Introduction
The term "aphtha" is derived from the Greek word "aphthi," signifying inflammation or a burning sensation. It was coined by Hippocrates, who initially used these terms to describe oral diseases.1 The term "recurrent aphthous stomatitis" (RAS) is appropriate for individuals in whom an identifiable cause cannot be determined, requiring a diagnosis based on exclusion.2
RAS is one of the frequently encountered conditions affecting the oral mucosa that primarily affects individuals in the age range of 10-40 years, with an estimated prevalence ranging from 5 to 25%.3 Painful, round ulcers with distinct red borders and a grayish-yellow pseudo membranous base seen in typically healthy individuals characterize RAS. A burning sensation may occur 2 to 48 hours before the ulcers develop.4 RAS exhibit a site predilection for the non-keratinized mucosa, occurring primarily on the buccal & labial mucosa, lateral and ventral tongue surfaces, and the floor of the mouth.5
RAS may be categorized into three forms: Minor (accounting for over 70% of cases), major (occurring in 10-15% of cases), and herpetiform (present in 5-10% of cases). These types vary in terms of morphology, distribution, severity, and prognosis.2 Despite its high prevalence, the precise etiology of RAS remains obscure.6 The prevailing theory on the development of RAS suggests a local immune dysfunction in which T-lymphocytes play a crucial role.7
Currently, there is no established treatment protocol for RAS, and the management primarily relies on alleviating pain, minimizing inflammation, and facilitating wound healing. Topical steroids are considered the standard first-line pharmacotherapy for RAS, however, prolonged use of steroids can lead to various side effects.2, 3, 4, 5, 6
Amlexanox (C16H14N2O4) is a topical anti-inflammatory drug authorized for the treatment of RAS. It acts by inhibiting the formation and release of histamine, tumor necrosis factor-α (TNF-α), and leukotrienes from mast cells, neutrophils, and mononuclear cells.8 Currently, 5% Amlexanox oral paste is the only therapeutic product for RAS approved by the Food and Drug Administration (FDA) US.9
Topical therapy solely does not result in diminution of a new lesion development and may not be an adequate therapy for patients with major RAS or those experiencing frequent episodes of multiple minor RAS.2, 10
Rebamipide is a commonly employed therapy for Behcet’s disease patients, particularly those presenting oral aphthous as the primary symptom.11 Furthermore, it may also be beneficial in the prevention and treatment of RAS. 12 The drug is easy to administer, exhibits patient compliance, and helps reduce both the count of aphthae and pain scores. It functions by reducing oxygen radicals, enhancing vascularity, and stimulating the production of protective prostaglandins in ulcerated mucosa, thereby expediting the healing process.12, 13
The evolving treatment strategy for RAS involves the topical application of 5% Amlexanox oral paste and the systemic ingestion of Rebamipide tablets. Published literature has demonstrated that 5% Amlexanox oral paste and Rebamipide tablets play a crucial role in the pharmacotherapy of RAS.8, 11, 13
Case Presentation
A 37-year-old male was referred by a private practitioner to our Outpatient Department for the evaluation of non-healing oral ulcers for the last 20 days. History revealed that he has been experiencing multiple episodes of oral ulcerations for the past one year. However, the frequency of ulcer episodes had increased in the past 3 months. His medical and family history was non-contributory, and the patient denied the intake of any systemic medications. There was no history of any fever, weight loss, hemoptysis, anemia, abdominal pain, or diarrhoea. The patient had sought advice from various private practitioners and had been prescribed medications. Past prescriptions included the topical application of Metrohex gel (0.25% chlorhexidine gluconate and 1% metronidazole), Turbocort oromucosal paste (triamcinolone acetonide 0.1%), and systemic intake of tablet Betnesol (Betamethasone, 0.5 mg twice daily) for 10 days. Nevertheless, the ulcers showed no improvement with the prescribed therapy. The general physical examination was non-contributory, with no systemic and nodal involvement.
Figure 1
(A) Ulcer on the left labial mucosa (B) Ulcer at the right lateral of tongue (C) Ulcer on the floor of mouth
Table 1
Summarizing the various forms of aphthous stomatitis
On intraoral examination, an ovoid shallow ulcer on the left labial mucosa measuring 1.5 cm × 1.2 cm was seen. Similar presenting ulcers were also seen on the right lateral border of tongue and floor of the mouth, roughly measuring 1.2 cm x 1 cm in diameter and 2 cm x 1.5 cm respectively. The ulcers were surrounded by perilesional erythema and covered with a yellowish pseudomembrane. Mild tenderness (VAS score of 7) and induration on palpation was also elicited [Figure 1 (A-C)].
A diagnosis of major RAU was given based on the history, symptoms, and clinical examination. The patient reported hematological, biochemical, and radiographic investigations that had been done a week prior, following the private practitioner's recommendation. Hematologic investigations including complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum levels of iron, and ferritin were in the normal range. The Mantoux test showed a non-reactive result, and a chest radiograph (PA) view revealed normal lung fields and bronchovascular markings bilaterally. The colonoscopy reports, which were normal and showed no signs of inflammatory bowel disease. The patient was prescribed topical application of 5% Amlexenox oral paste (lexenox oral paste) three times daily and Rebamipide (tablet Rebagen) 100mg TDS for 10 days. The patient was reviewed after 10 days and the ulcers showed complete healing [Figure 2 (A-C)]. There was no recurrences observed in the 6 month follow-up period.
