Background: Commonly termed canker sores, aphthous ulcers, or aphthous stomatitis, have been the focus of study and research for many years, although the exact etiology of the lesions has yet to be identified. Categorized as an idiopathic disease, aphthous ulcers frequently are misdiagnosed, treated incorrectly, or simply ignored.

Recurrent aphthous ulcers (RAU), or recurrent aphthous stomatitis (RAS), represent a chronic inflammatory disease characterized by painful oral ulcers recurring with varying frequency. Children, who may reduce oral food and fluid intake because of the pain, may become dehydrated; thus, aggressive therapy for the lesions can be important.

RAU may appear initially as erythematous indurated papules that erode to form sharply circumscribed necrotic ulcers with a gray fibrinous exudate and an erythematous halo. The 3 categories of RAU lesions are as follows:

• Minor aphthous ulcers (80-85% of RAU cases) are 1-10 mm in diameter and heal spontaneously within 7-10 days.

• Major aphthous ulcers (also termed Sutton disease) constitute 10-15% of RAU cases. These lesions are greater than 10 mm in diameter, take 10-30 days or more to heal, and may leave scars.

• Herpetiform ulcers (5-10% of RAU cases) are multiple, clustered, 1- to 3-mm lesions that may coalesce into plaques and usually heal within 7-10 days.

Pathophysiology: The pathophysiology of aphthous ulcers remains incompletely understood. The primary disorder appears to be the result of activation of the cell-mediated immune system. Early lesions show a cluster of macrophages and lymphocytes (predominantly cytotoxic and natural killer T cells) at the pre-ulcerative base, followed by formation of an ulcer with a neutrophilic base and an erythematous lymphocytic ring.

Patients with RAU have increased cytotoxic CD8⁺ cells and decreased helper CD4⁺ cells in peripheral blood. Lesions have elevated levels of interferon gamma, tumor necrosis factor-a, interleukin (IL)–2, IL-4, and IL-5 and functional deficit of IL-10. Some lesions also have been noted to exhibit mast cell activation and degranulation. In vitro cytotoxicity to oral keratinocyte targets is greater in patients with active RAU than in control subjects or in patients with traumatic ulcers. As expected with this abnormal immunologic activity, corticosteroids provide effective therapy.

Aphthous ulcers may exhibit abnormalities in cell communication and epithelial integrity. Lesions have increased expression of an adhesion molecule termed vascular cell adhesion molecule-1 (VCAM-1), E selectin, and keratinocyte intercellular adhesion molecule-1 (ICAM-1). Connexins (markers for the presence of gap junctions) are present in RAU-affected oral mucosa in amounts similar to those present in normal mucosal tissue. Experimental treatment with irsogladine maleate, which reinforces gap junctional intercellular communication, is effective.

Factors predisposing patients to RAU may include trauma, emotional stress, poor nutritional status, malabsorption, celiac disease, regional enteropathy, menstruation, food hypersensitivity, allergic reaction, and exposure to toxins (eg, nitrates in drinking water).

Frequency:

• In the US: Although RAU is commonly believed to occur in approximately 20% of the general population, a study of medical and dental students revealed a prevalence of 31-66%.

• Internationally: Worldwide incidence is similar to that in the United States. Aphthous ulcers are found in all ethnic groups and geographic locations. Prevalence may be increased in affluent countries and socioeconomic classes.

Mortality/Morbidity: Aphthous ulcers are associated with local pain and discomfort. Symptoms usually last 2-10 days with minor and herpetiform ulcers and up to 30 days with major ulcers. Most cases are self-limited and heal without sequelae within 7-14 days; however, major ulcers heal slowly over 10-30 days or longer. Major aphthous ulcers have been known to leave significant scars. The primary morbidity with any type of aphthous ulcer in the pediatric population is dehydration due to poor oral intake. Secondary bacterial infections are uncommon.

Race: Race does not appear to influence the frequency or severity of RAU.

Sex: Aphthous ulcers may be slightly more common in females than in males. Outbreaks occur more frequently during ovulation or before menstruation, and remissions are common during pregnancy.

• Fever

• Malaise

• Myalgias

• Arthralgias

• Headache

• Cough

• Nausea

• Vomiting

• Abdominal pain

• Diarrhea

• Sore throat

• Swollen or painful lymphadenopathy

• Rash

• Genital or conjunctival lesions

• Previous ulcers: The natural history of individual lesions is important because it is the benchmark against which treatment benefits are measured. Age at onset should be noted, since major RAU begins after puberty, and herpetiform ulcers are uncommon in children. Duration, location, and size of previous lesions should be noted, as well as the therapy received. An ulcer diary kept by the patient and documenting 1-3 months may be useful.

