Recurrent aphthous stomatitis, or RAS is the most common inflammatory oral mucosal disease with the recurrent and painful, often shallow ulcerations characterized by recurrent lesions which have serious impacts on the quality of life of patients [1].  

They are most characteristically localized to the non-keratinized oral mucosa, or more correctly the buccal and labial mucosa, ventral tongue, and soft palate. Clinically, RAS is divided into three: minor, major, and herpetiform ulcers, characterized by differences in size, number, and healing time and morbidity with scarring [2]. Minor aphthous ulcers represent 70%–85% of all RAS with healing that occurs within 10–14 days without scars. The major ulcers and herpetiform variants have greater morbidity and a longer healing time [3].

Despite its very high prevalence, affecting up to 25% of the world's population, the etiology of RAS remains obscure; hence, its management continues to be a challenge in clinical practice [4]. A multifactorial origin is accepted, including genetic predisposition; immune dysregulation; nutritional deficiencies, such as zinc, folate, and vitamin B12 deficiencies; stress; hormonal imbalance; and local trauma. For example, systemic diseases such as inflammatory bowel disease, celiac disease, and Behçet's syndrome, as well as infectious agents such as Helicobacter pylori and certain viruses have been shown to contribute to its pathogenesis [4-6]. Amplification of mucosal inflammation due to oxidative stress and immune imbalance is central to the pathogenesis of RAS, thereby further complicating the etiology.

Current approaches to diagnosing RAS are mainly clinical, employing exclusion of other conditions that could cause oral ulcerations, such as infections, autoimmune diseases, and neoplastic conditions. Although histopathology and immunological markers provide an adjunctive framework, there are no biomarkers specifically identifiable with RAS and, therefore, a need for improved diagnostic tools [7-8].

Management strategies for RAS are mainly focused on palliative care, such as alleviation of symptoms, promotion of wound healing, and prevention of recurrence. Topical interventions, especially corticosteroids, antiseptic mouthwashes, and mucoadhesive formulations, are the cornerstone of first-line treatments because they act locally with lesser systemic side effects [8]. Systemic interventions, such as immunomodulators, colchicine, dapsone, and thalidomide, are used in the treatment of severe resistant cases but their use is limited by adverse effects. The list of emerging modalities gaining acceptance include low-level laser therapy and probiotic supplementation for modulating local inflammation and promoting mucosal healing [9-12]. Further research is also currently being conducted using natural and plant-based agents, like caffeic acid and zinc sulfate, which also indicates an increasing trend toward safer and more economical alternatives. However, the lack of consistency in therapeutic responses in different populations of patients and the failure to reach any consensus on standardized treatment protocols still continue to impede optimum care.

In light of the enormity of the clinical burden imposed by RAS and in view of the persistence of gaps in the understanding of its pathophysiology and effective management, a comprehensive review of recent developments in diagnosis and treatment assumes a great deal of importance. This systematic review brings together the best evidence to date to outline emerging techniques of diagnosis and evolving methods of therapy and provides clinicians with a solid framework for an evidence-based approach towards management of RAS and identifies areas that need further investigation

PECOS Protocol and PRISMA Framework

The PECOS framework was created to establish criteria for eligibility in this systematic review. Therefore, all literature pertinent to the diagnosis and treatment of recurrent aphthous stomatitis (RAS) would be included. It was set out: Population(P) is defined as patients diagnosed with RAS at any age, gender, or location. The Exposure (E) was diagnostic and therapeutic interventions that were used to treat RAS. Comparators will include no treatment, placebo, and standard care. The Outcomes or results (O) assessed are based on the key endpoints: pain improvement, healing period of ulcer, and recurrence rate. Secondary outcomes include adverse events and quality of life. The study design (S) is limited only to RCTs for high-quality evidence. This protocol was developed strictly to the PRISMA standards [13] with a standardized process in identifying, screening, and including studies to assure maximum transparency and replicability.

Selection Criteria

The inclusion criteria were RCTs on diagnosis or treatment of RAS published as peer-reviewed articles in the English language. Topical and systemic therapies, including new approaches like laser and probiotic therapy, or advanced diagnostic methods, were included in this review. Articles needed to describe primary outcomes like relief of pain, healing time of ulcers, or recurrence rate sufficiently in detail, to be synthesised.

Exclusion criteria included observational studies, case reports, reviews, non-RCT designs, and studies where full texts were not available. Trials involved on conditions other than RAS, oral lichen planus, or Behçet's disease. Also excluded were studies with inadequate outcome data, duplicate publications, or pediatric-only studies with no subgroup analysis.

