Efficacy and safety of thalidomide for recurrent aphthous stomatitis: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is considered as the most common oral mucosal lesion affecting up to 25% of people worldwide. Thalidomide has been reported for the treatment of RAS, but the evidence has not been systematically evaluated. We first systematically reviewed the efficacy and safety of thalidomide for the treatment of RAS. METHODS: We searched The Cochrane Library, PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wanfang Data, and VIP information from inception to December 2023. Randomized controlled trials (RCTs) comparing thalidomide with control for RAS were included in the analysis. The primary outcome were complete response and overall response, and the secondary outcome were recurrence interval (RI), ulcer number and size, healing time, visual analogue scale (VAS), immunological data, and adverse events. Meta-analysis was conducted using the Review Manager 5.4 software. RESULTS: Twenty-one trials involving 1668 patients were included in this review. The results of our meta-analysis showed that thalidomide significantly improved the complete response rate and overall response rate, prolonged the recurrence interval, accelerated the healing process, reduced the number and size of ulcers, and lowered TNF-α levels in the treatment of RAS. However, thalidomide significantly increases adverse events. RESULTS: Thalidomide has a significant benefit in the treatment of RAS. However, considering the potential side effects of thalidomide, it may be an optimal treatment option for major RAS patients or cases that do not respond to topical agents. TRIAL REGISTRATION: PROSPERO registration number: CRD42024495038.

Dietary Antioxidant Index and the Risk of Recurrent Aphthous Stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common condition that affects the oral mucosa. Antioxidants are crucial in neutralizing free radicals in the body and may have a preventive role against RAS. This study aims to examine the association between dietary antioxidant index (DAI) and RAS occurrence. METHODS: This cross-sectional study was conducted on 144 individuals with RAS and 135 individuals without RAS. The dietary intake of the participants was assessed using the food frequency questionnaire. The DAI was applied to measure the antioxidant capacity of the diet. Logistic regression models were applied to assess the link between RAS and DAI after adjusting the confounding variables. RESULTS: There was a significant negative association between RAS and DAI of zinc (OR = 0.639, CI95%: 0.456-0.896, P = .009) and total score of DAI (OR = 0.802, CI95%: 0.682-0.944, P = .008) after adjustment for age. The results remained significant after further adjustment for body mass index and calorie intake. CONCLUSION: The present study indicated a possible negative association between the risk of RAS and the DAI score as a measure of the antioxidant potential of diet. Further studies are warranted.

The Relationship Between Iron and Zinc Deficiency and Aphthous Stomatitis: A Systematic Review and Meta-Analysis.

Background: Recurrent aphthous stomatitis (RAS) is known as the most common ulcerative lesion in the oral mucosa. Aphthous has an unknown etiology and is considered a multifactorial disease. This study was conducted to investigate the relationship between iron and zinc deficiency and the occurrence of RAS. Materials and Methods: This systematic review and metaanalysis was performed according to the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines. Data were obtained through an electronic search in international databases, including PubMed, Medline, Embase, ISI Web of Science, Scopus, Springer, ProQuest, ScienceDirect, Clinical Key, and Google Scholar, and domestic Persian databases, including SID, Magiran, and Iran Medex, until April 2021. New-castle Ottawa Scale (NOS) was used to determine the eligibility of studies by evaluating the title and summary of the articles and a partial evaluation of the full text. Comprehensive Metaanalysis (CMA) software was used for data analysis. Results: Initially, a total of 1383 articles were retrieved, of which 941 were duplicate studies. Further, 384 studies were excluded after evaluation of the title and abstract, and 36 studies were excluded after considering the inclusion and exclusion criteria. Finally, 22 articles were included in the metaanalysis. The standardized mean difference value was -0.421 (-0.623--0.20) for iron factor, -0.309 (-0.463--0.154) for iron factor in men, -0.483 (-0.375--0373) for iron factor in women, and -0.955 (-0.282--1.628) for the zinc factor. Conclusion: In general, the serum iron level (in general, in male and female patients separately) and the zinc serum level in patients with RAS were significantly lower than those of healthy people.

Treatment of recurrent aphthous stomatitis with oral roflumilast, a multicenter observational study.

