Aliment Pharmacol Ther 2003; 18: 949962.
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
SUMMARY
Oral ulceration is a common complaint of patients
attending out-patient clinics. The aim of this review is to
provide the gastroenterologist with a differential
diagnosis of oral ulceration, and a practical guide for
the management of recurrent aphthous stomatitis,
including topical and systemic therapy. The association
of recurrent aphthous stomatitis with Behcets disease
and other systemic disorders, including coeliac disease,
is discussed. Recent evidence concerning the immuno-
pathogenesis of Behcets disease is reviewed, including
THE DIFFERENTIAL DIAGNOSIS OF ORAL
ULCERATION
The principal causes of oral ulceration are trauma,
recurrent aphthous stomatitis, microbial infections,
mucocutaneous disease, systemic disorders, squamous
cell carcinoma and drug therapy1, 2 (see Table 1 and
Figures 16).
RECURRENT APHTHOUS STOMATITIS
Recurrent aphthous stomatitis (RAS) is characterized by
recurrent bouts of one or several shallow, rounded or
ovoid, painful ulcers, that recur at intervals of a few
days or up to 23 months. RAS is a common oral
mucosal condition and has been reported as affecting
Correspondence to: Dr E. A. Field, Oral Medicine Unit, Liverpool Uni-
versity Dental Hospital and School, Pembroke Place, Liverpool L3 5PS, UK.
E-mail: e.a.field@liv.ac.uk
2003 Blackwell Publishing Ltd
doi: 10.1046/j.0269-2813.2003.01782.
renewed interest in the role of Streptococcus sanguis and
possible infectious triggering of an inappropriate immu-
noinflammatory response, resulting in tissue damage.
The efficacy and limitations of conventional treatment
for this mutisystem disorder are outlined together with
the potential role of novel biological agents, such as
anti-tumour necrosis factor-a therapy. Oral ulceration,
as a manifestation of inflammatory bowel disease and a
complication of drug therapy, is described. Guidance is
given concerning indications for referral of patients with
oral ulceration to an oral physician/surgeon for further
investigations, including biopsy if appropriate.
20% of the general population at any time.3 The peak
age of RAS onset is during childhood, with a tendency
to decrease in severity and frequency with age.4
Clinical features
Three clinical presentations of RAS are recognized:
minor recurrent aphthous stomatitis (MiRAS), major
recurrent aphthous stomatitis (MjRAS) and herpetiform
ulceration. The clinical presentation of these types of
RAS are shown in Table 2.1 Patients may sometimes
present with a mixed pattern of RAS, but this is
relatively uncommon.
Minor recurrent aphthous stomatitis (MiRAS)
This is the most common form of RAS and approxi-
mately 80% of patients have lesions of this type.4 In its
most characteristic form, MiRAS presents the picture of
a number of small ulcers (one to five) appearing on the
949
950 E. A. FIELD & R. B. ALLAN

Table 1. Principal causes of oral ulceration
Solitary ulcer*
Trauma
Squamous cell carcinoma
Infections (e.g. syphilis, tuberculosis)
Recurrent bouts of one or more ulcers healing spontaneously
Recurrent aphthous stomatitis (RAS)
Behcets disease
Aphthous-like ulcers due to systemic disease or drug therapy.
Recurrent erythema multiforme
Single bout of ulceration, preceded by vesicles and affecting
multiple oral sites
Viral infections (e.g. herpangina and primary herpetic
stomatitis)
Erythema multiforme
Persistent oral ulceration affecting different sites
Mucocutaneous disease (e.g. oral lichen planus, Fig. 2)
Immunobullous disease (e.g. oral pemphigus)
Gastrointestinal disease (e.g. Crohns disease)
Haematological (e.g. leukaemia)
Drug therapy (e.g. nicorandil)
* 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
malignant, unless proven otherwise.
