Aphthous stomatitis

{{Short description|Common oral condition lasting 7–10 days}} {{Use mdy dates|date=July 2014}} {{Good article}} {{Infobox medical condition (new) | name = Aphthous stomatitis | synonyms = Recurrent aphthous stomatitis (RAS), recurring oral aphthae, recurrent aphthous ulceration | image = Aphtha2.jpg | caption = Canker sore on the lower lip | field = Oral medicine, dermatology | symptoms = A round, often painful sore inside the mouth that is white or gray with a red border; tingling or burning sensation prior to sore development; fever, sluggishness, and/or swollen lymph nodes (severe cases only) | complications = Cellulitis (a bacterial skin infection); fever; sores that appear outside of the mouth; pain while brushing teeth, eating, and/or talking | onset = 1 to 2 days, before visual appearance | duration = 7–10 days | types = | causes = Behçet's disease; celiac disease; food allergies; HIV infection; lupus; oral injuries; poor oral hygiene; SLS; stress; vitamin deficiency | risks = Anyone can develop canker sores | diagnosis = | differential = | prevention = Avoiding foods that irritate the mouth, including acidic, hot, or spicy foods; avoiding irritation from gum chewing; avoiding oral hygiene products containing sodium lauryl sulfate; brushing with a soft-bristled brush after meals and flossing daily | treatment = Mouth rinses; nutritional supplements; oral medication | medication = Good oral hygiene; topical agents | prognosis = | frequency = ~20% of people to some degree<ref name=Bru2009>{{cite book|last1=Bruch|first1=Jean M.|last2=Treister|first2=Nathaniel | name-list-style = vanc |title=Clinical Oral Medicine and Pathology|date=2009|publisher=Springer Science & Business Media |isbn=978-1-60327-520-0 |page=53 |url=https://books.google.com/books?id=04rNw8qgJUAC&pg=PA53}}</ref> | deaths = None reported }}

'''Aphthous stomatitis''',<ref>{{etymology|grc|''ἄφθα'' (áphtha)|mouth ulcer||''στόμα'' (stóma)|mouth||''-ῖτις'' (-îtis)|pertaining to}}</ref> or '''recurrent aphthous stomatitis''' ('''RAS'''), commonly referred to as a '''canker sore''' or '''salt blister''', is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals.

The cause is not completely understood but involves a T cell-mediated immune response triggered by a variety of factors which may include nutritional deficiencies, local trauma, stress, hormonal influences, allergies, genetic predisposition, certain foods, dehydration, some food additives, or some hygienic chemical additives like SDS (common in toothpaste).

These ulcers occur periodically and heal completely between attacks. In the majority of cases, the individual ulcers last about 7–10 days, and ulceration episodes occur 3–6 times per year. Most appear on the non-keratinizing epithelial surfaces in the mouth – i.e., anywhere except the attached gingiva, the hard palate, and the dorsum of the tongue. However, the more severe forms, which are less common, may also involve keratinizing epithelial surfaces. Symptoms range from a minor nuisance to interfering with eating and drinking. The severe forms may be debilitating, even causing weight loss due to malnutrition.

The condition is very common, affecting about 20% of the general population to some degree.<ref name=Bru2009/> The onset is often during childhood or adolescence, and the condition usually lasts for several years before gradually disappearing. There is no cure, but treatments such as corticosteroids aim to manage pain, reduce healing time and reduce the frequency of episodes of ulceration.

==Signs and symptoms== [[File:Aphthous ulcer.jpg|thumb|upright=1.3|The lower lip is retracted, revealing aphthous ulcers on the buccal mucosa (note erythematous "halo" surrounding ulcers)]] thumb|Ulcers can take many shapes and sizes. This one is long and narrow.

Individuals with aphthous stomatitis typically exhibit no detectable systemic symptoms or signs (i.e., outside the mouth).<ref name=Scully2013 /> Generally, symptoms may include prodromal sensations such as burning, itching, or stinging, which may precede the appearance of any lesion by some hours; and pain, which is often out of proportion to the extent of the ulceration and is worsened by physical contact, especially with certain foods and drinks (e.g., if they are acidic or abrasive). Pain is worst in the days immediately following the initial formation of the ulcer, and then recedes as healing progresses.<ref name=Treister2010 /> If there are lesions on the tongue, speaking and chewing can be uncomfortable. Ulcers on the soft palate, back of the throat, or esophagus can cause painful swallowing.<ref name=Treister2010 /> Signs are limited to the lesions themselves.

Ulceration episodes usually occur about 3–6 times per year.<ref name=Altenburg2008 /> However, severe disease is characterized by virtually constant ulceration (new lesions developing before old ones have healed) and may cause debilitating chronic pain and interfere with comfortable eating. In severe cases, this prevents adequate nutrient intake, leading to malnutrition and weight loss.<ref name=Treister2010 />

Aphthous ulcers typically begin as erythematous macules (reddened, flat area of mucosa) which develop into ulcers that are covered with a yellow-grey fibrinous membrane that can be scraped away. A reddish "halo" surrounds the ulcer.<ref name=Neville2008 /> The size, number, location, healing time, and periodicity between episodes of ulcer formation are all dependent upon the subtype of aphthous stomatitis.

