Abstract
Recurrent ulceration of the mouth is a common complaint of patients attending their GP with an oral problem. The majority will have recurrent aphthae, also known as recurrent aphthous stomatitis. This is a painful condition that can significantly affect a patient's quality of life by interfering with eating and speaking. There are a number of other causes of recurrent oral ulceration that are less common but need to be considered by the GP. This article describes the management of patients complaining of recurrent mouth ulcers and provides guidance concerning referral to secondary care.
The GP curriculum and oral health
Manage primary contact with patients who have an ear, nose and throat (ENT) or facial problem Be aware of National Institute for Health and Clinical Excellence (NICE) Clinical Guidelines concerning referral for suspected head and neck cancer
Recurrent aphthous stomatitis
Recurrent aphthous stomatitis (RAS) is a condition characterized by recurrent bouts of one or several, shallow, circular (or oval) painful ulcers, occurring at intervals of a few days or up to 2–3 months. The cause of RAS is unknown but is likely to be multifactorial and in some cases there are recognizable precipitating factors. Nearly half of the individuals who suffer from RAS give a family history of ulceration and there is a high correlation of RAS in identical twins. ‘Aphthous-like’ ulcers have the physical characteristics of RAS but may not exhibit the classical behaviour or clinical pattern of RAS. These ulcers are usually associated with an underlying systemic disease or condition.
Precipitating factors for RAS
Although a number of precipitating factors have been implicated in the development of RAS, there is no convincing evidence for many of these. Clinically significant factors include trauma, i.e. from sharp teeth or fillings or toothbrushing, and smoking cessation. A number of patients report that their RAS is worse during stressful periods although it is difficult to demonstrate a definite link. Others relate the onset of ulceration to specific food triggers. A few women report that their RAS is worse during certain phases of their menstrual cycle but a definite association has yet to be proven.
There does, however, appear to be a negative association between smoking and RAS and cessation can precipitate mouth ulcers in some individuals. The reason for this is unclear but it has been postulated that tobacco may increase mucosal keratinization and therefore make it less susceptible to RAS; alternatively, the stress of giving up smoking may precipitate RAS.
Systemic conditions
Behçet's disease
The majority of patients with Behçet's disease suffer from recurrent aphthae and many have accompanying genital ulceration. Patients with Behçet's disease may also have eye, skin, joint, neurological and vascular disease. Criteria for diagnosis are shown in Box 1.
Diagnostic criteria for Behcet's disease
Recurrent oral aphthae plus any two of:
Recurrent genital ulceration Eye lesions (anterior uveitis, posterior uveitis and retinal vasculitis) Skin lesions (erythema nodosum and papulopustular lesions) Positive pathergy test (read by a physician over 24–28 hours)
Nutritional deficiencies
Up to 20% of patients with recurrent aphthae have a haematinic deficiency and deficiencies in iron, folic acid or vitamin B12 have been reported to be twice as common in RAS patients as in controls. Replacement therapy or removal of an underlying cause has not, however, proved to be successful in reducing the frequency of aphthous ulceration in all patients.
Gastrointestinal disease
The prevalence of coeliac disease in patients who present with recurrent aphthae is now thought to be 5% or less; however, this association needs to be considered, particularly with patients who present with recurrent aphthae and complain of gastrointestinal symptoms and/or are found to have a haematinic deficiency. Some patients with oral Crohn's disease, also known as orofacial granulomatosis (OFG), suffer from aphthous ulcers but others have persistent mouth ulcers. Systemic disorders associated with aphthous ulcers are listed in Box 2.
Systemic conditions associated with ‘aphthous ulcers
Behçet's disease Nutritional disorders Gastrointestinal disease Human immunodeficiency virus (HIV) infections Drug reactions Rare conditions (e.g. cyclical neutropenia)
Clinical features of RAS
There are three clinical presentations of RAS: minor, major and herpetiform. The clinical features of these are shown in Table 1 and Figs. 1 –3.
Clinical features of RAS
Unless a number of ulcers coalesce.
Minor aphthous ulcers on tongue.
Major aphthous ulcer on labial mucosa: 8 weeks duration.
Multiple, herpetiform aphthous ulcers on ventral surface of tongue.
Evaluation RAS
History
A diagnosis of RAS is mainly dependent on the history of the patient's ulceration. Document the frequency and duration of ulcers together with associated pain or discomfort and impact on quality of life, including problems with eating and speaking. Any precipitating factors, such as trauma, are important to note and whether any topical treatments (over the counter or prescribed) have been successful. A history of genital ulceration or gastrointestinal symptoms is highly relevant. A number of medicines [e.g. non-steroidal anti-inflammatory drugs (NSAIDs)] have been associated with ‘aphthous-like’ ulcers but this type of adverse drug reaction is uncommon.
Examination
The clinical appearance of RAS is fairly characteristic with shallow ulcers, circular or ovoid in shape with a grey base and erythematous halo. The mucosa adjacent to an aphthous ulcer feels soft on palpation. Note the site and size of the ulcers together with the presence of any mucosal scarring which is characteristic of major RAS.
Investigation
Biopsy is not required for the diagnosis of RAS; however, it may be indicated to exclude other causes of recurrent oral ulceration. Solitary oral ulcers lasting more than 3 weeks need urgent referral and probable biopsy. Patients who present with mild or infrequent attacks of RAS, which respond to simple topical medication, need to be reassured but may not require any further investigations.