INTRODUCTION: Severe recurrent aphthous stomatitis (RAS) represents a therapeutic challenge because of its impact on the patient's quality of life. Additionally, no approved systemic therapies are available. Roflumilast, a phosphodiesterase-4 inhibitor, has shown promise in other inflammatory dermatological conditions. This study aimed to assess the characteristics, effectiveness, and safety of roflumilast in treating RAS in routine clinical practice. METHODS: This is a single cohort ambispective observational study conducted in five Spanish centers. Twenty-two patients with RAS treated with roflumilast participated. Data collection included demographic, clinical, and outcome variables. Statistical analysis compared the outcomes of 12 weeks of roflumilast treatment with a similar prior period without treatment. RESULTS: During treatment with roflumilast, a significant reduction in flare-ups (88%) and oral ulcers (94%) was observed compared to the untreated period. A reduction in pain (66%) and ulcer duration (63%) was observed. Adverse effects (AEs) occurred in 13 patients, predominantly headache and gastrointestinal disturbances. Most of these were self-limiting or manageable with dose adjustment. Treatment was withdrawn in three cases, mainly because of AEs. CONCLUSIONS: This study suggests that roflumilast may effectively treat RAS by reducing the number of flare-ups and ulcers, their duration, and the symptomatology produced by the ulcers. In addition, roflumilast has a good safety profile, is well tolerated at low doses, and does not require close monitoring. These characteristics and its favorable economic profile make roflumilast a promising therapeutic option in this pathology.

Effectiveness of low-level laser therapy in reducing pain score and healing time of recurrent aphthous stomatitis: a systematic review and meta-analysis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common chronic inflammatory oral disease that negatively impacts the quality of life. Current therapies aim to reduce pain and healing process yet challenges such as rapid loss due to salivary flushing in topical drugs and adverse effects due to prolonged use of systemic medications require further notice. Low-level laser therapy is reported with immediate pain relief and faster healing thus preserving the potential for optimal treatment modalities. This review critically analyses and summarizes the effectiveness of LLLT in reducing pain scores and healing time of RAS. METHODS: A systematic search was conducted in ScienceDirect, PubMed, and Scopus using keywords of low-level laser therapy, photo-biomodulation therapy, and recurrent aphthous stomatitis. RCTs between 1967 to June 2022, presenting characteristics of the laser and reporting pain score and/or healing time of RAS after irradiation were included. Animal studies and recurrent aphthous ulcers with a history of systemic conditions were excluded. Studies were critically appraised using the RoB 2 tool. A meta-analysis was performed using inverse variance random effects. RESULTS: Fourteen trials with a total of 664 patients were included. Reduced pain was reported in 13 studies, while shortened healing time was presented in 4. The pooling of two studies after CO2 irradiation demonstrated faster healing time compared to placebo (MD - 3.72; 95% CI - 4.18, - 3.25). CONCLUSION: Pain score and healing time of RAS were reduced after irradiation with LLLT. RoB resulted in "some concerns" urging well-designed RCTs with larger samples to further assess each laser application for comparison. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022355737.

A bibliometric study on research trends and hotspots of recurrent aphthous stomatitis.

Background/purpose: Recurrent aphthous stomatitis (RAS) is a common oral mucosal disease. Despite a variety of scientific articles have been available till date, merely a few scientometric analyses have been systematically carried out in this field. The objective of this study was to recognize the hotspots and research trends related to RAS via bibliometric approach. Materials and methods: The Elsevier's Scopus database was searched to retrieve qualified literature through an advanced search strategy on 9 Feb 2023. The basic information was collected as following: article type, publication year, journals, impact factor, the count of citations, citation density, keywords, authors, contributing institutions and country. Results: A list of 986 publications were identified from 1933 to 2022, and the number of citations for each paper varied from 0 to 283. A steady increasing trend in the number of documents could be observed each decade with the summit in 2010s. Controlled study (n = 334) and major clinical study (n = 192) were the most common types of study design. Scully C (n = 26) was identified as the most productive author. United States (n = 166) and Turkey (n = 101) top the list of dedicating countries. Conclusion: This report would offer profound insight into the current status of RAS research and serve as a reference source for anyone planning to enhance the quality of future work.

Depression, Anxiety, Stress, and Pain Severity in Patients With Recurrent Aphthous Stomatitis: A Cross-Sectional Study.

