eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Aphthous Stomatitis

Jeffrey M Casiglia, DMD, DMSc, Lecturer, Harvard School of Dental Medicine; Private Practice, Salem, Massachusetts
Ginat W Mirowski, MD, DMD, Adjunct Associate Professor, Departments of Oral Pathology, Medicine, and Radiology, Indiana University School Medicine; Christy L Nebesio, MD, Dermatologist

Updated: Feb 6, 2009

Introduction

Background

Recurrent aphthous ulcers (RAUs), or canker sores, are among the most common oral mucosal lesions physicians and dentists observe. Recurrent aphthous ulcer is a disorder of unknown etiology that can cause clinically significant morbidity. One or several discrete, shallow, painful ulcers are visible on the unattached mucous membranes. Individual ulcers typically last 7-10 days. Larger ulcers may last several weeks to months and can scar when healing.

Although the process in idiopathic disease is usually self-limiting, in some individuals, the ulcer activity can be almost continuous. Similar ulcers can be noted in the genital region. Behçet syndrome, systemic lupus erythematosus, and inflammatory bowel disease are systemic diseases associated with oral recurrent aphthous ulcers.

Pathophysiology

The classic categorization of recurrent aphthous ulcer is division into 3 clinical forms: recurrent aphthous ulcer minor, recurrent aphthous ulcer major, and herpetiform recurrent aphthous ulcer. Recurrent aphthous ulcer affects the following nonkeratinized or poorly keratinized surfaces of the oral mucosa:

• Labial and buccal mucosa
• Maxillary and mandibular sulci
• Unattached gingiva
• Soft palate
• Tonsillar fauces
• Floor of the mouth
• Ventral surface of the tongue

Recurrent aphthous ulcer minor

Recurrent aphthous ulcer minor is the most common form, accounting for 80% of all cases. Discrete, painful, shallow, recurrent ulcers smaller than 1 cm in diameter characterize this form. At any time, one or more ulcers can be present. Lesions heal without scarring within 7-10 days. The periodicity varies between individuals, with some having longer ulcer-free episodes and some never being free from ulcers.

Recurrent aphthous ulcer major

Recurrent aphthous ulcer is formerly known as periadenitis mucosa necrotica recurrens. This form is less common than the others and is characterized by oval ulcers greater than 1 cm in diameter. In this relatively severe form, many major aphthae may be present simultaneously. Ulcers are large and deep, may have irregular borders, and may coalesce. Upon healing, which may take as long as 6 weeks, ulcers can leave scarring, and severe distortion of oral and pharyngeal mucosa may occur.

Herpetiform recurrent aphthous ulcer

This least common form (5-10% of cases) has the smallest of the aphthae, commonly no larger than 1 mm in diameter. The aphthae tend to occur in clusters that may consist of tens or hundreds of minute ulcers. Clusters may be small and localized, or they may be distributed throughout the soft mucosa of the oral cavity.

Frequency

United States

• Recurrent aphthous ulcers are the most common oral mucosal disease in North America. They affect 20% of the population, with the incidence rising to more than 50% in certain groups of students in professional schools. Children from high socioeconomic groups may be affected more than those from low socioeconomic groups.¹

International

• Recurrent aphthous ulcers occur worldwide and are reported on every populated continent. Recurrent aphthous ulcers affect 2-66% of the international population.²

Mortality/Morbidity

• Unless recurrent aphthous ulcer is associated with a systemic disease, such as Behçet syndrome or inflammatory bowel disease, it rarely leads to clinically significant morbidity or mortality.

Sex

• In children and in some adult communities who are affected, the incidence of recurrent aphthous ulcer is higher in female individuals than in male individuals.

Age

• Recurrent aphthous ulcer minor is the most common form of childhood recurrent aphthous ulcer. Approximately 1% of American children may have recurrent aphthous ulcers, with onset before age 5 years. The percentage of patients who are affected decreases after the third decade.
• Recurrent aphthous ulcer major has a typical onset after puberty and can persist for the remainder of an individual's life, although after late adulthood episodes become much less common.
• Herpetiform recurrent aphthous ulcer first occurs in the second decade of life; the majority of persons have onset when younger than 30 years. The frequency and the severity of episodes may increase during the third and fourth decades and then decrease with advancing age.

