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Recurrent aphthous stomatitis

Recurrent aphthous stomatitis
Literature review current through: Jan 2024.
This topic last updated: Dec 18, 2023.

INTRODUCTION — Recurrent aphthous stomatitis (RAS), also known as "canker sores," is a common disease of unknown etiology that affects the oral mucosa and is characterized by the repeated development of one to many discrete, painful ulcers that usually heal within 7 to 14 days [1-6]. The lesions are typically 3 to 5 mm, round to oval ulcers with a peripheral rim of erythema and a yellowish, adherent exudate centrally. The frequency of ulcer development is highly variable, with some patients noting only an occasional lesion and others experiencing such recurrent episodes that they almost have continuous ulcer activity [1-6].

This topic will discuss the pathogenesis, clinical manifestations, and management of RAS. Other causes of oral and genital ulceration are discussed separately.

(See "Oral lesions".)

(See "Clinical manifestations and diagnosis of Behçet syndrome".)

(See "Approach to the patient with genital ulcers".)

(See "Acute genital ulceration (Lipschütz ulcer)".)

CLINICAL SUBTYPES — Clinical subtypes of RAS include:

Minor aphthous stomatitis – Minor aphthous stomatitis represents the most common form [7]. The ulcers are shallow, <1 cm in diameter, can be single or multiple, and have a typical round shape. They are often painful, last 5 to 10 days, and heal without scarring. Most patients report a few episodes in one year.

Major aphthous stomatitis – Major aphthous stomatitis is a less common form. Lesions are larger (usually >1 cm in diameter), deep, extremely painful, and last for weeks or months. In some cases, major aphthae may be misdiagnosed as a vesiculobullous disorder, squamous cell carcinoma, or granulomatous disease. The lesions may heal with scar formation. In patients with human immunodeficiency virus (HIV), recurrent aphthous ulcers are often >1 cm in diameter.

Herpetiform aphthous stomatitis – Herpetiform aphthous stomatitis is a rare variant characterized by multiple ulcers, similar to those of the minor form but much smaller (measuring a few millimeters), that also heal within 7 to 10 days. They resemble herpes simplex virus-related ulcers.

Severe aphthous stomatitis – Patients with this RAS variant are almost never ulcer free. They typically develop new ulcers when the previous ones are healing and often present with chronic pain, malnutrition, and weight loss. Both the keratinized and nonkeratinized mucosa may be affected.

EPIDEMIOLOGY — RAS is seen throughout the world, with the greatest prevalence in the Middle East, the Mediterranean region, and South Asia [6,8]. In North America, it occurs approximately in one out of five individuals and is the most common cause of acute recurrent oral ulcers. Most individuals first develop RAS during adolescence, although it is not uncommonly seen in children. The disease may continue into adulthood but typically wanes with increasing age. It is unusual for patients over the age of 40 to develop new-onset RAS.

PATHOGENESIS — The pathogenesis of RAS is unknown and is likely multifactorial [1-6]. Most investigations have supported the concept of immune dysregulation involving T cells and tumor necrosis factor (TNF)-alpha leading to an exaggerated, proinflammatory process or a relatively weak, anti-inflammatory response [9-16].

Genetic susceptibility – There appears to be a genetic predisposition to developing RAS, as it is common for patients to have a family history of RAS. Several specific human leukocyte antigens (HLAs) have been associated with RAS (HLA-A2, HLA-B5, HLA-B12, HLA-B44, HLA-B51, HLA-B52, HLA-DR2, HLA-DR7, and HLA-DQ), supporting the inherited nature of this disease [17]. In a systematic review and meta-analysis of 23 studies, polymorphisms of serotonin transporter (L/S), interleukin (IL) 10-819 (T/C), IL-10-592 (C/A), IL-10-1082 (G/A), IL-1-beta-511 (C/T), IL-6-174 (G/C), and IL-1-beta+3954 (T/C) were associated with susceptibility to RAS [18]. In another study that included 60 patients with RAS and 40 age- and sex-matched controls without RAS, gene polymorphisms for cytokines IL-10 at loci -592 and -819 and gene polymorphisms for transforming growth factor (TGF)-beta-1 at codon 10 were detected more frequently in patients with RAS [19].

Microbiota alterations – Studies examining the oral flora diversity in patients with RAS compared with controls without RAS provided conflicting results, with some reporting reduced normal commensal flora and increased prevalence of uncommon species (eg, Prevotella, Bacteroides) [20-23] The role of viral infections (eg, Cytomegalovirus, varicella zoster virus, and human herpes virus) remains uncertain.

Other factors

Micronutrient deficiency – Vitamin and mineral deficiencies (in particular, vitamin B12, vitamin D, iron, folate, and zinc) have been implicated in the pathogenesis of RAS, although the role of vitamin supplementation in the treatment of RAS remains uncertain and reserved to patients with documented deficiencies [24,25].