==Causes== The cause is not entirely clear,<ref name=Scully2013 /> but is thought to be multifactorial.<ref name=Brocklehurst2012>{{cite journal | vauthors = Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J, Walsh T, Riley P, Yates JM | title = Systemic interventions for recurrent aphthous stomatitis (mouth ulcers) | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | article-number = CD005411 | date = September 2012 | pmid = 22972085 | doi = 10.1002/14651858.CD005411.pub2 | pmc = 12193993 }}</ref> It has been suggested that aphthous stomatitis is not a single entity, but rather a group of conditions with different causes.<ref name=Scully2013 /> Multiple research studies have attempted to identify a causative organism, but aphthous stomatitis appears to be non-contagious, non-infectious, and not sexually transmissible.<ref name=Scully2013 /> The mucosal destruction is thought to be the result of a T cell (T lymphocyte) mediated immune response which involves the generation of interleukins and tumor necrosis factor alpha (TNF-α).<ref name=Brocklehurst2012 /> Mast cells and macrophages are also involved, secreting TNF-α along with the T cells. When early aphthous ulcers are biopsied, the histologic appearance shows a dense inflammatory infiltrate, 80% of which is made up of T cells.<ref name=Neville2008 /> Persons with aphthous stomatitis also have circulating lymphocytes which react with peptides 91–105 of heat shock protein 65–60,<ref name=Scully2013 /> and the ratio of CD4+ T cells to CD8+ T cells in the peripheral blood of individuals with aphthous stomatitis is decreased.<ref name=Neville2008 />

Aphthous stomatitis has been associated with other autoimmune diseases, namely systemic lupus erythematosus, Behçet's disease and inflammatory bowel diseases. However, common autoantibodies are not detected in most patients, and the condition tends to resolve spontaneously with advancing age rather than worsen.

Evidence for the T cell-mediated mechanism of mucosal destruction is strong. The exact triggers for this process are unknown and are thought to be multiple and varied from one person to the next. This suggests that there are several possible triggers, each of which is capable of producing the disease in different subgroups. In other words, different subgroups appear to have different causes for the condition. These can be considered in three general groups, namely primary immuno-dysregulation, decrease of the mucosal barrier and states of heightened antigenic sensitivity (see below).<ref name=Neville2008 /> Risk factors in aphthous stomatitis are also sometimes considered as either host-related or environmental.<ref name=Millet2004 />

===Immunity=== At least 40% of people with aphthous stomatitis have a positive family history, suggesting that some people are genetically predisposed to developing oral ulceration.<ref name=Brocklehurst2012 /> HLA-B12, HLA-B51, HLA-Cw7, HLA-A2, HLA-A11, and HLA-DR2 are examples of human leukocyte antigen types associated with aphthous stomatitis.<ref name=Scully2013 /><ref name=Neville2008 /> However, these HLA types are inconsistently associated with the condition, and also vary according to ethnicity.<ref name=Preeti2011 /> People who have a positive family history of aphthous stomatitis tend to develop a more severe form of the condition, and at an earlier age than is typical.<ref name=Preeti2011 />

Stress has effects on the immune system, which may explain why some cases directly correlate with stress. It is often stated that in studies of students with the condition, ulceration is exacerbated during examination periods and lessened during periods of vacation.<ref name=Scully2013 /><ref name=Neville2008 /> Alternatively, it has been suggested that oral parafunctional activities such as lip or cheek chewing become more pronounced during periods of stress. Hence, the mucosa is subjected to more trauma.<ref name=Preeti2011 />

Aphthous-like ulceration also occurs in conditions involving systemic immuno-dysregulation, e.g., cyclic neutropenia and human immunodeficiency virus infection. In cyclic neutropenia, more severe oral ulceration occurs during periods of severe immuno-dysregulation, and resolution of the underlying neutropenia is associated with healing of the ulcers. The relative increase in percentage of CD8+ T cells, caused by a reduction in numbers of CD4+ T cells may be implicated in RAS-type ulceration in HIV infection.<ref name=Neville2008 />

===Mucosal barrier=== The thickness of the mucosa may be an important factor in aphthous stomatitis. Usually, ulcers form on the thinner, non-keratinizing mucosal surfaces in the mouth. Factors which decrease the thickness of the mucosa increase the frequency of occurrence, and factors which increase the thickness of the mucosa correlate with decreased ulceration.<ref name=Neville2008 />

The nutritional deficiencies associated with aphthous stomatitis (vitamin B12, folate, and iron) can all cause a decrease in the thickness of the oral mucosa (atrophy).<ref name=Neville2008 />

Local trauma is also associated with aphthous stomatitis. It is known that trauma can decrease the mucosal barrier. Trauma could occur during injections of local anesthetic in the mouth, or otherwise during dental treatments, frictional trauma from a sharp surface in the mouth, such as a broken tooth, or from tooth brushing.<ref name=Preeti2011 />

Hormonal factors can alter the mucosal barrier. In one study, a small group of females with aphthous stomatitis had fewer occurrences of aphthous ulcers during the luteal phase of the menstrual cycle or with use of the contraceptive pill.<ref name=Scully2013 /><ref name=Neville2008 /> This phase is associated with a fall in progestogen levels, mucosal proliferation and keratinization. This subgroup often experiences remission during pregnancy. However, other studies report no correlation between aphthous stomatitis and menstrual period, pregnancy or menopause.<ref name=Preeti2011 />

Aphthous stomatitis is less common in people who smoke,<ref name=Brocklehurst2012 /><ref>{{cite journal | vauthors = Souza PR, Duquia RP, Breunig JA, Almeida HL | title = Recurrent aphthous stomatitis in 18-year-old adolescents – Prevalence and associated factors: a population-based study | journal = Anais Brasileiros de Dermatologia | volume = 92 | issue = 5 | pages = 626–629 | date = September 2017 | pmid = 29166496 | pmc = 5674692 | doi = 10.1590/abd1806-4841.20174692 }}</ref>{{Unreliable medical source|sure=y|date=August 2018}} and there is also a correlation between habit duration and severity of the condition.<ref name=Slebioda2013 /> Tobacco use is associated with an increase in keratinization of the oral mucosa.<ref name=Neville2008 /> In extreme forms, this may manifest as leukoplakia or stomatitis nicotina (smoker's keratosis). This increased keratinization may mechanically reinforce the mucosa and reduce the tendency for ulcers to form after minor trauma, or present a more substantial barrier to microbes and antigens, but this is unclear. Nicotine is also known to stimulate the production of adrenal steroids and reduce the production of TNF-α, interleukin-1 and interleukin-6.<ref name=Preeti2011 /> Smokeless tobacco products also seem to protect against aphthous stomatitis.<ref name=Slebioda2013>{{cite journal | vauthors = Slebioda Z, Szponar E, Kowalska A | title = Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 62 | issue = 3 | pages = 205–15 | date = June 2014 | pmid = 24217985 | pmc = 4024130 | doi = 10.1007/s00005-013-0261-y }}</ref> Cessation of smoking is known to sometimes precede the onset of aphthous stomatitis in people previously unaffected, or exacerbate the condition in those who were already experiencing aphthous ulceration.<ref name=Scully2013 /> Despite this correlation, starting smoking again does not usually lessen the condition.<ref name=Odell2010 />