Clinical

History

Recurrent aphthous ulcers consist of one or multiple round-to-ovoid, shallow, punched-out–appearing, painful oral ulcers that recur at intervals of a few days to a few months. To evaluate oral ulcers as recurrent aphthous ulcers, ascertain the following information:

• Nature of the lesions (number, size, duration, recurrence)
• The prodromal stage (when present) begins with a pricking or burning sensation on the mucosa.
• The ulcers develop within 24-48 hours.
• Pain lasts 3-4 days or until a thicker fibrinous cover develops or early epithelialization occurs.
• Healing is complete in 7-10 days.
• Age of the patient at onset
• Cutaneous or mucosal changes
• Symptoms of other organ system involvement
• Current medications
• Host factors associated with recurrent aphthous ulcer (see Causes)
• With regard to genetic factors, a family history is evident in some cases.
• Hematinic deficiency may play a role. Iron, folic acid, or vitamin B-6 and B-12 deficiencies are possible.
• Immune dysregulation may play possibly play a role.
• Physical or emotional stress is often reported by patients as associated with recurrent outbreaks.
• Environmental factors associated with recurrent aphthous ulcer
• Local, chemical, or physical trauma may initiate ulcer development in patients who are susceptible (pathergy).
• Allergy or sensitivity to chemicals or food additives may stimulate an outbreak.
• The role of microbial infection is debated.
• HIV infection (associated with lesions)³
• Aphthouslike oral ulcerations involving all 3 types of recurrent aphthous ulcers are observed. Approximately 66% of patients who are HIV positive have herpetiform and major recurrent aphthous ulcers.
• Unlike in healthy individuals, these ulcerations may be present on both keratinized and nonkeratinized surfaces, making it even more critical to rule out opportunistic infections.
• Ulcerations must be distinguished from those caused by HIV medications and fungal, viral, or bacterial infections. Biopsy is indicated.
• Behçet syndrome (associated with lesions)^4,5,6,7,8,9
• This complex, multisystemic inflammatory disorder of unknown cause is characterized by recurrent oral aphthae and at least 2 of the following findings: genital aphthae, synovitis, cutaneous pustular vasculitis, posterior uveitis, or meningoencephalitis.
• Oral aphthae of Behçet syndrome are clinically similar to those in recurrent aphthous ulcers but are accompanied by ocular and genital lesions.
• The incidence is highest in Japan, Southeast Asia, the Middle East, and southern Europe and in persons aged 30-40 years.
• Behçet syndrome is strongly associated with HLA-B51.
• Gluten-sensitive enteropathy (also known as celiac sprue)^10,11,12
• Oral lesions occur in most cases of gluten-sensitive enteropathy (GSE) and can often precede abdominal symptoms.
• Less than 5% of patients with recurrent aphthous ulcers have GSE, also known as celiac disease, or other minor mucosal abnormalities of the small intestine.
• Bowel symptoms may not be present, but patients may have folate deficiency, and they sometimes have reticulin antibodies.

Physical

Regardless of the clinical form of recurrent aphthous ulcer, ulcers are confined to the nonkeratinized mucosa of the mouth, sparing the dorsum of the tongue, the attached gingiva, and the hard palate mucosae, that are keratinized. Although patients may have submandibular lymphadenopathy, fever is rare. Most patients are otherwise well.

• Recurrent aphthous ulcer minor
  • Recurrent aphthous ulcer minor is characterized by discrete shallow ulcers smaller than 1 cm in diameter.
  • The ulcers are covered by a yellow-gray pseudomembrane (fibrinous exudate) and are surrounded by an erythematous halo.
• Recurrent aphthous ulcer major
  • Recurrent aphthous ulcer major is characterized by oval ulcers that are larger (>1 cm in diameter) and deeper than those observed in recurrent aphthous ulcer minor.
  • The ulcers may coalesce and often have an irregular border.
• Herpetiform recurrent aphthous ulcer
  • Herpetiform recurrent aphthous ulcer is characterized by crops of smaller ulcers; tens of ulcerations may be present in clusters.
  • The ulcers can coalesce to produce a widespread area of irregular ulceration.

