Aphthous Stomatitis 

Updated: May 14, 2018
Author: Ginat W Mirowski, MD, DMD; Chief Editor: William D James, MD 

Overview

Background

Aphthous stomatitis, also known as recurrent aphthous ulcers or canker sores, is among the most common oral mucosal lesion physicians and dentists observe. Aphthous stomatitis is a disorder of unknown etiology that may cause significant morbidity. One or several discrete, shallow, painful ulcers are visible on the unattached oral mucous membranes. Individual ulcers typically last 7-10 days and heal without scarring. Larger ulcers may last several weeks to months and can scar when healing.

Pathophysiology

Although the process in idiopathic recurrent aphthous ulcers is usually self-limiting, in some individuals, 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.

Recurrent aphthous ulcers occur on nonkeratinized or poorly keratinized surfaces of the mucosa such as following:

  • Labial and buccal mucosa

  • Maxillary and mandibular sulci

  • Unattached gingiva

  • Soft palate

  • Tonsillar fauces

  • Floor of the mouth

  • Ventral surface of the tongue

  • Inferior lateral surface of the tongue

The clinical presentation of aphthous ulcers is defined by the number of recurrences and severity of disease. Clinically, the number and size of the ulcers are the two main criteria used to divide ulcers into three forms: minor, major, and herpetiform. Simple aphthae are common and considered mild, with 1-4 episodes per year. In general, there are few lesions of the minor or herpetiform form. In contrast, complex aphthosis has a severe clinical course, with an almost continuous presence of minor or major ulcers. These may be debilitating and may also involve the genitalia of both men and women. It is imperative that these patients be evaluated to rule out Behçet disease as well as inflammatory bowel disease.

Recurrent aphthous ulcer minor (Mikulicz ulcer)

This is the most common form, accounting for 80-85% of cases. Discrete, painful, shallow, recurrent ulcers smaller than 1 cm in diameter characterize this form, shown in the image below. At any time, one or multiple ulcers can be manifest. These ulcers heal within 7-14 days without scarring. The periodicity varies among individuals, with some having long ulcer-free episodes and some never being free from ulcers.

Minor aphthous ulcer: Small superficial oval erosi Minor aphthous ulcer: Small superficial oval erosions with yellow pseudomembrane and an erythematous border are evident on the labial aspect of the left lower lip.

Recurrent aphthous ulcer major (Sutton ulcer, periadenitis mucosa necrotica recurrens)

This form accounts for about 5-10% of cases and present as round or oval ulcers that range in size from 2-3 cm in diameter, as shown in the image below. Major aphthae typically present as a single ulcer, but multiple ulcers may occur. The ulcers present on the soft palate, lips, or oropharynx. They may be deep with smooth or irregular borders. The ulcers may coalesce. Healing, which may take 6 weeks or even months, results in scarring; severe distortion of oral and pharyngeal mucosa may occur. These are more common in patients with HIV disease.

Major aphthous ulcer: Large oval ulcer with white Major aphthous ulcer: Large oval ulcer with white pseudomembrane and raised red border located on the right upper labial mucosa adjacent to the buccal commissure. Note the irregular margin so typical in major aphthae.

Herpetiform recurrent aphthous ulcer

In this rare form (<5% of cases), ulcers are typically about 1-2 mm in diameter. The aphthae tend to occur in clusters or crops consisting of 10-100 ulcers. Clusters may be small and localized, or they may be distributed throughout the soft mucosa of the oral cavity. These too occur predominantly on unkeratinized mucosa, as shown in the image below. It is important to differentiate these ulcers from herpes simplex virus (HSV), which also may appear as recurrent crops. HSV is an infectious disease that often presents with vesicles that quickly ulcerate and involve the keratinized mucosa of the hard palate, dorsal tongue and attached gingiva.

Herpetiform aphthous ulcer: Grouped and single tin Herpetiform aphthous ulcer: Grouped and single tiny white to yellow ulcers scattered on the labial mucosa and on the ventral aspect of the tongue.

