Aphthous Stomatitis

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Background

Aphthous stomatitis (also known as recurrent aphthous ulcers or canker sores) is among the most common oral mucosal lesions observed by physicians and dentists. It 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. These ulcers may be broadly classified as minor, major (see the image below), or herpetiform (see Pathophysiology). Individual ulcers typically last 7-10 days and heal without scarring. Larger ulcers may last several weeks to months and can scar when healing.



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Major aphthous ulcer. Large oval ulcer with white pseudomembrane and raised red border is located on right upper labial mucosa adjacent to buccal comm....

Selection of treatment from among the many therapeutic options that have been described should be guided by the severity of disease, the level of supporting evidence available, the cost, and the adverse effect profile. Treatment of recurrent aphthous ulcers focuses on palliating symptoms, shortening the healing time, and preventing future episodes. (See Treatment.)

Pathophysiology

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

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

The clinical presentation of aphthous ulcers (see Presentation) is defined by the number of recurrences and the severity of disease. Clinically, the number and size of the lesions are the two main criteria used to divide ulcers into the following three forms:

Simple aphthae are common and considered mild, with one to four 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 IBD.

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. At any time, one or multiple ulcers may 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 of ulcers.

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

This form accounts for about 5-10% of cases and presents as round or oval ulcers that range in size from 2-3 cm in diameter. 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.

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. It is important to differentiate these ulcers from those caused by herpes simplex virus (HSV), which also may appear as recurrent crops. HSV infection often presents with vesicles that quickly ulcerate and involve the keratinized mucosa of the hard palate, dorsal tongue, and attached gingiva.

Etiology

Although the clinical characteristics of recurrent aphthous ulcer have been well defined, the precise etiology and the pathogenesis 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 its 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.[1]

Associations between specific human leukocyte antigen (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 the inflammasome-related gene NLRP3 and in the promoter region for the IL6 gene were found to be significantly associated with recurrent aphthous ulcers in a small cohort of patients.[2, 3]  Still, host susceptibility is clearly variable, with a polygenic inheritance pattern, and penetrance likely depends on other factors.[4]

Hematinic deficiency

In several studies, hematinic deficiencies (ie, deficiencies of iron, folic acid, or vitamin B6 or B12) 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.[5]  Lower dietary intake of folate and vitamin B12 is more common among persons with aphthous ulcers.[6]  Treatment with vitamin B12 1000 μg/day has shown benefit in some individuals, regardless of serum B12 levels.[7, 8]  

A small group of adolescents were shown to have reduced incidence and pain from recurrent aphthous stomatitis when given 2000 mg/day of ascorbic acid.[9]  Vitamin D deficiency is also more prevalent in patients with recurrent aphthous stomatitis, though no correlation has been established between vitamin D levels and a patient’s clinical course, including number of ulcers, duration of ulcers, or frequency of ulcer development.[10]

Thus, serologic workup is warranted. Hemoglobin and red blood cell (RBC) indices are not sufficient in all cases.

Immune dysregulation

Although no unifying theory of the immunopathogenesis of recurrent aphthous ulcer has been established, immune dysregulation appears to play a significant role. Cytotoxic action of lymphocytes and monocytes on the oral epithelium may cause the ulceration, but the trigger remains unclear. Upon histologic analysis, recurrent aphthous ulcer consists of mucosal ulcerations with mixed inflammatory cell infiltrates. Helper T (Th) cells predominate in the preulcerative and healing phases, whereas suppressor T cells predominate in the ulcerative phase.

Other findings associated with immune dysregulation include the following:

Microbial infection

Researchers have disagreed about the role of microbes in the development of recurrent aphthous ulcers. The 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 HSV, human herpesvirus (HHV), varicella-zoster virus (VZV), or cytomegalovirus (CMV) in the development of aphthous ulcers.[18]

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 damage to oral mucosa. Helicobacter pylori has been detected in lesional tissue of oral ulcers, and a 2014 meta-analysis found H pylori infection to be associated with an increased risk of recurrent aphthous stomatitis.[19]  Still, the frequency of serum immunoglobulin G (igG) antibodies to H pylori has not been found to be increased in recurrent aphthous ulcers, and this organism has not been proved to be causative.[20, 21, 22]

A study by Hijazi et al identified imbalances in the oral mucosal microbiome in patients with recurrent aphthous stomatitis.[23] 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 would be required to determine whether these microbiome imbalances play a causative role in aphthous stomatitis and to define how diet and oral hygiene influence the oral mucosal microbiome.

