S), IL-10-819(T/C), IL-10-592(C/A), IL-10-1082(G/A), IL-1ß-511(C/T), IL-6-174(G/C), and IL-1ß+3954 (T/C) polymorphisms are associated with susceptibility to RAS. These variants could be potential predictors of RAS and could be used for the developing clinically effective genetic panel for RAS.

The expression of TNF-α in recurrent aphthous stomatitis: A systematic review and meta-analysis.

OBJECTIVE: The pathogenesis of recurrent aphthous stomatitis (RAS) is related to an increase of pro-inflammatory cytokine, namely tumor necrosis factor α (TNF-α). This cytokine plays an important role in the development of ulcer lesions, both in saliva, tissues and blood. This systematic review analyzed the differences of TNF-α in lesions, salivary and blood and can be used as a reliable method of diagnosis for RAS. METHODS: A comprehensive search of PubMed, Scopus databases, Web of Science, Scielo, Google Scholar and Embase with keywords. The inclusion criteria were studies that assessed the saliva, serum, and RAS lesion, with the outcome reporting the mean of saliva, serum and tissue expression of TNF-α. The risk of bias was also assessed. RESULT: Healthy individuals showed significantly lower TNF-α than RAS (SMD = -1.517, 95% CI [-2.25, -0.78]). Although there is a significant difference between sample (i.e., saliva, serum) and detection type (i.e., cytometry bead array, ELISA), both methods can detect a significant difference in TNF-α between healthy individuals and RAS patients. CONCLUSIONS: The TNF-α is a useful diagnostic marker for RAS. We encourage saliva to detect changes in TNF-α during ulceration as it provides accuracy, reliability, and non-invasive procedure compared to a blood draw.

A Randomized controlled clinical trial on dose optimization of thalidomide in maintenance treatment for recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disease, and ulcer-free periods are a major concern for patients. Thalidomide has been shown to be an effective systemic drug in the treatment of RAS, but the value of undertaking a trial to evaluate various maintenance doses was warranted. METHODS: We performed this randomized controlled clinical trial with a two-stage design. Firstly, all the 125 cases of RAS received prednisone at a starting dose of 15 mg/d for one week as an initial therapeutic drug. Secondly, the 100 cases of RAS in the experimental group received thalidomide (50 mg/d vs. 25 mg/d) as a maintenance drug to observe its efficacy and safety. RESULTS: During maintenance medication at the fourth and eighth weekend, the two doses (50 and 25 mg/d) of thalidomide were equivalent in reducing the incidence of ulcers, ulcer number, and ulcer pain, respectively (all p > 0.05). Notably, the ulcer-free period in the group using 25 mg/d thalidomide for eight weeks was longer (mean, >3 months) than those in the other groups (all p < 0.05). Importantly, the total adverse events in the group using 25 mg/d thalidomide were significantly less than those in the group using 50 mg/d (p < 0.001). Moreover, the effect of 50 mg/d thalidomide on the levels of various salivary cytokines was not superior to 25 mg/d medication (p > 0.05). CONCLUSION: This dose optimization study concluded that 25 mg/d thalidomide had a long-term effect on extending the recurrence interval of RAS with better safety.

Role of biologics in refractory recurrent aphthous stomatitis.

Refractory recurrent aphthous stomatitis (RRAS) manifests as severe ulcerative lesions of the oral mucosa with poor healing and a poor response to conventional therapy, with or without systemic diseases. Its treatment remains a clinical challenge owing to the lack of effective therapies. Recently, biologics have emerged as promising targeted therapies for RRAS. The biologics targeting specific inflammatory pathways involved in the pathogenesis of RRAS, including tumor necrosis factor-alpha inhibitors and interleukin inhibitors, offer a more precise and promising therapeutic approach for RRAS. These targeted therapies have been shown to promote healing and decrease recurrence frequency in, and improve the quality of life of patients with RRAS. Herein, the types and mechanisms of biologics currently used to treat RRAS have been reviewed; furthermore, the dose, duration, therapeutic efficacy, and adverse effects of RRAS with or without certain associated systemic diseases, and the current problems and future directions have been discussed.

Recurrent aphthous stomatitis: A comprehensive review and recommendations on therapeutic options.

Recurrent aphthous stomatitis (RAS) is a common chronic disease in the oral mucosa that affects about 20% of the population. It is characterized by solitary or multiple, recurrent, small ulcers with erythematous haloes and yellow/gray floors. RAS can be managed through a wide variety of preventative measures and therapies, intending to reduce ulcer pain, stimulate ulcer healing, and/or prevent ulcer recurrence. First-line treatment options include topical medications in the form of corticosteroids (triamcinolone acetonide), anti-inflammatory drugs (amlexanox), antibiotics (doxycycline), and antiseptics (lidocaine). In more severe cases of RAS where local treatment is insufficient, systemic drugs in the form of corticosteroids (prednisone), immunomodulatory drugs (thalidomide), and antibiotics/antimicrobials (clofazimine) can prove effective. This review will summarize current treatment options for RAS with discussion of prevention, topical measures, natural treatments, systemic therapies, and new potential therapies. Furthermore, this review will provide recommendations on therapeutic options for RAS based on disease severity and patient circumstances.

Validity and responsiveness of pain rating scales in patients with chronic oral mucosal diseases.

