Aetiology
A genetic predisposition may contribute to recurrent aphthous stomatitis (RAS). A positive family history may be found in up to 40% of patients.[1][10] Studies show a high correlation between stress, depression and anxiety, and RAS.[11]
An association with a variety of human leukocyte antigen (HLA) haplotypes has been reported.[12] Further clarification is required.[13]
In addition, further predisposing factors such as cytokine polymorphism have been suggested.[14]
Patients with RAS are usually non-smokers, and there is a lower prevalence and severity of ulcers in heavy compared with moderate smokers.[15][16] Some patients report an onset of ulcers parallel to smoking cessation, whereas others report control on re-initiation of smoking. The use of smokeless tobacco is also associated with a significantly lower prevalence of ulcers. Nicotine-containing tablets also appear to control the frequency of aphthae.[6]
Haematinic (iron, folic acid, or vitamin B12) deficiencies may be twice as common in some groups of patients with RAS as in healthy control subjects.[1][6][17][18]
There are patients whose ulcers coincide with the luteal phase of the menstrual cycle and often remit with oral contraceptives or during pregnancy.[6]
Local trauma may trigger ulcers in susceptible people.[1][6][19] Increased level of anxiety has been reported in some patients with RAS.[6]
RAS may be more prevalent in cows' milk-fed children.[20] Certain foods (e.g., chocolate, peanuts, coffee, and gluten products) have been reported to trigger episodes of RAS.[3] An increased frequency of RAS related to sodium lauryl sulfate-containing dentifrice has been reported, although other studies found no such association.[21] In another trial, researchers found that sodium lauryl sulfate-free toothpaste did not reduce the number or frequency of ulcers, but the participants self-reported feeling less pain and that they thought the ulcers healed slightly faster.[22]
Pathophysiology
A mononuclear (lymphocytic) cell infiltrate in the epithelium in the pre-ulcerative stage is followed by a localised papular swelling as a result of keratinocyte vacuolisation surrounded by a reactive, erythematous halo representing vasculitis.[23] The lesion then ulcerates and a fibrous membrane covers the ulcer, which is infiltrated mainly by neutrophils, lymphocytes, and plasma cells. Finally, there is healing with epithelial regeneration.
Evidence suggests that immunopathogenesis may involve cell-mediated responses, involving T cells and tumour necrosis factor alpha (TNF-alpha) production by these and other infiltrating leukocytes (macrophages and mast cells).[24] TNF-alpha induces inflammation by its effect on endothelial cell adhesion and neutrophil chemotaxis.[25] There has also been evidence of the association of toll-like receptors (TLR).[26][27]
Other cytokines, such as interleukin (IL)-2 and IL-10, and natural killer cells activated by IL-2 also have a role in RAS.[1][23]
Classification
Clinical classification[1][2][3]
There are three clinical presentations of recurrent aphthous stomatitis (RAS), which suggests disease heterogeneity.
Minor aphthous ulcers (around 75% to 85% of all RAS cases): [Figure caption and citation for the preceding image starts]: Recurrent aphthous stomatitis (RAS): minor aphthaeFrom the personal collection of Crispian Scully, MD, PhD, FDSRCS, FRCPath [Citation ends].
Small round or ovoid ulcers less than 10 mm in diameter (usually less than 5 mm in diameter)
Occur in groups of 1 to 6 at a time
Found mainly on the non-keratinised mucosa of the lips, cheeks, floor of the mouth, sulci, or ventrum of the tongue
Heal in 7-10 days without scarring
Frequency of episodes varies and patients can experience ulcer-free periods
Occur mainly in people aged between 10 and 40 years.
Major aphthous ulcers (around 10% to 15% of all RAS cases): [Figure caption and citation for the preceding image starts]: Recurrent aphthous stomatitis (RAS): major aphthaeFrom the personal collection of Crispian Scully, MD, PhD, FDSRCS, FRCPath [Citation ends].
Often more painful and persistent than minor aphthae
Large round or ovoid ulcers greater than 10 mm in diameter
Occur in groups of 1 to 6 at a time
Involve any oral site, including the keratinised mucosa (palate and dorsum of tongue)
Heal slowly over 10-40 days, or occasionally longer
Recur frequently and may heal with scarring
Occur mainly in people aged 10-40 years.
Herpetiform aphthous ulcers: [Figure caption and citation for the preceding image starts]: Recurrent aphthous stomatitis (RAS): herpetiform ulcerationFrom: Scully C, Flint S, Porter SR, et al. Oral and Maxillofacial diseases. London UK; 2004. Used with permission [Citation ends].
Rarer than major and minor aphthous ulcers
Multiple (5-100) pinhead-sized discrete ulcers that can increase in size and coalesce to leave large areas of ulceration
Mimics herpes simplex stomatitis, but are not preceded by vesicles or blistering, and are not communicable
Often extremely painful
Involve any oral site, including the keratinised mucosa (palate and dorsum of tongue)
Heal in 10 days or longer
Recur so frequently that ulceration may seem continuous
Occur in a slightly older age group than the other forms of RAS and mainly in women.
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