Causes

Although the clinical characteristics of recurrent aphthous ulcer are well-defined, the precise etiology and the pathogenesis of recurrent aphthous ulcer remain unclear. Many possibilities have been investigated. Recurrent aphthous ulcer is a multifactorial condition, and it is likely that immune-mediated destruction of the epithelium is the common factor in recurrent aphthous ulcer pathogenesis. Host risk factors associated with recurrent aphthous ulcer are described below.

• Genetics
  • A family history of recurrent aphthous ulcers is evident in some patients. A familial connection includes a young age of onset and symptoms of increased severity.
  • Recurrent aphthous ulcer is highly correlated in identical twins.¹³
  • Associations between specific HLA haplotypes and recurrent aphthous ulcer have been investigated. No consistent association has been demonstrated, most likely because of the lack of any immunogenetic basis for recurrent aphthous ulcer. However, host susceptibility is clearly variable, with a polygenic inheritance pattern, and penetrance depends on other factors.
• Hematinic deficiency
  • In several studies, hematinic (iron, folic acid, vitamins B-6 and B-12) deficiencies were twice as common in patients with recurrent aphthous ulcers than in control subjects. As many as 20% of patients with recurrent aphthous ulcer had a deficiency.
  • Serologic workup is warranted. Hemoglobin and RBC indices are not sufficient in all cases.
• Immune dysregulation
  • At present, no unifying theory of the immunopathogenesis of recurrent aphthous ulcer exists, but immune dysregulation may play a significant role.
  • Cytotoxic action of lymphocytes and monocytes on the oral epithelium seems to cause the ulceration, but the trigger remains unclear.
  • Upon histologic analysis, recurrent aphthous ulcer consists of mucosal ulcerations with mixed inflammatory cell infiltrates. T-helper cells predominate in the preulcerative and healing phases, whereas T-suppressor cells predominate in the ulcerative phase.
  • Other findings associated with immune dysregulation include the following:
    • Reduced response of patients' lymphocytes to mitogens
    • Circulating immune complexes
    • Alterations in the activity of natural killer cells in various stages of disease¹⁴
    • Increased adherence of neutrophils
    • Reduced quantities and functionality of regulatory T cells in lesional tissue
    • Release of tumor necrosis factor-alpha (TNF-alpha)¹⁵
    • Significant involvement of mast cells in the pathogenesis of recurrent aphthous ulcer
    • Reduced cellular expression of heat shock protein 27 and interleukin 10  in aphthous lesions^16,17
    • Elevated levels of salivary and serum cortisol, as well as increased anxiety¹⁸
• Microbial infection
  • Researchers disagree about the role of microbes in the development of recurrent aphthous ulcers. Emphasis has been on a microbial agent as a primary pathogen or an antigenic stimulus.
  • Numerous studies have failed to provide strong evidence to support the role of herpes simplex virus, human herpesvirus, varicella-zoster virus, or cytomegalovirus in the development of aphthous ulcers.^19,20
  • Recurrent aphthous ulcer formation may be a T-cell–mediated response to antigens of Streptococcus sanguis that cross-react with the mitochondrial heat shock proteins and induce oral mucosa damage.
  • Helicobacter pylori has been detected in lesional tissue of oral ulcers, but the frequency of serum immunoglobulin G antibodies to H pylori is not increased in recurrent aphthous ulcers, and the organisms have never proven causative.^{21,22,23,24,25}

Differential Diagnoses

Other Problems to Be Considered

• Local, traumatic ulceration
• Drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], chemotherapy, gold)
• Contact stomatitis (eg, oral hygiene products, gum, candies)
• Deep fungal disease (major aphthae)
• Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome
• Systemic lupus erythematosus
• GI diseases (Crohn disease, ulcerative colitis, celiac disease or GSE, malabsorption)
• Sweet syndrome
• Cyclic neutropenia
• Benign familial neutropenia
• PFAPA syndrome (a periodic syndrome with fever, pharyngitis, adenitis, and oral ulceration)²⁶
• Hematinic deficiencies (iron, folic acid, vitamin B-12)
• Deficiency of vitamins B-1, B-2, or B-6
• Primary and secondary immunodeficiencies, including HIV infection
• Reactive arthritis

Workup

Laboratory Studies

• Complete blood cell count
• Measurement of erythrocyte sedimentation rate
• Determination of iron, ferritin, folate, and vitamin B-6 and B-12 levels²⁷
• Tzanck smears, viral cultures, or even skin biopsy: These may be necessary to exclude herpes simplex virus infection if the patient is severely immunocompromised, such as with advanced HIV disease.