Food allergy Although certain foods may exacerbate RAS, and some studies have reported sensitivity to foods, preservatives, or other agents in 35 to 50 percent of patients with a diagnosis of RAS [26], there is no evidence to suggest an etiologic role for food allergy.

Drugs – Certain drugs (eg, beta blockers, methotrexate, nicorandil) have been documented to induce oral ulcers similar to aphthous ulcers [27,28]. The ulcers typically resolve when the drug is discontinued.

Smoking – Although a few observational studies reported a temporary increase of RAS in the first few weeks after smoking cessation, other studies have not found any relationship between RAS and smoking [8,29-31].

Stress – Emotional stress may lead to an exacerbation of disease [32].

Triggers – Many patients with RAS experience an exacerbation of their disease following trauma to the oral mucosa, such as biting the inside of the cheek or undergoing a dental procedure. In these patients, one or more ulcers will predictably develop in the area of trauma over the next couple of days [11,33]. Other possible precipitating factors include psychologic stress, anxiety, hormonal fluctuations, certain foods, and sodium lauryl sulfate-containing toothpaste.

CLINICAL MANIFESTATIONS

Age of onset – Most patients with RAS first experience oral ulcers during adolescence and early adulthood. They may develop one to several lesions, which are self-limited in nature, at a time. Patients may continue to develop lesions through middle age, but the frequency typically diminishes over time.

Morphology – Lesions of RAS have a very characteristic appearance [1-6]. They are discrete; round or oval; with an erythematous rim and adherent, yellowish exudate centrally (picture 1A-C).

Number and size of lesions Patients with minor aphthosis typically have one to five discrete ulcers limited to the oral mucosa that are <1 cm in diameter [4]. However, in patients with the major form, ulcers are >1 cm. The herpetiform variant is characterized by small ulcers (1 to 3 mm in diameter), often occurring in clusters. (See 'Clinical subtypes' above.)

Location – The oral lesions of RAS most commonly develop on the nonkeratinized oral mucosa, typically buccal and labial mucosae. The gingival sulci, lateral and ventral tongue, soft palate, and anterior pharynx may also be involved. The involvement of the keratinized mucosae, such as hard palate and attached gingivae, is much less common.

Time course of progression – A lesion typically progresses from a painful, pinpoint papule into an ulcer over a period of one to two days; patients are often able to identify lesions in this early stage and initiate treatment promptly. The ulcer gradually expands to its final size over the next three to four days and then stabilizes before beginning to heal. In some patients, lesions may come and go within four to five days, but in most individuals, they resolve in 10 to 14 days. Major ulcers may take four to eight weeks to resolve.

Most patients will go for weeks to months between episodes. However, some patients may report such frequent episodes that they almost always have at least one ulcer present. (See 'Management' below.)

Pain and systemic symptoms – The ulcers may be very painful and, in some cases, may interfere with the ability to eat, drink, and talk. Although patients may be very uncomfortable, only a few experience systemic symptoms or signs associated with outbreaks of their aphthous ulcers.

EVALUATION AND DIAGNOSIS

Clinical diagnostic criteria — The diagnosis of RAS is typically made clinically, based on patient history and physical examination.

Key elements in the diagnosis of minor RAS include [1-6]:

History of recurrent, self-limited, painful ulcers of the oral mucosa that heal within two weeks without scarring

Discrete, shallow, round to oval ulcers, usually <1 cm in diameter, with an erythematous rim and yellowish exudate (picture 1A-C)

Absence of systemic symptoms (eg, fever, malaise, myalgias, cervical lymphadenopathy)

Elements that suggest the diagnosis of major RAS include:

History of recurrent, extremely painful ulcers of the oral mucosa that last for weeks or months and may heal with scarring

Discrete, deep ulcers, usually >1 cm in diameter

Systemic symptoms generally absent

However, additional evaluation is required for patients presenting with systemic symptoms/comorbidities to exclude other conditions associated with oral ulcerations. (See 'Differential diagnosis' below.)

Patient evaluation

Patient history — A history of recurrent, self-limited oral lesions that demonstrate the characteristic appearance of discrete, round or oval ulcers with an erythematous rim and yellowish exudate and persist for several days to up to several weeks is characteristic of RAS. The history of developing an ulcer at a site of trauma is very common in patients with RAS.

Below is a list of suggested questions for patients with oral ulcers:

When did the condition start or get worse?

What is the natural history of the lesions? Do they come and go? Come and persist?

Does trauma tend to precipitate a new lesion?

Are the lesions symptomatic?

Is there a history of skin disease involving other body sites? Specifically ask about the anogenital region.

Does the patient have any symptoms suggestive of other sites of mucosal involvement (eg, dysphagia, hoarseness, stridor, ocular irritation, dysuria, dyspareunia, hematuria)?

