It is important to note that individual aphthae last only a limited period of time, before they heal spontaneously. This is quite a different history from ulcers that persist without healing, such as malignant ulcers and those associated with vesiculobullous disorders such as pemphigoid and pemphigus.
There is a genetic predisposition shown by a positive family history in about one-third of patients and by an increased frequency of HLA types (HLA-A2, A11, B12 and DR2). There is an association between RAS and inheritance of a single-nucleotide polymorphism of the NOS2 gene (encoding inducible nitric oxide synthase). Inheritance of the G/G genotype of both interleukins IL-1B and IL-6 is a particularly strong predictor for RAS:
Haematinic deficiency may be relevant in a minority. In up to 20% of patients, deficiencies of iron, folic acid (folate) or vitamin B are found and sometimes the correction of this may relieve the ulceration. Iron deficiency is usually due to chronic haemorrhage (e.g. from the gastrointestinal or genitourinary tract). Folic acid is found in green leafy vegetables especially, and body stores are small; deficiencies may be dietary, or related to malabsorption or drugs (alcohol, anticonvulsants, carbamazepine, and some cytotoxic drugs). Vitamin B12 is found especially in meat, is absorbed via intrinsic factor from the gastric parietal cells in the ileum and stored in the liver for about 3 years. Dietary B12 deficiency can arise particularly in vegans, in pernicious anaemia and after gastrectomy, and in ileal disease (e.g. Crohn disease). Histamine H2 receptor antagonists (cimetidine, ranitidine, omeprazole) can also impede vitamin B12 absorption.
Endocrine factors are relevant in some women where RAS are related to the fall in progestogen level in the luteal phase of the menstrual cycle, or to the contraceptive pill, and then RAS may regress temporarily in pregnancy.
The diagnosis of RAS is not infrequently misapplied to the similar ulcers (aphthous-like ulcers), which may be seen in a range of systemic conditions. The history and examination should be directed to eliciting any cutaneous, gastrointestinal, genital, ocular, joint problems or history of fever, which might point to these conditions. They include conditions such as:
Autoinflammatory conditions such as periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome, which is seen in children, appears related to a disorder of innate immunity with complement activation and IL-1β/-18, resolves spontaneously and rarely has long-term sequelae. Corticosteroids are highly effective symptomatically; tonsillectomy and cimetidine treatment have been effective in a few patients.
The aetiology of RAS is not entirely clear, and therefore aphthae are termed ‘idiopathic’. Indeed, RAS may not be a single condition, but rather may be the manifestation of a group of disorders of quite different aetiology.
It seems likely that a minor degree of immunological dysregulation underlies aphthae, and a genetic tendency to ulceration, and cross-reacting antigens between the oral mucosa and microorganisms may be involved. Reactions to heat shock proteins (HSP) are one possibility. Patients with RAS have circulating lymphocytes reactive with peptide 91-105 of HSP 65-60. HSP27 is a powerful inductor of interleukin IL-10, a major inhibitor of Th1 response and in RAS, there is a reduced cellular expression of HSP27 and IL-10. Decreased IL-10 suggests a failure of the immune system to suppress inflammation.
HSP can block the production of pro-inflammatory cytokines (e.g. tumour necrosis factors (TNFs) and interleukins (IL-1β, IL-6 and IL-8)) through inhibition of NF-κB and mitogen-activated protein kinase (MAPK) pathways, or activate antiinflammatory cytokines (e.g. transforming growth factor-β1), and therefore control the magnitude of the immune response.
IL-1β and IL-6 gene polymorphisms are associated with an increased risk for RAS. Systemic immunological abnormalities in RAS include increased plasma levels of IL-8 and IL-6. Serum IL-6 (via IL-1β over-production) typically fluctuates in auto-inflammatory syndromes, which also manifest with recurrent ulceration.
Patients with RAS have no clinically detectable systemic symptoms or signs; if ulceration affects the genitals or other mucosae, the diagnosis cannot be of RAS alone – rather of aphthous-like ulceration.
|Percentage of all aphthae||75–85||10–15||5–10|
consists of small round or ovoid ulcers 2–4 mm in diameter (Fig. 34.3), in groups of only a few ulcers (1–6) at a time, with initially yellowish floors surrounded by an erythematous halo and some oedema, but the floors assume a greyish hue as healing and epithelialization proceeds