Epidemiology

US and international statistics

In North America, recurrent aphthous ulcers are the most common oral mucosal disease. The incidence is approximately 20% overall, rising to more than 50% in certain groups of students in professional schools. Children from higher socioeconomic groups may be affected more than those from lower socioeconomic groups. A 2004 study cited the following point prevalence and lifetime prevalence rates[24] :

Internationally, recurrent aphthous ulcers have been reported on every populated continent, with frequencies ranging from 2% to 66%. Epidemiologic studies have been conducted in various subpopulations and have provided data on both point prevalence and lifetime prevalence, as follows:

Age- and sex-related demographics

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.[35]

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.[35]

Herpetiform recurrent aphthous ulcer typically occurs first in the second decade of life; in the majority of cases, onset comes before age 30 years. The frequency and the severity of episodes may increase during the third and fourth decades and then decrease with advancing age.[35]

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.[25]

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, the following should be addressed:

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.

With regard to genetic factors, a family history is evident in some cases. Hematinic deficiency may play a role. Deficiencies in iron, folic acid, or vitamins B6 and B12 are possible.[36, 5] Immune dysregulation may play a role. Physical or emotional stress is often reported by patients as associated with recurrent outbreaks[37] ; this stress appears to affect the onset of episodes but not their duration or severity.[38]

With regard to environmental factors, 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.

In HIV infection, aphthouslike oral ulcerations involving all three types of recurrent aphthous ulcers (ie, minor, major, and herpetiform) are observed. Approximately 66% of patients who are HIV-positive have herpetiform and major recurrent aphthous ulcers. These ulcers, unlike those in healthy individuals, may be present on both keratinized and nonkeratinized surfaces; this makes it even more critical to rule out opportunistic infections. It is essential to distinguish aphthous ulcerations from those caused by HIV medications and fungal, viral, or bacterial infections. Tissue biopsy for pathologic evaluation and for culture is indicated.

Behçet syndrome is a complex multisystemic inflammatory disorder of unknown cause that is characterized by recurrent oral aphthae and at least two of the following findings[39, 40, 41] :

The oral aphthae of Behçet syndrome are clinically similar to those of 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 has been strongly associated with human leukocyte antigen (HLA)-B51. Studies have also demonstrated an association between interleukin (IL)-18 gene polymorphisms and Behçet syndrome, which was not observed in patients with aphthous stomatitis.[42]

Oral lesions occur in most cases of GSE and can often precede abdominal symptoms. Fewer than 5% of patients with recurrent aphthous ulcers have GSE or other minor mucosal abnormalities of the small intestine. Because celiac disease is not universally agreed to be causative, the need for patients with aphthosis to be screened for this disease is unclear.[43, 44] Bowel symptoms may not be present, but patients may have folate deficiency, and they sometimes have reticulin antibodies

Xerostomia or dry mouth may be a precipitating or aggravating factor in many patients, given that saliva is a lubricating agent with antimicrobial properties.[45]

No specific laboratory tests for aphthous stomatitis are available. It is important to exclude other disorders by means of a medical history and, when indicated, a comprehensive laboratory evaluation.

Physical Examination

Regardless of the clinical form of recurrent aphthous ulcer, the lesions 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 the image below) 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.



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Minor aphthous ulcer. Small superficial oval erosions with yellow pseudomembrane and erythematous border are evident on labial aspect of left lower li....

Recurrent aphthous ulcer major (see the image below) is characterized by oval ulcers that are larger in diameter (>1 cm; often 2-3 cm) and deeper than those observed in recurrent aphthous ulcer minor. The ulcers may coalesce and often have an irregular border.



View Image

Major aphthous ulcer. Large oval ulcer with white pseudomembrane and raised red border is located on right upper labial mucosa adjacent to buccal comm....

