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Aliment Pharmacol Ther 2003; 18: 949962. doi: 10.1046/j.0269-2813.2003.01782.

Review article: oral ulceration aetiopathogenesis, clinical diagnosis


and management in the gastrointestinal clinic
E. A. FIELD & R. B. A LLAN
Oral Medicine Unit, Liverpool University Dental Hospital and School, Liverpool, UK
Accepted for publication 15 August 2003

renewed interest in the role of Streptococcus sanguis and


SUMMARY
possible infectious triggering of an inappropriate immu-
Oral ulceration is a common complaint of patients noinflammatory response, resulting in tissue damage.
attending out-patient clinics. The aim of this review is to The efficacy and limitations of conventional treatment
provide the gastroenterologist with a differential for this mutisystem disorder are outlined together with
diagnosis of oral ulceration, and a practical guide for the potential role of novel biological agents, such as
the management of recurrent aphthous stomatitis, anti-tumour necrosis factor-a therapy. Oral ulceration,
including topical and systemic therapy. The association as a manifestation of inflammatory bowel disease and a
of recurrent aphthous stomatitis with Behcets disease complication of drug therapy, is described. Guidance is
and other systemic disorders, including coeliac disease, given concerning indications for referral of patients with
is discussed. Recent evidence concerning the immuno- oral ulceration to an oral physician/surgeon for further
pathogenesis of Behcets disease is reviewed, including investigations, including biopsy if appropriate.

20% of the general population at any time.3 The peak


THE DIFFERENTIAL DIAGNOSIS OF ORAL
age of RAS onset is during childhood, with a tendency
ULCERATION
to decrease in severity and frequency with age.4
The principal causes of oral ulceration are trauma,
recurrent aphthous stomatitis, microbial infections,
Clinical features
mucocutaneous disease, systemic disorders, squamous
cell carcinoma and drug therapy1, 2 (see Table 1 and Three clinical presentations of RAS are recognized:
Figures 16). minor recurrent aphthous stomatitis (MiRAS), major
recurrent aphthous stomatitis (MjRAS) and herpetiform
ulceration. The clinical presentation of these types of
RECURRENT APHTHOUS STOMATITIS
RAS are shown in Table 2.1 Patients may sometimes
Recurrent aphthous stomatitis (RAS) is characterized by present with a mixed pattern of RAS, but this is
recurrent bouts of one or several shallow, rounded or relatively uncommon.
ovoid, painful ulcers, that recur at intervals of a few
days or up to 23 months. RAS is a common oral
Minor recurrent aphthous stomatitis (MiRAS)
mucosal condition and has been reported as affecting
This is the most common form of RAS and approxi-
mately 80% of patients have lesions of this type.4 In its
Correspondence to: Dr E. A. Field, Oral Medicine Unit, Liverpool Uni-
versity Dental Hospital and School, Pembroke Place, Liverpool L3 5PS, UK. most characteristic form, MiRAS presents the picture of
E-mail: e.a.field@liv.ac.uk a number of small ulcers (one to five) appearing on the

2003 Blackwell Publishing Ltd 949


950 E. A. FIELD & R. B. ALLAN

Table 1. Principal causes of oral ulceration does not depend on the dimensions of the lesions alone,
but on a number of clinical features. The appearance of
Solitary ulcer*
Trauma the ulcer base is greyyellow, often with a red and
Squamous cell carcinoma slightly raised margin, and, unless influenced by the site
Infections (e.g. syphilis, tuberculosis) (as in the depth of the buccal sulcus where they appear
Recurrent bouts of one or more ulcers healing spontaneously elongated), they are usually oval in shape. The ulcers
Recurrent aphthous stomatitis (RAS)
are painful, particularly if the tongue is involved, and
Behcets disease
Aphthous-like ulcers due to systemic disease or drug therapy.
may make eating or speaking difficult. The course of
Recurrent erythema multiforme these ulcers varies from a few days to a little over
Single bout of ulceration, preceded by vesicles and affecting 2 weeks, but usually their duration is of the order of
multiple oral sites 10 days. Minor aphthae heal without scar formation.
Viral infections (e.g. herpangina and primary herpetic Following healing of the ulcers, there is a variable ulcer-
stomatitis)
free interval; 34 weeks is most common. In a few
Erythema multiforme
Persistent oral ulceration affecting different sites patients the recurrence of the ulcers appears to be
Mucocutaneous disease (e.g. oral lichen planus, Fig. 2) entirely random, and in some cases there may not be an
Immunobullous disease (e.g. oral pemphigus) ulcer-free period between attacks, with new aphthae
Gastrointestinal disease (e.g. Crohns disease) developing before existing ones have healed.
Haematological (e.g. leukaemia)
Drug therapy (e.g. nicorandil)
Major recurrent aphthous stomatitis (MjRAS)
* If a single persistent oral ulcer shows no sign of healing 1014 days
after any putative trauma is removed, then it must be considered as MjRAS (Figure 1) accounts for approximately 1015%
malignant, unless proven otherwise.
Patients may report intermittent oral ulceration if these conditions of cases,4 and it varies from the minor form in a number
undergo periods of remission. of important clinical features. The ulcers tend to be
larger than those of MiRAS, and they are of greater
buccal mucosa, the labial mucosa, the floor of the duration, up to a period of months in some cases.1 As a
mouth or the tongue.1 Moreover, the ulcers are usually result of the long periods of time involved, there is
concentrated in the anterior part of the mouth; the probably a tendency for the production of a heaped-up
pharynx and tonsillar fauces are rarely implicated in margin which, when a single ulcer is seen in isolation,
this form of ulceration. The prodromal stage of ulcer- may lead to the suspicion that the lesion is malignant.
ation is variable, but there is usually a sensation On eventual healing, the ulcers may leave a substantial
described as burning or prickling for a short period scar and this, together with the tissue destruction which
before the ulcers appear. Following this phase, ulcer- may occur during the active phase of ulceration, may
ation occurs directly by loss of the epithelium. The lead to gross distortion of the involved tissues. MjRAS
ulcers are usually less than 1 cm in diameter and, in may produce lesions throughout the entire oral cavity,
most instances, their size is approximately 45 mm in including the soft palate and tonsillar areas, and
diameter. However, the classification of minor RAS ulceration may extend to the oropharynx.