===Antigenic sensitivity=== Various antigenic triggers have been implicated as a trigger, including L forms of streptococci, herpes simplex virus, varicella-zoster virus, adenovirus, and cytomegalovirus.<ref name=Neville2008 /> Some people with aphthous stomatitis may show herpes virus within the epithelium of the mucosa, but without any productive infection. In some persons, attacks of ulceration occur at the same time as asymptomatic viral shedding and elevated viral titres.<ref name=Neville2008 />

In some instances, recurrent mouth ulcers may be a manifestation of an allergic reaction.<ref name=mayoclinic>{{cite web|title=Canker sore|url=http://www.mayoclinic.org/diseases-conditions/canker-sore/basics/causes/con-20021262|publisher=Mayo Foundation for Medical Education and Research|access-date=July 7, 2014|date=March 24, 2012}}</ref> Possible allergens include certain foods (e.g., chocolate, coffee, strawberries, eggs, nuts, tomatoes, cheese, citrus fruits, benzoates, cinnamaldehyde, and highly acidic foods), toothpastes, and mouthwashes.<ref name=Millet2004 /><ref name=mayoclinic /> Where dietary allergens are responsible, mouth ulcers usually develop within about 12–24 hours of exposure.<ref name=Millet2004 />

Sodium lauryl sulphate (SLS), a detergent present in some brands of toothpaste and other oral healthcare products, may produce oral ulceration in some individuals.<ref name=Scully2013 /> It has been shown that aphthous stomatitis is more common in people using toothpastes containing SLS, and that some reduction in ulceration occurs when an SLS-free toothpaste is used.<ref name="Alli Erinoso Olawuyi 2019 pp. 358–364">{{cite journal | last1=Alli | first1=Babatunde Y. | last2=Erinoso | first2=Olufemi A. | last3=Olawuyi | first3=Adetokunbo B. | title=Effect of sodium lauryl sulfate on recurrent aphthous stomatitis: A systematic review | journal=Journal of Oral Pathology & Medicine | publisher=Wiley | volume=48 | issue=5 | date=2019-03-27 | issn=0904-2512 | doi=10.1111/jop.12845 | pages=358–364| pmid=30839136 | s2cid=73484189 }}</ref>

===Systemic disease=== {| class="wikitable" style="float: right; width:20em;" ! style="background-color: #CCEEEE;" | Systemic disorders associated with aphthous-like ulceration<ref name=Neville2008>{{cite book|vauthors=Neville BW, Damm DD, Allen CM, Bouquot JE |title=Oral & maxillofacial pathology|year=2008|publisher=W.B. Saunders|location=Philadelphia|isbn=978-1-4160-3435-3|pages=331–36|edition=3rd}}</ref> |- | :Behçet's disease :Celiac disease :Cyclic neutropenia :Nutritional deficiencies :IgA deficiency :Immunocompromised states, e.g. HIV/AIDS :Inflammatory bowel disease :MAGIC syndrome :PFAPA syndrome :Reactive arthritis :Sweet's syndrome :Ulcus vulvae acutum |} {{main|Oral ulceration}} Aphthous-like ulceration may occur in association with several systemic disorders (see table). These ulcers are clinically and histopathologically identical to the lesions of aphthous stomatitis, but this type of oral ulceration is not considered to be true aphthous stomatitis by some sources.<ref name=Brocklehurst2012 /><ref name=RieraMatute2011 /> Some of these conditions may cause ulceration on other mucosal surfaces in addition to the mouth, such as the conjunctiva or the genital mucous membranes. Resolution of the systemic condition often decreases the frequency and severity of oral ulceration.<ref name=Neville2008 />

Behçet's disease is a triad of mouth ulcers, genital ulcers and anterior uveitis.<ref name=Millet2004 /> The main feature of Behçet's disease is aphthous-like ulceration, but this is usually more severe than seen in aphthous stomatitis without a systemic cause, and typically resembles major or herpetiform ulceration or both.<ref name=Brocklehurst2012 /><ref name=ScullyPorter2008 /> Aphthous-like ulceration is the first sign of the disease in 25–75% of cases.<ref name=Neville2008 /> Behçet's is more common in individuals whose ethnic origin is from regions along the Silk Road (between the Mediterranean and the Far East).<ref name=Dalvi2012>{{cite journal | vauthors = Dalvi SR, Yildirim R, Yazici Y | title = Behcet's Syndrome | journal = Drugs | volume = 72 | issue = 17 | pages = 2223–41 | date = December 2012 | pmid = 23153327 | doi = 10.2165/11641370-000000000-00000 | s2cid = 31095457 }}</ref> It tends to be rare in other countries such as the United States and the United Kingdom.<ref name=Millet2004 /> MAGIC syndrome is a possible variant of Behçet's disease, and is associated with aphthous-like ulceration. The name stands for "mouth and genital ulcers with inflamed cartilage" (relapsing polychondritis).<ref name=Preeti2011 />

PFAPA syndrome is a rare condition that tends to occur in children.<ref name=Preeti2011 /> The name stands for "periodic fever, aphthae, pharyngitis (sore throat) and cervical adenitis" (inflammation of the lymph nodes in the neck). The fevers occur periodically about every 3–5 weeks. The condition appears to improve with tonsillectomy or immunosuppression, suggesting an immunologic cause.<ref name=ScullyPorter2008 />

