Aphthae (recurrent aphthous stomatitis)

Key Points

Aphthae are multiple recurrent small, round or ovoid ulcers which have circumscribed margins, erythematous haloes, and yellow or grey floors, appearing first in childhood or adolescence

A minor degree of immunological dysregulation underlies aphthae

A family history of aphthae is common

Most patients appear otherwise well and predisposing factors are unclear

Topical corticosteroids control most aphthae

INTRODUCTION

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

With multiple recurrent, round or ovoid ulcers known as aphthae or canker sores, which have circumscribed margins, erythematous haloes, and yellow or grey floors (Fig. 34.1):

Fig. 34.1 Minor aphthae; typical round shape, yellow sunken ulcer floor and erythematous halo

on non-keratinized and mobile mucosae – they are rare on gingivae or palate.

With first onset in childhood or adolescence.

With no systemic disease.

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.

INCIDENCE

RAS affects at least 10% of the population, and the highest prevalence (up to 25%) is in resource-rich groups.

PREDISPOSING FACTORS

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:

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

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

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

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.

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

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

APHTHOUS-LIKE ULCERS (ALU) (see Table 34.3)

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:

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

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

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.

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

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.

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

Drug use, especially NSAIDs and nicorandil.

AETIOLOGY AND PATHOGENESIS

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):

Fig. 34.2 Pathogenesis of aphthae (see text)

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

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

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.

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.

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,

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

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

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.

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

CLINICAL FEATURES

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

minor aphthous ulcers (~ 80% of all RAS)

major aphthous ulcers

herpetiform ulcers.

MINOR APHTHOUS ULCERS (MiAU; MIKULICZ ULCER)

This type of RAS:

occurs mainly in the 10–40 year age group

often causes minimal symptoms

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