Does the patient have other medical conditions, including immunosuppression?

Does the review of systems suggest any underlying disease?

Is the patient currently taking any suspect medications?

Physical examination — Aphthous ulcers have a very characteristic appearance. The ulcers are discrete and usually 3 to 5 mm in diameter (picture 1A-C). They have an erythematous halo at the margin and a yellowish exudate centrally. They may be found throughout the oral mucosa but are especially common on the buccal and labial mucosae and the lateral and ventral tongue. (See 'Clinical manifestations' above.)

When evaluating the patient with oral ulcers, a physical examination of all mucocutaneous surfaces, including the scalp, nails, and anogenital region, may be useful to exclude other underlying skin disease, such as autoimmune bullous diseases or lichen planus.

Biopsy — The diagnosis of RAS is typically made clinically. However, in more severe or atypical presentations, a biopsy may be useful to rule out other mucosal disease.

A biopsy at the periphery of an early, ulcerative lesion is the most useful. If the disease is extensive enough to mimic an autoimmune bullous disease (eg, pemphigus vulgaris or cicatricial pemphigoid), performing a biopsy for direct immunofluorescence examination may be helpful. (See "Skin biopsy techniques" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Diagnosis'.)

Histopathology of an active ulcer shows epithelial necrosis and a neutrophilic infiltrate centrally. At the periphery, the infiltrate is predominantly lymphocytic with some exocytosis and epithelial degeneration [34]. Direct immunofluorescence is nonspecific, with possible deposition of C3 or immunoglobulin M (IgM) in blood vessels.

Laboratory tests — For most patients with minor aphthosis, no laboratory assessment is needed. For patients with more severe or worsening disease or those who develop the process later in life, it is reasonable to search for an underlying cause. A complete blood count, erythrocyte sedimentation rate, C-reactive protein, and assessment of nutritional deficiencies (eg, vitamin B12, folate, iron, vitamin D) may reveal a disorder that, when corrected, could potentially lead to resolution or improvement of the ulcers [35-37]. Additional laboratory assessment may be considered in individuals with signs or symptoms suggesting an underlying or associated systemic disease. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS

Mucocutaneous diseases associated with oral ulcers

Herpes simplex virus infection – Primary herpetic gingivostomatitis may present with extensive oral and pharyngeal ulcerations. Fever, malaise, myalgias, and cervical lymphadenopathy are common accompanying symptoms. Recurrent oral-labial herpes simplex virus type 1 infections (also called herpes labialis, "cold sores," or "fever blisters") usually involve the cutaneous lip and infrequently develop within the oral cavity (picture 2). When this does occur, lesions typically develop on the hard palate or gingival mucosa, in contrast with RAS, which involves the buccal and labial mucosa, ventral tongue, and soft palate in most cases. Recurrent intraoral herpes simplex virus may also raise suspicion for underlying immunosuppression [38]. Viral culture or polymerase chain reaction can confirm the diagnosis. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Oral infections'.)

Oral erosive lichen planus – The oral lesions of major aphthosis may heal with scarring that resembles the white, reticular network seen in oral erosive lichen planus. However, in oral lichen planus, the lesions tend to be more limited in distribution and more chronic in nature. The more characteristic discrete, circular ulcers of RAS are not seen. (See "Oral lichen planus: Pathogenesis, clinical features, and diagnosis".)

Autoimmune bullous disease – The mucosal lesions of major aphthosis can sometimes be extensive enough that this process may be confused with an autoimmune bullous dermatosis (eg, pemphigus vulgaris or cicatricial pemphigoid). However, even in severe major aphthosis, there is usually an episodic nature to the disease, as opposed to the chronicity seen in pemphigus or pemphigoid. These entities may be distinguished from RAS by biopsy, including direct immunofluorescence. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

Drug-induced mucosal ulcers – Nicorandil, used for treating angina, has been reported to induce aphthous-like ulcers. This drug is not available in the United States. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been implicated in the development of aphthous stomatitis. (See "Oral lesions", section on 'Nicorandil-induced ulceration'.)

Systemic diseases associated with oral ulcers

Behçet syndrome – Behçet syndrome is a rare disease characterized by recurrent oral aphthae and any of several systemic manifestations, including genital aphthae, ocular disease, skin lesions, gastrointestinal disease, neurologic disease, vascular disease, and arthritis [39]. The diagnosis is based on the presence of recurrent oral ulcerations plus at least two additional findings, including recurrent genital ulcerations, eye lesions, skin lesions, and positive pathergy test (table 1). Oral ulcers, clinically and histologically indistinguishable from common aphthae, are the most common feature (affecting 92 to 100 percent of patients), followed by genital ulcers (57 to 93 percent) and cutaneous lesions (38 to 99 percent) [40].