In cyclic neutropenia, there is a reduction in the level of circulating neutrophils in the blood that occurs about every 21 days. Opportunistic infections commonly occur, and aphthous-like ulceration is worst during this time.<ref name=ScullyPorter2008 />

Hematinic deficiencies (vitamin B12, folic acid and iron), occurring singly or in combination,<ref name=Millet2004 /> and with or without any underlying gastrointestinal disease, may be twice as common in people with RAS. However, iron and vitamin supplements only infrequently improve the ulceration.<ref name=ScullyPorter2008 /> The relationship to vitamin B12 deficiency has been the subject of many studies. Although these studies found that 0–42% of those with recurrent ulcers have a vitamin B12 deficiency, an association with deficiency is rare. Even in the absence of deficiency, vitamin B12 supplementation may be helpful due to unclear mechanisms.<ref name=Baccaglinietal2011>{{cite journal | vauthors = Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC, Latortue MC, Carrozzo M, Rogers RS | title = Urban legends: recurrent aphthous stomatitis | journal = Oral Diseases | volume = 17 | issue = 8 | pages = 755–70 | date = November 2011 | pmid = 21812866 | pmc = 3192917 | doi = 10.1111/j.1601-0825.2011.01840.x }}</ref> Hematinic deficiencies can cause anemia, which is also associated with aphthous-like ulceration.<ref name=Brocklehurst2012 />

Gastrointestinal disorders are sometimes associated with aphthous-like stomatitis, e.g., most commonly celiac disease, but also inflammatory bowel disease such as Crohn's disease or ulcerative colitis.<ref name=Brocklehurst2012 /> The link between gastrointestinal disorders and aphthous stomatitis is probably related to nutritional deficiencies caused by malabsorption.<ref name=ScullyPorter2008 /> Less than 5% of people with RAS have celiac disease, which can present with a wide range of non-specific symptoms, especially in adults. Sometimes aphthous-like ulcerations can be the only sign of celiac disease.<ref name=Preeti2011 /> For persons with celiac disease, following a strict gluten-free diet can often end the outbreaks of painful mouth ulcers.

Other examples of systemic conditions associated with aphthous-like ulceration include reactive arthritis,<ref name=Brocklehurst2012 /> and recurrent erythema multiforme.<ref name=Brocklehurst2012 />

==Diagnosis== {{See also|Oral ulceration#Diagnostic approach}} [[File:Photographic Comparison of a Canker Sore, Herpes, Angular Cheilitis and Chapped Lips..jpg|thumb|367px|Photographic comparison of:<ref>Dorfman J, [http://www.nycdentist.com/dental-photo-detail/2471/215/Oral-Pathology-chapped-lips-herpes-canker-sore-angular-cheilitis-cyst The Center for Special Dentistry] {{Webarchive|url=https://web.archive.org/web/20150801221151/http://www.nycdentist.com/dental-photo-detail/2471/215/Oral-Pathology-chapped-lips-herpes-canker-sore-angular-cheilitis-cyst |date=August 1, 2015 }}</ref> {{Ordered list |list_style_type=decimal |Canker sore (inside the mouth)|Herpes simplex |Angular cheilitis |Chapped lips }}]] [[File:Vacutainerrainbow small.jpg|thumb|right|Blood is often taken to assess the hemoglobin, iron, folate and vitamin B12 levels]] [[File:Epikutanni-test.jpg|thumb|right|200px|A patch test is sometimes carried out. Areas of the skin on the back are stimulated with various common allergens. The ones which cause an inflammatory reaction may also be involved in recurrent oral ulceration.]]

Diagnosis is based on the clinical appearance and the medical history.<ref name=Scully2013 /> The most important diagnostic feature is a history of recurrent, self-healing ulcers at fairly regular intervals.<ref name=Cawson2008 /> Although there are many causes of oral ulceration, ''recurrent'' oral ulceration has relatively few causes, most commonly aphthous stomatitis, but rarely Behçet's disease, erythema multiforme, ulceration associated with gastrointestinal disease,<ref name=Odell2010>{{cite book|last=Odell W|title=Clinical problem solving in dentistry|year=2010|publisher=Churchill Livingstone|location=Edinburgh|isbn=978-0-443-06784-6|edition=3rd|pages=87–90}}</ref><ref name=Cawson2008 /> and recurrent intra-oral herpes simplex infection. A systemic cause is more likely in adults who suddenly develop recurrent oral ulceration with no prior history.<ref name=ScullyPorter2008 />

Special investigations may be indicated to rule out other causes of oral ulceration. These include blood tests to exclude anemia, deficiencies of iron, folate or vitamin B12, or celiac disease.<ref name=Millet2004 /> However, the nutritional deficiencies may be latent, and the peripheral blood picture may appear relatively normal.<ref name=Millet2004 /> Some suggest that screening for celiac disease should form part of the routine workup for individuals complaining of recurrent oral ulceration.<ref name=Preeti2011 /> Many of the systemic diseases cause other symptoms apart from oral ulceration, which is in contrast to aphthous stomatitis, where there is isolated oral ulceration. Patch testing may be indicated if allergies are suspected (e.g., a strong relationship between certain foods and episodes of ulceration). Several drugs can cause oral ulceration (e.g., nicorandil), and a trial substitution to an alternative drug may highlight a causal relationship.<ref name=Scully2013 />

Tissue biopsy is not usually required, unless to rule out other suspected conditions such as oral squamous cell carcinoma.<ref name=Cawson2008 /> The histopathologic appearance is not pathognomonic (the microscopic appearance is not specific to the condition). Early lesions have a central zone of ulceration covered by a fibrinous membrane. In the connective tissue deep to the ulcer there is increased vascularity and a mixed inflammatory infiltrate composed of lymphocytes, histiocytes and polymorphonuclear leukocytes. The epithelium on the margins of the ulcer shows spongiosis and there are many mononuclear cells in the basal third. There are also lymphocytes and histiocytes in the connective tissue surrounding deeper blood vessels near to the ulcer, described histologically as "perivascular cuffing".<ref name=Neville2008 /><ref name=Cawson2008 />

