|Classification and external resources|
Canker sore on the lower lip
|eMedicine||ent/700 derm/486 ped/2672|
Aphthous stomatitis (also termed canker sores, recurrent aphthous stomatitis, RAS, recurring oral aphthae and recurrent aphthous ulceration) is a common cause of benign and non-contagious mouth ulcers (canker sores). This condition is characterized by the repeated formation of ulcers on the mucous membrane of the oral cavity (the lining of the mouth), in otherwise healthy individuals. These ulcers occur periodically and heal completely between attacks. Symptoms range from a minor nuisance to interfering with eating and drinking. The cause is not completely understood, but may involve a T cell mediated immune response which is triggered by a variety of factors. Different people may have different triggers, including nutritional deficiencies, local trauma, stress, hormonal influences, allergies, and a genetic predisposition. The condition is very common, affecting about 20% of the general population. There is no cure, and treatments are aimed at reducing pain and speeding the healing process. Often, the onset of the condition is during childhood or adolescence and usually lasts for several years before gradually disappearing, with or without any form of treatment.
Three variants of aphthous stomatitis exist, distinguished by the size, number and location of the lesions, the healing time of individual ulcers and whether a scar is left after healing.
Minor aphthous ulceration 
This is the most common type of aphthous stomatitis, accounting for about 80% of all cases. This subtype is termed minor aphthous ulceration (MiAU), 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 and affect non-keratinized mucosal surfaces (i.e. the labial and buccal mucosa, lateral borders of the tongue and the floor of the mouth). Usually several ulcers 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 before the next episode occurs.
Major aphthous ulceration 
This subtype makes up about 10% of all cases of aphthous stomatitis. It is termed major aphthous ulceration (MaAU) or major recurrent aphthous stomatitis (MaRAS). Major aphthae (major aphthous ulcers) are similar to minor aphthae, but are more than 10 mm in diameter and the ulceration is deeper. 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. Major aphthous ulceration usually affects non keratinized mucosal surfaces, but less commonly keratinized mucosa may also be involved.
Herpetiform ulceration 
Also termed stomatitis herpetiformis, herpetiform ulcers, or herpes-like ulcerations, this type of aphthous stomatitis is so named because the lesions resemble a primary infection with herpes simplex (primary herpetic gingivostomatitis). However, herpetiform ulceration is not caused by herpes viruses. As with all types of aphthous stomatitis, it is not contagious. These 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. 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. Females are affected slightly more frequently than males.
RAS type ulceration 
Aphthous stomatitis occurs in individuals with no associated systemic disease. Persons with certain systemic diseases may be prone to oral ulceration, but this is secondary to the underlying medical condition. Examples include Behçet's disease, Reiter's syndrome, recurrent erythema multiforme, celiac disease, Crohn's disease, ulcerative colitis, anemia and hematinic deficiency (vitamin B12, folic acid and iron). Recurrent oral ulceration associated with systemic conditions is termed "RAS type ulceration", "RAS like ulceration" or "aphthous-like ulcers". This kind of ulceration is considered to be separate from true aphthous stomatitis.
Signs and symptoms 
Persons with aphthous stomatitis have no clinically detectable systemic symptoms or signs (i.e. outside the mouth). 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. acidic). Pain is worst in the days immediately following the initial formation of the ulcer, and then recedes as healing progresses. If there are lesions on the tongue, speaking and chewing can be uncomfortable, and ulcers on the soft palate, oropharynx or esophagus can cause odynophagia (painful swallowing). Severe disease, characterized by virtual constant ulceration (new lesions developing before old ones have healed), may cause debilitating chronic pain, weight loss and malnutrition. Signs are limited to the lesions themselves. Aphthous ulcers typically begin as erythematous macules (reddened, flat area of mucosa) which develops into ulcers that are covered with a yellow-grey fibrinous membrane which can be scraped away. An erythematous "halo" surrounds the ulcer. The size, number, location, healing time and periodicity between episodes of ulcer formation are all dependent upon the subtype of aphthous stomatitis (see classification).
