AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Recurrent aphthous ulcers (RAUs), or canker sores, are among the most common oral mucosal lesions physicians and dentists observe. RAU is a disorder of unknown etiology that causes clinically significant morbidity. One to several discrete, shallow, painful ulcers are visible on the unattached mucous membranes. Individual ulcers typically last 1-2 weeks. Large ulcers may last several weeks to months.

Although the process is self-limited, in some individuals, the ulcer activity is almost continuous. Similar ulcers can be noted in the genital region. Behçet syndrome and inflammatory bowel disease are systemic diseases associated with oral and genital RAUs.

Pathophysiology

RAU is classically divided into 3 clinical forms: RAU minor, RAU major, and herpetiform RAU. RAU 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

RAU minor

RAU minor is the most common form, accounting for 80% of all RAUs. Discrete, painful, shallow, recurrent ulcers measuring 3 mm to smaller than 1 cm in diameter characterize this form. At any time, 1-5 ulcers can be present. RAU minor occurs on the labial and buccal mucosa and on the floor of the mouth. Lesions heal without scarring within 7-10 days.

RAU major

RAU is formerly known as periadenitis mucosa necrotica recurrens. This form is less common than the others and is characterized by oval ulcers 1-3 cm in diameter. In this relatively severe form, 1-10 major aphthae may be present simultaneously. Ulcers are large and deep, they may coalesce, and they often have a raised and irregular border. On healing, which may take as long as 6 weeks, the ulcers leave extensive scarring, and severe distortion of oral and pharyngeal mucosa may occur. This form most commonly affects the lips, the soft palate, and the fauces.

Herpetiform RAU

This least common form has the smallest of the aphthae, measuring 1-3 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

RAUs 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.

International

RAUs occur worldwide and are reported on every populated continent. RAUs affect 2-66% of the international population.

Mortality/Morbidity

Unless RAU 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 RAU is higher in female individuals than in male individuals.

Age

• RAU minor is the most common form of childhood RAU. About 1% of American children may have RAUs, with onset before age 5 years. The percentage of patients who are affected rises with age.
• RAU major has a typical onset after puberty and persists for as long as 20 years.
• Herpetiform RAU first occurs in the second decade of life; 67-85% 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

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

RAUs consist of 1 or several rounded, shallow, punched-out appearing, painful oral ulcers that recur at intervals of a few days to a few months. To evaluate oral ulcers as RAUs, ascertain the following information:

• Nature of the lesions (number, size, duration, recurrence)
• • The prodromal stage 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 RAU (see Causes)
• • Genetic - Family history evident in some cases
  • Hematinic deficiency - Iron, folic acid, or vitamin B-12 deficiencies possible
  • Immune dysregulation - Possible role
  • Stress - Physical or emotional stress often reported by patients as associated with recurrent outbreaks
• Environmental factors associated with RAU
• • Local, chemical, or physical trauma may initiate ulcer development in patients who are susceptible (pathergy).
  • Allergy may stimulate an outbreak.
  • The role of microbial infection is debated.
• HIV infection (associated with lesions)
• • Aphthouslike oral ulcerations involving all 3 types of RAUs are observed. About 66% of patients who are HIV positive have herpetiform and major RAUs.
  • Ulcerations must be distinguished from those caused by HIV medications and fungal, viral, or bacterial infections.
• Behçet syndrome (associated with lesions)
• • 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 similar to those in RAUs, though they are more extensive and frequent.
  • 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 human leukocyte antigen B51 (HLA-B51).
• Gluten-sensitive enteropathy
• • Less than 5% of patients with RAUs have gluten-sensitive enteropathy (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 RAU, 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 often have submandibular lymphadenopathy, fever is rare. Most patients are otherwise well.

• RAU minor
• • RAU minor is characterized by 1-5 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.
• RAU major
• • RAU major is characterized by oval ulcers that are larger (1-3 cm in diameter) and deeper than those observed in RAU minor.
  • The ulcers may coalesce and often have a raised, irregular border.
• Herpetiform RAU
• • Herpetiform RAU is characterized by crops of smaller ulcers measuring 3 mm in diameter, with sometimes more than 100 lesions present at 1 time.
  • The ulcers can coalesce to produce a widespread area of irregular ulceration.