Herpetiform recurrent aphthous ulcer (see the image below) 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.



View Image

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

Approach Considerations

In 2013, Tappuni et al introduced the Ulcer Severity Score (USS) in response to the lack of standardized assessment methods for aphthous stomatitis.[60] The USS incorporates six ulcer characteristics: number, size, duration, ulcer-free period, site, and pain. This scoring template, though not widely used at present, may be of value to future studies assessing treatment efficacy. Challacombe et al suggested using the USS in combination with the Oral Health Related Quality of Life (OHR-QoL) score to obtain a better estimate of the impact of clinically significant aphthous stomatitis on patients.[61]

Laboratory Studies

The following laboratory studies may be helpful:

Other Tests

If other disease is suspected, the following may be indicated :

Histologic Findings

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

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,[64, 65] and prophylaxis against future episodes.

It should be noted that many of the treatments for this condition have been used in the absence of research demonstrating therapeutic results that are specific to aphthous stomatitis. A 2012 Cochrane review of systemic treatments for aphthous stomatitis found that data from four major trials lacked methodologic rigor and concluded that no single therapy could be recommended on the basis of the data available at the time of review.[66]

Medical Care

Topical therapy

Topical agents used to treat aphthous stomatitis are as follows:

Topical corticosteroids employed in this setting include dexamethasone,[67] triamcinolone, fluocinonide, and clobetasol.[48]

Immunomodulatory agents include retinoids, cyclosporine, and amlexanox.[68]  Cyclosporine has been tested as a systemic agent and a topical paste, with mixed reports of efficacy, but it is most often used as an oral rinse.[69, 70] 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.[71, 72] Researchers have also found systemic isotretinoin to be an effective therapy for recurrent aphthous ulcers.[73]

One case-control study examined the use of the calcineurin inhibitor tacrolimus in the treatment of recurrent aphthous stomatitis and found it to be more effective than triamcinolone 0.1% in the short term.[74]

Antimicrobials include tetracycline,[75] chlorhexidine gluconate,[76] and dilute hydrogen peroxide.

Anesthetics include lidocaine and benzocaine.[77]

Occlusive and bioadherent agents include oral bioadherent (Gelclair),[78] sucralfate, bismuth subsalicylate, and 2-octyl cyanoacrylate.[79] Some studies have reported improvement in the symptoms and duration of ulcers with sucralfate,[80] whereas others have not found sucralfate to be effective for treating recurrent aphthous ulcers.[81] Some clinicians have advised patients to include bismuth subsalicylate in mouthwash recipes along with other ingredients, such as liquid diphenhydramine.[82, 83]

Systemic therapy

Systemic agents are as follows:

Systemic steroids employed in this setting include prednisone and dexamethasone.[84]

Immunomodulatory agents include colchicine,[61]  azathioprine, montelukast,[84] clofazimine,[85] sulodexide,[86] and thalidomide.[87, 61] Close follow-up, including nerve conduction studies and electromyography (EMG) every 6 months, is recommended for patients treated with thalidomide.[88] Montelukast has been reported to be as efficacious as prednisone in the treatment of recurrent aphthous stomatitis while causing fewer adverse effects.[84]

Instances of successful treatment with the phosphodiesterase 4 (PDE4) inhibitors apremilast[89, 90]  and roflumilast[91] have been reported.

Other medical therapy

Other medical treatments for aphthous stomatitis include the following:

Surgical Care

Because of the recurrent nature of recurrent aphthous ulcers, no surgical treatment has been employed effectively.[102]

Diet

An elimination diet may help control outbreaks of aphthous stomatitis by revealing suspected allergic stimuli that give rise to oral lesions. If food exposure is thought to be the culprit, a food diary can be helpful. Patients should be advised to avoid salt and hot spices so as 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 (GSE; also referred to as celiac disease or celiac sprue) control outbreaks of aphthae.[44]

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

Although some patients may have demonstrable hematinic deficiencies, daily multivitamin therapy has not been shown to prevent recurrent aphthous stomatitis episodes.[103]

Prevention

Some studies have suggested an association between smoking and a reduced incidence of recurrent aphthous ulcer. 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.[104, 105]  It was suggested that this reduced incidence might be dose-dependent and limited to heavy smokers.[106]  Tobacco, by increasing mucosal keratinization, could reduce 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.