Discussion
Recurrent aphthous stomatitis (RAS) is considered a chronic inflammatory oral mucosal disorder.14 Stanley has classified RAS into three distinct clinical variants. 15 The different types of RAS are summarized in Table 1. 1, 8, 14, 16, 17
The exact cause of RAS is unknown, necessitating careful clinical observation and offering various therapeutic options, albeit with limited relief.8, 18 Cell-mediated immunity plays a role in the immunopathogenesis of RAS. TNF-α, produced by T cells, macrophages, and mast cells triggers mucosal inflammation by promoting the endothelial cells adhesion and neutrophils chemotaxis.18 Various recognized predisposing factors encompass genetic alterations, nutritional and hematinic deficiencies, chronic mucosal trauma, smoking cessation, endocrine and immune dysfunction, food and drug allergies, and psychosomatic diseases like stress, anxiety, stress, and depression. RAS-like lesions may also be seen in various systemic conditions like inflammatory Bowel Disease and cyclic neutropenia, and syndromes such as Behcet’s syndrome, Reiter syndrome, PFAPA syndrome, MAGIC syndrome, and Sweet syndrome.2, 3, 8
The diagnosis of RAS relies on the patient's history and clinical features.10 Herpetic ulcers, traumatic ulcers, malignant ulcers, oral tuberculous ulcers, syphilitic ulcers, and RAS-like ulcers are given a place in the differential diagnosis of aphthous ulcers.19 Natah et al.20 proposed the diagnostic criteria for minor RAS.
The primary therapeutic objectives are to alleviate pain, diminish the size and duration of ulcers, and restore normal oral function. Secondary goals involve decreasing the frequency and severity of ulcer recurrences. Various treatments have been explored, encompassing topical agents, systemic medications, physical approaches, as well as natural and home therapies.17
Topical treatment is deemed effective for managing minor recurrent aphthous ulcers (MiRAU) and is also considered as a supplementary approach for treating major recurrent aphthous ulcers (MaRAU). Currently, recognized effective topical treatments include topical medication, cryotherapy, laser therapy, and cautery.21 However, systemic pharmacotherapy (systemic steroids, azathioprine, colchicine, cyclosporine, thalidomide, levamisole) is allocated for patients with multiple minor aphthae, major RAS, and cases refractory to topical therapies.8, 22
Amlexanox exhibits anti-inflammatory, anti-allergic, and immunomodulatory properties.21, 23 It inhibits the formation and release of histamine and leukotrienes from mast cells, neutrophils, and mononuclear cells, possibly through an increase in intracellular cyclic AMP content in inflammatory cells and a membrane-stabilizing effect, or by inhibiting calcium influx.17, 23 5% amlexanox is the most effective pharmacotherapy for minor RAS, demonstrating a triple effect in preventing recurrence, reducing healing time, and alleviating pain. It is particularly effective when applied from the prodromal phase until complete healing, four times a day, yielding statistically significant results.20, 22
Amlexanox oral paste is specifically prepared to enhance mucosal adherence, thus, minimizing the risk of the drug being rubbed or rinsed away by saliva, as indicated by the manufacturer's instructions (Macleods Pharmaceuticals, Mumbai, India).24 Topical application of 5% amlexanox has infrequently demonstrated adverse effects like mild and transient tingling sensations, a metallic taste, xerostomia, and bleeding at the application site.8, 25
Rebamipide 2-(4-chlorobenzoyllamine)-3-[2-(1H)-quinolinon-4-yl) is a mucoprotective medication that preserves the vitality of epithelial cells and facilitates the restoration of damaged tissue through multi-modal actions.8, 11, 26
It enhances the preservation of existing epithelial cells by increasing the content of soluble mucus, increasing the gastric concentrations of PGE2 and PGI2, down regulation of 15- hydroxyprostaglandin dehydrogenase, increasing mucosal blood flow through enhanced nitric oxide synthase activity, decreasing the expression of neutrophil adhesion molecules (CD11b/CD18), inhibiting the secretion of TNF; α by inhibiting the synthesis of inflammatory E; selectin and has a free radical scavenging effect on reactive oxygen species. It also restores the damaged tissues by increasing the expression of epidermal growth factor and EGF receptors. This eventually leads to angiogenesis, increased production of granulation tissue, and epithelization of ulcer healing.12, 27
The mechanism of action of Rebamipide is illustrated in a flowchart [Figure 3].
Rebamipide has demonstrated effective improvement in various mucosal conditions, including gastric ulceration and erosions.28 Rebamipide also decreases both the number and pain of oral ulcers in patients with Behcet’s disease. 13 Published studies have demonstrated the efficacy of Rebamipide in the pharmacotherapy of Behcet’s disease and RAS,8, 12, 13 supporting its recommendation as a long-term treatment for recurrent oral aphthous ulcers.16
Uncommon mild gastrointestinal side effects, such as nausea, vomiting, diarrhea, and constipation, have been observed with Rebamipide therapy.8
Conclusion
Extensive research has confirmed that RAS has a multifactorial etiology, and there is no established and precise treatment approach for the condition. Given that the primary concerns for most patients are pain and irritation resulting from aphthous stomatitis, the majority of treatments focus on relieving pain and addressing the patient's symptoms.
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