Epidemiology

US frequency

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] Note the following point prevalence and lifetime prevalence rates[2] :

  • Point prevalence in the pediatric population in the United States: 1.2-1.5%
  • Lifetime prevalence in the pediatric population in the United States: 40.18%

International frequency

Recurrent aphthous ulcers occur worldwide and are reported on every populated continent. Recurrent aphthous ulcers affect 2-66% of the international population.[3] . Epidemiologic studies have been conducted in various subpopulations and report data on both point prevalence and lifetime prevalence, as follows:

  • Lifetime prevalence in the adult population in the United States and Canada: 46.4-69.4% [4]
  • Europe lifetime prevalence: 36-37% [4]
  • Sweden point prevalence: 0.5-2% [5, 6]
  • Turkey point prevalence: 1.2-2.3% [7, 8]
  • Jordan lifetime prevalence: 78% [9]
  • Iran lifetime prevalence: 25.2% [10]
  • Sulaimani City, Iraq lifetime prevalence: 28.2% [11]
  • India point prevalence: 1.5% in Northern India [12]
  • India lifetime prevalence: 50.3% [13]

Sex

In children and in some adult communities who are affected, the incidence of recurrent aphthous ulcer is higher in women and girls than in men or boys.[4]

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.[14]

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.[14]

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.[14]

Patient Education

For patient education resources, visit the Oral Health Center. Also, see the patient education article Canker Sores.

 

Presentation

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) may begin 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 7-14 days.

  • Age of the patient at onset

  • Cutaneous or mucosal changes

  • Symptoms of other organ system involvement

  • Current medications, including herbal medications and vitamins

  • 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.[15, 16] Immune dysregulation may play possibly play a role. Physical or emotional stress is often reported by patients as associated with recurrent outbreaks.[17] This stress appears to affect onset but not duration or severity of episodes.[18]

  • 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)[19] : 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. Tissue biopsy for pathologic evaluation and for culture is indicated.

  • Behçet syndrome (associated with lesions)[20, 21, 22, 23, 24, 25] : 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. Studies also demonstrate an association between IL-18 gene polymorphisms and Behçet syndrome, which was not observed in patients with aphthous stomatitis.[26]

  • Gluten-sensitive enteropathy (also known as celiac sprue)[27, 28, 29] : 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. However, celiac disease is not universally agreed to be causative; thus, the need for patients with aphthosis to be screened for celiac disease is unclear.[30, 31] Bowel symptoms may not be present, but patients may have folate deficiency, and they sometimes have reticulin antibodies.

  • Xerostomia or dry mouth: This may be a precipitating or aggravating factor in many patients since saliva is a lubricating agent with antimicrobial properties.[32]

No specific laboratory tests are available. It is important to exclude other disorders by medical history and a comprehensive laboratory evaluation when indicated.

Physical Examination

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, which are keratinized unless the patient is HIV positive. Although patients may have submandibular lymphadenopathy, fever is rare. Most patients are otherwise well. Different gradations and their findings are as follows:

  • Recurrent aphthous ulcer minor (see image below): 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.

  • Minor aphthous ulcer: Small superficial oval erosi Minor aphthous ulcer: Small superficial oval erosions with yellow pseudomembrane and an erythematous border are evident on the labial aspect of the left lower lip.
  • Recurrent aphthous ulcer major (see image below): Recurrent aphthous ulcer major is characterized by oval ulcers that are larger (>1 cm in diameter; often 2-3 cm) and deeper than those observed in recurrent aphthous ulcer minor. The ulcers may coalesce and often have an irregular border.

  • Major aphthous ulcer: Large oval ulcer with white Major aphthous ulcer: Large oval ulcer with white pseudomembrane and raised red border located on the right upper labial mucosa adjacent to the buccal commissure. Note the irregular margin so typical in major aphthae.
  • Herpetiform recurrent aphthous ulcer (see image below): 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.

  • Herpetiform aphthous ulcer: Grouped and single tin Herpetiform aphthous ulcer: Grouped and single tiny white to yellow ulcers scattered on the labial mucosa and on the ventral aspect of the tongue.