Database Search Protocol

The literature search was performed in six databases including PubMed, Scopus, Embase, Web of Science, Cochrane Library, and CINAHL. Boolean operators and MeSH terms were used to ensure maximum sensitivity and specificity in searching. Keywords "recurrent aphthous stomatitis," "oral ulcers," "treatment," "diagnosis, and "randomized controlled trials" were used along with Boolean operators of AND and OR and MeSH terms such as "Stomatitis, Aphthous" and "Therapeutics" to search for the relevant reports to be reviewed (Table 1). Inclusions of filters placed in terms of languages, type of study (RCTs), and publication status (peer-reviewed) was put in place.

Protocol for Data Extraction

A preconceived data extraction form would ensure consistency in the process of data extraction. The two reviewers independently extracted data from the studies included and resolved any discrepancies on consensus or with the involvement of a third reviewer. The items extracted were: features of studies: authors, year, place, design; population characteristics; sample size; age, gender; intervention characteristics; type, dose, duration; comparator; outcome measures: scores, ulcer size, healing time, recurrence rates, adverse events; statistical methods; and key findings. Authors of studies were contacted in order to clarify missing or ambiguous data, if feasible.

Bias Assessment Protocol

The methodological quality of included RCTs was assessed using the Cochrane Risk of Bias 2.0 tool [14]. Each study was judged across five domains - the process of randomization, deviations from the implemented interventions, loss of outcome data, measurement of outcomes, and reporting selection. For each domain, bias was rated as "low," "some concerns," or "high," and an overall risk-of-bias judgment was assigned. A two-step approach was undertaken with disagreements resolved either by discussion or through third-party adjudication. This ensured thorough scrutiny and thus reliable assessment of the study's quality.

248 records were identified through database searches with no record found from the register search (Figure 1). After removing 41 duplicate records, screening was done for 207 records. No record was excluded at the screening stage. Of these, 207 reports were sought for retrieval and 39 reports could not be retrieved. The remaining 168 reports were thus eligible for assessment. At the stage of eligibility, 71 studies were excluded because they did not meet PECOS criteria, 47 were excluded because they were off-topic and 40 were excluded because they were in-vitro studies. In the end, 10 studies [15-24] met the inclusion criteria and were included in the review.

Legend

Table 1: Search strings utilised across the databases

Demographic variables assessed

Table 2 shows the demographic characteristics of the included studies [15-24]. Studies cover a wide range of dates since the year of publication ranged from 2009 [20,24] to 2024 [23]; hence, studies reflect historical perspectives as well as the latest advancement in terms of managing RAS. As far as geographical location is concerned, different research activities were carried out in different locations such as Egypt [15], Italy [16], Iran [17, 21, 22, 23], China [18], the USA [19], Brazil [20], and Israel [24], indicating that RAS issues are of interest in different populations and under different healthcare provisions.

The sample size varied considerably as well, with the smallest involving only 21 participants [20], in a small open label investigation, to the highest number of 160 participants [19] in an increased size and scope of the placebo-controlled investigation. The other mean participant ages were heterogeneous because pediatric-focused studies reported a mean age of 8.5 years [16], while other studies that focused on adults had mean ages that ranged from 29.7 years [23] to 40.0 years [17]. One study did not report the mean age of participants, and that may limit interpretability for demographic analyses [19].

Gender distribution in the case studies also skewed predominantly female. Male to female ratios included 19:27 [17] and 21:39 for adult groups [15]. Some reported separate pediatric and adult ratios [15], while others did not provide gender data [21, 22, 23]. This variability suggests there may be gender differences in RAS prevalence and health-seeking behavior.

The follow-up periods also varied considerably, ranging from short-term assessment of 7 days [17, 18, 21, 22, 23] to longer time durations of 6–12 months [20, 24] and whether immediate therapeutic outcomes or recurrence rates at the end of several months later were being targeted. For example, those studies with a follow-up period of 6 months presumably followed the effects of interventions on recurrence rates [15, 24] while those of shorter duration centered on immediate efficacy in therapeutics and healing time [17, 21].

Table 2: Demographic Variables Assessed

Groups Assessed

Table 3 shows the technical characteristics of the included studies. The studies included various intervention and control groups, ranging from laser therapy and topical agents to systemic drugs and dietary supplements. Comparisons predominantly involved novel treatments like probiotics [15], atorvastatin [21], and caffeic acid [23] against traditional therapies or placebo groups. Several studies utilized emerging modalities such as laser therapy [16, 18] or dietary supplementation like vitamin B12 [24]. Such diversity in the approaches utilized in the RAS management exemplified the multifaceted aspects explored.

Table 3: Technical Characteristics of Studies

Primary Outcome Measure

The main outcome measured in most of the studies was reduction in pain and the size of the ulcer [15, 16, 17, 18, 21, 22, 23]. The other outcomes measured included time taken to heal [18], frequency of recurrence [19, 24], and rates of complete remission [20]. Several measures were consistently used, such as VAS for pain and the direct diameter of the ulcer, allowing for standard measurement across the studies [16, 17, 21].