===Classification=== Aphthous stomatitis has been classified as a non-infectious stomatitis (inflammation of the mouth).<ref name=Cawson2008 /> One classification distinguishes "common simple aphthae", accounting for 95% of cases, with 3–6 attacks per year, rapid healing, minimal pain and restriction of ulceration to the mouth; and "complex aphthae", accounting for 5% of cases, where ulcers may be present on the genital mucosa in addition to mouth, healing is slower and pain is more severe.<ref name=Altenburg2008>{{cite journal | vauthors = Altenburg A, Zouboulis CC | title = Current concepts in the treatment of recurrent aphthous stomatitis | journal = Skin Therapy Letter | volume = 13 | issue = 7 | pages = 1–4 | date = September 2008 | pmid = 18839042 | url = http://www.skintherapyletter.com/2008/13.7/1.html }}</ref> A more common method of classifying aphthous stomatitis is into three variants, distinguished by the size, number and location of the lesions, the healing time of individual ulcers and whether a scar is left after healing (see below).

====Minor aphthous ulceration==== This is the most common type of aphthous stomatitis, accounting for about 80–85% of all cases.<ref name=Millet2004 /> This subtype is termed minor aphthous ulceration (MiAU),<ref name=Scully2013 /> or minor recurrent aphthous stomatitis (MiRAS). The lesions themselves may be referred to as minor aphthae or minor aphthous ulcers. These lesions are generally less than 10 mm in diameter (usually about 2–3 mm),<ref name=Millet2004 /> and affect non-keratinized mucosal surfaces (i.e. the labial and buccal mucosa, lateral borders of the tongue and the floor of the mouth). Several ulcers usually appear at the same time, but single ulcers are possible. Healing usually takes seven to ten days and leaves no scar. Between episodes of ulceration, there is usually an ulcer-free period of variable length.<ref name=Brocklehurst2012 />

====Major aphthous ulceration==== This subtype comprises 10% of all cases of aphthous stomatitis.<ref name=Neville2008 /> It is termed major aphthous ulceration (MaAU) or major recurrent aphthous stomatitis (MaRAS). Major aphthous ulcers (major aphthae) are similar to minor aphthous ulcers, but are more than 10 mm in diameter and the ulceration is deeper.<ref name=Neville2008 /><ref name=Brocklehurst2012 /> Because the lesions are larger, healing takes longer (about twenty to thirty days), and may leave scars. Each episode of ulceration usually produces a greater number of ulcers, and the time between attacks is less than seen in minor aphthous stomatitis.<ref name=Neville2008 /> Major aphthous ulceration usually affects non-keratinized mucosal surfaces. However, less commonly, keratinized mucosa may also be involved, such as the dorsum (top surface) of the tongue or the gingiva (gums).<ref name=Preeti2011 /> The soft palate or the fauces (back of the throat) may also be involved,<ref name=Preeti2011 /> the latter being part of the oropharynx rather than the oral cavity. Compared to minor aphthous ulceration, major aphthae tend to have an irregular outline.<ref name=Millet2004 />

====Herpetiform ulceration==== Herpetiform ulcers,<ref name=Brocklehurst2012 /> (also termed stomatitis herpetiformis,<ref name=ICD-10>{{cite web|title=International Classification of Diseases-10|url=http://apps.who.int/classifications/icd10/browse/2010/en#/K12.0|publisher=World Health Organization|access-date=February 16, 2013}}</ref> or herpes-like ulcerations) is a subtype of aphthous stomatitis so named because the lesions resemble a primary infection with herpes simplex virus (primary herpetic gingivostomatitis).<ref name=Neville2008 /> However, herpetiform ulceration is not caused by herpes viruses. As with all types of aphthous stomatitis, it is not contagious. Unlike true herpetic ulcers, herpetiform ulcers are not preceded by vesicles (small, fluid-filled blisters).<ref name=Preeti2011 /> Herpetiform ulcers are less than 1 mm in diameter and occur in variably sized crops up to one hundred at a time. Adjacent ulcers may merge to form larger, continuous areas of ulceration. Healing occurs within fifteen days without scarring.<ref name=Millet2004 /> The ulceration may affect keratinized mucosal surfaces in addition to non keratinized. Herpetiform ulceration is often extremely painful, and the lesions recur more frequently than minor or major aphthous ulcers. Recurrence may be so frequent that ulceration is virtually continuous. It generally occurs in a slightly older age group than the other subtypes,<ref name=Preeti2011 /> and females are affected slightly more frequently than males.<ref name=Scully2013 />

====RAS type ulceration==== Recurrent oral ulceration associated with systemic conditions is termed "RAS-type ulceration", "RAS-like ulceration", or "aphthous-like ulcers".<ref name=Scully2013>{{cite book|last=Scully C|title=Oral and maxillofacial medicine: the basis of diagnosis and treatment|year=2013|publisher=Churchill Livingstone|location=Edinburgh|isbn=978-0-7020-4948-4|edition=3rd|pages=226–34}}</ref> Aphthous stomatitis occurs in individuals with no associated systemic disease.<ref name=Brocklehurst2012 /> Persons with certain systemic diseases may be prone to oral ulceration, but this is secondary to the underlying medical condition (see the systemic disease section).<ref name=Brocklehurst2012 /> This kind of ulceration is considered by some to be separate from true aphthous stomatitis.<ref name=Brocklehurst2012 /><ref name=RieraMatute2011>{{cite journal | vauthors = Riera Matute G, Riera Alonso E | title = [Recurrent aphthous stomatitis in Rheumatology] | journal = Reumatologia Clinica | volume = 7 | issue = 5 | pages = 323–8 | date = September–October 2011 | pmid = 21925448 | doi = 10.1016/j.reuma.2011.05.003 }}</ref> However, this definition is not strictly applied. For example, many sources refer to oral ulceration caused by anemia and/or nutritional deficiencies as aphthous stomatitis, and some also consider Behçet's disease to be a variant.<ref name=Neville2008 /><ref name=Millet2004 />