Caution should be used in making the diagnosis of Behçet syndrome in patients with aphthosis, especially in patients who are not from areas where this disease is more prevalent (eg, the Silk Road, from Japan to the Middle East and Mediterranean countries). In a United States study of 64 patients with major aphthosis, only 10 (16 percent) met the diagnostic criteria for Behçet syndrome [41]. (See "Clinical manifestations and diagnosis of Behçet syndrome".)

Systemic lupus erythematosus – Oral or nasopharyngeal ulcers satisfy one criterion for the diagnosis of systemic lupus erythematosus (picture 3). Biopsy shows a lichenoid pattern of inflammation, which differs from typical RAS [42]. In addition, photosensitivity, malar rash, arthritis, and other systemic involvement would be anticipated in patients with systemic lupus erythematosus. (See "Overview of cutaneous lupus erythematosus", section on 'Mucosal manifestations'.)

Cyclic neutropenia – Cyclic neutropenia is a rare autosomal dominant disorder of bone marrow progenitor cells characterized by the cyclic occurrence of fever, malaise, pharyngitis, aphthous-like ulcers, and neutropenia beginning during infancy or early childhood. Neither the predictability nor the systemic symptoms are seen in typical RAS [43]. (See "Cyclic neutropenia".)

PFAPA syndrome – PFAPA (periodic fever with aphthous stomatitis, pharyngitis, and adenitis) syndrome is the most common periodic fever syndrome in children. Like cyclic neutropenia, PFAPA syndrome tends to follow a pattern of recurrence approximately once a month. However, there is no associated neutropenia [44]. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

MAGIC syndrome – MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome represents an overlap syndrome of relapsing polychondritis and Behçet syndrome [45]. Associated findings may include aortitis and thoracic aortic aneurysm [46-48]. (See "Clinical manifestations of relapsing polychondritis".)

Celiac disease – There is evidence of an association between celiac disease and aphthous stomatitis [49-51]. In patients presenting with RAS, it is reasonable to inquire about a history of gastrointestinal complaints or known gluten intolerance. The prevalence of aphthous stomatitis in patients with celiac disease ranges from 3 to 61 percent [35]. Dental enamel defects are also common oral manifestations of celiac disease. Antitissue transglutaminase immunoglobulin A antibody (tTG-IgA) and antiendomysial immunoglobulin A antibody (EMA-IgA) should be performed in patients with recurrent aphthous lesions who also have gastrointestinal complaints and/or dental enamel defects to exclude or confirm a diagnosis of celiac disease. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

Inflammatory bowel disease – An association between inflammatory bowel disease and oral ulcers has been reported [52]. In Crohn disease, the ulcerations may have a characteristic linear shape (picture 4). Other oral features of Crohn disease may include cobblestoned buccal mucosa, angular cheilitis, and granular gingival swelling. In the patient presenting with RAS, it is reasonable to inquire about a history of gastrointestinal complaints [53]. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents".)

HIV infection – RAS, especially major aphthosis, can be a significant problem in patients with HIV infection. In general, major aphthosis has become less common in HIV-positive patients since the advent of successful antiretroviral therapy [54-56]. (See "Initial evaluation of adults with HIV".)

Reactive arthritis – Oral lesions, including painless mucosal ulcers often located on the hard palate, can occur in patients with reactive arthritis (previously called Reiter syndrome) (picture 5). The diagnosis is usually clinical, based on the presence of arthritis and other extra-articular symptoms (eg, conjunctivitis, urethritis, keratoderma blennorrhagicum, circinate balanitis) in patients with a preceding or concurrent enteric or genitourinary infection. (See "Reactive arthritis", section on 'Extraarticular signs and symptoms'.)

Hyperimmunoglobulin D syndrome – Hyperimmunoglobulin D syndrome is a rare autosomal recessive genetic disorder characterized by recurrent, febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D level. Aphthous ulcers, and sometimes genital ulcers, are seen in approximately one-half of the patients with hyperimmunoglobulin D syndrome [57]. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Mucocutaneous manifestations'.)

Agranulocytosis – Agranulocytosis is defined as having a neutrophil count <500/mm3 in the absence of anemia and thrombocytopenia. The vast majority of cases are drug induced. Agranulocytosis may be accompanied by oral ulcerations, fever, pharyngitis, dysphagia, and sepsis. (See "Drug-induced neutropenia and agranulocytosis".)

MANAGEMENT

Goals of therapy — Treatment of aphthae is not always necessary, as the pain is often bearable and does not interfere with daily life activities. The goals of treatment, when indicated or requested by patients, are to provide relief from pain, speed up the healing of ulcers, decrease the frequency of episodes, and increase lesion-free periods. However, there is no uniformly effective therapy for RAS, and many topical or systemic agents have been used with variable success. Despite the common nature of this disorder, there is a paucity of high-quality studies evaluating treatments for RAS [58-65]. Management is based on limited evidence from low-quality, randomized trials and clinical experience [35,59,66,67].