Table 2. Clinical features of recurrent aphthous stomatitis (RAS)

Minor (MiRAS) Major (MjRAS) Herpetiform ulceration

Peak age of onset 2nd decade 1st and 2nd decades 3rd decade
Number of ulcers/bout 15 13 520 (?100)
Size of ulcers (mm) < 10 > 10 12
Duration 714 days 2 weeks 3 months 714 days
Heal with scarring No Yes No*
Site Non-keratinized mucosa, especially Keratinized plus Non-keratinized mucosa but
labial/buccal mucosa. Dorsum nonkeratinized mucosa particularly floor of mouth and
and lateral borders of tongue. particularly soft palate. ventral surface of tongue.

* Unless a number of ulcers coalesce.

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REVIEW: ORAL ULCERATION 951

Figure 1. Major aphthous ulceration affecting the labial mucosa.


Figure 2. Ulcerative lichen planus affecting the oral mucosa.

The number of ulcers present at one time varies from last for approximately 714 days, and the period of
one to 10 in MjRAS. Frequently, a single ulcer will remission between attacks is variable. Where many
persist for a long period, while other (usually smaller) ulcers are present they may coalescence to form larger
ulcers fade. Unlike MiRAS, there does not appear to be confluent areas of ulceration, usually with marked
a cyclical pattern in MjRAS, and the ulcers are usually erythema. Healing with scar formation has been
unpredictable in their onset. Long periods of remission described in herpetiform ulceration, but this is probably
may be followed by intervals of intense ulcer activity, a result of coalescence.
without any obvious precipitating factor.1 The pro-
longed and painful ulceration may present significant
Aetiopathogenesis of RAS
problems to the patient; difficulty eating, speaking
and swallowing can severely affect a patients quality Genetic factors are likely to predispose patients to RAS,
of life. and more than 40% of affected individuals have first-
degree relatives with RAS.5 The aetiology of RAS is
unknown, but a number of predisposing factors have
Herpetiform ulceration
been implicated and include trauma, stress, smoking
This distinctive form of RAS differs in many ways from cessation, hormonal imbalance and food hypersensitiv-
both MiRAS and MjRAS, and is less common, affecting ity.1 Although some patients report that stressful life
510% of cases.4 In herpetiform ulceration the ulcers events (e.g. taking examinations in the case of students)
are small (12 mm) and multiple (as many as a can provoke an outbreak of ulcers, there is little
hundred ulcers may be present at the same time). substantive evidence to link stress to RAS.6 There
Although any nonkeratinized oral mucosa may be appears to be a negative association between smoking
involved, characteristically the affected sites are the and RAS, and some patients report the onset of oral
lateral margins of the tongue and the floor of the ulcers after smoking cessation.7 Interestingly, nicotine-
mouth. Individual ulcers are grey and without a containing tablets appear to control the frequency of
delineating erythematous border, making them quite RAS.8 Some patients report being free from aphthae
difficult to visualize: they resemble ulcers of primary whilst taking oral contraceptives or when pregnant,9
Herpes simplex virus (HSV) infection. In spite of their and a minority of women with RAS have cyclical oral
small size, these ulcers are very painful and may make ulceration related to the luteal phase of the menstrual
eating and speaking difficult. A single crop of ulcers may cycle.10 There is no convincing evidence linking