==Treatment==  The vast majority of people with aphthous stomatitis have minor symptoms and do not require any specific therapy. The pain is often tolerable with simple dietary modification during an episode of ulceration such as avoiding spicy and acidic foods and beverages.<ref name=Treister2010 /> Many different topical and systemic medications have been proposed (see table), sometimes showing little or no evidence of usefulness when formally investigated.<ref name=Brocklehurst2012 /> Some of the results of interventions for RAS may in truth represent a placebo effect.<ref name=ScullyPorter2008 /> No therapy is curative, with treatment aiming to relieve pain, promote healing and reduce the frequency of episodes of ulceration.<ref name=Brocklehurst2012 />

===Medication=== The first line of therapy for aphthous stomatitis is topical agents rather than systemic medication,<ref name=Brocklehurst2012 /> with topical corticosteroids being the mainstay treatment.<ref name=Scully2013 /><ref name=ScullyPorter2008 /> Systemic treatment is usually reserved for severe disease due to the risk of adverse side effects associated with many of these agents. A systematic review found that no single systemic intervention was found to be effective.<ref name=Brocklehurst2012 /> Good oral hygiene is important to prevent secondary infection of the ulcers.<ref name=Scully2013 />

Occasionally, in females where ulceration is correlated to the menstrual cycle or birth control pills, progestogen or a change in birth control may be beneficial.<ref name=Scully2013 /> Use of nicotine replacement therapy for people who have developed oral ulceration after stopping smoking has also been reported.<ref name=Preeti2011 /> Starting smoking again does not usually lessen the condition.<ref name=Odell2010 /> Trauma can be reduced by avoiding rough or sharp foodstuffs and by brushing teeth with care. If sodium lauryl sulfate is suspected to be the cause, avoidance of products containing this chemical may be useful and prevent recurrence in some individuals.<ref name=Baileyetal2011 /> Similarly, patch testing may indicate that food allergy is responsible, and the diet is modified accordingly.<ref name=Scully2013 /> If investigations reveal deficiency states, correction of the deficiency may result in resolution of the ulceration. For example, there is some evidence that vitamin B12 supplementation may prevent recurrence in some individuals.<ref name=Baileyetal2011 />

{| class="wikitable" style="border:solid 1px #999999; margin:0 0 1em 1em;" |- ! colspan="3" style="background-color: #CCEEEE;" | Medications |- ! Drug type !! Intended action !! Example(s) |- | Topical covering agents / barriers || Reduce pain || Orabase (often combined with triamcinolone).<ref name=McBride2000>{{cite journal | vauthors = McBride DR | title = Management of aphthous ulcers | journal = American Family Physician | volume = 62 | issue = 1 | pages = 149–54, 160 | date = July 2000 | pmid = 10905785 | url = http://www.aafp.org/afp/2000/0701/p149.html }}</ref> |- | Topical analgesics / anesthetics / anti-inflammatory agents || Reduce pain || Benzydamine hydrochloride mouthwash or spray,<ref name=ScullyPorter2008 /> Amlexanox paste,<ref name=McBride2000 /><ref name=Baileyetal2011>{{cite journal | vauthors = Bailey J, McCarthy C, Smith RF | title = Clinical inquiry. What is the most effective way to treat recurrent canker sores? | journal = The Journal of Family Practice | volume = 60 | issue = 10 | pages = 621–32 | date = October 2011 | pmid = 21977491 }}</ref> viscous lidocaine,<ref name=McBride2000 /> diclofenac in hyaluronan.<ref name=Scully2013 /> |- | Topical antiseptics || Speed healing (prevent secondary infection) ||Doxycycline,<ref name=Brocklehurst2012 /> tetracycline,<ref name=Brocklehurst2012 /> minocycline,<ref name=McBride2000 /> chlorhexidine gluconate,<ref name=ScullyPorter2008 /> triclosan.<ref name=ScullyPorter2008 /> |- | Topical mild potency corticosteroids || Reduce inflammation || Hydrocortisone sodium succinate.<ref name=Scully2013 /> |- | Topical moderate potency corticosteroids || Reduce inflammation || Beclomethasone dipropionate aerosol,<ref name=Scully2013 /> fluocinonide,<ref name=ScullyPorter2008 /> clobetasol,<ref name=Scully2013 /> betamethasone sodium phosphate,<ref name=Scully2013 /> dexamethasone.<ref name=McBride2000 /> |- | Systemic medications || Various, mostly modulating immune response || Prednisolone,<ref name=Brocklehurst2012 /> colchicine,<ref name=Brocklehurst2012 /> pentoxifylline,<ref name=Brocklehurst2012 /> azathioprine, thalidomide,<ref name=Brocklehurst2012 /> dapsone,<ref name=Brocklehurst2012 /> mycophenolate mofetil,<ref name=Brocklehurst2012 /> adalimumab,<ref name=ScullyPorter2008 /> vitamin B12,<ref name=Brocklehurst2012 /> Clofazimine,<ref name=Brocklehurst2012 /> Levamisole,<ref name=Brocklehurst2012 /><ref name=ScullyPorter2008 /> Montelukast,<ref name=Brocklehurst2012 /> Sulodexide,<ref name=Brocklehurst2012 /> |}