General measures for all patients — General measures aimed at maintaining good oral hygiene, avoiding exacerbating factors, and reducing pain are appropriate for essentially all patients with RAS.

Oral hygiene – It is important to maintain good dental hygiene, while at the same time avoiding trauma. A soft toothbrush, waxed tape-style dental floss, and a soft-tipped gum stimulator to gently remove plaque are generally well tolerated. A non-alcohol-containing mouthwash is often less irritating, but still effective, in decreasing microbial overgrowth. Toothpaste containing sodium lauryl sulfate (SLS; also called sodium dodecyl sulfate) may exacerbate RAS in some patients. A trial of using SLS-free toothpaste could be considered [68].

Regular, professional dental cleaning is advised.

Avoidance of exacerbating factors – Where possible, reduce traumatic factors inside the mouth (eg, sharp/rough dental restorations, braces). Avoid habits that cause trauma (eg, biting cheeks or lips) and foods that seem to exacerbate the process.

Pain control – Topical anesthetics and coating agents can provide temporary relief of discomfort if used prior to eating and performing dental hygiene.

Viscous lidocaine 2% or benzocaine 10% – Viscous lidocaine (available by prescription) may be applied directly to the surface of ulcers or used as a swish and spit.

Diphenhydramine liquid – 12.5 mg/5 mL; 5 mL swish and spit.

Dyclonine lozenges – Dissolve slowly in mouth.

Aluminum hydroxide, magnesium hydroxide, and simethicone suspension – 5 to 10 mL swish and spit.

Attapulgite suspension – 600 to 750 mg/15 mL; 5 to 10 mL swish and spit.

Control of secondary infection – Although topical antimicrobial therapy is generally not warranted in the routine management of patients with mild to moderate RAS, it may be helpful for some patients with extensive oral ulceration, especially if they are using topical or oral immunosuppressive agents. In this setting, topical therapies that are used to control overgrowth of Candida or bacteria include (see "Oropharyngeal candidiasis in adults"):

Chlorhexidine 1% gel applied directly to the ulcers or 0.12% mouth rinse (at a dose of 15 mL) swish and spit twice daily

Clotrimazole troches (at a dose of 10 mg) four to five times daily

Nystatin suspension (at a dose of 400,000 to 600,000 units) swish and swallow four times daily

Initial therapy

Topical corticosteroids — High-potency topical corticosteroids (table 2) are the first-line treatment for patients with RAS (including the major form). They are more effective if they are initiated early and used frequently for at least a few days. Ideally, the patient should have the medication readily available so it can be started at the first indication of an outbreak.

Dexamethasone elixir 0.5 mg/5 mL can be an excellent first choice. However, if this preparation is not available or has not been effective, medium- to high-potency topical corticosteroid preparations (eg, gel, ointment, paste) can be used.

Administration

Dexamethasone elixir 0.5 mg/5 mL – 5 mL swish and spit three to four times daily. It is important to keep the medication in the mouth for five minutes prior to spitting it out. Do not rinse afterward and avoid eating or drinking for 30 minutes.

Clobetasol 0.05% gel or ointment – Apply a small amount to the area of involvement two to three times daily. This will work better if the mucosa is dried with a piece of gauze prior to the application of the medication. Do not rinse afterward and avoid eating or drinking for 30 minutes.

Triamcinolone acetonide 0.1% in Orabase – Orabase is a thick, paste-like material that may adhere better to isolated lesions but does not appeal to many patients.

Efficacy – The efficacy of topical corticosteroids for the treatment of RAS was evaluated in a randomized trial including 240 patients with minor RAS treated with dexamethasone ointment or placebo three times per day for five days [69]. Ulcer healing occurred in a higher proportion of patients in the dexamethasone ointment group than in the placebo group (88 versus 55 percent). Mild adverse effects occurred in 12 patients (4 in the treatment group and 8 in the control group) and included perioral rash, burning sensation in the larynx, and pain at the application site.

In a 2011 systematic review of 43 randomized trials of topical and systemic therapies conducted in patients with RAS not associated with systemic diseases, a variety of topical (eg, topical corticosteroids, topical tetracyclines, amlexanox), systemic (systemic corticosteroids, colchicine) and destructive therapies (topical silver nitrate, laser therapy) were reported as effective in reducing pain and promoting ulcer healing [35].

Other topical agents — Other topical agents that can be used in combination or as an alternative to topical corticosteroids include:

Topical tetracyclines – Topical minocycline and doxycycline (as mouth rinses, gels, or pastes) have been reported as effective in reducing pain or healing time of RAS in a few randomized trials [70-72]. These synthetic tetracyclines have multiple anti-inflammatory effects, including inhibition of collagenases and reduction of prostaglandin release. A pooled analysis of three small clinical trials found that a single application of topical doxycycline (a 100 mg tablet crushed and mixed with saline and adhesive paste) was more effective than placebo in reducing the healing time (mean difference [days] -1.77, 95% CI -2.11 to -0.91) [73].