OBJECTIVES: To validate the Visual Analog Scale (VAS) and Numerical Rating Scale (NRS) for measuring pain intensity in chronic oral mucosal diseases. METHODS: Secondary analyses of data including the VAS, NRS, demographic, clinical and quality-of-life outcomes at baseline and 4-month follow-up were retrieved from a clinical study of chronic oral mucosal diseases. Construct and criterion validity and responsiveness of the VAS and NRS were assessed through testing hypotheses based upon strength of Spearman's correlation coefficients. RESULTS: Data of 500 and 290 patients with chronic oral mucosal diseases were used for the assessment of validity and responsiveness, respectively. Moderate-to-high correlations between both pain scores and scores of clinical and quality-of-life outcomes were observed, supporting construct validity of the VAS and NRS. Their criterion validity was confirmed by significantly strong association between scores of both scales. Responsiveness of both scales was adequate based on moderate association between their change scores and global rating of change scale. CONCLUSION: The present results provide evidence supporting validity and responsiveness of the VAS and NRS for pain intensity assessment in patients with chronic oral mucosal diseases. Future research examining other pain intensity domains and standardizing composite scores for pain intensity in this population is required.

The efficacy of herbal medicine in the treatment of recurrent aphthous stomatitis: A systematic review of randomized clinical trials.

This systematic review was undertaken with the main aim of assessing the therapeutic effects of herbal medicines in recurrent aphthous stomatitis (RAS). A comprehensive search was performed in PubMed, Scopus, ISI Web of Science, and Google Scholar up to July 2021 to identify randomized clinical trials investigated the effects of herbal medicines on RAS. Thirty-three papers comprising 2,113 patients met the eligibility criteria, of which 30 studies had a high quality based on the Jadad scale. Totally, 22 out of 30 studies which assessed the pain showed that herbal agents significantly decreased the pain compared with the control group or placebo. In 17 out of 25 studies that evaluated ulcer size, herbal agents significantly reduced the size of ulcers compared with the control or placebo groups. In 15 out of 18 studies that assessed the healing time, herbal agents significantly reduced healing time in the intervention groups compared with the placebo or control groups. Few adverse events were reported only in four studies. Findings of the current review indicated medicinal plants and phytochemicals as effective and safe agents that for the treatment of RAS.

Role of vitamin B12 in treating recurrent aphthous stomatitis: A review.

Vitamin B12, a water-soluble vitamin, plays a vital role in the formation of hematopoietic stem cells and has been associated with oral mucosal diseases, mainly recurrent aphthous stomatitis (RAS). The latter is a debilitating condition, and B12 was proposed as a potential treatment given its role in regenerating oral mucosal tissue. There is conflicting evidence that B12 deficiency causes RAS. Five of the seven randomized controlled trials reviewed used the inactive form of B12 (cyanocobalamin) as intervention, while the other two used the active form (methylcobalamin). Of the latter two, buccal discs (500 µg B12) showed significant improvement and reduced perceived pain in 77% of the subjects, and submucosal injections showed a significant difference in pain, starting from the second day. Moreover, three studies administered vitamin B12 sublingually with different dosages, which revealed that the higher dose (1000 µg) achieved a significant reduction in outbreaks, number, and duration of ulcers, especially after six months. Multivitamins showed no difference in new RAS episodes and duration. Injectable B12 was compared with the oral form, and nearly 50% of the injection group reported a desired response by the eighth week. An ointment form (500 µg) showed a significant reduction in pain levels after two days of treatment. Based on the available literature, we suggest that a daily dose of 1000 µg of vitamin B12 sublingually for six months can be used to treat RAS. Nevertheless, this conclusion should be considered tentative due to the lack of high quality, large scale studies.

Changes in Th1/Th2-related cytokine expression in the saliva of patients with recurrent aphthous stomatitis before and after prednisone treatment.

OBJECTIVES: To investigate the changes of T helper cell (Th)1/Th2-related cytokine expression in the saliva of minor recurrent aphthous stomatitis (RAS) patients before and after treatment with systemic prednisone. METHODS: A total of 101 patients with RAS and 15 participants with normal oral mucosa as controls were enrolled in this study. The levels of cytokine expression in the whole unstimulated saliva were examined using a multiplex bead-based cytometric bead array before and after prednisone treatment at a starting dose of 15 mg/day. RESULTS: The levels of salivary interleukin (IL)-4, IL-5, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor-α (TNF-α) in RAS patients were significantly higher than those of the normal controls (all P < 0.001). Importantly, the levels of salivary IL-6, IL-10, IFN-γ, and TNF-α in RAS patients were significantly decreased following prednisone treatment (all P < 0.001). Moreover, the IFN-γ to IL-4 ratio (mean: 26.9) was significantly (P < 0.001) decreased after treatment, which almost returned to normal (mean: 24.4; P > 0.05). CONCLUSION: This preliminary study demonstrates for the first time that prednisone exerts a significant therapeutic role against RAS through decreasing salivary cytokine levels and promoting a Th1/Th2 balance. CLINICAL RELEVANCE: Salivary cytokine profiles may provide a noninvasive, convenient, and effective approach to monitoring the course of RAS and may even be helpful to identify key pathogenic factors and potential mechanisms.