Background Recurrent aphthous stomatitis (RAS) is a chronic oral ulcerative condition with an elusive etiology that is associated with excruciating pain. Psychological factors have been suspected as a possible risk factor in its onset and development. Depression, anxiety, and stress play pivotal roles in how people experience pain. Hence, we aimed to explore the relationship between depression, anxiety, stress, and the severity of pain perceived due to recurrent ulcers in RAS patients. Materials and methods A cross-sectional comparative study was conducted on 248 patients, comprising 124 diagnosed with RAS and 124 healthy subjects without this oral condition. Patients from both of these groups were matched with regard to age and sex and recruited over a period of one year from a dental hospital in Bengaluru, India. Patients with any other oral lesions, painful oral conditions, or systemic and psychological illnesses were excluded. Depression, anxiety, and stress were assessed in these patients using the Depression Anxiety Stress Scale 21 (DASS-21). Utilizing a Visual Analog Scale, ulcer-related pain was assessed in patients with RAS. The data were analyzed using the chi-square test and Pearson's correlation test in IBM SPSS Statistics for Windows, Version 26.0 (released 2019, IBM Corp., Armonk, NY). Results The chi-square analysis showed that participants with RAS showed a statistically significant higher prevalence of extreme stress (n = 39, 31.5%), extreme anxiety (n = 82, 66.1%), and depression (n = 38, 30.6%) as opposed to those without this oral condition. A moderately positive correlation was observed in the Pearson's test between the severity of pain experienced and stress and anxiety (r = 0.65 and 0.60, respectively, p < 0.05), while a mild positive correlation was observed between the severity of pain and depression (r = 0.35, p < 0.05). Conclusion Depression, anxiety, and stress influenced the severity of pain in these lesions, dictating the need for a holistic approach that integrates psychological interventions in the management of such chronic oral conditions with psychological links.

Evaluation of the Effects of Punica granatum Flower Tablets on Pain and Healing of Minor Recurrent Aphthous Stomatitis: A Randomized Clinical Trial.

OBJECTIVES: The purpose of this study was to determine the therapeutic effect of the Punica granatum (PG) flower on recurrent aphthous stomatitis in comparison with corticosteroid therapy. MATERIALS AND METHODS: This cross-over randomized clinical trial was conducted on the patients who had been referred to Shiraz Dental School for their RAS in 2021. All the participants used both P. granatum flower tablets and Triadent a month apart for wash-out time and all compared themselves. In the experimental group, 30 patients received pomegranate flower tablets, three tablets daily, for 6 days. In the control group, oral paste Triadent has been prescribed three times a day for 6 days. The visual analog scale (VAS) and the size of RAS were evaluated on Days 0-6. Data were analyzed by SPSS version 21. The Wilcoxon test was used. RESULTS: The mean age of participants was 27.8 ± 14.77 years old. In this study, 15 patients (50%) were men and 15 patients (50%) were women. The mean value of VAS after using prescribed treatment in both evaluated groups on all days was significantly different such that the VAS values were lower for PG flower tablets than Triadent (p value < 0.05). The size of oral lesions in participants who used PG flower tablets was significantly less than those who used Triadent on all evaluation days (p value < 0.05) except on Day 1 (p value = 0.29). The descending slope of VAS from Days 1 to 6 for both Triadent and PG flower tablet users was significant and noticeable. (p value < 0.05). CONCLUSION: According to the result of this study, both P. granatum flower tablet and Triadent are useful in reducing the size, period of healing, and VAS of patients with RAS, but the PG flower tablet is more effective.

Natural and Synthetic Drugs Approached for the Treatment of Recurrent Aphthous Stomatitis Over the Last Decade.

Recurrent aphthous stomatitis (RAS) refers to a sore and frequently recurring inflammation of the oral tissues, distinguished by the presence of small ulcers that cause significant discomfort and cannot be attributed to any underlying disease. Different treatments have been used for RAS. This review aims to provide a comprehensive overview of the treatment options over the past decade for recurrent aphthous stomatitis (RAS), encompassing both natural and synthetic treatments. It will utilize clinical efficacy studies conducted in vivo and in vitro, along with a focus on the pharmaceutical approach through advancements in drug delivery development. We conducted a thorough literature search from 2013 to 2023 in prominent databases such as PubMed, Scopus, and Cochrane, utilizing appropriate keywords of recurrent aphthous stomatitis, and treatment. A total of 53 clinical trials with 3022 patients were included, with 35 using natural materials in their research and a total of 16 articles discussing RAS treatment using synthetic materials. All the clinical trials showed that natural and synthetic medicines seemed to benefit RAS patients by reducing pain score, ulcer size, and number of ulcers and shortening the healing duration.