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962


952 E. A. FIELD & R. B. ALLAN

hypersensitivity to foods and RAS other than in coeliac are likely to share some common immunopathogenic
disease,11 but some patients recognize that foods such mechanisms the reasons why RAS lesions are confined
as chocolate, cheese and tomatoes can precipitate to the oral cavity, and the oral lesions in Behcets
attacks of RAS. disease are associated with multisystem disease remains
There is strong evidence from histopathological and unclear.16
immunological studies that T-cell-mediated immune
responses are implicated in RAS.1113 Three stages are
Systemic conditions and aphthous-like lesions
recognized in the development of an aphthous ulcer.12
Microscopic examination during the pre-ulcerative Table 3 lists the principal systemic conditions associated
stage reveals a mononuclear (lymphocytic) cell infiltrate with aphthous-like ulcers. These frequently start in
in the epithelium focal vacuolation and is followed by adulthood with no previous history of oral ulceration.
degeneration of the suprabasal epithelial cells accom-
panied by a mononuclear, mainly lymphocytic infiltrate
Gastrointestinal disorders
in the lamina propria. As the ulcerative stage approa-
ches there is increased infiltration of the tissues, Crohns disease and ulcerative colitis may occasionally
particularly the epithelium, by mononuclear cells and be associated with RAS20 but are more likely to manifest
accompanied by more extensive oedema and degener- as other types of oral ulceration. The association of RAS
ation of the epithelium progressing to frank ulceration with coeliac disease is well established. A number of
with a fibrinous membrane covering the ulcer. During studies have suggested up to 5% of out-patients who
the healing phase there is regeneration of the epithe- initially present with RAS11, 21, 22 have gluten-sensitive
lium. The immunopathogenesis of RAS has yet to be enteropathy (GSE). These RAS patients may not always
fully elucidated, but the infiltration of the epithelium by have gastrointestinal symptoms or other clinical fea-
T lymphocytes is likely to be in response to some, as yet tures of coeliac disease but usually have folate deficiency
unidentified, keratinocyte-associated antigen. Keratino- and sometimes reticulin antibodies,21 particularly
cyte death is thought to be mediated by the differentiation immunoglobulin-A-class reticulin and/or gliaden anti-
of cytotoxic T cells and involves the production of tuour bodies.23 A recent study has demonstrated that the
necrosis factor-a (TNFa) by these and other leuco- prevalence of RAS in a population with coeliac disease
cytes.14 TNFa induces inflammation by its effect on did not significantly differ from an unaffected matched
endothelial cell adhesion and neutrophil chemotaxis.14 population without coeliac disease. The authors con-
Other cytokines, e.g. interleukin and interleukin-2, may clude therefore that coeliac disease should be referred to
also play a role in the immunopathogenesis of RAS.15 as a risk indicator not a risk factor for RAS.24 A high
Oral streptococci were previously suggested as import- prevalence of HLA-DRW10 and DQW1 has been
ant in the pathogenesis of RAS and Behcets disease, associated with RAS.25 RAS in patients with coeliac
either as direct pathogens or an antigenic stimulus, disease appears to remit completely on a gluten-free
culminating in the genesis of antibodies that may diet;26 however, there is conflicting evidence concern-
conceivably cross-react with keratinocyte antigenic ing the remission of RAS in patients without GSE, who
determinants.16 More recently a common antigen was undergo dietary withdrawal of gluten. There may be a
demonstrated between oral mucosa and the 65 kDa few RAS patients, with no detectable clinical or
heat shock protein (HSP). As there is a high degree of histological evidence on jejunal biopsy, who may
homology between the microbial 65 kDa and human
60 kDa HSP, the hypothesis was suggested that an Table 3. Systemic conditions and aphthous-like lesions
autoimmune response to the endogenous HSP might be
Behcets disease
responsible for the pathological changes in Behcets
Nutritional deficiencies
disease.17 The role of the cd T-cell subset in the Gastrointestinal disorders
immunopathology of RAS and Behcets disease and Cyclical neutropenia
their participation in the immune response to bacteria- HIV infection
derived and autologous antigens in these conditions is MAGIC syndrome
FAPA syndrome
currently under investigation (see section on Behcets
Drug reactions
disease).13, 18, 19 Although RAS and Behcets disease