Figure 1: PRISMA flowchart representation of the study selection process

Intervention Details

The interventions used were highly heterogeneous: topical applications included mucoadhesive patches containing cinnamaldehyde [22] or zinc sulfate [17] and tablets containing caffeic acid [23] or atorvastatin [21]. Systemic therapies included thalidomide, colchicine, and pentoxifylline [20], while the laser therapy protocols showed diode lasers with different parameters [16, 18]. The intervention durations ranged from 3 days [16] to 6 months [24]. Thus, they employed ranging goals from short-term alleviation of symptoms to long-term prevention of recurrence.

Results observed

The majority of the studies reported significant improvement in their primary outcomes for intervention groups versus controls. For example, laser therapy showed marked pain relief and reduction of ulcer size at day 4 [16, 18]. Topical zinc sulfate and atorvastatin also proved to be cases of notable ulcer size reduction and pain relief in 7 days [17, 21]. Caffeic acid was rapid, as improvements were noted from day 2 onwards [23]. Vitamin B12 resulted in a reduction in recurrence rates and a 74% ulcer-free status for participants during the 6-month study [24]. On the other hand, multivitamin supplementation had no impact on ulcer frequency or duration [19].

Adverse Events Recorded

Most of the reviewed studies did not report adverse events [15, 16, 17, 18, 21, 22, 23, 24]. Thalidomide and dapsone-based systemic treatments were associated with significant side effects, involving potential toxicities [20]. The absence of reported adverse effects by newer topical treatments creates safety profiles for the interventions, which may potentially offer a significant advantage in clinical practice.

Figure 2: Bias assessment protocol

Statistical Methods Used

Rigorous statistical analysis was done on the data. Non-parametric tests were used, such as Mann-Whitney U and Friedman tests on non-normal distribution [16, 17, 21, 22, 23]. Repeated measures tests were further used to evaluate longitudinally collected data. A generalized estimating equation for multivariate comparisons was applied. Advanced statistical models like ANCOVA and linear mixed models gave strong evaluations of multivitamin efficacy [19].

Quality assessment

Bias assessment indicated considerable variability across studies in terms of methodological rigor (Figure 2). Most of the studies were low risk in almost all domains, including randomization, for instance, [16, 20, 21], and outcome measurement, for example, [17, 21]. However, some concerns were observed in terms of deviation from intended interventions, for instance, [15, 16, 18], and missing data handling, for instance, [15, 16, 19]. Generally, studies like [15, 20, 21] demonstrated a very low risk throughout and, therefore, high methodological quality; studies such as [16, 19, 22] showed concerns across various domains and represent moderate limitations

Several of the studies included herein, such as Aggour et al. [15], Ghorbani et al. [17], Molania et al. [21], Molania T et al. [22], and Salehi et al. [23], showed significant pain and ulcer size reductions in patients with RAS, which indicated these topical and oral interventions were similarly effective. Differences in the rate and extent of improvement in symptoms are also observed within these studies; for example, Salehi et al. [23] reported improvements as early as day two with caffeic acid, while Ghorbani et al. [17] and Molania et al. [21] achieved important outcomes on day three or later with zinc sulfate and atorvastatin, respectively.

Bardellini et al. [16] and Huo et al. [18] investigated laser therapy, both finding positive efficacy regarding pain attenuation and reduction in size of ulcers; however, healing outcomes were relatively less pronounced in Huo et al. [18], making its results slightly less comparable to other topical and oral treatments. Systemic therapies tested in the study of Mimura et al. [20] proved to be effective for the most severe forms of RAS but were hampered by adverse events and marked a difference from safer topical and oral therapies noted in other studies.

Vitamin B12 supplementation, studied by Volkov et al. [24], and probiotics examined by Aggour et al. [15], showed long-term benefits, including reduced recurrence rates, and closely matched in their outcomes. On the other hand, Lalla et al. [19] found that multivitamin supplementation did not significantly impact a reduction of RAS episodes or duration, thus differing from the other treatments examined.

RAS management does not follow an accepted standardized procedure [25]. Treatment is generally aimed at reducing the impact of the lesions for as long as possible and maintaining a good side-effect profile [26]. In general, treatment approaches are designed according to the degree of pain, number of episodes, and the patient's overall medical condition and tolerance to drugs [4]. Pre-treatment evaluation should involve determination of the predisposing factors like nutritional deficiencies or stress, which is believed to be a fundamental step before proceeding to targeted therapy [4].

