This systematic review and meta-analysis aimed to evaluate the expression levels of various T helper (Th) cell-secreted cytokines in recurrent aphthous stomatitis (RAS). Case-control studies comparing the serum or salivary levels of cytokines between RAS patients and healthy controls were searched in PubMed, EMBASE, Web of Science, and Google Scholar prior to September 30, 2023. Cytokines produced by Th1 (interleukin [IL]-1, IL-2, IL-8, IL-12, tumor necrosis factor alpha [TNF-α], interferon gamma [IFN-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), and Th17 (IL-17A) cells were investigated. The standard mean difference (SMD) with 95% confidence interval (CI) was calculated to detect the difference. A total of 20 studies comprising 1070 RAS patients and 536 healthy controls were included. RAS patients had significantly higher salivary levels of IL-2 (SMD = 4.15, 95%CI 0.83-7.48), IL-5 (SMD = 0.53, 95%CI 0.05-1.00), IL-6 (SMD = 0.48, 95%CI 0.12-0.84), IL-12 (SMD = 0.94, 95%CI 0.18-1.71), and TNF-α (SMD = 1.31, 95%CI 0.44-2.18) compared to healthy controls. Serum levels of IL-6 (SMD = 0.48, 95%CI 0.30-0.66), TNF-α (SMD = 0.70, 95%CI 0.22-1.17), and IFN-γ (SMD = 0.72, 95%CI 0.17-1.28) were significantly increased, while serum IL-10 levels (SMD = -2.25, 95%CI -3.99 to -0.52) were reduced in RAS patients. Patients diagnosed with major RAS had markedly elevated serum IL-8 levels (SMD = 0.39, 95%CI 0.07-0.71) and a trend toward higher serum IL-6 levels (SMD = 0.51, 95%CI -0.02 to 1.04) than those with minor RAS. In conclusion, Th1/Th2-related cytokines, especially IL-2, IL-6, and TNF-α, are involved in the pathogenesis of RAS development and progression and are potential therapeutic targets for RAS.

To explore the antiinflammatory mechanism of agarwood on recurrent aphthous stomatitis (RAS). RAS is the most common mucosal disease in the oral cavity. The clinical application of traditional Chinese medicine found that agarwood has significant curative effect on peptic ulcer, but the effect and mechanism of agarwood on RAS remain unclear. This study is intended to predict the potential antiinflammatory mechanisms by which agarwood acts on RAS through network pharmacology and molecular docking. TCMSP database was used to screen the active components of agarwood. RAS targets were screened in Genecards, DisGeNET, and OMIM database. Venny, an online tool, screens for interacting genes between the two. Cytoscape software was used to construct the gene regulation map of active compounds target of agarwood. String Database building protein-protein interaction network. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways were enriched in DAVID database. The key active ingredients and core targets were further verified by molecular docking. There were 9 effective compounds and 186 target genes in agarwood; RAS has 793 target genes. There were 41 interacting genes between agarwood and RAS. Interleukin 6, tumor necrosis factor, interleukin 1 beta, and cellular component motif ligand 2 may be key targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses predicted multiple pathways associated with RAS. Molecular docking results showed that the active compounds of agarwood combined well and stably with the target. The Chinese herbal medicine agarwood can relieve the inflammation of RAS through multiple targets and various ways. Its active compounds may be nominated as candidates for antiinflammatory drugs of RAS.

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.
CONCLUSIONS: 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.
CONCLUSIONS: Low-dose long-term thalidomide maintenance treatment was supported for recurrent aphthous stomatitis.
BACKGROUND: Trial registration number of ChiCTR-IPR-16009759 at http://www.chictr.org/index.aspx .