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REVIEW: ORAL ULCERATION 953

respond to a gluten-free diet,27, 28 but a study by tinic deficiency. This includes a full blood count and
Hunter et al.29 showed no significant benefit for RAS film, and measurement of inflammatory markers and
patients without evidence of coeliac disease. haematinics (serum ferritin, serum B12, serum and red
cell folate). If there is any suspicion of coeliac disease,
either due to the patients history or evidence of
Other systemic conditions and factors
malabsorption on routine testing, then serological
Haematinic deficiencies (iron, folic acid or vitamin B12) testing for anti-endomysial antibody and other appro-
have been reported to be twice as common in RAS priate investigations should be undertaken: is debatable
patients than in controls.16 One US study, however, did whether all RAS patients should undergo screening for
not report any iron or folic acid deficiency in RAS coeliac disease. Table 4 lists some of the therapeutic
patients,30 and there is no convincing evidence of B6 or options available for the management of patients with
zinc deficiency in individuals with RAS. Replacement RAS.1 The choice of therapy for RAS depends on the
therapy has not met with uniform success, although severity and frequency of ulceration, but the objectives
RAS may improve in some patients who are nutrition- of treatment are to relieve discomfort, reduce secondary
ally deficient.31 HIV-associated ulcers tend to occur in infection, promote healing of existing ulceration and
crops of five or less on nonkeratinized mucosa, and may prevent new ulcers occurring.
resemble minor or major aphthae. The ulcers are Topical analgesic sprays or rinses such as benzydamine
frequently very painful and last for several months; hydrochloride can be used to reduce discomfort; how-
they can be extremely debilitating in these patients and ever, 2% lignocaine (lidocaine) gel, diluted as a rinse, is
can cause problems with eating. Care must be taken to more effective for severe cases of RAS. Care must be
exclude HSV or cytomegalovirus infection in HIV- taken if used in the posterior part of the mouth, as
infected patients presenting with oral ulceration. Large stronger analgesic preparations can affect the laryngeal
major-aphthous-type ulcers are likely to be seen in HIV reflexes: long-term use of topical lignocaine (lidocaine)
patients with low CD4T lymphocyte counts.32, 33 It has
been postulated that the immune imbalance associated
with HIV disease may amplify the local breakdown in Table 4. Therapeutic options for recurrent aphthous stomatitis
immunoregulation in RAS and lead to more severe (RAS)1
ulcers.33 A significant number of patients with cyclical
Topical antiseptic Chlorhexidine gluconate (mouthwash)
neutropenia present with aphthous-type ulceration
Topical analgesics: Benzydamine hydrochloride
which occurs at intervals (often monthly), reflecting (mouthwash)
their neutropenic status.16 Patients who are function- Lignocaine (lignocaine (lidocaine)) rinse
ally neutropenic, for example those with chronic Topical corticosteroids: Hydrocortisone hemisuccinate (pellets)
granulomatous disease or benign familial neutrope- Triamcinolone acetonide
nia,34 are also susceptible to aphthous-type ulcer- (in adhesive paste)
Betamethasone valerate (mouthwash)
ation.35 Other systemic conditions associated with this Beclometasone dipropionate (spray)
type of ulcer include MAGIC (mouth and genital ulcers Budesonide (spray)
with inflamed cartilage) syndrome36 FAPA (periodic Triamcinolone (with or without
fever, aphthous ulcers, pharyngitis and cervical adeni- chlortetracycline) mouthwash
tis) syndrome,37 and Sweets syndrome.38 Topical antibiotic: Chlortetracycline mouthwash
Systemic Prednisolone
immunomodulators: Azathioprine
Management of RAS Colchicine
Ciclosporin
The diagnosis of RAS is not usually difficult and may be Thalidomide
deduced, in most cases, from the history and charac- Other therapies that have been advocated
teristic clinical appearance. If there is any doubt about Cimetedine Low-energy laser
the diagnosis then appropriate diagnostic tests should Carbenoxolone Levamisole
be arranged to exclude other causes of oral ulceration. 5-Aminosalicylic acid Nicotine
Dapsone Interferon-a
Patients with persistent and troublesome RAS should
Pentoxphylline Sucralfate
undergo screening to check for an underlying haema-

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954 E. A. FIELD & R. B. ALLAN

is not advisable, as it may be absorbed. Several pastes times daily) is adhered to. In severe MiRAS unrespon-
and gels can be used to coat the surface of the ulcers sive to these preparations and in MjRAS it may be
and form a protective barrier against secondary infec- necessary to use a more potent steroid preparation1
tion and further mechanical irritation. Some difficulty such as a betamethasone sodium phosphate rinse
may be experienced in applying some of these prepara- (dissolve 0.5 mg in 5 mL of water and rinse for
tions, particularly to large ulcers and to those at the 23 min), steroid aerosol (e.g. beclometasone dipropr-
back of the mouth. Antiseptic mouthwashes containing ionate, 100 lg/puff), or a high-potency topical cortico-
chlorhexidine are widely used for the symptomatic steroid, such as clobetasol 0.05% in orabase (1 : 1) or
treatment of RAS and are considered helpful by many fluocinonide 0.05% in orabase (1 : 1).39 Prolonged use
patients, particularly if oral hygiene is difficult to of potent topical corticosteroids carries a risk of systemic
maintain because of oral ulceration. Extrinsic staining absorption and associated adverse effects; it may also
of teeth associated with long-term use of chlorhexidine predispose to oral candidosis.
may be a problem. A more effective measure in the relief In severe cases of RAS, particularly MjRAS, it may be
of symptoms caused by secondary infection is the necessary to use some form of systemic therapy
application of topical antibiotics. A mouthwash contain- (Table 4); however, all drugs have side-effects and risks
ing tetracycline (dissolve soluble tetracycline capsule which must be weighed against their benefits for RAS.
250 mg in 510 mL water and rinse) or chlortetracy- Apart from prednisolone, a number of systemic drug
cline is often highly effective in reducing the pain therapies has been advocated for the treatment of
caused by severe ulceration, and as a result of the much MjRAS and in some cases Behcets disease. Thalidomide
less heavily colonized environment the ulcers often heal has been used successfully for severe RAS which has
more rapidly than otherwise. The treatment of herpe- failed to respond to other treatment modalities; it has
tiform ulceration depends largely on this therapy, and also been advocated for use in HIV-associated oral
response to the antibiotic mouthwash is often rapid and ulceration.4 Thalidomide is a TNFa inhibitor that has
complete. There are obvious disadvantages, however, in anti-inflammatory effects; however, its use is limited
the use of broad-spectrum antibiotics for this purpose, because of teratogenic and other adverse effects
the risk of hypersensitivity reactions and the encour- (e.g. irreversible polyneuropathy). The potential use
agement of growth of resistant organisms being the of anti-TNF therapy by novel biological agents
most important. Local secondary infection by oppor- (e.g. infliximab) for recurrent aphthae in Behcets
tunists such as Candida species may be a problem and disease is discussed in the next section. Colchicine inhib-
limits long-term use. its cell-mediated immune responses and has been used
Topical corticosteroids can be effective drugs in the in does of 1.51.8 mg/day successfully in two small,
treatment of RAS. Patient response is variable, and open studies involving 23 patients with RAS.40, 41
there are some individuals who gain little or no relief
from their use. Corticosteroids used in this manner have
BEHC ETS DISEASE
two modes of action; their anti-inflammatory action
modifies, in a minor way, the progress of the ulceration Behcets disease is a multisystem, chronic relapsing
at all stages and to some extent reduces the discomfort inflammatory disease of unknown cause, which is
experienced. The second effect of steroids, i.e. the specific characterized by recurrent oral (aphthous) ulcers,
blocking effect of the T lymphocyte ) epithelial cell genital ulcers, uveitis and skin lesions.42 There may
interaction, is much more important in the present be a variety of other manifestations including joint,
context. Since the concentration of sensitized lympho- central nervous system, vascular and intestinal lesions
cytes occurs before and during the early stages of oral of variable severity.42
ulceration, it follows that the drugs exert their maxi- In 1990 the International Study Group for Behcets
mum effect at this time. The drugs most commonly disease proposed criteria for the diagnosis of the disease
adopted for local oral application in RAS are hydrocor- (Table 5).43 According to these criteria, RAS must be
tisone hemisuccinate (as pellets of 2.5 mg) and triam- present as well as at least two of the following: recurrent
cinolone acetonide (in an adhesive paste containing genital ulceration, eye lesions, skin lesions and a
0.1% of the steroid). There is little risk of adrenal positive pathergy test. Behcets disease has diverse
suppression provided that the recommended dose (four clinical manifestations and lacks any pathognomonic