A Novel Therapeutic Approach of 980 nm Photobiomodulation Delivered with Flattop Beam Profile in Management of Recurrent Aphthous Stomatitis in Paediatrics and Adolescents-A Case Series with 3-Month Follow-Up.

Background/Objectives: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal lesions and a very debilitating lesion, especially in paediatric and adolescent patients. The current pharmacotherapy offers a pain relief but not without side effects, and therefore photobiomodulation (PBM) can be an alternative therapy. To the authors' best knowledge, no published study has explored the efficacy of λ 980 nm laser PBM in the management of all RAS subtypes in paediatric and adolescent patients, and therefore, this prospective observational clinical study was conducted to bridge this gap by evaluating λ 980 nm laser PBM efficacy in symptomatic RAS management in paediatric and adolescent patients. The objectives were to evaluate (1) pain intensity alleviation; (2) wound healing rate; (3) wound size closure; (4) a complete resolution; (5) evidence of recurrence; and (6) patients' treatment satisfaction. Methods: The study's variables were assessed at the following timepoints: T0: pre-treatment; T1: immediately after first PBM session; T2: 5 hours (h) post first PBM session (via telephone call); T3: immediately after second PBM session (three days post first PBM session); T4: three-day follow-up (after complete PBM treatments); T5: two-week follow-up; and T6: three-month follow-up. The following PBM dosimetry and treatment protocols were employed: λ 980 nm; 300 mW; 60 s; 18 J; CW; flattop beam profile of 1 cm2 spot size; 18 J/cm2; and twice-a-week irradiation (72 h interval). Results: At T1, significant immediate pain intensity relief was reported. 33.33% recorded "4" and 66.67% reported "5" on the quantitative numeric pain intensity scale (NPIS), and this continued to improve significantly (83.33%) at T2. All the subjects reported "0" on the NPIS at T3, T4, T5 and T6. There was a significant reduction in the lesion surface area (>50% complete healing) at T3 compared to T0. Complete healing (100%) with no evidence of scarring and lesion recurrence observed at T4, T5 and T6. Very good patients' satisfaction was reported at all timepoints. Conclusions: This is the first report demonstrating λ980 nm efficacy in all RAS subtype management in paediatric and adolescent patients with a 3-month follow-up, whereby its PBM dosimetry and treatment protocols were effective from scientific and practical standpoints, and hence multicentre RCTs with large data are warranted to validate its reproducibility and to enrich the knowledge of PBM application in all RAS subtypes.

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.

Optimization and preparation of a compound cod liver oil film former agent: an orthogonal design.

Background: Cod liver oil has anti-inflammatory properties and could help regulate recurrent aphthous stomatitis (RAS). An orthogonal experiment was used to evaluate and improve the dosage form of compound cod liver oil, which has replaced the previously used liniment preparation based on film method. Methods: An orthogonal experiment was adopted, and the appearance and film-forming time of the film coating agents were used as indicators. The optimal ratio in the preparation process for the compound cod liver oil film agent was then optimized. A method for determination of compound cod liver oil film was established using High-Performance Liquid Chromatography (HPLC). Results: The results indicate that the blank films prepared using 55 mg polyvinyl alcohol (PVA) (PVA low), 45 mg of PVA (PVA medium), and 10 mg glycerol had the optimal performance, which was defined as PVAa. The drug-carrying film prepared from 3 mL PVAa (i.e., film-forming material with the optimal proportion), 30 mg dexamethasone acetate, and 30 mg metronidazole had the optimal performance. The verified sample has a complete and smooth appearance, uniform thickness and color, and no evident bubbles, which meets the requirements for a film agent defined in the Chinese Pharmacopoeia, 2020 edition. HPLC was used to determine the major components: dexamethasone acetate, metronidazole, and dyclonine hydrochloride, and the optimal separation effect was obtained. The method has advantages of good specificity, good linear results, high recovery rate, and good repeatability. Conclusion: This study proposes an optimized compound cod liver oil film former agent and preparation method. The results indicate that the compound cod liver oil film former agent had good performance, reflecting the high feasibility of this research method. The detection method of compound cod liver oil film was established by HPLC. The method was feasible, and the validity and stability of the formulation and preparation technology were guaranteed. The role of the newly developed agent in patients with RAS should be investigated further.