===Other=== Surgical excision of aphthous ulcers has been described, but it is an ineffective and inappropriate treatment.<ref name=Neville2008 /> Silver nitrate has also been used as a chemical cauterant.<ref name=ScullyPorter2008 /> Apart from the mainstream approaches detailed above, there are numerous treatments of unproven effectiveness, ranging from herbal remedies to otherwise alternative treatments, including ''Aloe vera'', ''Myrtus communis'', ''Rosa damascena'', potassium alum, nicotine, polio virus vaccine and prostaglandin E2.<ref name=Scully2013 /> A 2023 Master Thesis by a student in Western Cape University, South Africa, found that supplementation with vitamin B12, zinc sulfate and omega-3 seem to be beneficial in the management of RAS.<ref name="Mirza 2023">{{cite web | last=Mirza | first=Waqas | title=Oral supplemental interventions for the management of recurrent aphthous stomatitis (RAS) – A systematic review and meta-analysis | website=ETD Home | date=2023-01-10 | url=https://uwcscholar.uwc.ac.za/bitstreams/0917740c-7dab-4b76-a7f9-ac416567afcd/download | access-date=2023-02-03}}</ref>

==Prognosis== By definition, there is no serious underlying medical condition, and most importantly, the ulcers do not represent oral cancer, nor are they infectious. However, aphthae are capable of causing significant discomfort. There is a spectrum of severity, with symptoms ranging from a minor nuisance to disabling.<ref name=Treister2010 /> Due to pain during eating, weight loss may develop as a result of not eating in severe cases of aphthous stomatitis. Usually, the condition lasts for several years before spontaneously disappearing in later life.<ref name=Scully2013 />

==Epidemiology==

Aphthous stomatitis affects between 5% and 66% of people, with about 20% of individuals in most populations having the condition to some degree.<ref name=Neville2008 /><ref name=Millet2004>{{cite book|vauthors=Millet D, Welbury R |title=Clinical problem solving in orthodontics and paediatric dentistry|date=2004|publisher=Churchill Livingstone|location=Edinburgh|isbn=978-0-443-07265-9|pages=143–44}}</ref> This makes it the most common disease of the oral mucosa.<ref name=Cawson2008>{{cite book|vauthors=Cawson RA, Odell EW, Porter S |title=Cawson's essentials of oral pathology and oral medicine|year=2008|publisher=Churchill Livingstone|location=Edinburgh|isbn=978-0-443-10125-0|pages=220–24|edition=8th}}</ref> Aphthous stomatitis occurs worldwide, but is more common in developed countries.<ref name=Scully2013 />

Within nations, it is more common in higher socioeconomic groups.<ref name=Scully2013 /> Males and females are affected in an equal ratio, and the peak age of onset is between 10 and 19 years.<ref name=Brocklehurst2012 /> About 80% of people with aphthous stomatitis first developed the condition before the age of 30.<ref name=Neville2008 /> There have been reports of ethnic variation. For example, in the United States, aphthous stomatitis may be three times more common in white-skinned people than black-skinned people.<ref name=ScullyPorter2008>{{cite journal | vauthors = Scully C, Porter S | title = Oral mucosal disease: recurrent aphthous stomatitis | journal = The British Journal of Oral & Maxillofacial Surgery | volume = 46 | issue = 3 | pages = 198–206 | date = April 2008 | pmid = 17850936 | doi = 10.1016/j.bjoms.2007.07.201 }}</ref>

==History, society and culture== "Aphthous affectations" and "aphthous ulcerations" of the mouth are mentioned several times in the treatise "Of the Epidemics" (part of the Hippocratic corpus, in the 4th century BCE),<ref>Wikisource:Of the Epidemics</ref> although it seems likely that this was oral ulceration as a manifestation of some infectious disease, since they are described as occurring in epidemic-like patterns, with concurrent symptoms such as fever.

Aphthous stomatitis was once thought to be a form of recurrent herpes simplex virus infection, and some clinicians still refer to the condition as "herpes" despite this cause having been disproven.<ref name=Glick2003>{{cite book|vauthors=Greenberg MS, Glick M |title=Burket's oral medicine diagnosis & treatment|url=https://archive.org/details/burketsoralmedic00burk |url-access=limited |year=2003|publisher=BC Decker|location=Hamilton, Ont.|isbn=1-55009-186-7|page=[https://archive.org/details/burketsoralmedic00burk/page/n76 63]|edition=10th}}</ref>

The informal term "canker sore" is sometimes used, mainly in North America,<ref>{{cite web|title=Canker|publisher=Oxford dictionaries|url=http://www.oxforddictionaries.com/definition/english/canker|archive-url=https://web.archive.org/web/20120712102104/http://oxforddictionaries.com/definition/english/canker|archive-date=July 12, 2012|access-date=July 12, 2014}}</ref> either to describe this condition generally, or to refer to the individual ulcers of this condition,<ref>{{cite web|title=Aphthous stomatitis|url=http://www.merriam-webster.com/medical/aphthous%20stomatitis|publisher=Merriam-Webster, Incorporated|access-date=July 12, 2014}}</ref> or mouth ulcers of any cause unrelated to this condition. The origin of the word "canker" is thought to have been influenced by Latin, Old English, Middle English and Old North French.<ref name="Etymology online">{{cite web|title=Chancre and Canker|url=http://www.etymonline.com/index.php?allowed_in_frame=0&search=chancre&searchmode=none|publisher=Douglas Harper |access-date=September 1, 2013}}</ref> In Latin, ''cancer'' translates to "malignant tumor" or literally "crab" (related to the likening of sectioned tumors to the limbs of a crab). The closely related word in Middle English and Old North French, ''chancre'', now more usually applied to syphilis, is also thought to be involved.<ref name="Etymology online" /> Despite this etymology, aphthous stomatitis is not a form of cancer but rather entirely benign.