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REVIEW: ORAL ULCERATION 955

Table 5. International Study Group for


Manifestations Prevalence (%) Description
Behcets Disease (ISGBD): Criteria for diag-
nosis of Behcets disease43 Recurrent oral 100 Minor aphthous.
ulceration Major aphthous or herpetiform ulceration
observed by a physician or reported
reliably by patient.
Recurrent at least three times in one
12-month period.
Plus two of:
Recurrent genital 80 Recurrent genital aphthous ulceration
ulceration or scarring, especially in male patients,
observed by physician or reliably reported
by patient.
Eye lesions 6070 Anterior uveitis.
Posterior uveitis.
Cells in vitreous on slit lamp examination.
Or
Retinal vasculitis observed by qualified
physician (ophthalmologist)
Skin lesions 6080 Erythema nodosum-like lesions observed
by physician or reliably reported by patient.
Pseudofolliculitis.
Papulopustular lesions.
Or
Acneiform nodules consistent with Behcets
disease observed by physician and in
post-adolescent patients not receiving
corticosteroids
Positive pathergy Variable An erythematous papule, > 2 mm, at the prick
test 48 h after the application of sterile needle,
2022 gauge, which obliquely penetrated
avascular skin to a depth of 5 mm;
read by a physician at 48 h.

symptoms or diagnostic laboratory markers: conse- onset or family history. Scrutiny of clinical photo-
quently it is often difficult to diagnose. graphs taken of Behcets disease patients in this study
suggested that both herpetiform-type and aphthous-
type ulcers appeared atypical.44 Clinical observations
Oral ulceration in Behcets disease
in oral medicine clinics suggest that aphthous ulcers in
RAS is seen in all patients with Behcets disease; it patients with Behcets disease appear to be associated
commonly precedes other systemic features and can be with increased tissue oedema and appear to have an
of major, minor or herpetiform types. However, it is intensely erythematous border. The aphthae in
difficult to predict with any certainty those patients Behcets disease often occur in the soft palate and
initially presenting with RAS who will subsequently oropharynx and have been observed on the hard
proceed to develop multisystem involvement as part of palate, which is an unusual site for RAS in patients
Behcets disease. Two studies have addressed this without Behcets disease.44 Patches of mucosal ery-
problem; in one, a clinical comparison between 38 thema may be observed in patients with the disease,
patients with Behcets disease and RAS-only controls indicating possible instability of the oral mucosa prior
showed an increased number of concurrent ulcers and to ulceration. Patients may paradoxically report no
involvement of the soft palate and oropharynx in those painful symptoms during active disease, despite exten-
diagnosed with Behcets disease.44 No differences were sive oral ulceration being clinically evident. A Korean
detected with respect to duration, frequency, age of study examined the prognosis of the clinical relevance