The following are considered fundamental goals for treatment: reduce symptoms; limit size and number of ulcers; promote healing; increase periods without recurrence [2, 4]. RAS is usually well tolerated and can be managed by simple treatments that include NSAIDs and topical application of corticosteroids: benzydamine and chlorhexidine mouthwashes to reduce inflammation and prevent bacterial secondary infections [27]. In some cases, topical tetracycline is used in conjunction with corticosteroids. For major aphthous ulcers and the most severe episodes, a short course of systemic steroids, prednisone for example, may be needed, but long-term use is generally avoided due to the risk of side effects [28]. The treatment of herpetiform ulcers is similar to that of minor aphthous ulcers.

Chlorhexidine gluconate mouthwash and topical corticosteroids are the most popular agents for decreasing the severity and duration of aphthous ulcers. They do not, however seem to affect the recurrence rate [29]. Chlorhexidine mouthwash reduces bacterial colonization, protecting against secondary bacterial infections and promoting ulcer healing [2]. Topical corticosteroids may also be most effective if administered during the prodromal phase of the ulcer, when tingling or burning occurs, potentially halting progression of the ulcer itself [30].

Our systematic review findings exhibit both convergence and divergence with other reviews carried out in this regard [31-36]. Comparative analysis brings out both areas of agreement and discordance. Both our review and Liu et al. [31] stressed the effectiveness of probiotics and laser therapy in treating RAS. Probiotics proved beneficial in long-term recurrence reduction [15, 24], with agreement with Liu et al. [31], which reported that probiotics are helpful for maintenance phases. Laser therapy was found to induce pain reduction and size decrease in our study [16, 18] according to Liu et al. [31], who and Amorim et al. [32], who supported laser therapy as being safe and applicable to treatment.

Our results on the efficacy of vitamin B12 in reducing recurrence rate and achieving ulcer-free status [24] are in agreement with Taleb et al. [36], who also reported sublingual B12 as effective, especially at a 1000 μg for six months. Moreover, our meta-analysis result showing that multivitamins were ineffective [19] is similar to the finding of Taleb et al. [36], who found no meaningful benefit with the use of multivitamins in RAS.

Curcumin's implication in pain relief and decrease in size of the ulcer was discussed by Al-Maweri et al. [33]. This relates to the overall positive results acquired from other plant-based treatments in this review, such as caffeic acid [23].

Contrary to our study, Mashrah et al. [35] did not find statistically significant variations in the pain diminution or healing period between topical treatments and suggested that some interventions such as zinc sulfate [17], atorvastatin [21], and cinnamaldehyde [22] may not be more significant than others. Similarly, although doxycycline was identified as the most potent treatment for healing in Mashrah et al. [35], our systematic review also did not find or report any evidence about doxycycline.

Our review was able to identify significant benefits from laser therapy for reduction in size of ulcers and relief of pain [16, 18], although Amorim et al. [32] reported discrepancies in laser parameters and challenged future studies, representing some methodological drawbacks to the evaluation of the treatment. Furthermore, Wang et al. [34] addressed the complexity of RAS pathogenesis but failed to emphasize interventions, which is not the case in our intervention-oriented analysis.

Limitations

This study had several limitations, especially due to the heterogeneity of interventions, outcome measures, and study designs. The used studies applied very diverse treatment modalities-the topical agents and systemic therapies, laser, and dietary supplements, among others-making direct comparisons impossible. Furthermore, although most of the reports showed high efficacy in pain and ulcer size reduction, long-term endpoints like recurrence were sporadically assessed. Also, methodological issues with some studies such as failure to maintain intent-to-treat interventions and partial handling of data might have led to bias, which ultimately affected the generalizability of findings. Lastly, in many reports, adverse events were not reported, meaning that the safety profiles of the interventions may not have been reflected, underestimating potential risks.

Recommendations

As such, well-designed large-scale randomized controlled trials should be undertaken with standardized protocols for intervention and standardized outcome measures and standardized duration of follow-up to better enhance comparability. Diverse populations should be included in the studies with regard to efficacy both in the short term and later on, especially concerning recurrences or improvement of quality of life in patients. Clearly, more research is needed on the safety and efficacy of novel therapies such as probiotics, laser therapy, and plant-based agents, especially in combination or as adjuncts to traditional treatments. Apart from efficacy, rigorous reporting of adverse events would also greatly clarify safety profiles. Advanced statistical techniques and robust methodologies also may enable subsequent findings to be made more reliable, hence helping in developing evidence-based management strategies for recurrent aphthous stomatitis.

The reviewed studies demonstrated the benefits of new therapies with probiotics, laser therapy, and other plant-based compounds in the management of RAS. Although systemic treatments appeared to be beneficial for more serious cases, the side effects restricted their application. Topical agents such as zinc sulfate and caffeic acid were discovered to be safe for application in effective pain alleviation and size reduction of ulcers; such avenues may, therefore, present bright opportunities for future study and applications. However, multivitamin supplementation showed very low efficacy, again underlining the necessity for targeted interventions in view of mechanistic insights. The obtained findings underscored the importance of personalized approaches in optimizing RAS management strategies.

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