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.[33, 34]

Associations between specific HLA haplotypes (eg, HLA- B51) and recurrent aphthous ulcer have been investigated. No consistent association has been demonstrated. However, in two Iranian studies, polymorphisms in an inflammasome-related gene, NLRP3, and in the promoter region for the IL6 gene were found to be significantly associated with recurrent aphthous in a small cohort of patients.[35, 36] Still, host susceptibility is clearly variable, with a polygenic inheritance pattern, and penetrance likely depends on other factors.[37]

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 as in control subjects. As many as 20% of patients with recurrent aphthous ulcer have a hematinic deficiency, with some studies also reporting notable elevations of blood homocysteine.[16] Lower dietary intake of folate and vitamin B-12 is more common among persons with aphthous ulcers[38] and treatment with 1000 mcg/d has shown benefit in individuals regardless of serum B-12 levels.[39, 40] A small group of adolescents were shown to have reduced incidence and pain from recurrent aphthous stomatitis when given 2000 mg/d of ascorbic acid.[41] Vitamin D deficiency is also more prevalent in patients with recurrent aphthous stomatitis, although there is no correlation between vitamin D levels and a patient’s clinical course, including number of ulcers, duration of ulcers, or frequency of ulcer development.[42]

Thus, 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 disease[43]

  • Increased adherence of neutrophils

  • Reduced quantities and functionality of regulatory T cells in lesional tissue

  • Increased expression of pro-inflammatory Th1 genes[44]

  • Release of tumor necrosis factor-alpha (TNF-alpha)[45]

  • 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[46, 47]

  • Elevated levels of salivary and serum cortisol, as well as increased anxiety[48]

  • Increased Toll-like receptor activity[49]

  • Oxidative stress (altered levels and balance of glutathione and malondialdehyde)[50, 51]

  • Increased levels of autoimmune thyroid-related problems and antithyroid antibodies, although the significance is unclear[52]

  • Immunogenetic factors, including single nucleotide polymorphisms in immune modulatory genes[35, 36]

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.[53, 54]

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, and a 2014 meta-analysis found H pylori infection was associated with an increased risk of recurrent aphthous stomatitis.[55] Still, the frequency of serum immunoglobulin G antibodies to H pylori is not increased in recurrent aphthous ulcers, and the organisms have never proven causative.[56, 57, 58, 59, 60]

Imbalances in the oral mucosal microbiome have been identified in patients with recurrent aphthous stomatitis. Although no phylum-level differences were appreciated between nonulcerated sites in these patients and healthy controls, patients with recurrent aphthous stomatitis did exhibit an increased abundance of Bacteroidales species. Further investigation is required to understand if these microbiome imbalances play a causative role in aphthous stomatitis and how diet and oral hygiene influence the oral mucosal microbiome.[61]

 

DDx

Diagnostic Considerations

Also consider the following:

  • Local, traumatic ulceration
  • Environmental triggers: Food (eg, figs, cheese, tomato, tomato sauce, vinegar, lemon, pineapple, milk, wheat flour) [62] ; sodium lauryl sulfate, a detergent used as an emulsifier and surface cleanser and found in many toothpastes and oral rinses [63, 64]
  • Drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], [65] chemotherapies and cytotoxic drugs, Nicorandil, gold) [66]
  • Hematinic deficiencies (up to 20%) (iron, folic acid, vitamin B-12; rarely vitamin B-1 and B-6) [16]
  • Deep fungal disease (major aphthae) [67]
  • Rheumatologic diseases, including systemic lupus erythematous and reactive arthritis [68]
  • GI diseases (3%) (eg, Crohn disease, ulcerative colitis, celiac disease or gluten sensitive enteropathy [HLA –DRW 10 and DQW1], malabsorption, pernicious anemia) [69]
  • Sweet syndrome [70]
  • Causes of systemic neutropenia, including cyclic neutropenia and benign familial neutropenia [71]
  • PFAPA syndrome (periodic fever, pharyngitis, adenitis, and oral ulceration) [72, 73]
  • MAGIC (mouth and genital ulcers with inflamed cartilage) [74]
  • Primary and secondary immunodeficiencies, including HIV infection [75]
  • Trisomy 8, myelodysplasia [76]
  • Behçet disease [77, 78]  (For information on diagnostic criteria for Behçet disease, see the Medscape article Behçet disease.)

 

Differential Diagnoses

 

Workup

Approach Considerations

In 2013, Tappuni et al introduced the Ulcer Severity Score (USS) because of the lack of standardized assessment methods for aphthous stomatitis.[79] The USS incorporates six ulcer characteristics: number, size, duration, ulcer-free period, site, and pain. This scoring template may be of value to future studies assessing treatment efficacy, although at present it is not widely used. Challacombe et al suggest using the USS in combination with the Oral Health Related Quality of Life (OHR-QoL) score in order to better estimate the impact of clinically significant aphthous stomatitis on patients.[80]

Laboratory Studies

The following laboratory studies may be helpful:

  • Complete blood cell count; to rule out cyclic neutropenia, 5 consecutive weekly evaluations should be obtained
  • Measurement of erythrocyte sedimentation rate[81]

  • HIV status

  • Determination of iron, ferritin, total iron-binding capacity, folate, homocysteine, and vitamin B-6, B-12, B-1, and B-2 levels[16, 42, 82]

  • Serum antiendomysium antibody and transglutaminase assay (positive in celiac disease).