Patients may report intermittent oral ulceration if these conditions
undergo periods of remission.
buccal mucosa, the labial mucosa, the floor of the
mouth or the tongue.1 Moreover, the ulcers are usually
concentrated in the anterior part of the mouth; the
pharynx and tonsillar fauces are rarely implicated in
this form of ulceration. The prodromal stage of ulcer-
ation is variable, but there is usually a sensation
described as burning or prickling for a short period
before the ulcers appear. Following this phase, ulcer-
ation occurs directly by loss of the epithelium. The
ulcers are usually less than 1 cm in diameter and, in
most instances, their size is approximately 45 mm in
diameter. However, the classification of minor RAS
does not depend on the dimensions of the lesions alone,
but on a number of clinical features. The appearance of
the ulcer base is greyyellow, often with a red and
slightly raised margin, and, unless influenced by the site
(as in the depth of the buccal sulcus where they appear
elongated), they are usually oval in shape. The ulcers
are painful, particularly if the tongue is involved, and
may make eating or speaking difficult. The course of
these ulcers varies from a few days to a little over
2 weeks, but usually their duration is of the order of
10 days. Minor aphthae heal without scar formation.
Following healing of the ulcers, there is a variable ulcer-
free interval; 34 weeks is most common. In a few
patients the recurrence of the ulcers appears to be
entirely random, and in some cases there may not be an
ulcer-free period between attacks, with new aphthae
developing before existing ones have healed.
Major recurrent aphthous stomatitis (MjRAS)
MjRAS (Figure 1) accounts for approximately 1015%
of cases,4 and it varies from the minor form in a number
of important clinical features. The ulcers tend to be
larger than those of MiRAS, and they are of greater
duration, up to a period of months in some cases.1 As a
result of the long periods of time involved, there is
probably a tendency for the production of a heaped-up
margin which, when a single ulcer is seen in isolation,
may lead to the suspicion that the lesion is malignant.
On eventual healing, the ulcers may leave a substantial
scar and this, together with the tissue destruction which
may occur during the active phase of ulceration, may
lead to gross distortion of the involved tissues. MjRAS
may produce lesions throughout the entire oral cavity,
including the soft palate and tonsillar areas, and
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.

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962


Figure 1. Major aphthous ulceration affecting the labial mucosa.
The number of ulcers present at one time varies from
one to 10 in MjRAS. Frequently, a single ulcer will
persist for a long period, while other (usually smaller)
ulcers fade. Unlike MiRAS, there does not appear to be
a cyclical pattern in MjRAS, and the ulcers are usually
unpredictable in their onset. Long periods of remission
may be followed by intervals of intense ulcer activity,
without any obvious precipitating factor.1 The pro-
longed and painful ulceration may present significant
problems to the patient; difficulty eating, speaking
and swallowing can severely affect a patients quality
of life.
Herpetiform ulceration
This distinctive form of RAS differs in many ways from
both MiRAS and MjRAS, and is less common, affecting
510% of cases.4 In herpetiform ulceration the ulcers
are small (12 mm) and multiple (as many as a
hundred ulcers may be present at the same time).
Although any nonkeratinized oral mucosa may be
involved, characteristically the affected sites are the
lateral margins of the tongue and the floor of the
mouth. Individual ulcers are grey and without a
delineating erythematous border, making them quite
difficult to visualize: they resemble ulcers of primary
Herpes simplex virus (HSV) infection. In spite of their
small size, these ulcers are very painful and may make
eating and speaking difficult. A single crop of ulcers may
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962
REVIEW: ORAL ULCERATION 951
Figure 2. Ulcerative lichen planus affecting the oral mucosa.
last for approximately 714 days, and the period of
remission between attacks is variable. Where many
ulcers are present they may coalescence to form larger
confluent areas of ulceration, usually with marked
erythema. Healing with scar formation has been
described in herpetiform ulceration, but this is probably
a result of coalescence.