Causes

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

• Genetics
• • A family history of RAUs is evident in some patients. A familial connection includes a young age of onset and symptoms of increased severity.
  • RAU is highly correlated in identical twins.
  • Associations between specific HLA haplotypes and RAU have been investigated. No consistent association has been demonstrated, most likely because of the lack of any immunogenetic basis for RAU. 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, vitamin B-12) deficiencies were twice as common in patients with RAUs than in control subjects. As many as 20% of patients with RAU 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 RAU exists. Immune dysregulation may play a role.
  • Cytotoxic action of lymphocytes and monocytes on the oral epithelium seems to cause the ulceration, but the trigger remains unclear.
  • On histologic analysis, RAU 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 (NK) cells in various stages of disease
    • Increased adherence of neutrophils
    • Release of tumor necrosis factor-alpha (TNF-alpha)
    • Significant involvement of mast cells in the pathogenesis of RAU
• Microbial infection
• • Researchers disagree about the role of microbes in the development of RAUs. 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 (HSV), human herpesvirus (HHV), varicella-zoster virus (VZV), or cytomegalovirus (CMV) in the development of aphthous ulcers.
  • RAU 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 ill-defined oral ulcers, but the frequency of serum immunoglobulin G (IgG) antibodies to H pylori is not increased in RAU.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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
FAPA syndrome (a periodic syndrome with fever and pharyngitis)
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
Reiter syndrome (see Reactive Arthritis on list above)

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• CBC determination
• Measurement of erythrocyte sedimentation rate (ESR)
• Determination of iron, ferritin, folate, and vitamin B-12 levels
• Potassium hydroxide (KOH) examination of the lesion
• Tzanck smears, viral cultures, or even skin biopsy to exclude HSV

Other Tests

• The following procedures may be indicated if other disease is suspected:
• • Colonoscopy
  • Biopsy with hematoxylin-eosin stains and cultures
• Swab the ulcer to obtain material for a polymerase chain reaction to identify H pylori DNA.

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

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

RAUs are treated by using a variety of agents for palliative, prophylactic, and curative purposes. Many of the treatments are used without substantial research demonstrating therapeutic results.

Therapy for RAU must be directed by the extent of the condition, as determined by the patient and the clinician. Patients often complain of 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 limit inflammatory effect and reduce bacterial counts.
    • Chlorhexidine gluconate
    • Betadine, tetracycline, and dilute salt water rinses
    • Dilute hydrogen peroxide
    • Topical lidocaine or benzocaine
• Systemic agents
• • Colchicine 0.6 mg 3 times a day (tid)
  • Cimetidine 200 mg 2 or 4 times a day (bid/qid)
  • Azathioprine (Imuran) 50 mg per day (qd)
  • Thalidomide (This is the only treatment the US Food and Drug Administration [FDA] had 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.
  • Eliminate sodium laurel sulfate from the patient's use.

Surgical Care

No surgical treatment has been used effectively because of the recurrent nature of RAUs.

Diet

• An elimination diet may help control outbreaks by revealing allergic stimuli that stimulate oral lesions.
• A gluten-free diet helps patients with GSE (celiac disease) control outbreaks of aphthae.
• Patients with oral lesions should adhere to a diet of soft foods.
• Advise avoidance of salt and spices to prevent unnecessary aphthae irritation. Some patients report aphthae after exposure to English walnuts or pineapple. In such cases, remission may be achieved by avoiding the inciting agent.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Therapy for this condition is aimed at reducing inflammation, reducing pain, preventing overgrowth of bacterial flora, and promoting ulcer healing.

Drug Category: 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.

Drug Category: Anesthetics

These agents locally relieve pain of RAU.

Drug Category: Coating agents

These agents protect and bolster natural mucosal barrier.

Drug Category: Anti-inflammatory agents

These agents combat inflammatory destruction of mucosal surfaces that result in ulceration.

Drug Category: Histamine H2-receptor antagonist

These agents combat the postulated role that histamine may play in RAU.

Drug Category: Immunosuppressants

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

Drug Category: Mouth and throat products

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

Drug Category: Antibacterial agents

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

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Deterrence/Prevention

• An association between smoking and reducing the occurrence of RAU has been reported. In 1 epidemiologic study, the incidence of RAU was lower in all groups using any form of tobacco than in people not using tobacco.
• 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.
  • However, 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

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Oct 2, 2006