Sucralfate suspensionSucralfate is a sulfated polysaccharide complexed with aluminum hydroxide that can provide a protective barrier for mucosal ulceration. In three small randomized trials, sucralfate suspension (eg, 1 g in 10 mL) rinses four times/day was more effective than placebo in decreasing pain and duration of lesions in patients with RAS and in patients with oral and genital ulcers associated with Behçet syndrome [74-76].

Topical hyaluronate – Topical hyaluronic acid (also known as hyaluronan) has been reported to provide pain relief and accelerated healing of RAS lesions. In a systematic review of nine clinical trials, the efficacy of topical hyaluronic acid in reducing pain and ulcer size was comparable with that of other interventions (topical corticosteroid, placebo, diode laser) [77]. The authors concluded that the evidence was inconclusive based on the heterogeneity of the included studies and high risk of bias in some of the studies. Hyaluronic acid is available without prescription as a 0.2% gel or mouth rinse.

Amlexanox – Amlexanox is a topical anti-inflammatory agent that has been evaluated for the treatment of RAS in a few small trials, although its precise mechanism of action is unknown.

In one study including 100 patients with simple RAS, amlexanox 5% paste applied to early lesions four times daily was more effective than placebo for reducing ulcer size and pain [78]. Mild adverse effects occurred in eight patients in the amlexanox group and included stinging or cooling sensation at the application site and metallic taste.

In another study including 96 patients with RAS, topical 5% amlexanox was as effective as 0.05% clobetasol propionate in reducing pain and ulcer size [79]. Amlexanox is no longer available in the United States.

Refractory/major aphthosis

Systemic corticosteroids — For patients with RAS that does not respond to topical corticosteroids alone, we suggest a short course of systemic corticosteroids [80]. For most patients, the use of topical agents and intermittent use of prednisone (up to three times per year) is sufficient treatment.

Administration – Oral prednisone 20 to 40 mg per day for four to seven days is the standard approach. In cases of major aphthosis, treatment can be prolonged until improvement of the ulcer and associated symptoms is noted and then tapered down. Systemic corticosteroids can be used intermittently (eg, up to three times per year) as an adjunctive treatment to topical therapies.

In patients requiring more frequent or longer courses of prednisone, alternate systemic agents used on a chronic basis should be considered.

Efficacy – The use of systemic corticosteroids is based on limited evidence from two small, low-quality randomized trials and clinical experience [80,81]. In one trial including 40 patients with severe RAS uncontrolled by topical corticosteroids, prednisone (at a dose of 25 mg per day for two weeks and then tapered off in six weeks) was more effective than placebo in decreasing pain, time to ulcer healing, and number of new ulcers during treatment and at four months [80]. Treatment was generally well tolerated, but minor adverse events were more frequent in the prednisone group.

Colchicine/dapsone — Colchicine is an alternative treatment for RAS that is not controlled with intermittent use of systemic corticosteroids in adjunct to topical therapies. Dapsone can be added to that regimen if there is inadequate response to the colchicine alone or only a low dose of colchicine is tolerated.

Administration

Colchicine – The usual starting dose is 0.6 mg orally once daily. After one week, if tolerated, the dose is increased to 0.6 mg twice daily or 1.2 mg once daily. It can be further increased to 0.6 mg three times daily, but very few patients tolerate this dose without developing significant gastrointestinal complaints. In one study, gastrointestinal complications (17 percent), neutropenia (4 percent), and liver enzyme elevation (4 percent) occurred within two weeks of initiating treatment [82].

Dapsone – The usual starting dose is 25 to 50 mg daily, which may be increased to a maximum of 150 mg daily, as tolerated. A baseline glucose-6-phosphate dehydrogenase (G6PD) level is recommended, and blood cell counts should be followed carefully, especially during the first three months of therapy.

Efficacy Colchicine has been used for the long-term treatment of major RAS and mucosal ulcers in Behçet syndrome with favorable results [82-84].

In a small randomized trial, dapsone showed efficacy in the treatment of mucosal ulcers in Behçet syndrome [85].

In a 12-month randomized trial, 106 adult patients with RAS were treated with betamethasone mouthwash (obtained by dissolving a 500 mcg tablet in 10 mL of water) four times per day, oral colchicine 500 mcg per day, or a combination of the two treatments [86]. At 12 months, the Ulcer Severity Score decreased by approximately 54 percent in the betamethasone group, 46 percent in the colchicine group, and 48 percent in the combination therapy group.