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956 E. A. FIELD & R. B. ALLAN

of recurrent oral ulceration in Behcets disease, and antigens.19 cd T Cells have also been reported as
investigators found that approximately half the producing several cytokines, with the cytokine profile
patients who were initially diagnosed as RAS-only dependent on the nature of antigen, enabling the cd
developed other manifestations of Behcets disease at T cells to influence the nature of the immune
an average of 7.7 years after onset.45 Highly recurrent response.50 Levels of circulating TNFa, interleukin-
RAS appeared to be a warning signal for Behcets 1-b and interleukin-8 have been reported as elevated
disease in this study.45 in Behcets disease, and it has been postulated that
these cytokines may be involved in the activation of
neutrophils.51 Bank et al. have recently demonstrated
Aetiopathogenesis of Behcets disease
and substantiated data from a number of other studies
The aetiology of Behcets disease is poorly understood, indicating that cd T cells have increased in Behcets
but interactions between environmental and genetic disease relative to healthy and disease controls, and in
factors are likely to influence the susceptibility and addition the cd T-cell population increases with the
development of the disease,46 as well as being impli- active disease.19 This group also examined the prolif-
cated in its pathogenesis. Susceptibility to Behcets eration of a subset of cd T cells in response to bacterial
disease is associated with the HLA-B51 MHC class 1 products obtained from patients with the active
allele, and it has been reported that individuals in the mucocutaneous disease, and concluded that an exag-
appropriate geographical setting (i.e. living in areas gerated proliferative response to products released by
along the Silk Route) who express this allele have an micro-organisms present in oral (aphthous) ulcers may
eight- to ten-fold greater risk of developing the play a role in the expansion of cd T cells in Behcets
disease.42 The relative risk of the disease among disease.19 This raises the possibility that therapeutic
carriers of HLA-B5I is much less in Western countries, control of the oral environment, or manipulation of
indicating that other genetic factors may be important cd T-cell-derived cytokines by drugs such as anti-
in these individuals.42 The HLA-51 allele also affects TNFa, provides effective strategies against aphthous
the severity of Behcets disease, since it is more ulceration and thereby controls systemic manifesta-
commonly detected in patients with posterior uveitis tions of the disease.48
or progressive central nervous system disease than
those with milder disease.42 Investigation of the
Treatment of Behcets disease
aetiology of Behcets disease has focused predomin-
antly on herpes simplex virus immunopathology, Patients with Behcets disease usually have repeated
autoimmunity to oral mucosa or cross-reactive micro- exacerbations and remission of their clinical symptoms,
bial antigens, and streptococcal infection.47 Its im- and in these individuals treatment is essentially symp-
munopathogenesis is likely to involve a T-cell-mediated tomatic. The choice of therapy depends on whether the
response, and it has been demonstrated that lympho- clinical manifestations of the disease are local or
cyte function is abnormal in patients with the systemic. Multidisciplinary involvement in the manage-
disease.13 There has been renewed interest in the role ment of Behcets disease is essential, and patients should
of Streptococcus sanguis as a causative agent,48 and ideally be treated in centres with extensive experience of
recent advances have resurrected the theory of infec- treating the disease.
tious triggering of the immune cascade in Behcets Local treatment with corticosteroids often controls oral
disease and have been strengthened by work with and genital ulcers, and immunosuppressive therapy is
heat-shock protein and the concept of a molecular reserved for severe cases of mucocutaneous involve-
mimicry mechanism.49 It has been suggested that ment.52 The oral lesions may respond well to topical
bacterial products such as heat-shock proteins corticosteroid preparations (Table 4), but it is important
may incite an inappropriate immunoinflammatory to monitor the patients for signs or oral candidosis and
response.19 Recent studies have investigated the role treat this with appropriate antifungal agents. Patients
of the cd T-cell subset in the immunopathology of with painful oral ulceration also benefit from analgesic
Behcets disease.13, 18, 19 These T cells participate in mouthwashes, e.g. benzydamine hydrochloride or ligno-
the immune response to infections and in autoimmu- caine (lidocaine). The choice of systemic drug treatment
nity by recognizing bacteria-derived and autologous for Behcets disease is dictated by the patients clinical