• Ask the patient about medication use, chemotherapy, radiation therapy, vitamin supplementation, and recent dietary changes.

• Assess for a family history of the following:

• Aphthous ulcers

• Inflammatory bowel disease

• Gluten-sensitive enteropathy

• Behçet disease

• Systemic lupus erythematosus

• Past medical history: Consider Behçet disease, HIV infection or AIDS, cancer, Crohn disease, immunocompromised state, cyclic neutropenia, MAGIC syndrome (mouth and genital ulcers with inflamed cartilage), and systemic lupus erythematous.

Physical: Aphthous ulcers occur on areas of the mouth in which the mucosa is nonkeratinized and loosely attached, particularly the buccal mucosa, labial mucosa, floor of the mouth, ventral surface of the tongue, and soft palate. Ulcers may appear as single or multiple lesions but can be distinguished easily from primary or secondary viral infections, bacterial infections (eg, necrotizing ulcerative gingivitis), dermatologic conditions (lichen planus, cicatricial pemphigoid, pemphigus), and traumatic injuries (contusions, lacerations, burns) by the healthy appearance of adjacent tissues and the lack of distinguishing systemic features.

• Minor ulcers are seldom larger than 5 mm but may be as large as 1 cm. They may be single or multiple in number. The ulcers are round to oval, covered by a gray or yellowish fibrinous surface, and surrounded by an erythematous border.

• Major recurrent aphthous ulcers can range from 1-3 cm in diameter. They are deeper than minor ulcers and often have a raised, irregular, erythematous border. Patients with a history of major RAU often have residual scarring in the oral mucosa resulting from previous lesions.

• Herpetiform aphthous ulcers appear as small (seldom >3 mm in diameter) tightly clustered lesions. They typically number from 2-10 but may number as many as 100. They are not related to herpes simplex infections and do not present as, or develop into, vesicular lesions. The ulcers appear identical to minor aphthous ulcers with the exception of their smaller size, closer proximity to other lesions, and greater numbers. Confusion may arise if the lesions coalesce into a larger lesion resembling major aphthous stomatitis.

• The remainder of the mouth should appear normal. However, halitosis and necrotic, exudative, or bleeding gums may be present with (1) necrotizing ulcerative gingivostomatitis, (2) erythematous tonsils with periodic fever, aphthous pharyngitis, and adenopathy (PFAPA) syndrome, and (3) vesicular-ulcerative palatal lesions with coxsackievirus infection.

• Vital signs should be normal. Fever may be caused by a secondary bacterial infection, PFAPA syndrome, primary viral infection, or rheumatologic disorder.

• Clinical evidence of dehydration may be provided by decreased weight, tachycardia, hypotension, cool extremities, delayed capillary refill, depressed fontanelle, dry mucous membranes, decreased skin turgor, or decreased axillary moisture. Plotting the weight and height may reveal a trend toward lower percentiles for age, suggesting nutritional deficiency or malabsorption syndrome.

• Skin findings should be normal, but rash may be present with Behçet syndrome, erythema multiforme, hand-foot-and-mouth disease, herpes simplex infection, lichen planus, MAGIC syndrome, pemphigus, pemphigoid, Sweet syndrome, syphilis, systemic lupus erythematosus, varicella (chickenpox), or varicella zoster.

• Joint findings should be normal, but joints may be tender with effusion, erythema, or decreased range of motion in Reiter syndrome, systemic lupus erythematosus, or MAGIC syndrome.

• Eye findings should be normal but may reveal conjunctival lesions in patients with Behçet syndrome or cicatricial pemphigoid. Uveitis or iritis may be present with Reiter syndrome or Behçet syndrome.

• Cervical adenopathy should be minimal. Tender or markedly enlarged lymph nodes suggest PFAPA syndrome.

Causes: Precipitating factors include trauma, salivary gland dysfunction, stress, genetic predisposition, local infections, nutritional deficiencies, GI tract disorders, systemic disorders, food allergy or hypersensitivity, hormonal fluctuations, and chemical exposure.

• Trauma: Local injury, such as caused by an accidental bite, dental injection, toothbrush bristle, or ingestion of sharp food, may precipitate aphthous ulcers in individuals who are susceptible. Traumatic piercing occurs less often in keratinized mucosal epithelium, and RAU is rare in keratinized mucosa.

• Stress: The role of psychological and physiologic stress as risk factors for aphthous ulcers is controversial. Individuals with aphthous ulcers have been noted to have higher-than-average anxiety scores and cortisol levels. Antidepressant therapy may be effective in some patients.

• Genetic predisposition: Family history of RAU is common, although familial penetrance has not been identified as a specific category. RAU may be associated with the human leukocyte antigen (HLA) haplotypes B51 (also common in Behçet syndrome), Cn7, A2, B12, and Dr5.

