Recurrent aphthous stomatitis (RAS) is a common condition, restricted to the mouth, that typically starts in childhood or adolescence as recurrent small, round, or ovoid ulcers with circumscribed margins, erythematous haloes, and yellow or gray floors. A positive family history of similar ulcers is common, and the natural history is typically of resolution in the third decade of life.
Not all ulcers that recur are RAS and this has led to some significant confusion in this field. Ulcers with similar clinical features but rarely resolving spontaneously with age may be associated with systemic conditions such as Behçet syndrome, auto-inflammatory syndromes, gastrointestinal disease.
A genetic basis exists for some RAS. This is shown by a positive family history in about one third of patients with RAS, an increased frequency of HLA types A2, A11, B12, and DR2, and susceptibility to RAS which segregates in families in association with HLA haplotypes. RAS probably involves cell-mediated mechanisms, but the precise immunopathogenesis remains unclear. Phagocytic and cytotoxic T cells probably aid in destruction of oral epithelium that is directed and sustained by local cytokine release.
Patients with active RAS have an increased proportion of gamma-delta T cells compared with control subjects and patients with inactive RAS. Gamma-delta T cells may be involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Compared with control subjects, individuals with RAS have raised serum levels of cytokines such as interleukin (IL)–6 and IL-2R, soluble intercellular adhesion modules (ICAM), vascular cell adhesion modules (VCAM), and E-selectin; however, some of these do not correlate with disease activity.
Cross-reactivity between a streptococcal 60- to 65-kd heat shock protein (hsp) and the oral mucosa has been demonstrated, and significantly elevated levels of serum antibodies to hsp are found in patients with RAS. Lymphocytes of patients with RAS have reactivity to a peptide of Mycobacterium tuberculosis. Some cross-reactivity exists between the 65-kd hsp and the 60-kd human mitochondrial hsp. Monoclonal antibodies to part of the 65-kd hsp of M tuberculosis react with Streptococcus sanguis. RAS thus may be a T cell–mediated response to antigens of S sanguis, which cross-react with the mitochondrial hsp and induce oral mucosal damage. RAS patients have an anomalous activity of the toll-like receptor TLR2 pathway that probably influences the stimulation of an abnormal Th1 immune response.
Predisposing factors found may include any of the following:
- Cessation of smoking: This may precipitate or exacerbate RAS in some cases.
- Stress: This underlies RAS in some cases; ulcers appear to exacerbate during school or university examination times.
- Trauma: Biting of the mucosa and wearing of dental appliances may lead to some ulcers; RAS is uncommon on keratinized mucosae.
- Endocrine factors in some women: RAS is clearly related to the progestogen level fall in the luteal phase of the menstrual cycle, and ulcers may then temporarily regress in pregnancy.
- Allergies to food: Food allergies occasionally underlie RAS; the prevalence of atopy is high. Patients with aphthae may occasionally have a reaction to cow's milk, and may have been weaned at an early age.
- Sodium lauryl sulphate (SLS): This is a detergent in some oral healthcare products that may aggravate or produce oral ulceration.
Aphthous-like ulcers may be seen in the following:
- Hematinic deficiency: Up to 20% of patients are deficient of iron, folic acid (folate), or vitamin B.
- Malabsorption in gastrointestinal disorders: About 3% of patients experience these disorders, particularly celiac disease (gluten-sensitive enteropathy) but, occasionally, Crohn disease, pernicious anemia, and dermatitis herpetiformis. HLA DRW10 and DQW1 may predispose patients with celiac disease to oral ulceration.
- Immune deficiencies: Ulcers (aphthous-like ulcers) may be seen in patients with HIV, neutropenias, and some other immune defects.
- Drugs, especially NSAIDs, alendronate, and nicorandil  : These may produce mouth ulcers, but the history should distinguish them from RAS.