  • Tzanck smears and viral cultures: 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

Approach Considerations

Many therapeutic options, with varying degrees of supporting evidence, are recommended for the treatment of aphthous stomatitis. The choice should be guided by disease severity, level of evidence, cost, and adverse effect profile. Treatment for recurrent aphthous ulcers is directed at palliation of symptoms, shortening of healing time,[83, 84] and prophylaxis against future episodes.

Of note, many of the treatments are used without research demonstrating therapeutic results specific to aphthous stomatitis. A 2012 Cochrane review of systemic treatments for aphthous stomatitis found that data from four major trials lacked methodological rigor and concluded that no single therapy could be recommended given the data currently available.[85]

 

Medical Care

Please refer to medications section for specific information regarding recommended dosage and mechanism of action.

Topical regimens may include the following:

  • Topical corticosteroids, including dexamethasone,[86] triamcinolone, fluocinonide, and clobetasol[66]

  • Immunomodulatory agents, including retinoids, cyclosporine, and amlexanox[87, 88] : Cyclosporine has been tested as a systemic agent and a topical paste with mixed reports of efficacy, but it is now most often used effectively as an oral rinse.[89, 90, 91] Isotretinoin (0.1% gel), tretinoin in an adhesive base (0.1%), and retinoic acid in an oral base (0.05%) have been used in the treatment of oral lichen planus with reported efficacy, and they may also be useful in the treatment of recurrent aphthous ulcers.[92, 93] Researchers have also found systemic isotretinoin to be an effective therapy for recurrent aphthous ulcers.[94]

  • Antimicrobials, including tetracycline,[95] chlorhexidine gluconate,[96] and dilute hydrogen peroxide

  • Anesthetics such as topical lidocaine or benzocaine[97]

  • Occlusive and bioadherents agents such as oral bioadherent (Gelclair),[98] sucralfate, bismuth subsalicylate, and 2-octyl cyanoacrylate[99] : Some studies have reported improvement in symptomology and duration of ulcers,[100] while other studies have found that sucralfate is not effective in the treatment of recurrent aphthous ulcers.[101]  Some clinicians advise patients to include bismuth subsalicylate in mouthwash recipes along with other ingredients, such as liquid diphenhydramine.[102, 103]

Systemic agents may include the following:

  • Systemic steroids such as prednisone and dexamethasone[104]

  • Immunomodulatory agents such as colchicine,[80, 105, 106] azathioprine,[107] montelukast,[104] clofazimine,[108] sulodexide,[109] and thalidomide[80] : Close follow-up, including nerve conduction studies and electromyography every 6 months, is recommended in patients using thalidomide.[110]  Montelukast is reported to have equal efficacy as prednisone in the treatment of recurrent aphthous stomatitis, with fewer adverse effects.[104, 109]

Miscellaneous medical treatments are as follows:

  • Pentoxifylline: Hemorheologic agents may be beneficial in patients who do not respond to other therapies; they are not first-line treatment.[111]

  • Quercetin[112, 113]

  • Secretagogues such as cevimeline (Evoxac) or pilocarpine (Salagen)[32]

Laser therapy has been reported to provide pain relief and lesion resolution for isolated lesions, but it does not affect episodic recurrence.[114, 115]

Surgical Care

No surgical treatment has been used effectively because of the recurrent nature of recurrent aphthous ulcers.[116]

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.[117, 118, 119] Advise avoidance of salt and hot spices to prevent pain from unnecessary aphthae irritation. Some patients report aphthae after exposure to figs, pineapple, cheese, and sodium lauryl sulfate, which is found in certain toothpastes and oral rinses. In such cases, remission may be achieved by avoiding the inciting agent.

A gluten-free diet helps patients with gluten-sensitive enteropathy (celiac disease) control outbreaks of aphthae.[31]

Patients with oral lesions should avoid hard or sharp foods that may gouge existing ulcers or create new ones (Koebnerization).