These findings notwithstanding, recommending the use of tobacco or nicotine to control this condition cannot be justified. Other, less harmful treatments are available. In addition, subsequent work has suggested the possibility of a causal relation between smoking and and an increased risk of recurrent aphthous stomatitis.[107] Nicotine replacement therapy may help ameliorate lesions that have resulted from cessation of a tobacco habit.[108]

It has been suggested that various foods and environmental triggers play a role in causing or exacerbating recurrent aphthous ulcers. Accordingly, avoidance of these potential triggers (including pineapple, tomato, figs, cheese, and sodium lauryl sulfate) may prevent or reduce the severity of episodes.[109, 46]

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.[103]

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context: 

Dexamethasone (Baycadron, Decadron DSC, Dexamethasone Intensol)

Clinical Context: 

Triamcinolone topical (Kenalog Orabase, Kenalog topical, Pediaderm TA)

Clinical Context: 

Fluocinonide (Lidemol, Lidex, Lyderm)

Clinical Context: 

Clobetasol (Clobex, Clobex Spray, Cormax)

Clinical Context: 

Benzocaine (EjectDelay)

Clinical Context: 

Lidocaine topical (AneCream, AneCream5, Derma Numb)

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Cevimeline (Evoxac)

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Pilocarpine (Pilocarpine PO, Salagen)

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Azathioprine (Azasan, Imuran)

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Thalidomide (Thalomid)

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Sucralfate (Carafate)

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

Clinical Context: 

Bioadherent oral (Gelclair)

Clinical Context: 

2-octyl cyanoacrylate (Dermabond)

Clinical Context: 

Pentoxifylline (Pentoxifylline SR, Pentoxil, Trental)

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Colchicine (Colcrys, Gloperba, Lodoco)

Clinical Context: 

Montelukast (Singulair)

Clinical Context: 

Clofazimine (Lamprene)

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Amlexanox (Aphthasol)

Clinical Context: 

Cyclosporine (Gengraf, Neoral, Sandimmune)

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Tretinoin topical (Altreno, Atralin, Avita)

Clinical Context: 

Isotretinoin (Absorica, Absorica LD, Amnesteem)

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Quercetin

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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)?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)?Which clinical conditions are considered in the differential diagnosis of aphthous stomatitis (canker sore)?What are the differential diagnoses for Aphthous Stomatitis?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)?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?What are the goals of drug treatment for aphthous stomatitis?Which medications in the drug class Antigout Agents 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 Wound Care are used in the treatment of Aphthous Stomatitis?Which medications in the drug class Oral Rinses are used in the treatment of Aphthous Stomatitis?Which medications in the drug class H pylori Agents are used in the treatment of Aphthous Stomatitis?Which medications in the drug class Gastrointestinal Agents, Other 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 Salivary Stimulants are used in the treatment of Aphthous Stomatitis?Which medications in the drug class Anesthetics, Topical are used in the treatment of Aphthous Stomatitis?Which medications in the drug class Corticosteroids, Topical are used in the treatment of Aphthous Stomatitis?Which medications in the drug class Corticosteroids are used in the treatment of Aphthous Stomatitis?

Author

Ginat W Mirowski, MD, DMD, Adjunct Associate Professor, Departments of Oral Pathology, Medicine, and Radiology, Indiana University School Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Diana V Messadi, DDS, MMSc, DMSc, Professor of Dentistry, Associate Dean for Education and Faculty Development, Chair, Section of Oral Medicine and Orofacial Pain, University of California, Los Angeles, School of Dentistry

Disclosure: Nothing to disclose.

Heather C Rosengard, MPH, Johns Hopkins University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Christy L Nebesio, MD, Dermatologist

Disclosure: Nothing to disclose.

Jeffrey M Casiglia, DMD, DMSc, Lecturer, Harvard School of Dental Medicine; Private Practice, Salem, Massachusetts

Disclosure: Nothing to disclose.

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

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

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

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

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

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

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