Other Tests

• The following procedures may be indicated if other disease is suspected:
  • Colonoscopy
  • Biopsy with hematoxylin and eosin stain and cultures
  • Skin pathergy test
  • Evaluation for uveitis
  • Laboratory studies for antinuclear antibody
  • Patch or sensitivity testing

Histologic Findings

Nonspecific ulcers with chronic mixed inflammatory cells are observed. The pseudomembrane covering of aphthae is a combination of oral bacteria and fungi, as well as necrotic keratinocytes and sloughed oral mucosa.

Treatment

Medical Care

Recurrent aphthous ulcers are treated using a variety of agents. These are directed at palliation of symptoms, shortening of healing time,^28,29 and prophylaxis against future episodes. Many of the treatments are used without research demonstrating therapeutic results specific to aphthous stomatitis. Many episodes can be prevented by avoidance of common triggers such as walnuts and pineapple.

Therapy for recurrent aphthous ulcers must be directed by the extent of the condition, as determined by the patient and the clinician. Patients often report great pain when clinical examination reveals only a minor ulcer of 1-2 mm in diameter. In addition, the frequency and the extent of involvement should direct therapy.

• Topical regimens
  • Anti-inflammatory (eg, corticosteroids) and immunomodulatory agents (eg, retinoids, cyclosporin) are used initially.
    • Topical gels
    • Creams
    • Pastes
    • Ointments
    • Sprays
    • Rinses
  • Adjuvant rinses reduce bacterial loads, which is thought to reduce inflammation and shorten healing.
    • Chlorhexidine gluconate
    • Dilute hydrogen peroxide
    • Topical lidocaine or benzocaine
• Systemic agents
  • Colchicine (0.6 mg 3 tid can be used.
  • Prednisone (20-80 mg/d) is another possibility.
  • Azathioprine use (50 mg/d) has been reported.
  • Thalidomide is the only treatment the US Food and Drug Administration (FDA) has approved for the treatment of major aphthae in individuals with HIV infection.
• Miscellaneous
  • Bismuth subsalicylate (Kaopectate) may protect raw mucosa and accelerates reepithelialization.
  • Multivitamins with iron are recommended but do not have any clear benefit unless the patient has laboratory-confirmed hematinic deficiency.
  • Strongly recommend the patient avoid using sodium laurel sulfate.  This agent is a detergent found in most dentifrices, and it disrupts the surface of the epithelium. Although it has not been proven causative in recurrent aphthous ulcers, results are equivocal in whether elimination of the agent prevents episodes of ulceration.

Surgical Care

No surgical treatment has been used effectively because of the recurrent nature of recurrent aphthous ulcers.³⁰

Diet

• An elimination diet may help control outbreaks by revealing suspected allergic stimuli that initiate oral lesions. If food exposure is thought to be the culprit, a food diary can be helpful.^31,32,33
• A gluten-free diet helps patients with GSE (celiac disease) control outbreaks of aphthae.
• Patients with oral lesions should avoid hard or sharp foods that may gouge existing ulcers or create new ones (koebnerization).
• Advise avoidance of salt and hot spices to prevent pain from unnecessary aphthae irritation. Some patients report aphthae after exposure to nuts, pineapple, cinnamon, or other agents. In such cases, remission may be achieved by avoiding the inciting agent.

Medication

Therapy for this condition is aimed at palliating symptoms, shortening healing time, and reducing the number of episodes (prophylaxis)

Corticosteroids

Topical steroids are the first-line therapy. They are used to suppress immunologic- and inflammatory-mediated attacks resulting in ulceration. They are used to treat idiopathic and acquired autoimmune disorders. The great variety of vehicles includes topical gels, creams, pastes, ointments, sprays, and rinses.