Aetiopathogenesis of RAS
Genetic factors are likely to predispose patients to RAS,
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
been implicated and include trauma, stress, smoking
cessation, hormonal imbalance and food hypersensitiv-
ity.1 Although some patients report that stressful life
events (e.g. taking examinations in the case of students)
can provoke an outbreak of ulcers, there is little
substantive evidence to link stress to RAS.6 There
appears to be a negative association between smoking
and RAS, and some patients report the onset of oral
ulcers after smoking cessation.7 Interestingly, nicotine-
containing tablets appear to control the frequency of
RAS.8 Some patients report being free from aphthae
whilst taking oral contraceptives or when pregnant,9
and a minority of women with RAS have cyclical oral
ulceration related to the luteal phase of the menstrual
cycle.10 There is no convincing evidence linking
952 E. A. FIELD & R. B. ALLAN
hypersensitivity to foods and RAS other than in coeliac
disease,11 but some patients recognize that foods such
as chocolate, cheese and tomatoes can precipitate
attacks of RAS.
There is strong evidence from histopathological and
immunological studies that T-cell-mediated immune
responses are implicated in RAS.1113 Three stages are
recognized in the development of an aphthous ulcer.12
Microscopic examination during the pre-ulcerative
stage reveals a mononuclear (lymphocytic) cell infiltrate
in the epithelium focal vacuolation and is followed by
degeneration of the suprabasal epithelial cells accom-
panied by a mononuclear, mainly lymphocytic infiltrate
in the lamina propria. As the ulcerative stage approa-
ches there is increased infiltration of the tissues,
particularly the epithelium, by mononuclear cells and
accompanied by more extensive oedema and degener-
ation of the epithelium progressing to frank ulceration
with a fibrinous membrane covering the ulcer. During
the healing phase there is regeneration of the epithe-
lium. The immunopathogenesis of RAS has yet to be
fully elucidated, but the infiltration of the epithelium by
T lymphocytes is likely to be in response to some, as yet
unidentified, keratinocyte-associated antigen. Keratino-
cyte death is thought to be mediated by the differentiation
of cytotoxic T cells and involves the production of tuour
necrosis factor-a (TNFa) by these and other leuco-
cytes.14 TNFa induces inflammation by its effect on
endothelial cell adhesion and neutrophil chemotaxis.14
Other cytokines, e.g. interleukin and interleukin-2, may
also play a role in the immunopathogenesis of RAS.15
Oral streptococci were previously suggested as import-
ant in the pathogenesis of RAS and Behcets disease,
either as direct pathogens or an antigenic stimulus,
culminating in the genesis of antibodies that may
conceivably cross-react with keratinocyte antigenic
determinants.16 More recently a common antigen was
demonstrated between oral mucosa and the 65 kDa
heat shock protein (HSP). As there is a high degree of
homology between the microbial 65 kDa and human
60 kDa HSP, the hypothesis was suggested that an
autoimmune response to the endogenous HSP might be
responsible for the pathological changes in Behcets
disease.17 The role of the cd T-cell subset in the
immunopathology of RAS and Behcets disease and
their participation in the immune response to bacteria-
derived and autologous antigens in these conditions is
currently under investigation (see section on Behcets
disease).13, 18, 19 Although RAS and Behcets disease
are likely to share some common immunopathogenic
mechanisms the reasons why RAS lesions are confined
to the oral cavity, and the oral lesions in Behcets
disease are associated with multisystem disease remains
unclear.16
Systemic conditions and aphthous-like lesions
Table 3 lists the principal systemic conditions associated
with aphthous-like ulcers. These frequently start in
adulthood with no previous history of oral ulceration.