• Local infection: Although several infectious agents have been identified in aphthous ulcer lesions (including human herpesvirus (HHV)–6, varicella zoster virus, Helicobacter species, and L-forms of streptococci), authorities generally agree that aphthous ulcers and RAU do not represent acute infections.

• Nutritional deficiencies: Deficiencies of iron, folic acid, zinc, and vitamins B-1, B-2, B-6, B-12, and C have all been implicated in RAU.

• GI tract disorders, such as regional enteropathy (Crohn disease), ulcerative colitis, and celiac disease (gluten-sensitive enteropathy), may result in aphthous ulcers. The ulcers may be the only presenting symptom or the only symptom that is evident for a number of years in patients with GI tract disorders; therefore, a high degree of suspicion should be maintained when patients present with RAU.

• Systemic disorders, such as cyclic neutropenia, Reiter syndrome, Behçet disease, or HIV infection, may result in aphthous ulcers.

• Food allergy and hypersensitivity: Flavoring agents, essential oils, benzoic acid, cinnamon, gluten, cow milk, coffee, chocolate, potatoes, cheese, figs, nuts, citrus fruits, and certain spices have been implicated in some individuals with RAU.

• Hormonal fluctuations: In some women, RAU is associated with the menstrual cycle, with outbreaks more common during ovulation or before menstruation. Diminished incidence of RAU during pregnancy has been reported.

• Chemical exposures: High levels of nitrates in drinking water have been associated with aphthous ulcers, possibly by inducing cytochrome b₅ reductase activity. Sodium lauryl sulfate (SLS), a detergent commonly used in toothpaste, may be a trigger of aphthous ulceration in some individuals. Smoking and nicotine exposure do not increase, and actually may decrease, the risk of aphthous ulcers.

• In severe cases of RAU, laboratory testing should be guided by the clinical picture. CBC, chemistry panel, and nutritional workup may be necessary.

• Patients in whom malabsorption or a nutritional deficiency is suggested should undergo immediate screening. Consider screening patients presenting with a history of RAU lasting 6 months or longer.

• CBC results usually are within the reference range in patients with RAU. Findings of neutropenia suggest Sweet syndrome or cyclic neutropenia; findings of leukocytosis suggest PFAPA syndrome.

• Serum iron levels may be low in RAU.

• If a patient is dehydrated and catabolic, urinalysis may reveal an elevated specific gravity and ketone levels. In small children, serum chemistry testing may be performed to exclude hypoglycemia and metabolic acidosis (low serum bicarbonate levels and elevated anion gap).

Imaging Studies:

• No imaging studies are indicated.

Other Tests:

• Histopathologic examination of biopsy specimens does not reveal unique findings and rarely is indicated except to exclude other diagnoses, such as pemphigus, pemphigoid, carcinoma, and Behçet disease.

Medical Care: Most patients with minor or herpetiform aphthae should be treated empirically before extensive and costly studies are initiated.

The primary goals of medical therapy are pain relief, maintenance of fluid and nutrition intake, early resolution, and prevention of recurrence.

• If the ulcers are small and few in number, local anesthetics may suffice. Local agents are particularly useful when patients notice the symptoms while eating or drinking. Many patients will have already tried mild over-the-counter local anesthetics such as those containing benzocaine. If not, local anesthetics can be suggested. In minor ulcers, 2% lidocaine gel applied as needed with a cotton-tipped applicator can be of great use but has caused toxicity in children. Some patients may obtain relief with diphenhydramine used as a swish-and-spit mouth rinse or applied locally with a cotton-tipped applicator as needed.

• Local injectable anesthetics may be needed in patients with more severe pain. Injectable anesthetics are effective, but relief is brief.

• Locally applied topical corticosteroids are used widely as a treatment option.

• High-potency corticosteroid gels, creams, or ointments (with or without adhesive bases) have proven successful in promoting healing and shortening the clinical course of RAU, especially if applied in the prodromal stage or early in the development of the lesions. The gel form tends to adhere better to oral mucosa than creams or ointments; therefore, gel can be more effective. Effects of these preparations are limited when lesions are numerous or difficult to reach with the cotton applicator.

• Corticosteroids increase the risk of candidiasis and other secondary infections. The mixtures are applied to affected areas 2-4 times daily, with one application always occurring at bedtime. Applications continue until lesions subside and can be reinitiated at the prodromal stage of the next outbreak. Spray-based corticosteroids (eg, beclomethasone sprays) are an alternative to topical preparations when the area that needs coverage is large. Topical preparations are preferred because they limit the medication delivered and thus reduce systemic adverse effects.

• Patients have shown significant benefit from local injections of steroids in the submucosal tissue. For additional comfort, the site can be prepared with a topical anesthetic.