Data from small observational studies suggest that the combination of colchicine and dapsone may be beneficial for patients with unsatisfactory response to either agent alone [41,87]. Moreover, patients may be able to use lower doses of each of these medications, which minimizes potential side effects. (See "Treatment of Behçet syndrome", section on 'Oral aphthae and genital ulcers'.)

Other therapies — Therapies that have been used in patients with severe, recalcitrant RAS include:

ThalidomideThalidomide has been used for the treatment of severe aphthous stomatitis and the mucocutaneous lesions of Behçet syndrome (based upon its immunomodulatory properties) as well as for treatment of oral ulcers in HIV-positive patients [41,56,88,89].

The usual dose is 50 to 100 mg daily, but 25 mg daily may be useful as a maintenance dose [90].

Thalidomide is a known teratogen. In the United States, thalidomide can only be prescribed through a Risk Evaluation and Mitigation Strategy (REMS) program (www.thalomidrems.com), a registration and monitoring program for the safe use of thalidomide [91]. There are also concerns about the development of peripheral neuropathy, which may be irreversible.

ApremilastApremilast is an oral phosphodiesterase 4 (PDE4) inhibitor that inhibits production of proinflammatory cytokines and is approved for the treatment of Behçet syndrome, psoriasis, and psoriatic arthritis.

In a small series of five patients with RAS refractory to treatment with topical corticosteroids and colchicine, apremilast at a dose of 30 mg twice daily induced a complete clearance in four of five patients and an almost complete clearance in one patient over a period of two to six weeks [92]. In another study that included 15 patients with RAS refractory to conventional therapy and not previously treated with systemic medications, treatment with apremilast 30 mg daily for 16 weeks induced a reduction in the visual analog scale pain score [93]. However, recurrence occurred after treatment discontinuation.

MontelukastMontelukast, a leukotriene inhibitor, may improve pain and healing of oral ulcers when taken at a dose of 10 mg per day for one month followed by 10 mg every other day [80].

PentoxifyllinePentoxifylline 400 mg three times daily may have some limited benefits in aphthous stomatitis [94].

Anti-TNF-alpha agents – Anti-tumor necrosis factor (TNF)-alpha agents, including etanercept, adalimumab, infliximab, and golimumab, have all been successfully used to treat severe and recalcitrant RAS [95,96]. In one patient series, 16 of 18 patients with RAS experienced complete or almost complete clearance of their lesions following treatment with one or more of these agents over a period of 3 to 77 months [95].

Although potentially effective, these agents should be reserved for patients with disabling disease that has failed to respond to more conservative measures.

Laser therapy – The efficacy of low-level laser therapy for the treatment of RAS has been evaluated in a few randomized trials and systematic reviews [63-65,97-99].

A 2020 systematic review of five randomized trials that compared low-level laser therapy using different types of lasers (eg, neodymium-doped yttrium aluminum garnet [Nd:YAG] laser, aluminum gallium indium phosphide [AlGaInP] diode laser) with topical therapies (eg, triamcinolone acetonide, amlexanox) indicated that laser therapy was associated with immediate pain reduction and more rapid re-epithelization compared with topical agents [99]. However, all included studies were deemed to be at high risk of bias.

A 2023 systematic review focusing on clinical trials published in the previous five years and evaluating the efficacy of food supplements, topical treatments, and systemic treatments for RAS found acceptable evidence that laser therapy using different types of lasers (eg, Nd:YAG laser, AlGaInP diode laser) was more effective than other topical treatments in reducing pain, decreasing ulcer size, and decreasing the time to healing [67].

Unproven therapies

Vitamin supplementation — The role of vitamin supplementation in patients with RAS remains controversial. However, appropriate supplementation should be given to patients with documented nutritional deficiency.

One small randomized trial suggested that vitamin B12 may be beneficial in all patients with RAS regardless of vitamin B12 level [100]. In this study including 58 patients with RAS treated with sublingual vitamin B12 (at a dose of 1000 mcg daily) or placebo for six months, vitamin B12 was more effective than placebo in reducing the number of RAS episodes and oral pain regardless of initial vitamin B12 levels in the blood. Moreover, after six months of treatment, 74 percent of individuals in the intervention group were free of ulceration compared with 32 percent of individuals in the control group. No adverse effects were reported in either group. (See "Treatment of vitamin B12 and folate deficiencies".)

In a randomized trial of similar design that included 160 adults with a history of minor RAS, multivitamin supplementation for up to one year was no more effective than placebo in reducing the number and duration of RAS episodes [24]. This study was judged at a lower risk of bias compared with the one summarized above [59].

Probiotics — The role of oral or topical probiotics in the management of RAS has been evaluated in a systematic review and meta-analysis of seven randomized trials [101]. Most of the included studies did not find a beneficial effect on ulcer severity, number and size of ulcers, and healing time. However, probiotics have shown some beneficial effects in reducing pain compared with placebo [102-105].