Consider blood tests including full blood count, erythrocyte sedimentation rate, ferritin, folate and vitamin B12 for those with severe or frequent attacks of mouth ulcers, in order to rule out a haematinic deficiency or other abnormality. Screening for coeliac disease may also be indicated.
Differential diagnosis
Although the majority of patients with recurring bouts of oral ulceration will suffer from RAS, it is important to consider other diagnosis or an underlying systemic illness. GPs should be alerted to any of the following in the history: • sudden or late onset of mouth ulcers, particularly in middle or old age
persistent oral ulceration at one or more sites any associated skin or gut involvement genital ulceration
A single bout of multiple oral ulcers, which may involve the lips, is likely to be due to a viral infection, commonly a primary herpetic stomatitis. Erythema multiforme (EM) can produce widespread oral ulceration, often accompanied by crusting of the lips. A single attack is usually due to an adverse drug reaction (e.g. to co-trimoxazole); however, recurrences of EM can occur.
Persistent oral ulceration, lasting weeks or months and involving various sites of the mouth, may be due to:
mucocutaneous disease affecting the mouth (e.g. oral lichen planus) bullous (blistering) conditions (e.g. pemphigoid and pemphigus) blood disorders (e.g. leukaemia, neutropenia, agranulocytosis) drugs such as nicorandil, methotrexate and other cytotoxic agents gastrointestinal disease, such as Crohn's disease immunocompromised states (e.g. HIV infection) chronic infection including syphilis and tuberculosis
Patients with nicorandil-induced oral ulceration are increasingly being referred to oral medicine units (Box 3). Ulcers caused by nicorandil tend to affect the buccal mucosa and tongue. They can be intermittent but are usually large and persistent. Nicorandil can also cause ulceration elsewhere in the gastrointestinal tract (e.g. the anal mucosa). The ulceration resolves once the nicorandil is stopped (Box 3). Nicorandil-induced oral ulceration appears to be dose related in some patients. Figure 4 shows a nicorandil-induced ulcer on the tongue which was extremely painful and developed following a change in dose of the drug.
Nicorandil-induced oral ulcer on tongue.
Nicorandil-induced oral ulceration
Nicorandil is a potassium channel activator used for the treatment of angina Oral ulceration is a recognized side effect of nicorandil Oral ulcers predominantly affect the tongue and buccal mucosa Oral ulcers are painful and often large and persistent Ulceration may be dose related in some patient Stopping nicorandil results in resolution of oral ulceration
Primary care management
Any precipitating factors for RAS that can be eliminated need to be addressed. Advise patients to see their dentist so that any trauma from sharp teeth, dentures or broken restorations can be addressed. Some patients who develop RAS after stopping smoking may consider restarting and should be encouraged to persevere as ulcers usually settle with time. Nictotine replacement therapy may be helpful.
Symptomatic treatment to reduce oral discomfort while ulcers are present includes the use of a topical analgesic, e.g. benzydamine hydrochloride mouth rinse (Difflam). This is particularly helpful before meals. An antimicrobial mouthwash, e.g. chlorhexidine gluconate, may reduce any secondary infection and reduce the accumulation of plaque on teeth.
Topical corticosteroids are the therapy of choice for RAS and can be applied in a number of different preparations (Box 4). A low-potency topical corticosteroid such as hydrocortisone oromucosal tablets should be used to begin with. If ineffective, then a higher potency drug such as betamethasone mouthwash can be substituted. There is a potential risk of adrenal suppression following absorption of the topical steroid through the oral mucosa but this can be minimized by not exceeding the recommended dose. Topical corticosteroids should be used as soon as the patient is aware that an ulcer is developing for maximum benefit; they can reduce inflammation and pain associated with aphthae and may lessen the duration of ulceration.
Topical therapy for RAS
Covering agents (e.g. Orabase paste) Antimicrobial mouthwashes (e.g. chlorhexidine gluconate) Analgesic mouthwashes (e.g. benzydamine hydrochloride—Difflam) Topical corticosteroids Hydrocortisone oromuscosal tablets (Corlan)—low potency Betamethasone rinse—higher potency Beclomethasone diproprionate spray—higher potency
Systemic medication may be indicated for severe debilitating RAS that does not respond to topical measures, but this should normally only be started under specialist supervision and after the patient has been fully investigated. A number of immunomodulatory drugs have been used for RAS and include oral prednisolone, azathioprine, colchicine and thalidomide. In a few cases, anti-Tumour Necrosis Factor agents have been used for patients with severe aphthae, particularly in relation to Behçet's disease, which usually requires a systemic drug.
Referral
Patients who present with a solitary oral ulcer with no identifiable cause (e.g. trauma from a tooth) and which lasts longer than 3 weeks must be referred to an oral medicine or oral and maxillofacial surgery unit to exclude oral cancer. Patients should also be referred to an oral specialist if their RAS is atypical, frequent or debilitating and fails to respond to topical measures, including corticosteroids.
Key points
The majority of patients complaining of recurrent mouth ulcers will have a diagnosis of RAS Topical steroids are the treatment of choice for RAS The majority of patients with Behçet's disease suffer from recurrent oral aphthae Nicorandil may cause oral ulceration Patients presenting with a solitary ulcer that lasts longer than 3 weeks should be referred urgently to an oral specialist to exclude cancer