Although some patients may have demonstrable hematinic deficiencies, daily multivitamin therapy does not appear to prevent recurrent aphthous stomatitis episodes.[120]

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.[121, 122] This may be dose-dependent, and the reduced incidence may be limited to heavy smokers.[123]  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. Nicotine replacement therapy may help ameliorate lesions that have resulted from cessation of a tobacco habit.[124]

It has been suggested that various foods and environmental triggers have a role in causing or exacerbating recurrent aphthous ulcers. As such, avoidance of these potential triggers (including pineapple, tomato, figs, cheese, and sodium lauryl sulfate) may prevent or reduce the severity of episodes.[62, 63, 64]

Although many patients with recurrent aphthous ulcers have hematinic deficiencies, multivitamins with iron have not been shown to reduce the severity of aphthae or the frequency of ulcer development.[120]

 

Medication

Medication Summary

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

Corticosteroids

Class Summary

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.

Prednisone (Deltasone)

Prednisone is a systemic corticosteroid for cases of severe aphthae; it is inactive and must be metabolized to the active metabolite prednisolone. Close follow-up care and monitoring are required to monitor for candidiasis and other secondary infections and adverse reactions. Prednisone is available in a 5 mg/5 mL solution.

Dexamethasone (Decadron, Dexasone)

Dexamethasone is the drug of choice for recurrent aphthous ulcers and various inflammatory diseases. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability. An elixir of 0.5 mg/5 mL (high potency, substituted, fluorinated) may be used.

Triamcinolone topical (Aristocort)

Topical triamcinolone is for inflammatory dermatoses responsive to steroids; it decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. It is advisable when local disease is accessible to the patient. Use 0.1% gel.

Fluocinonide (Fluonex, Lidex)

Fluocinonide is a high-potency topical corticosteroid that inhibits cell proliferation; it is immunosuppressive and anti-inflammatory. It is advisable when local disease is accessible to the patient. Use 0.05% gel.

Clobetasol propionate (Temovate)

Clobetasol propionate is a class I superpotent topical steroid that suppresses mitosis and increases the synthesis of proteins that decrease inflammation and cause vasoconstriction. Use 0.05% gel.

Anesthetics

Class Summary

These agents locally relieve pain of recurrent aphthous ulcers.

Lidocaine anesthetic (Xylocaine)

Lidocaine anesthetic is an amide-type local anesthetic. It decreases permeability to sodium ions in neuronal membranes and inhibits depolarization, blocking the transmission of nerve impulses. Use 2% viscous solution.

Benzocaine (Americaine, Anbesol)

Benzocaine is a para-aminobenzoic acid (PABA) derivative, ester-type local anesthetic that is minimally absorbed. It inhibits neuronal membrane depolarization, blocking nerve impulses.

Coating agents

Class Summary

These agents protect and bolster natural mucosal barrier.

Sucralfate (Carafate)

Sucralfate is a sulfate-aluminum complex, which coats ulcer surfaces, forming a physical barrier. In this way, it protects the ulcer surface from irritation. Some studies have reported improvement in symptomology and duration of ulcers, while other studies have found that sucralfate is not effective in the treatment of recurrent aphthous ulcers.

Bismuth subsalicylate (Kaopectate, Kaopectate Extra Strength, Maalox Total Relief)

Bismuth subsalicylate has been used to reduce pain from oral ulcers by protecting raw mucosa. It may also accelerate reepithelialization, although its mechanism of action is largely unknown. Some clinicians advise patients to include bismuth subsalicylate in mouthwash recipes along with other ingredients, such as liquid diphenhydramine.

Bioadherent oral (Gelclair)

This oral bioadherent adheres to the mucosal surface of mouth and forms a protective coating that shields exposed and overstimulated nerve endings. Ingredients include water, maltodextrin, propylene glycol, polyvinylpyrrolidone (PVP), sodium hyaluronate, potassium sorbate, sodium benzoate, hydroxy ethylcellulose, polyethylene glycol (PEG)–40, hydrogenated castor oil, disodium edetate, benzalkonium chloride, flavoring, saccharin sodium, and glycyrrhetinic acid.

Topical occlusives

Class Summary

These agents are indicated for topical application to hold closed easily approximated skin edges of wounds. They may be helpful in aphthous ulcers.

2-Octyl cyanoacrylate

Over-the-counter formulations of cyanoacrylate (essentially Super Glue) form a waterproof occlusive barrier over ulcers.