An aphtha (plural ''aphthae'') is a non-specific term that refers to an ulcer of the mouth. The word is derived from the Greek word ''aphtha'' meaning "eruption" or "ulcer".<ref name=Preeti2011>{{cite journal | vauthors = Preeti L, Magesh K, Rajkumar K, Karthik R | title = Recurrent aphthous stomatitis | journal = Journal of Oral and Maxillofacial Pathology | volume = 15 | issue = 3 | pages = 252–6 | date = September 2011 | pmid = 22144824 | pmc = 3227248 | doi = 10.4103/0973-029X.86669 | doi-access = free }}</ref> The lesions of several other oral conditions are sometimes described as aphthae, including Bednar's aphthae (infected, traumatic ulcers on the hard palate in infants),<ref name=Tricarico2012>{{cite journal | vauthors = Tricarico A, Molteni G, Mattioli F, Guerra A, Mordini B, Presutti L, Iughetti L | title = Nipple trauma in infants? Bednar aphthae | journal = American Journal of Otolaryngology | volume = 33 | issue = 6 | pages = 756–7 | date = November–December 2012 | pmid = 22884485 | doi = 10.1016/j.amjoto.2012.06.009 | hdl = 11380/759649 | hdl-access = free }}</ref> oral candidiasis, and foot-and-mouth disease. When used without qualification, ''aphthae'' commonly refers to lesions of recurrent aphthous stomatitis. Since the word aphtha is often taken to be synonymous with ulcer, it has been suggested that the term "aphthous ulcer" is redundant, but it remains in common use.<ref name=Fischman1994>{{cite journal | vauthors = Fischman SL | title = Oral ulcerations | journal = Seminars in Dermatology | volume = 13 | issue = 2 | pages = 74–7 | date = June 1994 | pmid = 8060829 }}</ref> Stomatitis is also a non-specific term referring to any inflammatory process in the mouth, with or without oral ulceration.<ref>{{cite book|veditors =Stewart MG, Selesnick S |title=Differential diagnosis in otolaryngology – head and neck surgery|publisher=Thieme|location=New York|isbn=978-1-60406-279-3|url=https://books.google.com/books?id=p-rSREngtBUC&q=stomatitis+definition&pg=PT151|date=January 1, 2011}}</ref> It may describe many different conditions apart from aphthous stomatitis, such as angular stomatitis.

The current most widely used medical term is "recurrent aphthous stomatitis" or simply "aphthous stomatitis".<ref name=Treister2010>{{cite book|vauthors=Treister JM, Bruch NS |title=Clinical oral medicine and pathology|url=https://archive.org/details/clinicaloralmedi00bruc |url-access=limited |year=2010|publisher=Humana Press|location=New York|isbn=978-1-60327-519-4|pages=[https://archive.org/details/clinicaloralmedi00bruc/page/n63 53]–56}}</ref> Historically, many different terms have been used to refer to recurrent aphthous stomatitis or its sub-types, and some are still in use. Mikulicz's aphthae is a synonym of minor RAS,<ref name=Preeti2011 /> named after Jan Mikulicz-Radecki. Synonyms for major RAS include Sutton's ulcers (named after Richard Lightburn Sutton), Sutton's disease,<ref>{{cite journal | vauthors = Burruano F, Tortorici S | title = [Major aphthous stomatitis (Sutton's disease): etiopathogenesis, histological and clinical aspects] | journal = Minerva Stomatologica | volume = 49 | issue = 1–2 | pages = 41–50 | date = January–February 2000 | pmid = 10932907 }}</ref> Sutton's syndrome and periadenitis mucosa necrotica recurrens.<ref name=Scully2013 /><ref name=Preeti2011 /> Synonyms for aphthous stomatitis as a whole include (recurrent) oral aphthae, (recurrent) aphthous ulceration and (oral) aphthosis.<ref name=Neville2008 /><ref name=RieraMatute2011 />

In traditional Chinese medicine, claimed treatments for aphthae focus on clearing heat and nourishing Yin.<ref>{{cite book |author-first1=Chong |author-last1=Liu |author-first2=Angela |author-last2=Tseng |author-first3=Sue |author-last3=Yang |title=Chinese Herbal Medicine: Modern Applications of Traditional Formulas|date=2004|publisher=CRC Press|location=London|isbn=978-0-203-49389-2|page=533|url=https://books.google.com/books?id=PfipWsQCXeoC&pg=PA533}}</ref>

Rembrandt Gentle White toothpaste did not contain sodium lauryl sulfate, and was specifically marketed as being for the benefit of "canker sore sufferers". When the manufacturer Johnson & Johnson discontinued the product in 2014, it caused a backlash of anger from long-term customers, and the toothpaste began to sell for many times the original price on the auction website eBay.<ref name="chicagotribune1">{{cite web|url=https://www.chicagotribune.com/2014/03/05/loss-of-canker-sore-toothpaste-angers-loyal-users/ |title=''Loss of canker sore toothpaste angers loyal users''|author=Deardorff J|publisher=Chicago Tribune |date=March 5, 2014 |access-date=April 12, 2014}}</ref><ref>{{cite book|vauthors=Graedon J, Graedon T |title=The people's pharmacy guide to home and herbal remedies|date=2002|publisher=St. Martin's Press|page=122|location=New York|isbn=978-0-312-98139-6}}</ref>

==See also== * Acute necrotizing ulcerative gingivitis, also known as "trench mouth"—another painful, non-contagious mouth infection with similar symptoms * CankerMelts (licorice) *Mouth ulcer

== References == {{Reflist|30em}}

== External links == {{Medical resources | DiseasesDB = | ICD10 = {{ICD10|K|12|0|k|00}} | ICD9 = {{ICD9|528.2}} | ICDO = | OMIM = | MedlinePlus = 000998 | eMedicineSubj = ent | eMedicineTopic = 700 | eMedicine_mult = {{eMedicine2|derm|486}} {{eMedicine2|ped|2672}} | MeshID = D013281 }} {{Commons category|Aphthous ulcer}} * {{Wikiversity inline|Oral ulceration}}

{{DEFAULTSORT:Aphthous Ulcer}} Category:Laryngology Category:Conditions of the mucous membranes Category:Oral mucosal pathology