34: Aphthae (recurrent aphthous stomatitis)

Aphthae (recurrent aphthous stomatitis)


Recurrent aphthous stomatitis (RAS), is a common condition which is characterized by presenting typically:

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:

image Stress underlies RAS in some cases and ulcers appear to exacerbate during school or university examination times.

image Trauma from biting the mucosa or from dental appliances may lead to aphthae in some people.

image Cessation of smoking may precipitate or exacerbate RAS in some cases, but the reason is unclear.

image 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.

image 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.

image Allergies to food occasionally underlie RAS, and there is a high incidence of atopy.

image Sodium lauryl sulphate (SLS), a detergent in some toothpastes and other oral healthcare products, may produce oral ulceration.


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:

image Immune deficiencies such as HIV (Ch. 53), cyclical neutropenia and other immune defects.

image Behçet syndrome, where mouth ulcers are seen along with ulcers of the genitals (Ch. 36).

image Coeliac disease: in about 3% of patients with recurrent mouth ulcers, coeliac disease (gluten-sensitive enteropathy) – an allergic reaction to gluten in wheat – is seen.

image Crohn disease, where ulcers are seen with an enteropathy (Ch. 46).

image 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.

image Sweet syndrome, in which mouth ulcers are found with conjunctivitis, episcleritis and inflamed tender skin papules or nodules.

image Drug use, especially NSAIDs and nicorandil.


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.

Many studies have explored an infectious aetiology, but there is no evidence of transmissibility and RAS does not at present appear to be infectious, contagious, or sexually shared.

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.

Immune mechanisms that appear to play a role in a people with a genetic predisposition to oral ulceration include the following (Fig. 34.2):

image A local cell-mediated immune response involving cytotoxic CD8+ T-cells, natural killer (NK) cells, macrophages and mast cells.

image T-helper cells (gamma-delta cells), predominate in the early RAS lesions, along with some natural killer (NK) cells.

image Cytotoxic cells then appear in the lesions and there is evidence for an antibody-dependent cellular cytotoxicity (ADCC) reaction, and neutrophils and NK cells may be involved.

image 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.

image 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.

image There is increased intra-lesional expression of TNF-α and IL-2. Systemic immunological abnormalities in RAS include increased plasma levels of TNF-α and IL-2,

image There is an overly exuberant inflammation reaction which may be caused by derangement of toll-like receptor (TLR) gene expression.

image Regulatory T cells (TReg) CD4(+)CD25(+), crucial in regulating immune responses, are both functionally and quantitatively compromised in RAS.

image There is decreased constitutive expression of indoleamine 2,3-dioxygenase (IDO) in the oral mucosa in RAS which may lead to the loss of local immune tolerance.

image NOS2 (nitric oxide synthase) gene polymorphisms implicate a role of inducible nitric oxide synthase.


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.

There are three main clinical types of RAS (Table 34.1), though any significance of these distinctions is unclear (they could be three distinct disorders):

Table 34.1

Clinical characteristics of the different clinical types of aphthae

  Minor Major Herpetiform
Percentage of all aphthae 75–85 10–15 5–10
Size (mm) 2–5 >10 <5
Duration (days) 10–14 >14 10–14
Scarring No Yes No


Jan 9, 2015 | Posted by in Oral and Maxillofacial Pathology | Comments Off on 34: Aphthae (recurrent aphthous stomatitis)
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