Gastrointestinal disorders
Crohns disease and ulcerative colitis may occasionally
be associated with RAS20 but are more likely to manifest
as other types of oral ulceration. The association of RAS
with coeliac disease is well established. A number of
studies have suggested up to 5% of out-patients who
initially present with RAS11, 21, 22 have gluten-sensitive
enteropathy (GSE). These RAS patients may not always
have gastrointestinal symptoms or other clinical fea-
tures of coeliac disease but usually have folate deficiency
and sometimes reticulin antibodies,21 particularly
immunoglobulin-A-class reticulin and/or gliaden anti-
bodies.23 A recent study has demonstrated that the
prevalence of RAS in a population with coeliac disease
did not significantly differ from an unaffected matched
population without coeliac disease. The authors con-
clude therefore that coeliac disease should be referred to
as a risk indicator not a risk factor for RAS.24 A high
prevalence of HLA-DRW10 and DQW1 has been
associated with RAS.25 RAS in patients with coeliac
disease appears to remit completely on a gluten-free
diet;26 however, there is conflicting evidence concern-
ing the remission of RAS in patients without GSE, who
undergo dietary withdrawal of gluten. There may be a
few RAS patients, with no detectable clinical or
histological evidence on jejunal biopsy, who may
Table 3. Systemic conditions and aphthous-like lesions
Behcets disease
Nutritional deficiencies
Gastrointestinal disorders
Cyclical neutropenia
HIV infection
MAGIC syndrome
FAPA syndrome
Drug reactions
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962
 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-

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962

954 E. A. FIELD & R. B. ALLAN
is not advisable, as it may be absorbed. Several pastes
and gels can be used to coat the surface of the ulcers
and form a protective barrier against secondary infec-
tion and further mechanical irritation. Some difficulty
may be experienced in applying some of these prepara-
tions, particularly to large ulcers and to those at the
back of the mouth. Antiseptic mouthwashes containing
chlorhexidine are widely used for the symptomatic
treatment of RAS and are considered helpful by many
patients, particularly if oral hygiene is difficult to
maintain because of oral ulceration. Extrinsic staining
of teeth associated with long-term use of chlorhexidine
may be a problem. A more effective measure in the relief
of symptoms caused by secondary infection is the
application of topical antibiotics. A mouthwash contain-
ing tetracycline (dissolve soluble tetracycline capsule
250 mg in 510 mL water and rinse) or chlortetracy-
cline is often highly effective in reducing the pain
caused by severe ulceration, and as a result of the much
less heavily colonized environment the ulcers often heal
more rapidly than otherwise. The treatment of herpe-
tiform ulceration depends largely on this therapy, and
response to the antibiotic mouthwash is often rapid and
complete. There are obvious disadvantages, however, in
the use of broad-spectrum antibiotics for this purpose,
the risk of hypersensitivity reactions and the encour-
agement of growth of resistant organisms being the
most important. Local secondary infection by oppor-
tunists such as Candida species may be a problem and
limits long-term use.
Topical corticosteroids can be effective drugs in the
treatment of RAS. Patient response is variable, and
there are some individuals who gain little or no relief
from their use. Corticosteroids used in this manner have
two modes of action; their anti-inflammatory action
modifies, in a minor way, the progress of the ulceration
at all stages and to some extent reduces the discomfort
experienced. The second effect of steroids, i.e. the specific
blocking effect of the T lymphocyte ) epithelial cell
interaction, is much more important in the present
context. Since the concentration of sensitized lympho-
cytes occurs before and during the early stages of oral
ulceration, it follows that the drugs exert their maxi-
mum effect at this time. The drugs most commonly
adopted for local oral application in RAS are hydrocor-
tisone hemisuccinate (as pellets of 2.5 mg) and triam-
cinolone acetonide (in an adhesive paste containing
0.1% of the steroid). There is little risk of adrenal
suppression provided that the recommended dose (four
times daily) is adhered to. In severe MiRAS unrespon-
sive to these preparations and in MjRAS it may be
necessary to use a more potent steroid preparation1
such as a betamethasone sodium phosphate rinse
(dissolve 0.5 mg in 5 mL of water and rinse for
23 min), steroid aerosol (e.g. beclometasone dipropr-
ionate, 100 lg/puff), or a high-potency topical cortico-
steroid, such as clobetasol 0.05% in orabase (1 : 1) or
fluocinonide 0.05% in orabase (1 : 1).39 Prolonged use
of potent topical corticosteroids carries a risk of systemic
absorption and associated adverse effects; it may also
predispose to oral candidosis.
In severe cases of RAS, particularly MjRAS, it may be
necessary to use some form of systemic therapy
(Table 4); however, all drugs have side-effects and risks
which must be weighed against their benefits for RAS.