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REVIEW: ORAL ULCERATION 957

manifestations, but conventional therapy relies on anti-


ORAL ULCERATION AND INFLAMMATORY
inflammatory and immunomodulatory agents. There is
BOWEL DISEASE
a paucity of controlled clinical trails relating to drug
therapy, and prescribing for Behcets disease is, to a Oral involvement has for some time been recognized in
large extent, empirical.53 Ocular lesions in Behcets patients suffering from both Crohns disease and, to a
disease must be vigorously treated to prevent blindness, lesser extent, ulcerative colitis. Oral lesions may precede
and therapy aims to reduce both the severity and or accompany gastrointestinal disease and can be the
frequency of ocular attacks. Despite therapeutic inter- only site of involvement.
ventions, approximately 25% of all patients with ocular
manifestations of Behcets disease will become blind.54
Oral Crohns disease and orofacial granulatosis (OFG)
Systemic corticosteroids continue to be used extensively,
and may be administered as intravenous pulse therapy. Over the last decade there has been increasing attention
Ciclosporin is highly effective for ocular lesions, partic- paid to noninfectious granulomatous disorders of the
ularly in cases that have been refractory to other orofacial region, which include oral Crohns disease and
therapies, but its nephrotoxity restricts usage of the oral sarcoid, as well as clinical entities, known as the
drug.54 Azathioprine is a disease-modifying drug for MelkerssonRosenthal syndrome, and Miescheners
Behcets disease and helps reduce recurrences; it is now cheilitis granulomatosa (granulomatous cheilitis). The
considered to be the first-line drug for this condition. term orofacial granulomatosis (OFG) was introduced to
Thalidomide, despite its prescribing limitations and encompass these disorders and to describe a clinical
neurotoxic side-effects, has proved effective for the syndrome presenting with swelling of the face, lips or oral
management of mucocutaneous lesions in Behcets tissues in association with histological evidence of noncea-
disease56 but it is not disease-modifying, and with- seating granulomatous inflammation within these tis-
drawal of the drug can lead to severe rebound of sues.63 Recent studies have investigated the association of
symptoms.57 After teratogenicity, polyneuropathy is the OFG with intolerance to specific foods, food additives,
second most serious complication of thalidomide, and flavouring and the constituents of toothpastes. Cinnamon-
has been reported in up to 50% of patients taking the aldehyde and sodium benzoates have been particularly
drug.58 Thalidomide-related polyneuropathy appears to implicated in this respect, and in some series there was a
be dose-related and can be irreversible if not diagnosed clinical response to specific elimination diets. It remains
early. Mycophenolate mofetil does not appear to be unknown whether sensitivity to food additives is the
effective for Behcets disease.59 Colchicine is frequently primary factor for some patients with OFG or a secondary
used, and recent trials have demonstrated its beneficial aggravating factor to some underlying process.64, 65
effects on mucocutaneous symptoms, presumably by The prevalence of OFG has not been determined but
inhibiting neutrophil function.60 Cyclophosphamide, there does seem to be a geographical variation, for
with or without corticosteroids, may be indicated for example the west of Scotland, UK, appears to have a
central nervous system lesions.42, 52 higher number of cases.66 Oral medicine centres
Recognition of the possible pathogenetic role of TNFa throughout the UK are reporting an increased number
in Behcets disease has resulted in the use of anti-TNFa of cases of OFG, but this may be a result of increasing
therapy. Recent trials with novel anti-TNFa agents awareness and/or reporting of this condition. One study
(infliximab and etenercept)61 have indicated effective of 60 patients has reported that the median age of OFG
short-term remission. Infliximab (a chimeric anti-TNFa at presentation was 20 years,63 but clinical experience
monoclonal antibody) has been used successfully for the indicates that many patients are older children or
treatment of recalcitrant orogenital ulceration in Be- teenagers. The association of OFG with Crohns disease
hcets disease.62 These novel biological agents are, elsewhere in the gut has been the subject of debate, and
however, expensive compared with conventional treat- this inter-relationship has been fully explored in a
ment, and their long-term efficacy is yet to be proven in number of studies.67 The prevalence of symptomless
clinical trials. Overall, the goal of management in intestinal disease of Crohns in patients with OFG has
Behcets disease is to treat early to improve morbidity, to been reported as between 10% and 48% in various
avoid recurrences and irreversible damage to organs,57 studies.67 The clinical features of OFG are shown in
and to provide symptomatic relief for patients. Table 6.

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958 E. A. FIELD & R. B. ALLAN

Table 6. Clinical features of orofacial granulomatosis67

Swelling of lips and face*


Mucosal tags or cobblestoning
Oral ulceration (RAS and non-RAS)
Angular cheilitis
Lip fissures
Persistent lymphadenopathy
Peri-oral erythema and scaling of skin
Full-width gingivitis

* Fissured tongue (lingua plicata) and facial palsy are other manifes-
tations of the MelkersonRosenthal syndrome.

Oral ulceration and orofacial granulomatosis. Oral ulcer-


ation can be a particularly troublesome feature of
OFG, and persistent linear ulcers (non-RAS) tend to
occur at the base of hyperplastic tissue folds, partic-
ularly in the buccal and labial sulci, and can be
painful, particularly when eating (Figure 3). A thick-
ened buccal mucosa can also become traumatized
Figure 4. Pyostomatitis vegetans manifesting as snail-track
along the occlusal ridge, resulting in ulceration; this ulcers on the gingivae.
can be quite deep and may become secondarily
infected. Patients may also present with RAS, but
this is not specific to OFG. should be carried out by an experienced operator.
Histologically, noncaseating and epithelioid granulo-
Management of orofacial granulomatosis. Patients with mas, with or without multinucleated giant cells, are
OFG must be appropriately investigated, not only to seen in about 90% of cases. Granulomas are not always
confirm the diagnosis but to identify any provoking present, and their absence does not exclude the clinical
factors and signs and symptoms suggestive of an diagnosis of OFG. Granulomata may only be present in
underlying systemic condition, such as Crohns disease the underlying muscle, and it is therefore advisable to
or sarcoidosis. Biopsy of an affected site (usually the extend the biopsy deeper beyond the superficial tissue.
labial or buccal mucosa and occasionally the gingivae) Whether or not all patients with OFG should be patch-
tested to identify possible allergies to foods, or food
additives, is debatable. To date there is no totally
convincing evidence of a clinical response to elimination
diets, but there may be a therapeutic role for dietary
manipulation in some patients. If OFG presents as a
manifestation of underlying Crohns disease or sarcoi-
dosis then this must be appropriately managed. Symp-
tomatic therapy for associated oral ulceration and RAS
includes the use of topical steroids (Table 4) together
with antiseptic and analgesic mouthwashes. A large
number of systemic drugs have been used for OFG.
Short reducing courses of prednisolone may be helpful
for severe oral ulceration, but long-term steroids are
contra-indicated, particularly as many affected individ-
uals are children or teenagers. Azathioprine has proved
to be effective in some cases of OFG; other drugs advo-
Figure 3. Linear ulceration in the labial sulcus of a patient with cated for this condition include clofazimine, hydroxy-
oral Crohns disease. chloroquine, danazol, cyclosporin, sulazosulfapyridine,