Immunosuppressants

Class Summary

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

Colchicine (Colcrys, Mitigare)

Colchicine is an anti-inflammatory agent that inhibits microtubule polymerization.  Studies have shown that colchicine is effective in reducing pain from aphthous ulcers, as well as decreasing the frequency of ulcer formation. Adverse effects include gastrointestinal upset, such as diarrhea, and neutropenia. Use 0.6 mg thrice daily.

Montelukast (Singulair)

Montelukast sodium is an immunosuppressive agent that acts via leukotriene receptor antagonism. It blocks leukotrienes, downstream metabolic products of arachidonic acid, from binding to receptors located on neutrophils and macrophages and thereby blocks their activation, chemotaxis, and degranulation. It is reported to have equal efficacy as prednisone in the treatment of recurrent aphthous stomatitis, with fewer adverse effects.

Clofazimine (Lamprene)

Clofazimine is an immunosuppressive and anti-inflammatory agent with antibacterial properties that has shown efficacy in reducing the frequency of ulcers and symptoms in patients who continue to experience ulcers. Although its precise mechanism of action is unclear, it has been shown to accumulate in phagocytes, increase lysosomal enzyme production, and inhibit neutrophil migration.

Azathioprine (Imuran)

Azathioprine is largely converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid; it antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, lowering autoimmune activity. It may decrease the proliferation of immune cells, lowering autoimmune activity.

Thalidomide (Thalomid)

Thalidomide was the first FDA-approved therapy for recurrent aphthous ulcer. It is an immunomodulatory agent that may suppress excessive production of tumor necrosis factor (TNF)‒alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. Close follow-up, including nerve conduction studies and electromyography every 6 months, is recommended in patients using thalidomide.

Topical immunomodulators

Class Summary

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

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine is a potent immunosuppressant that binds cyclophilin on lymphocytes to inhibit calcineurin and thereby prevent the production of interleukin 2. In this way, it dampens the immune response and particularly the action of T cells. Cyclosporine has been tested as a systemic agent and a topical paste with mixed reports of efficacy, but it is now most often used effectively as an oral rinse.

Amlexanox (Aphthasol)

Amlexanox is an adhesive oral paste whose mechanism of action is unknown. It appears to accelerate the healing of aphthous ulcers. Amlexanox appears as a beige-colored paste. It is a potent inhibitor of the formation and release of inflammatory mediators (histamine and leukotrienes) from mast cells, neutrophils, and mononuclear cells in in vitro studies. Amlexanox is FDA approved for the treatment of recurrent aphthous stomatitis.

Retinoids

Class Summary

Retinoids are a class of drugs closely related to vitamin A. They are used to regulate epithelial cell differentiation and have also been shown to have immunomodulatory and anti-inflammatory effects.

Isotretinoin (Absorica, Amnesteem, Claravis)

Researchers have found systemic isotretinoin to be an effective therapy for recurrent aphthous ulcers. Additionally, isotretinoin (0.1% gel) has been used in the treatment of oral lichen planus with reported efficacy, and it may also be useful in the treatment of recurrent aphthous ulcers.

Tretinoin topical (Atralin, Avita, Refissa)

Tretinoin in an adhesive base (0.1%) has been used in the treatment of oral lichen planus with reported efficacy, and it may also be useful in the treatment of recurrent aphthous ulcers.

Retinoic acid

Retinoic acid in an oral base (0.05%) has been used in the treatment of oral lichen planus with reported efficacy, and it may also be useful in the treatment of recurrent aphthous ulcers.

Antibacterial agents

Class Summary

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

Chlorhexidine oral (Peridex, PerioChip, PerioGard)

Chlorhexidine gluconate is an adjunct treatment for gingival disease; it binds to negatively charged bacterial cell walls and extramicrobial complex, causing bacteriostatic and bactericidal effects. Chlorhexidine gluconate is an effective, safe, and reliable topical wash or oral mouthwash antiseptic.

Tetracycline

Tetracycline treats gram-positive and gram-negative organisms and mycoplasmal, chlamydial, and rickettsial infections. It inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits. Use the oral suspension. It may have an anti-inflammatory in addition to antibacterial mechanism of action.

Hemorheologic agents

Class Summary

Hemorheologic agents may be beneficial in patients who do not respond to other therapies; they are not first-line treatment.