Apart from prednisolone, a number of systemic drug
therapies has been advocated for the treatment of
MjRAS and in some cases Behcets disease. Thalidomide
has been used successfully for severe RAS which has
failed to respond to other treatment modalities; it has
also been advocated for use in HIV-associated oral
ulceration.4 Thalidomide is a TNFa inhibitor that has
anti-inflammatory effects; however, its use is limited
because of teratogenic and other adverse effects
(e.g. irreversible polyneuropathy). The potential use
of anti-TNF therapy by novel biological agents
(e.g. infliximab) for recurrent aphthae in Behcets
disease is discussed in the next section. Colchicine inhib-
its cell-mediated immune responses and has been used
in does of 1.51.8 mg/day successfully in two small,
open studies involving 23 patients with RAS.40, 41
BEHC ETS DISEASE
Behcets disease is a multisystem, chronic relapsing
inflammatory disease of unknown cause, which is
characterized by recurrent oral (aphthous) ulcers,
genital ulcers, uveitis and skin lesions.42 There may
be a variety of other manifestations including joint,
central nervous system, vascular and intestinal lesions
of variable severity.42
In 1990 the International Study Group for Behcets
disease proposed criteria for the diagnosis of the disease
(Table 5).43 According to these criteria, RAS must be
present as well as at least two of the following: recurrent
genital ulceration, eye lesions, skin lesions and a
positive pathergy test. Behcets disease has diverse
clinical manifestations and lacks any pathognomonic
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962

Table 5. International Study Group for
Manifestations
Behcets Disease (ISGBD): Criteria for diag-
nosis of Behcets disease43 Recurrent oral
ulceration
Plus two of:
Recurrent genital
ulceration
Eye lesions
Skin lesions
Positive pathergy
test
symptoms or diagnostic laboratory markers: conse-
quently it is often difficult to diagnose.
Oral ulceration in Behcets disease
RAS is seen in all patients with Behcets disease; it
commonly precedes other systemic features and can be
of major, minor or herpetiform types. However, it is
difficult to predict with any certainty those patients
initially presenting with RAS who will subsequently
proceed to develop multisystem involvement as part of
Behcets disease. Two studies have addressed this
problem; in one, a clinical comparison between 38
patients with Behcets disease and RAS-only controls
showed an increased number of concurrent ulcers and
involvement of the soft palate and oropharynx in those
diagnosed with Behcets disease.44 No differences were
detected with respect to duration, frequency, age of
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962
REVIEW: ORAL ULCERATION 955
Prevalence (%) Description
100 Minor aphthous.
Major aphthous or herpetiform ulceration
observed by a physician or reported
reliably by patient.
Recurrent at least three times in one
12-month period.
80 Recurrent genital aphthous ulceration
or scarring, especially in male patients,
observed by physician or reliably reported
by patient.
6070 Anterior uveitis.
Posterior uveitis.
Cells in vitreous on slit lamp examination.
Or
Retinal vasculitis observed by qualified
physician (ophthalmologist)
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
Variable An erythematous papule, > 2 mm, at the prick
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.
