Aphthous Ulcers 

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.

Ulcers with similar clinical features but rarely resolving spontaneously with age may be termed "aphthous-like ulcers," and may then be associated with systemic conditions such as Behçet syndrome, auto-inflammatory syndromes, gastrointestinal disease, or immune defects such as HIV/AIDS.

The etiology of recurrent aphthous stomatitis (RAS) is not entirely clear, and aphthae are therefore termed idiopathic. RAS may be the manifestation of a group of disorders of quite different etiology, rather than a single entity.

Despite many studies trying to identify a causal microorganism, RAS does not appear to be infectious, contagious, or sexually transmitted. Immune mechanisms appear at play in persons with a genetic predisposition to oral ulceration.

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:

• 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 RAS.
• 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.
• Immune deficiencies: Ulcers similar to RAS may be seen in patients with HIV, neutropenias and some other immune defects.
• Drugs, especially NSAIDs, alendronate, and nicorandil:^[1] These may produce lesions clinically similar to RAS.

Frequency

United States

RAS affects 5-66% of the population. Approximately 1% of children from higher socioeconomic groups in developed countries have RAS; however, 40% of selected groups of children can have a history of RAS, with ulceration beginning before age 5 years and with the frequency of affected patients increasing with age.

Mortality/Morbidity

Most patients with RAS are otherwise well.

Race

RAS have been reported in all races

Sex

A slight female predominance exists.

Age

RAS typically starts in childhood or adolescence.