PROGNOSIS — The overall prognosis for patients with minor aphthosis is excellent. It is a self-limited disease that can periodically result in moderate discomfort but is otherwise well tolerated. However, in some patients with major aphthosis, the pain and frequency of outbreaks may have a significant impact on the overall quality of life. Fortunately, both forms of RAS tend to improve as patients age.

SUMMARY AND RECOMMENDATIONS

Definition – Recurrent aphthous stomatitis (RAS) is a common disease of the oral mucosa characterized by the recurrent development of one to several discrete ulcers that typically heal within two weeks. (See 'Clinical manifestations' above.)

Clinical subtypes – Clinical subtypes of RAS include minor aphthous stomatitis (most common), major aphthous stomatitis, herpetiform aphthous stomatitis, and severe aphthous stomatitis. Minor aphthosis is the more common form of the disease. Patients experience several self-limited episodes per year, and involvement is limited to the oral mucosa. Patients with major aphthosis may have both the oral and genital mucosa involved. The lesions are more numerous, more painful, and larger, often taking up to four to six weeks to resolve. (See 'Clinical subtypes' above.)

Clinical presentation – RAS presents with round to oval, painful ulcers varying in size from a few millimeters to >1 cm. Ulcers typically show an erythematous rim and adherent, yellowish exudate centrally (picture 1A-C). Patients with minor aphthosis have one to five discrete ulcers that are generally <1 cm in diameter and most commonly develop on the nonkeratinized oral mucosa (typically buccal and labial mucosae). In most cases, lesions resolve in 10 to 14 days. (See 'Clinical manifestations' above.)

Diagnosis – The diagnosis of RAS is usually made on clinical grounds, based upon a typical history and physical examination. Most patients are otherwise healthy. In patients with more severe or recalcitrant disease, it is appropriate to evaluate for underlying disease. In patients with major aphthosis, the diagnosis of Behçet syndrome must be excluded. Biopsy of a lesion will not distinguish between these two entities. (See 'Evaluation and diagnosis' above and 'Differential diagnosis' above.)

Management – Treatment of aphthae is not always necessary, as the pain is often tolerable and does not interfere with daily life activities. When indicated or requested by patients, treatment is aimed at relieving pain, speeding up healing, and decreasing the frequency of episodes. However, there is no uniformly effective therapy for RAS. General measures aimed at oral hygiene, avoidance of trauma to the oral mucosa, and use of topical pain relievers and anti-inflammatory drugs are appropriate for all patients with RAS. (See 'General measures for all patients' above.)

Initial treatment – For all patients with RAS, we suggest the high-potency topical corticosteroid dexamethasone rather than other topical agents or no treatment (Grade 2C). We use dexamethasone elixir 0.5 mg/5 mL to swish and spit three to four times per day. Alternatively, clobetasol 0.05% gel or ointment can be applied to lesions two to three times per day. (See 'Topical corticosteroids' above.)

Other topical agents that can be used as alternatives or in combination with topical corticosteroids include sucralfate suspension, amlexanox (not available in the United States), and topical doxycycline. Based on limited clinical trial data, these agents appear to be safe and improve pain and ulcer healing compared with placebo. (See 'Other topical agents' above.)

The role of oral multivitamin supplementation, including vitamin B12 supplementation in patients without a documented deficiency, remains uncertain. (See 'Vitamin supplementation' above.)

Refractory aphthosis – For patients with refractory RAS, we suggest a short course of oral corticosteroids rather than colchicine or dapsone as initial therapy (Grade 2C). We typically use oral prednisone 20 to 40 mg per day for four to seven days. In patients with major aphthosis, treatment can be prolonged until improvement of aphthae and associated symptoms is noted and then tapered down. In most patients, intermittent use of systemic corticosteroids (up to three times per year) in combination with topical corticosteroids or other topical therapies is sufficient for disease control. (See 'Systemic corticosteroids' above.)

However, for patients with RAS who require more frequent or longer courses of systemic corticosteroids, colchicine and/or dapsone can be alternative treatments. The usual starting dose of colchicine is 0.6 mg orally once daily, which can be gradually increased to 1.2 mg once daily, as tolerated. Dapsone at a starting dose of 25 to 50 mg daily may be an alternative or an adjunct to colchicine for patients who tolerate only a low dose of colchicine. (See 'Colchicine/dapsone' above.)

Other systemic agents that have been used with some success in patients with severe, recalcitrant RAS include thalidomide, montelukast, pentoxifylline, cyclosporine, and anti-tumor necrosis factor (TNF)-alpha agents. (See 'Other therapies' above.)

Prognosis – In most patients, RAS resolves or subsides spontaneously with age. In a minority of patients with major aphthosis, the pain and frequency of outbreaks may have a significant impact on the overall quality of life. (See 'Prognosis' above.)

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Topic 112654 Version 14.0

References

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