Prednisone (Deltasone)

Systemic corticosteroid for cases of severe aphthae; inactive and must be metabolized to the active metabolite prednisolone. Close follow-up care and monitoring required to monitor for candidiasis and other secondary infections and adverse reactions. Available in 5 mg/5 mL elix.

Dosing

Adult

40-80 mg/d PO; short course initially; may be extended; taper if used for longer than 2-3 wk at this dosage

Pediatric

4-5 mg/m²/d PO or 1-2 mg/kg/d PO; short course initially; may be extended; taper if used >5 d

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, and fungal or tubercular skin infections; GI bleeding or ulceration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Dexamethasone (Decadron, Dexasone)

DOC for recurrent aphthous ulcer and various inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. May use elix 0.5 mg/5 mL (high potency, substituted, fluorinated).

Dosing

Adult

Swish and expectorate 5 mL qid (pc and hs); NPO for 30 min after each dose; patient may swallow if affected areas cannot be reached by gargling

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Contact time important for maximizing efficacy; instruct patients to gargle or swish for >5-10 min each time; expectorate each dose to limit systemic adverse effects; systemic absorption may cause Cushing syndrome, reversible suppression of HPA axis, hyperglycemia, and glycosuria

Triamcinolone acetonide (Aristocort)

For inflammatory dermatosis responsive to steroids; decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Advisable when local disease accessible to patient. Use 0.1% gel.

Dosing

Adult

Apply a thin film to affected areas; NPO 30-60 min; drying or wiping mucous membranes before application may increase potency.

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; viral or fungal oral infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increased risk of secondary candidal infections; systemic absorption may cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, and glycosuria

Fluocinonide (Fluonex, Lidex)

High-potency topical corticosteroid that inhibits cell proliferation; immunosuppressive and anti-inflammatory. Advisable when local disease accessible to patient. Use 0.05% gel.

Dosing

Adult

Apply thin film to affected areas; NPO 30-60 min; drying or wiping mucous membranes before application may increase potency; use of acrylic tray for gingival disease occludes gel and increases potency

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; viral or fungal oral infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increased risk of secondary candidal infections; may cause adverse systemic effects if used over large areas, on denuded areas, on occlusive dressings, or during prolonged treatment

Clobetasol propionate (Temovate)

Class I superpotent topical steroid that suppresses mitosis and increases synthesis of proteins that decrease inflammation and cause vasoconstriction. Use 0.05% gel.

Dosing

Adult

Apply thin film to affected areas; NPO 30-60 min; drying or wiping mucous membranes before application may increase potency; use of acrylic tray for gingival disease occludes gel and increases potency

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; viral or fungal oral infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May suppress adrenal function in prolonged therapy

Anesthetics

These agents locally relieve pain of recurrent aphthous ulcers.

Lidocaine (Xylocaine)

Amide-type local anesthetic. Decreases permeability to sodium ions in neuronal membranes; inhibits depolarization, blocking transmission of nerve impulses.
Use 2% viscous solution.

Dosing

Adult

Swish and expectorate 5 mL 5 min ac tid/qid

Pediatric

Administer as in adults

Interactions

Potential for interactions if systemically absorbed with antiarrhythmics, beta-blockers, or cimetidine

Contraindications

Documented hypersensitivity; avoid in Adams-Stokes syndrome and Wolff-Parkinson-White syndrome

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Must warn patients about risk of aspiration because of loss of sensation (loss of gag reflex) on soft palate and epiglottis

Benzocaine (Americaine, Anbesol)

Para-aminobenzoic acid (PABA) derivative, ester-type local anesthetic, minimally absorbed. Inhibits neuronal membrane depolarization, blocking nerve impulses.

Dosing

Adult

Apply 10-20% gel to affected areas qid prn

Pediatric

Apply as in adults

Interactions

Potential for interactions if systemically absorbed with cholinesterase inhibitors or sulfonamides

Contraindications

Documented hypersensitivity; may cause methemoglobinemia in infants

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not intended for use when infection present

Coating agents

These agents protect and bolster natural mucosal barrier.