Pentoxifylline (Pentoxil, Trental)

Pentoxifylline inhibits the production of TNF-alpha and reduces the migration of neutrophils. Its specific action in aphthous stomatitis is unclear, but it has been shown to reduce the severity and frequency of episodes.

Secretagogues

Class Summary

As xerostomia may exacerbate or even contribute to the development of aphthous ulcers, treatment with agents known to increase saliva production may be of benefit to some patients.

Cevimeline (Evoxac)

Cevimeline is a parasympathomimetic agent that acts via muscarinic acetylcholine receptors to induce salivation. Use cevimeline at 30 mg  orally thrice daily.

Pilocarpine (Pilocarpine PO, Salagen)

Pilocarpine is a parasympathomimetic agent that acts via muscarinic acetylcholine receptors to induce salivation. Use 5 mg, 1-2 tablets, 3-4 times per day, not to exceed 30 g/day.

Ear, Eye, Nose & Throat, Herbals

Class Summary

These agents may be used as adjunct topical treatments to shorten healing time and reduce pain.

Quercetin

Quercetin is a plant flavonoid that has been shown to stimulate gastric epithelial cell proliferation and may be used as an adjunct topical agent to shorten healing time and reduce pain.

 

Questions & Answers

Overview

What is aphthous stomatitis (canker sore)?

What is the pathophysiology of aphthous stomatitis (canker sore)?

Where in the mucosa does aphthous stomatitis (canker sore) occur?

How are aphthous stomatitis (canker sore) categorized?

What are characteristics of recurrent aphthous ulcer minor (Mikulicz ulcer)?

What are characteristics of recurrent aphthous ulcer major (Sutton ulcer, periadenitis mucosa necrotica recurrens)?

What are characteristics of herpetiform recurrent aphthous ulcers?

What is the prevalence of aphthous stomatitis (canker sore)?

What is the global prevalence of aphthous stomatitis (canker sore)?

How does the prevalence of aphthous stomatitis (canker sore) vary by sex?

How does the prevalence of aphthous stomatitis (canker sore) vary by age?

Where can patient education resources be found for aphthous stomatitis (canker sore)?

Presentation

What should be the focus of history in the evaluation of aphthous stomatitis (canker sore)?

Which physical findings are characteristic of aphthous stomatitis (canker sore)?

What causes aphthous stomatitis (canker sore)?

What is the role of genetics in the etiology of aphthous stomatitis (canker sore)?

What is the role of hematinic deficiency in the etiology of aphthous stomatitis (canker sore)?

What is the role of immune dysregulation in the etiology of aphthous stomatitis (canker sore)?

What are findings associated with immune dysregulation in patients with aphthous stomatitis (canker sore)?

What is the role of microbial infection in the etiology of aphthous stomatitis (canker sore)?

DDX

Which clinical conditions are considered in the differential diagnosis of aphthous stomatitis (canker sore)?

What are the differential diagnoses for Aphthous Stomatitis?

Workup

What is the Ulcer Severity Score (USS) for the assessment of aphthous stomatitis (canker sore)?

Which lab studies are performed in the diagnosis of aphthous stomatitis (canker sore)?

Which tests may be performed to differentiate aphthous stomatitis (canker sore) from other conditions?

Which histologic findings suggest aphthous stomatitis (canker sore)?

Treatment

What is the basis for treatment selection in aphthous stomatitis (canker sore)?

Which topical medications are used in the treatment of aphthous stomatitis (canker sore)?

Which systemic agents are used in the treatment of aphthous stomatitis (canker sore)?

What are less common medical treatment options for aphthous stomatitis (canker sore)?

What is the role of laser therapy in the treatment of aphthous stomatitis (canker sore)?

When is surgery indicated in the treatment of aphthous stomatitis (canker sore)?

How is dietary modification used in the treatment of aphthous stomatitis (canker sore)?

How are aphthous stomatitis (canker sore) prevented?

Medications

What are the goals of drug treatment for aphthous stomatitis?

Which medications in the drug class Ear, Eye, Nose & Throat, Herbals are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Secretagogues are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Hemorheologic agents are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Antibacterial agents are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Retinoids are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Topical immunomodulators are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Immunosuppressants are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Topical occlusives are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Coating agents are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Anesthetics are used in the treatment of Aphthous Stomatitis?

Which medications in the drug class Corticosteroids are used in the treatment of Aphthous Stomatitis?