• When lesions are severe or numerous, local steroid delivery can be achieved with liquid preparations. The liquid is swished around the oral cavity for 2 minutes 3-4 times a day, then expectorated.

• Patients in whom ulcers do not respond to local treatment may benefit from a short-term course of pulsed prednisone. Patients who arrive at this point in the treatment algorithm may require further screening to exclude additional diagnoses. If the patient does not respond to a short burst of corticosteroids, prednisone should be continued until the lesions subside and then tapered.

Surgical Care: Few patients are unresponsive to the local or systemic therapies described above; however, several other invasive and specialized treatments are available for patients with persistent or severe lesions.

• Laser therapy is perhaps one of the most intriguing treatments. Studies have found that most patients in whom aphthae are treated with laser therapy have immediate relief of pain, faster healing, and fewer recurrences. Limitations lie in the impracticality of the treatment. Lasers are expensive and require specialized training to operate. Patients who have severe disease or frequent recurrences may benefit from referral to a laser treatment center or specialist.

• Twice-daily application of low-intensity ultrasound may have a modest beneficial effect on RAU; however, as with laser treatment, ultrasound is neither cost effective nor practical for use by the common practitioner.

• One of the more controversial therapies involves removing biopsy specimens from lesions as a therapeutic modality. When biopsy is performed, the lesion is changed from an immune-mediated lesion to a traumatic lesion. Some feel that these traumatic lesions are less painful and heal faster than typical aphthous ulcers. Few data support this practice, and it cannot be recommended.

Consultations: Consultation may be necessary if an additional disease is strongly suggested or found. Patients with severe disease may be referred to a laser specialist for evaluation and treatment.

Drug Category: Local anesthetics -- Used to relieve localized pain.

Drug Category: Topical corticosteroids -- Decrease inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. The extent of mucocutaneous absorption is determined by many factors, including the vehicle, integrity of the mucosal barrier, amount of friction from adjacent structures, and the amount of salivation. The medical profile for triamcinolone is outlined below; other medications with the same or similar profiles include betamethasone valerate 0.1% (Valisone), clobetasol propionate 0.05% cream or ointment (Temovate), halobetasol propionate 0.05% ointment (Ultravate), and fluocinonide 0.05% gel (Lidex).

A benzocaine preparation (Orabase) sometimes is added to the corticosteroid, but the practice remains controversial. Some data suggest that Orabase helps keep the steroid in contact with the mucosal surface for a longer period of time; however, the addition of Orabase dilutes the mixture, lessening the steroid potency. To add Orabase to any of these topical steroid prescriptions, simply mix the steroid preparation 1:1 with Orabase.

Drug Name	Triamcinolone (Aristocort) -- Topical application of moderate-potency steroid reduces pain and inflammation at ulcer sites. Close follow-up care is required to monitor for candidiasis and other secondary infections and adverse effects. Available in cream or ointment forms in a variety of concentrations (0.1-0.5%).
Adult Dose	Apply to ulcer area tid; reduce frequency as lesions remit
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; fungal, viral, or bacterial skin infections; decreased mucosal circulation; not for use on face
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Prolonged use causes mucosal atrophy; limit use to 2 wk; systemic absorption may cause Cushing syndrome, reversible hypothalamic-pituitary axis suppression, hyperglycemia, and glycosuria; systemic absorption is increased by prolonged use, application over large surface areas, higher-potency steroids, and occlusive dressings

Drug Category: Local corticosteroid injections -- Decrease inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. The medical profile for triamcinolone diacetate is outlined below. Other medications with the same or similar profiles include betamethasone sodium phosphate/betamethasone acetate 6 mg/mL (Celestone Soluspan).

Drug Category: Topical corticosteroid elixirs -- Decrease inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. The extent of mucocutaneous absorption is determined by many factors, including the vehicle, integrity of the mucosal barrier, amount of friction from adjacent structures, and amount of salivation. This type of corticosteroid delivery is indicated when topical or local steroids are not effective, lesions are too numerous for practical application, or lesions are too difficult to reach with the cotton applicator.

Drug Category: Systemic corticosteroids -- Decrease inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.

Drug Category: Controversial therapies -- Controversial therapies include levamisole, colchicine, gamma-globulin, dapsone, estrogen replacement, thalidomide, MAOIs, silver nitrate sticks, and tetracycline. Of these, only silver nitrate sticks and tetracycline are used with enough frequency and efficacy to be mentioned here.

Silver nitrite sticks cause chemical cauterization. Research findings are split on whether this treatment, which changes the lesion from an ulcer to a burn injury, shortens or prolongs healing. All lesions must be anesthetized before cauterization. This treatment is particularly effective at relieving the pain associated with ulcers.