The cause is not entirely clear,  but is thought to be multifactorial. It has even been suggested that aphthous stomatitis is not a single entity but rather a group of conditions with different causes. Multiple research studies have attempted to identify a causative organism, but aphthous stomatitis appears to be non-contagious, non-infectious and non-sexually transmissible. The mucosal destruction is thought to be the result of a T cell mediated immune response which involves the generation of T cells, interleukins and tumor necrosis factor alpha. When early aphthous ulcers are biopsied, the histologic appearance shows a dense inflammatory infiltrate, 80% of which is made up of T lymphocytes. Persons with aphthous stomatitis have circulating lymphocytes which react with peptides 91-105 of heat shock protein 65-60. Despite this preferred theory of immuno-dysregulation held by most researchers, there is no association between aphthous stomatitis and other autoimmune diseases, and the common autoantibodies are not found, meaning that aphthous stomatitis is not a classical autoimmune disease. Aphthous stomatitis also tends to resolve spontaneously with advancing age rather than worsen. Usually, serum immunoglobulin is at normal levels. The triggers for the process of mucosal destruction are multiple. Different subgroups of individuals with aphthous stomatitis appear to have different causes for the condition. This suggests that there are a number of possible triggers, each of which is capable of producing the disease in different subgroups. These sub-groups have been considered to be in three general groups, namely primary immuno-dysregulation, decrease of the mucosal barrier and increase in antigenic exposure.
Primary immuno-dysregulation 
At least 40% of people with aphthous stomaitits have a positive family history, suggesting that some people are genetically predisposed to suffering with oral ulceration. HLA-B12, HLA-B51, HLA-Cw7, HLA-A2, HLA-A11, and HLA-DR2 are examples of human leukocyte antigen types associated (although inconsistently) with aphthous stomatitis. Stress has effects on the immune system, (see Effect of stress on the immune system), which may explain why some cases directly correlate with stress. E.g., ulceration is exacerbated during examination periods and lessened during periods of vacation. 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 prevents the cycle of ulceration. The relative increase in percentage of CD8+ T lymphocytes, caused by a reduction in numbers of CD4+ T lymphocytes may be implicated in RAS-type ulceration in HIV infection.
Decrease of the mucosal barrier 
The thickness of the mucosa may be an important factor in aphthous stomatitis. Usually, ulcers form on non keratinizing mucosal surfaces in the mouth. Factors which decrease the thickness of mucosa increase the frequency of occurrence, and factors which increase the thickness of the mucosa correlate with decreased ulceration. The nutritional deficiencies associated with aphthous stomatitis (B12, folate, and iron) all can cause a decrease in the thickness of the oral mucosa (atrophy). Local trauma is also associated with aphthous stomatitis, and it is known that trauma can decrease the mucosal barrier. Hormonal factors are capable of altering the mucosal barrier. In a small subgroup of females with aphthous stomatits, there are fewer occurrences of aphthae during the luteal phase of the menstrual cycle or with use of the contraceptive pill. This phase is associated with a fall in progestogen levels, mucosal proliferation and keratinization. This subgroup often experience remission during pregnancy. Aphthous stomatitis is uncommon in people who smoke. Tobacco use is associated with an increase in keratinization of the oral mucosa. In extreme forms, this may be diagnosed as stomatitis nicotina (smoker's keratosis). This increased keratinization may mechanically reinforce the mucosa and reduce the tendency of ulcers to form after minor trauma, or present a more substantial barrier to antigens, but this is unclear. 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. Despite this correlation, starting smoking again does not usually lessen the condition.
Increase in antigenic exposure 
Antigenic stimuli have been implicated as a trigger, e.g. L forms of streptococci, herpes simplex virus, varicella-zoster virus, adenovirus, and cytomegalovirus. 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 titers. In some subgroups, food allergy may be involved, and some may respond to strict elimination diets based on the results of patch testing. Sodium lauryl sulphate, a detergent present in some brands of toothpaste and oral healthcare products, may produce oral ulceration.
Systemic disease 
|Immunocompromise, e.g. HIV|
|Inflammatory bowel disease|
|Ulcus vulvae acutum|
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 may be not considered to be aphthous stomatitis. Some of these conditions may cause ulceration on other mucosal surfaces (conjunctiva, genitals). Resolution of the systemic condition often leads to a decreased frequency and severity of the oral ulceration. The main feature of Behçet disease is aphthous-like ulceration, but is usually more severe than seen in RAS, and typically resembles major or herpetiforme ulceration or both. MAGIC syndrome is a possible variant of Behçet disease. PFAPA (periodic aphthae, pharyngitis and cervical adenitis) is a rare condition that tends to occur in children. The condition appears to improve after tonsillectomy or immunosuppression, suggesting a immunologic cause. 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.
Nutritional deficiencies may occur without any underlying gastrointestinal disease. Iron, folic acid or vitamin B12 deficiencies may be twice as common in people with RAS, but iron and vitamin supplements only infrequently improve the ulceration. 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 suffer from 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.
