The cause is not entirely clear, but is thought to be multifactorial. It has been suggested that<unk>  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<unk>  appears to be non-contagious, non-infectious, and not sexually transmissible. 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). Mast cells and macrophages are also involved, secreting TNF-α along with the T cells. When early<unk>  ulcers are biopsied, the histologic appearance shows a dense inflammatory infiltrate, 80% of which is made up of T cells. Persons with<unk>  also have circulating lymphocytes which react with peptides 91–105 of heat shock protein 65–60, and the ratio of CD4+ T cells to CD8+ T cells in the peripheral blood of individuals with<unk>  is decreased.<unk>  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, but 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 a number of 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). Risk factors in<unk>  are also sometimes considered as either host-related or environmental. Immunity At least 40% of people with<unk>  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 with<unk> . However, these HLA types are inconsistently associated with the condition, and also vary according to ethnicity. People who have a positive family history of<unk>  tend to develop a more severe form of the condition, and at an earlier age than is typical. 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 sufferers who are students, ulceration is exacerbated during examination periods and lessened during periods of vacation. Alternatively, it has been suggested that oral parafunctional activities such as lip or cheek chewing become more pronounced during periods of stress, and hence the mucosa is subjected to more minor trauma.<unk> -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. Mucosal barrier The thickness of the mucosa may be an important factor in<unk> . 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. The nutritional deficiencies associated with<unk>  (vitamin B12, folate, and iron) can all cause a decrease in the thickness of the oral mucosa (atrophy). Local trauma is also associated with<unk> , and 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 broken tooth, or from tooth brushing. Hormonal factors are capable of altering the mucosal barrier. In one study, a small group of females with<unk>  had fewer occurrences of<unk>  ulcers 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 experiences remission during pregnancy. However, other studies report no correlation between<unk>  and menstrual period, pregnancy or menopause.<unk>  is more common in people who smoke, and there is also a correlation between habit duration and severity of the condition. Tobacco use is associated with an increase in keratinization of the oral mucosa. 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 of 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 production of adrenal steroids and reduce production of TNF-α, interleukin-1 and interleukin-6. Smokeless tobacco products also seem to protect against<unk> . Cessation of smoking is known to sometimes precede the onset of<unk>  in people previously unaffected, or exacerbate the condition in those who were already experiencing<unk>  ulceration. Despite this correlation, starting smoking again does not usually lessen the condition. 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. Some people with<unk>  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. In some instances, recurrent mouth ulcers may be a manifestation of an allergic reaction. 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. Where dietary allergens are responsible, mouth ulcers usually develop within about 12–24 hours of exposure. Sodium lauryl sulphate (SLS), a detergent present in some brands of toothpaste and other oral healthcare products, may produce oral ulceration in some individuals. It has been shown that<unk>  is more common in people using toothpastes containing SLS, and that some reduction in ulceration occurs when a SLS-free toothpaste is used. Some have argued that since SLS is almost ubiquitously used in oral hygiene products, there is unlikely to be a true predisposition for<unk>  caused by SLS. Systemic disease Systemic disorders associated with<unk> -like ulceration :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<unk> -like ulceration may occur in association with several systemic disorders (see table). These ulcers are clinically and histopathologically identical to the lesions of<unk> , but this type of oral ulceration is not considered to be true<unk>  by some sources. 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 leads to decreased frequency and severity of the oral ulceration. Behçet's disease is a triad of mouth ulcers, genital ulcers and anterior uveitis. The main feature of Behçet's disease is<unk> -like ulceration, but this is usually more severe than seen in<unk>  without a systemic cause, and typically resembles major or herpetiforme ulceration or both.<unk> -like ulceration is the first sign of the disease in 25–75% of cases. Behçet's is more common in individuals whose ethnic origin is from regions along the Silk Road (between the Mediterranean and the Far East). It tends to be rare in other countries such as the United States and the United Kingdom. MAGIC syndrome is a possible variant of Behçet's disease, and is associated with<unk> -like ulceration. The name stands for "mouth and genital ulcers with inflamed cartilage" (relapsing polychondritis). PFAPA syndrome is a rare condition that tends to occur in children. 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. 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<unk> -like ulceration is worst during this time. Hematinic deficiencies (vitamin B12, folic acid and iron), occurring singly or in combination, 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. 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,
Aphthous stomatitis
Herpes labialis
Contact stomatitis
Denture-related stomatitis
Bovine papular stomatitis
Oral candidiasis
Adenoviral keratoconjunctivitis
Dermatophagia