Attapulgite (Kaopectate)

Absorbent and protectant.

Dosing

Adult

Swish and expectorate 5 mL tid/qid

Pediatric

Administer as in adults

Interactions

If swallowed in sufficient volumes, may impair effective absorption of digoxin, clindamycin, tetracyclines, and penicillamine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause constipation at high doses when swallowed

Immunosuppressants

These agents blunt immunologically mediated destruction leading to mucosal ulceration. Systemic immunosuppressants are indicated for severe and recalcitrant cases of aphthous stomatitis.

Azathioprine (Imuran)

Largely converted to active metabolites 6-mercaptopurine and 6-thioinosinic acid; antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, lowering autoimmune activity.

Dosing

Adult

50-100 mg PO qd

Pediatric

Initial dose: 2-5 mg/kg/d PO/IV
Maintenance dose: 1-2 mg/kg/d PO/IV
Safety and efficacy not established

Interactions

Allopurinol increases risk of pancytopenia; captopril and ACE inhibitors may increase risk of anemia and leukopenia; may need to increase dose of warfarin; may need to increase dose of pancuronium for adequate paralysis; live virus vaccines; with cotrimoxazole, may increase risk of hematologic toxicity; with rifampicin, may cause transplant rejection; with clozapine, may increase risk of agranulocytosis

Contraindications

Absolute: Allergy to azathioprine; pregnancy or attempting pregnancy; clinically significant active infection
Relative: Concurrent use of allopurinol; previous treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan, others) because of high risk of neoplasia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor CBC count weekly to check for blood dyscrasia; increases risk of neoplasia; caution in liver disease and renal impairment; hematologic toxicities may occur; decreases efficacy of immunization vaccines
Check thiopurine methyl transferase (TPMT) level before therapy, and monitor liver, renal, and hematologic function; pancreatitis rare; TPMT testing not entirely reliable; involves testing TPMT activity in RBCs, which is correlated with systemic TPMT activity; functional enzyme test varies among test sites, and kits may contain various amounts of enzyme inhibitor
Alternatively, starting at low doses, monitoring for pancytopenia, then increasing dose; if clinical response not good, patient may be homozygote for high activity and may need increased dose; some recommend checking before treatment in all patients; if TPMT <5 U, no treatment; if 5-13.7 U, 0.5 mg/kg maximum dose; if 13.7-19 U, 1.5 mg/kg maximum dose; and if >19 U, 2.5 mg/kg maximum dose

Thalidomide (Thalomid)

Only FDA-approved therapy for recurrent aphthous ulcer. Immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.

Dosing

Adult

100-300 mg PO qd for 4 wk

Pediatric

Not established

Interactions

May increase sedation effects of alcohol, barbiturates, chlorpromazine, and reserpine; because of teratogenic effects, women must use 2 additional methods of contraception or abstain from intercourse; specific pregnancy prevention program should be started and followed

Contraindications

Documented hypersensitivity; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Because of sedation, may need to gradually increase dose to desired level; in addition to teratogenic effects, causes somnolence, dizziness, constipation, and peripheral neuropathy; perform pregnancy test within 24-h of start of therapy (weekly during first month and monthly tests in women with regular menstrual cycles or q2wk with irregular menstrual cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must enter STEPS program established by manufacturer

Topical immunomodulators

These agents are inhibitors of the formation and/or release of inflammatory mediators.

Amlexanox (Aphthasol)

Mechanism of action unknown. Appears to accelerate healing of aphthous ulcers. Potent inhibitor of formation and release of inflammatory mediators (histamine and leukotrienes) from mast cells, neutrophils, and mononuclear cells in in vitro studies.

Dosing

Adult

Apply 5% paste directly to ulcers with fingertips qid

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; contact mucositis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Discontinue if rash or contact mucositis occurs

Antibacterial agents

These agents treat inflammation of the oral mucosa caused by bacterial or fungal actions.