BACKGROUND: Recurrent aphthous stomatitis (RAS) is common in clinical practice and imposes both physical and psychological distress on patients.
OBJECTIVE: This study aimed to evaluate the clinical effectiveness of fire needle therapy for the treatment of RAS, providing a basis for clinical decision-making.
METHODS: Eight databases, in both Chinese and English, were searched from their inception until December 2022. All randomized controlled trials (RCTs) that utilized fire needle therapy, either alone or combined with other treatments for RAS, were considered. Data evaluation and extraction were conducted independently by 2 authors.
RESULTS: The revised Cochrane Risk of Bias Version 2 tool was employed to assess the risk of bias in the included RCTs. A meta-analysis was conducted using Review Manager 5.4 and Stata 15.0. Nine RCTs involving 1469 patients were selected for inclusion. The meta-analysis revealed that, compared to a non-fire-needle control group (primarily utilizing vitamin and transfer factor treatments), fire needle therapy for RAS significantly improved the total effective rate (relative risk = 1.25, 95% confidence interval [CI] [1.14, 1.36], P < .00001), reduced the visual analogue scale score (mean difference = -1.68, 95% CI [-1.82, -1.53], P < .0001), diminished the Traditional Chinese Medicine symptom score (standardized mean difference = -1.20, 95% CI [-1.76, -0.65], P < .0001), and shortened the healing time (mean difference = -1.66, 95% CI [-2.73, -0.59], P = .002). Notably, there was no significant difference in the recurrence rate between the groups (relative risk = -0.18, 95% CI [-0.36, 0.01], P = .06). Further subgroup analysis on total efficacy rate was performed based on variables such as experimental group intervention, control group intervention, and duration of therapy to explore potential sources of heterogeneity.
CONCLUSIONS: Fire needle therapy appears to be a clinically effective treatment for RAS, offering benefits such as pain alleviation, symptom improvement based on the Traditional Chinese Medicine parameters, and faster recovery. Nonetheless, the overall quality of the RCTs available raises concerns. Future research, involving high-quality RCTs, is essential to confirm the clinical efficacy and safety of this treatment. Registration number: PROSPERO (CRD42023387973).

The aetiology of oral mucosal diseases, such as recurrent aphthous ulcer (RAU), oral lichen planus (OLP) and burning mouth syndrome (BMS), involves many factors, and it remains difficult for clinicians to effectively relieve disease symptoms and formulate coping strategies. With the rapid development of psychology, the role of mental and psychological factors in RAU, OLP and BMS has gradually attracted researchers attention, but the specific mechanism has not been completely determined. This narrative review describes the potential neurobiological mechanism of oral mucosal diseases and detailed psychological factors after introducing relevant research into psychological factors and oral mucosal diseases. Future research strategies and innovations needed to understand and treat oral mucosal diseases and psychological factors, as well as how to prevent oral mucosal diseases by regulation of the neuroendocrine system, are also discussed.

OBJECTIVE: To test the hypothesis that cardiovascular diseases and risk factors are associated with ulcer relapse in after-retirement patients with recurrent aphthous stomatitis.
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.

BACKGROUND: The pain caused by recurrent aphthous stomatitis (RAS) and the recurrent nature of RAS lead to diminished quality of life for RAS patients. An alternative treatment for RAS is the oral administration of the Chinese herbal medicine Zhibai Dihuang pill (ZBDHP). Our study aims to investigate the clinical efficacy of ZBDHP when used in combination with Western medicine (WM) for the treatment of RAS and its effectiveness in preventing the recurrence of RAS.
METHODS: Following the PRISMA 2020 guidelines, we conducted a literature search on 7 electronic databases according to predefined criteria. The methodological quality of randomized controlled trials (RCTs) was evaluated based on the Cochrane Handbook, and data analysis was performed using RevMan 5.3 software.
RESULTS: A meta-analysis which included 7 studies and 669 participants in total was carried out in this study. The quantitative analysis revealed that the combined treatment of ZBDHP and WM has witnessed significantly improved overall clinical efficacy (RR = 1.20, 95% CI [1.12, 1.28], P < .05), reduced recurrence rate (RR = 0.24, 95% CI [0.13, 0.45], P < .05), decreased ulcer area (MD = -0.75, 95% CI [-0.91, -0.59], P < .05), and reduced pain visual simulation score (MD = -0.42, 95% CI [-0.52, -0.33], P < .05). No significant heterogeneity was observed among the studies. Qualitative analysis showed that the combination therapy significantly reduced serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 and interleukin-10, shortened ulcer healing time and pain disappearance time, with no adverse effects observed.
CONCLUSIONS: It was found that the combination of ZBDHP and WM is more effective in treating RAS than the use of WM alone, which thus provides clinicians with a more optimal treatment option. However, due to limitations in the methodological quality of the included original studies and the small sample size, we hold the opinion that more rigorous and scientific clinical trials are needed to further evaluate the efficacy of ZBDHP in treating RAS.