α-Mangostin hydrogel film with chitosan alginate base for recurrent aphthous stomatitis (RAS) treatment: study protocol for double-blind randomized controlled trial.

Background: Recurrent Aphthous Stomatitis (RAS) is a common ulcerative disease of the oral mucosa which is characterized by pain, and recurrent lesions in the oral cavity. This condition is quite painful, causing difficulty in eating, speaking and swallowing. Topical medications have been used for this condition, but the obstacle in using topical medications is the difficulty of achieving drug effects due to saliva wash out. This problem can be overcome by film hydrogel formulation which can protect the ulcer and reduce the pain to some extent. α-mangostin is a xanthone isolated from the rind of the mangosteen fruit. One of the activities of α-mangostin is anti-inflammatory effects, which operate through the characteristic mechanism of inhibiting the inflammatory response. This protocol study aims to investigate the efficacy of an α-mangostin hydrogel film with a chitosan alginate base for recurrent aphthous stomatitis (RAS) in comparison with a placebo over a period of 7 days. Study design: This is a two-arm, double blinding, randomized controlled trial enrolling patients with RAS. The efficacy test of α-mangostin Hydrogel Film will be tested against the placebo. Patients with RAS will be allocated randomly into the two arms and the hydrogel film will be administered for 7 days. The diameter of ulcer and visual analog scale (VAS) score will be used as the primary efficacy endpoint. The outcome measure will be compared between the two arms at the baseline, day 3, day 5, and at the end of 7 days. Discussion: The purpose of this clinical research is to provide scientific evidence on the efficacy of α-mangostin hydrogel film with a chitosan alginate basis in treating recurrent aphthous stomatitis. The trial is expected to improve our capacity to scientifically confirm the anti-inflammatory effectiveness of α-mangostin compounds in a final formulation that is ready to use. Trial registration: NCT06039774 (14 September 2023).

Association of neutrophil defects with oral ulcers but undetermined role of neutrophils in recurrent aphthous stomatitis.

Objective: Recurrent oral ulcers and severe periodontal diseases in patients with quantitative or qualitative neutrophil defects highlight the important role of neutrophils in maintaining oral mucosal barrier homeostasis. Recurrent aphthous stomatitis (RAS) is a common oral mucosal disease affecting up to 25% of the population, yet its etiopathogenesis remains unclear, and management is unsatisfactory. This review aims to gain insight into the pathogenesis of RAS. Design: This narrative review examines the characteristics of oral and blood neutrophils, the associations between neutrophil defects and the occurrence of oral ulcers, and the evidence for the involvement of neutrophils in RAS. To conduct the review, relevant literature was searched in PubMed and Google Scholar, which was then thoroughly reviewed and critically appraised. Results: Neutropenia, specifically a decrease in the number of oral neutrophils, impaired extravasation, and defective ROS production appear to be associated with oral ulcers, while defects in granule enzymes or NETosis are unlikely to have a link to oral ulcers. The review of the histopathology of RAS shows that neutrophils are concentrated in the denuded area but are latecomers to the scene and early leavers. However, the evidence for the involvement of neutrophils in the pathogenesis of RAS is inconsistent, leading to the proposal of two different scenarios involving either impaired or hyperactive neutrophils in the pathogenesis of RAS.

Systemic and local effect of oxidative stress on recurrent aphthous stomatitis: systematic review.