Gastrointestinal disorders are sometimes associated with aphthous-like stomatitis, e.g. Chron's disease, ulcerative colitis, Celiac disease, but the link is probably related to nutritional deficiencies caused by malabsorption. Less than 5% of people with RAS have Celiac disease. Again, removal of gluten from the diet does not usually improve the ulceration.
Diagnosis is mostly based on the clinical appearance and the medical history. The most important diagnostic feature is a history of recurrent, self healing ulcers at fairly regular intervals. 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 and ulceration associated with gastrointestinal disease. A systemic cause is more likely in adults who suddenly develop recurrent oral ulceration with no prior history. Tissue biopsy is not usually required, unless to rule out other suspected conditions such as oral squamous cell carcinoma. The histopathologic appearance is not pathognomonic (the appearance is non specific). Early lesions have a central zone of ulceration covered by a fibrinous membrane. In the conenctive 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 ("perivascular cuffing"). Special investigations may be indicated to rule out other causes of oral ulceration. These include blood tests (e.g. to exclude anemia / deficiencies of iron, folate or vitamin B12 or celiac disease). Many of the systemic diseases cause other symptoms apart from oral ulceration, e.g. genital ulceration in Behçet's syndrome, 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 substitution to another drug may highlight a causal relationship.
The vast majority of people with aphthous stomatitis have minor symptoms and do not require any specific therapy (the pain is tolerable with simple dietary modification during an episode of ulceration). Many different topical and systemic treatments have been proposed (see table), sometimes showing little or no evidence of efficacy when formally investigated. Some of the results of interventions for RAS may in truth represent a placebo effect. No therapy is curative, with treatment aiming to relieve pain, promote healing and reduce the frequency of episodes of ulceration.
|Topical covering agents / barriers||Reduce pain||Orobase (often combined with triamcinolone)|
|Topical analgesics / anesthetics / anti-inflammatory agents||Reduce pain||Benzydamine hydrochloride mouthwash or spray, Amlexanox paste, viscous lidocaine.|
|Topical antiseptics||Hasten healing (prevent secondary infection)||Doxycycline, tetracycline, minocycline, chlorhexidine gluconate|
|Topical mild potency corticosteroids||Reduce inflammation||Hydrocortisone sodium succinate|
|Topical moderate potency corticosteroids||Reduce inflammation||Beclomethasone dipropionate aerosol, fluocinonide, clobetasol, betamethasone sodium phosphate, dexamethasone|
|Systemic agents||Various, mostly modulating immune response||Prednisolone, colchicine, pentoxifylline, azathioprine, thalidomide, dapsone, mycophenolate mofetil, adalimumab|
Amlexanox applied topically is highly-studied and effective in healing; less conclusive research suggests that vitamin B12 supplementation and the avoidance of sodium lauryl sulfate in toothpaste prevent recurrence.
Occasionally, in females where ulceration is correlated to the menstrual cycle or to an oral contraceptive, progestogen or a change in oral contraceptive may be beneficial. 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. If investigations reveal deficiency states, correction of the deficiency may result in resolution of the ulceration. Similarly patch testing may indicate that food allergy is responsible, and the diet modified accordingly. 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.
By definition, there is no serious underlying medical condition, and importantly the ulcers do not represent oral cancer and they are not infectious. However, aphthae are capable of causing significant discomfort. There is a spectrum of severity, with symptoms ranging from a minor nuisance to disabling. Due to pain during eating, weight loss may develop as a result of severe aphthous stomatitis. Usually, the condition lasts for several years before spontaneously disappearing in later life.
Reported prevalence ranges from 5 to 66%, but is probably about 20% for most populations, making it the most common disease of the oral mucosa. Aphthous stomatitis occurs worldwide, but is more common in developed countries. There is a slightly higher prevalence in higher socioeconomic groups. There is no gender predilection, and the peak age of onset between ten and nineteen years. There have been reports of racial epidemiologic variation, e.g. in the United States of America, aphthous stomatitis may be three times more common in white skinned people than black skinned people.
The current most widely used medical term is "recurrent aphthous stomatitis" or simply "aphthous stomatitis", and colloquially, "canker sores". An aphtha 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". 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), 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. Stomatitis is also a non specific term meaning inflammation of the mucous membrane of the mouth, and again may describe many different conditions. Historically, many different terms have been used to refer to recurrent aphthous stomatitis or it's sub-types. Some of these are still in use, and include Mikulicz' aphthae (named after Jan Mikulicz-Radecki), Sutton's ulcers (named after Richard Lightburn Sutton), Sutton’s disease, Sutton's syndrome, pariadenitis mucosa necrotica recurrens, (recurrent) oral aphthae, (recurrent) aphthous ulceration and aphthosis.
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