Chlorhexidine gluconate (PerioGard, Peridex)

Adjunct treatment for gingival disease; binds to negatively charged bacterial cell walls and extramicrobial complex, causing bacteriostatic and bactericidal effects. Effective, safe, and reliable topical wash or PO mouthwash antiseptic.

Dosing

Adult

Swish 15 mL of 12% oral rinse for 30 seconds bid

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; anterior tooth restorations (potential for staining); periodontitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May stain tooth surfaces, restorations, and dorsum of tongue; studies showed increased calculus formation and altered taste perception; avoid contact with eyes and ears

Tetracycline Suspension

Treats gram-positive and gram-negative organisms and mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits. Use oral susp. May have anti-inflammatory in addition to antibacterial mechanism of action.

Dosing

Adult

15 mL swish and expectorate tid/qid

Pediatric

<8 years: Not recommended
>8 years: Administer as in adults

Interactions

If swallowed, can increase hypoprothrombinemic effects of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

If swallowed, photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Topical occlusives

2-Octyl cyanoacrylate

OTC formulations of cyanoacrylate (essentially Super Glue) form a waterproof occlusive barrier over ulcers

Dosing

Adult

Apply with package applicator tid/qid

Pediatric

Interactions

Contraindications

Hypersensitivity to active ingredient

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Avoid bonding to unintended surfaces

Hemorheologic agents

May be beneficial in patients who do not respond to other therapies; not first-line treatment.³⁴

Pentoxifylline (Pentoxil, Trental)

Inhibits production of TNF-alpha and reduces migration of neutrophils. Specific action in aphthous stomatitis unclear but has been shown to reduce severity and frequency of episodes.

Dosing

Adult

400 mg PO tid

Pediatric

Not established

Interactions

NSAIDS, warfarin, and other medications that can potentially impact hemostasis

Contraindications

Hypertension, pregnancy, myocardial infarction, renal or hepatic failure, porphyria, or hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal impairment

Follow-up

Deterrence/Prevention

An association between smoking and reducing the occurrence of recurrent aphthous ulcer has been reported. In one epidemiologic study, the incidence of recurrent aphthous ulcer was lower in all groups using any form of tobacco than in people not using tobacco.^35,36

Tobacco may increase keratinization of the mucosa, which, in turn, may decrease the susceptibility to ulceration. Nicotine, a locally absorbed substance, may play a role in preventing aphthae. Research subjects lose the protective effect when they stop smoking and they may experience rebound ulceration. Despite this, these findings do not justify recommending the use of tobacco or nicotine to control this condition. Other, less harmful treatments are available.

Patient Education

For excellent patient education resources, visit eMedicine's Teeth and Mouth Center. Also, see eMedicine's patient education article Canker Sores.

References

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Keywords

recurrent aphthous ulcers, aphthous stomatitis, canker sores, recurrent aphthous stomatitis, RAS, recurrent aphthous ulcers, RAU, periadenitis mucosa necrotica recurrens, RAU minor, RAU major, herpetiform RAU, Sutton's disease

Contributor Information and Disclosures

Author

Jeffrey M Casiglia, DMD, DMSc, Lecturer, Harvard School of Dental Medicine; Private Practice, Salem, Massachusetts
Jeffrey M Casiglia, DMD, DMSc is a member of the following medical societies: American Academy of Oral Medicine and American Dental Association
Disclosure: Nothing to disclose.

Coauthor(s)

Ginat W Mirowski, MD, DMD, Adjunct Associate Professor, Departments of Oral Pathology, Medicine, and Radiology, Indiana University School Medicine
Ginat W Mirowski, MD, DMD is a member of the following medical societies: American Academy of Dermatology and American Medical Women's Association
Disclosure: Nothing to disclose.

Christy L Nebesio, MD, Dermatologist
Christy L Nebesio, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Medical Editor

David P Fivenson, MD, Associate Director, St Joseph Mercy Hospital Dermatology Program, Ann Arbor, Michigan
David P Fivenson, MD is a member of the following medical societies: American Academy of Dermatology, Medical Dermatology Society, Michigan Dermatological Society, Michigan State Medical Society, Photomedicine Society, Society for Investigative Dermatology, and Wound Healing Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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