OBJECTIVE: To elucidate the effect of Jiaweidaochi powder on the Th1/Th2 ratio in rats with recurrent aphthous ulcers (RAU).
METHODS: 40 Sprague-Dawley rats were included in this study, randomly divided into a control group, a model group, and three treatment groups (0.5 g/ ml, 1 g/ml, 2 g/ml Jiaweidaochi powder). The RAU model of rats was established by autoantigen injection. The effects of Jiaweidaochi powder on the expression of INFG, IL-4, TBX21, and GATA3 mRNA were detected by real-time PCR. The expression of IFN-γ, IL-4, and IFN-γ/IL-4 proteins in oral ulcer tissue and serum of rats were analyzed by Western blot and ELISA, respectively. The proportion of Th1 cells and Th2 cells in RAU rats was analyzed by flow cytometry.
RESULTS: Jiaweidaochi powder reduced the number, diameter, and duration of oral ulcers in RAU rats. Real-time PCR showed that middle and high-dose Jiaweidaochi powder decreased the expression of INFG TBX21 mRNA and increased the expression of IL-4 and GATA3 mRNA in the oral tissue of RAU rats. ELISA and western blot confirmed that the expression of IFN-γ protein was significantly decreased, and the level of IL-4 protein was increased both in oral tissue and serum of RAU rats treated with middle or high doses of Jiaweidaochi powder. Flow cytometry found that the Jiaweidaochi powder decreased the proportion of Th1 cells and increased the proportion of Th2 cells in RAU rats.
CONCLUSIONS: This study found that Jiaweidaochi powder promoted the balance of Th1/Th2 in RAU rats, contributing to the healing of RAU.

OBJECTIVE: This meta-analysis was designed to provide new insights into the relationship between Helicobacter pylori (H. pylori) infection and recurrent aphthous stomatitis (RAS).
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.
CONCLUSIONS: H. pylori infection may be a risk factor for the pathogenesis of RAS.

BACKGROUND: The present network meta-analysis aims to answer the question \"what is the best topical intervention for the treatment of recurrent aphthous stomatitis that can provide an acceptable pain relief and promote wound healing?\"
METHODS: From inception to October 2022, PubMed, Embase, Scopus, Cochrane Library, and China National Knowledge Infrastructure were searched to identify all potentially eligible randomized controlled trials. The primary outcomes were pain scores and/or healing time, while the secondary outcomes were the associated side effects. The Bayesian network meta-analysis accompanied by a random effect model and 95% credible intervals were calculated.
RESULTS: Forty-three randomized controlled trials with a total of 3067 participants, comparing 20 different topical medications, were included. Concerning pain reduction, the network meta-analysis failed to show any statistically significant differences when different topical treatments were compared together or even with a placebo at different time intervals. Except for doxycycline, which showed a statistically significant difference in terms of accelerating healing time, other topical interventions showed no statistically significant differences when compared with placebo or with each other.
CONCLUSIONS: Within the limitations of the current network meta-analysis, it seems that: A low to moderate quality of evidence showed no superiority of any topical treatment over others concerning pain reduction, although rank probability tests revealed sucralfate, doxycycline, hyaluronic acid, and chamomile as the most efficacious treatment options at different evaluation times. Hence, further well-designed clinical trials with larger sample sizes are warranted. Topical doxycycline was shown to be the most efficacious intervention in promoting healing of recurrent aphthous stomatitis.