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962


REVIEW: ORAL ULCERATION 959

thalidomide, tacrolimus and antimicrobials, such as Other types of oral ulceration have been described in
metronidazole and cotrimoxazole.67 Overall, results of patients with inflammatory bowel disease; pyostomatitis
drug therapy for OFG and its associated oral ulceration gangrenosum is rare but manifests as deep, foul-
are disappointing and unpredictable.67 smelling ulceration (Figure 5) with an irregular outline
and rolled margins.71, 72
Pyostomatitis and inflammatory bowel disease
DRUG-INDUCED ORAL ULCERATION
Pyostomatitis vegetans is a rare oral disorder that is
consistently associated with chronic inflammatory Oral ulceration is a well recognized but under-appreciated
bowel disease and considered to be a highly specific adverse drug reaction produced by or implicated in a
marker for inflammatory bowel disease.67 The bowel number of prescribed and over-the-counter medications.73
symptoms often precede oral involvement by several The underlying mechanism in drug-induced oral ulcer-
months or years. Pyostomatitis vegetans has a distinct ation is often unclear, but it can be due to local application
clinical appearance with miliary abscesses and pustular of irritant preparations, such as aspirin74 and pancreatic
lesions affecting the oral mucosa and gingiva, which supplements,75 or the effects of systemic drugs.2 Patients
become thickened, erythematous and may exhibit with learning disabilities or the elderly may have difficulty
vegetations or cobblestoning.68 Pustular lesions often swallowing medication or may hold medication in the
rupture, leading to erosions and ulceration, with mouth, referred to as pouching, increasing the contact
fissuring, in a pattern described as snail-track ulcer- time of medication in localized areas.76
ation.69 The oral lesions predominantly affect the labial A wide spectrum of systemic drugs has been implicated
and buccal mucosa and the labial attached gingivae as causing oral ulceration,2 with clinical presentations
(Figure 5), although the hard and soft palate, vestibule ranging from superficial, nonspecific ulceration to
and tonsillar region can also be affected. The histological aphthous-like lesions or widespread erosions of the
features of pyostomatitis vegetans are often character- mucosa.2 Aphthous-like and nonspecific oral ulceration
istic, although not pathogenomonic, showing intraepit- may be caused by nicorandil (potassium channel
helial and subepithelial microabscesses containing large activator), captopril77 and some nonsteroidal anti-
numbers of eosinophils. Topical steroid therapy has been inflammatory drugs,78 but the exact pathogenic mech-
successful for the treatment of pyostomatitis vegetans, anisms remain unclear.2 There are increasing reports of
but in many cases systemic treatment, with or without nicorandil-induced oral ulceration (Figure 6),79 and in
azathiopine or sulfamethoxypyridazine, is required.70 one report of six cases from European centres, severe oral
Management of the associated inflammatory bowel ulceration appeared within 110 months of starting
disease may result in improvement of the oral lesions. nicorandil and mostly involved the tongue (Figure 6)

Figure 5. Pyostomatitis gangrenosum: ulceration on the dorsum Figure 6. Non-specific oral ulceration on the tongue, in a patient
of the tongue. taking nicorandil.

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962


960 E. A. FIELD & R. B. ALLAN

and buccal mucosa.80 Analysis of another six cases should be referred to an oral physician/surgeon for
suggested that a threshold dosage of 30 mg/day of further investigations, including biopsy if appropriate.
nicorandil might be necessary to induce the aphthous-
like lesions.81 Drugs used to suppress rheumatic dis-
ACKNOWLEDGEMENT
eases have been reported as causing oral ulceration, and
include penicillamine,82 gold75 and methotrexate.83 A We acknowledge the expert advice of Professor Farida
number of chemotherapeutic agents cause severe dis- Fortune BDS, FDSRCS, MB BS, FRCP, Professor of
comfort due to oral ulceration, and widespread mucosal Medicine in relation to Oral Health, Barts and the
involvement may necessitate opioid therapy or alter- Royal London, Queen Marys School of Medicine and
ation to the therapeutic regimen.84 Opportunistic infec- Dentistry, concerning Behcets disease.
tions secondary to cytoxic chemotherapy can also
manifest as oral ulceration.2 Patients who develop
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