Recurrent aphthous stomatitis (RAS) is a chronic and recurrent inflammatory disease of the mouth. It is characterised by the appearance of painful ulcers in the oral mucosa. RAS is believed to be a multifactorial disease with genetic predisposition, environmental factors and alterations in the immune system. Oxidative stress, caused by an imbalance between free radicals and the antioxidant system, also appears to be involved in the pathogenesis of RAS. Several risk factors, such as smoking, iron and vitamin deficiency and anxiety, may contribute to the development of the disease. Understanding the underlying mechanisms may help in the prevention and treatment of RAS. We searched PubMed, Scopus and Web of Science databases for articles on oxidative stress in patients with RAS from 2000 to 2023. Studies analysing oxidant and antioxidant levels in the blood and saliva of RAS patients and healthy controls were selected. Of 170 potentially eligible articles, 24 met the inclusion criteria: 11 studies on blood samples, 6 on salivary samples and 7 on both blood and salivary samples. Multiple oxidative and antioxidant markers were assessed in blood and saliva samples. Overall, statistically significant differences were found between RAS patients and healthy controls for most markers. In addition, increased oxidative DNA damage was observed in patients with RAS. Patients with RAS show elevated levels of oxidative stress compared to healthy controls, with a significant increase in oxidative markers and a significant decrease in antioxidant defences in saliva and blood samples.

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 .

Efficacy and Safety of Propolis for Treating Recurrent Aphthous Stomatitis (RAS): A Systematic Review and Meta-Analysis.

The systematic review assessed the efficacy and safety of propolis for treating recurrent aphthous stomatitis (RAS). The review adopted the PICO framework to examine the effects of topical and systemic propolis on RAS while also comparing it to established treatments, placebos, or no treatment. The main focus was on the healing time, pain levels, adverse effects, the likelihood of ulcer recurrence, and accompanying symptoms such as redness. The team included randomised controlled trials (RCTs) and quasi-randomised trials, excluding case reports and studies on oral ulcers other than RAS. In May 2022, the review team comprehensively searched nine databases and trial registries following the PRISMA guidelines. The protocol was registered in the PROSPERO database under the registration number CRD42022327123. Two review authors conducted a comprehensive and autonomous search for pertinent papers and extracted essential data. Where data permitted, the team utilised Review Manager 5 to conduct a random-effects meta-analysis, assessing the risk of bias and heterogeneity of the included studies. Where possible, the GRADE Pro programme was used to assess the certainty of the evidence for all the outcomes. This review included 10 RCTs, comprising 825 participants aged between 18 and 69 years. Seven studies evaluated the efficacy and safety of propolis when applied topically, all of which used different formulations, concentrations, and carriers. The remaining three studies assessed systemic administration in tablet form. The duration of investigations ranged from 5 days to 3 years. The review team classified two studies as having an overall 'high risk' of bias, while the remaining studies were categorised as having an overall 'uncertain risk'. The overall certainty of the evidence was 'very low'. The results indicate that topical and systemic propolis may decrease the duration of healing, alleviate pain, and reduce redness in patients with RAS compared to a placebo. However, the certainty of the evidence is very low. These may be due to the high risk of bias, substantial heterogeneity, and limited sample sizes in the included studies. For these reasons, the results of this review should be interpreted with caution. Nevertheless, the limited number of adverse effects observed suggests that propolis may have a favourable safety profile when used for a short period in treating RAS.

Serum level of vitamin D in patients with recurrent aphthous stomatitis: A systematic review and meta-analysis of case control studies.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is an ulcerative condition with unknown etiology. The effect of vitamin D in the etiology of RAS is still a matter of controversy. In this study, we aimed at review the available evidence on the role of vitamin D deficiency in RAS etiology. MATERIAL AND METHODS: PubMed, Cochrane Library for Systematic Reviews, ISI Web of Science, Scopus, and EmBase were systematically searched for evidence on RAS and vitamin D up to January 2020. Retrieved records were screened and assessed by two of the authors independently. Newcastle-Ottawa scale was used to assess the quality of individual studies. AMSTAR tool was used for assessing the quality of the study. RESULTS: Eight studies including 383 healthy control and 352 patients with RAS were eligible for the meta-analysis. Serum vitamin D levels were significantly lower in RAS patients. The weighted mean difference was -7.90 (95% CI: -11.96 to -3.85). CONCLUSIONS: The results highlighted the importance of vitamin D deficiency in the etiology of RAS. However, more studies are needed to reach a robust decision. The observed association between vitamin D and RAS is probably due to the effect of vitamin D on the immune system.

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.