onset or family history. Scrutiny of clinical photo-
graphs taken of Behcets disease patients in this study
suggested that both herpetiform-type and aphthous-
type ulcers appeared atypical.44 Clinical observations
in oral medicine clinics suggest that aphthous ulcers in
patients with Behcets disease appear to be associated
with increased tissue oedema and appear to have an
intensely erythematous border. The aphthae in
Behcets disease often occur in the soft palate and
oropharynx and have been observed on the hard
palate, which is an unusual site for RAS in patients
without Behcets disease.44 Patches of mucosal ery-
thema may be observed in patients with the disease,
indicating possible instability of the oral mucosa prior
to ulceration. Patients may paradoxically report no
painful symptoms during active disease, despite exten-
sive oral ulceration being clinically evident. A Korean
study examined the prognosis of the clinical relevance
956 E. A. FIELD & R. B. ALLAN
of recurrent oral ulceration in Behcets disease, and
investigators found that approximately half the
patients who were initially diagnosed as RAS-only
developed other manifestations of Behcets disease at
an average of 7.7 years after onset.45 Highly recurrent
RAS appeared to be a warning signal for Behcets
disease in this study.45
Aetiopathogenesis of Behcets disease
The aetiology of Behcets disease is poorly understood,
but interactions between environmental and genetic
factors are likely to influence the susceptibility and
development of the disease,46 as well as being impli-
cated in its pathogenesis. Susceptibility to Behcets
disease is associated with the HLA-B51 MHC class 1
allele, and it has been reported that individuals in the
appropriate geographical setting (i.e. living in areas
along the Silk Route) who express this allele have an
eight- to ten-fold greater risk of developing the
disease.42 The relative risk of the disease among
carriers of HLA-B5I is much less in Western countries,
indicating that other genetic factors may be important
in these individuals.42 The HLA-51 allele also affects
the severity of Behcets disease, since it is more
commonly detected in patients with posterior uveitis
or progressive central nervous system disease than
those with milder disease.42 Investigation of the
aetiology of Behcets disease has focused predomin-
antly on herpes simplex virus immunopathology,
autoimmunity to oral mucosa or cross-reactive micro-
bial antigens, and streptococcal infection.47 Its im-
munopathogenesis is likely to involve a T-cell-mediated
response, and it has been demonstrated that lympho-
cyte function is abnormal in patients with the
disease.13 There has been renewed interest in the role
of Streptococcus sanguis as a causative agent,48 and
recent advances have resurrected the theory of infec-
tious triggering of the immune cascade in Behcets
disease and have been strengthened by work with
heat-shock protein and the concept of a molecular
mimicry mechanism.49 It has been suggested that
bacterial products such as heat-shock proteins
may incite an inappropriate immunoinflammatory
response.19 Recent studies have investigated the role
of the cd T-cell subset in the immunopathology of
Behcets disease.13, 18, 19 These T cells participate in
the immune response to infections and in autoimmu-
nity by recognizing bacteria-derived and autologous
antigens.19 cd T Cells have also been reported as
producing several cytokines, with the cytokine profile
dependent on the nature of antigen, enabling the cd
T cells to influence the nature of the immune
response.50 Levels of circulating TNFa, interleukin-
1-b and interleukin-8 have been reported as elevated
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
and substantiated data from a number of other studies
indicating that cd T cells have increased in Behcets
disease relative to healthy and disease controls, and in
addition the cd T-cell population increases with the
active disease.19 This group also examined the prolif-
eration of a subset of cd T cells in response to bacterial
products obtained from patients with the active
mucocutaneous disease, and concluded that an exag-
gerated proliferative response to products released by
micro-organisms present in oral (aphthous) ulcers may
play a role in the expansion of cd T cells in Behcets
disease.19 This raises the possibility that therapeutic
control of the oral environment, or manipulation of
cd T-cell-derived cytokines by drugs such as anti-
TNFa, provides effective strategies against aphthous
ulceration and thereby controls systemic manifesta-
tions of the disease.48
Treatment of Behcets disease
Patients with Behcets disease usually have repeated
exacerbations and remission of their clinical symptoms,
and in these individuals treatment is essentially symp-
tomatic. The choice of therapy depends on whether the
clinical manifestations of the disease are local or
systemic. Multidisciplinary involvement in the manage-
ment of Behcets disease is essential, and patients should
ideally be treated in centres with extensive experience of
treating the disease.
Local treatment with corticosteroids often controls oral
and genital ulcers, and immunosuppressive therapy is
reserved for severe cases of mucocutaneous involve-
ment.52 The oral lesions may respond well to topical
corticosteroid preparations (Table 4), but it is important
to monitor the patients for signs or oral candidosis and
treat this with appropriate antifungal agents. Patients
with painful oral ulceration also benefit from analgesic
mouthwashes, e.g. benzydamine hydrochloride or ligno-
caine (lidocaine). The choice of systemic drug treatment
for Behcets disease is dictated by the patients clinical
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962

manifestations, but conventional therapy relies on anti-
inflammatory and immunomodulatory agents. There is
a paucity of controlled clinical trails relating to drug
therapy, and prescribing for Behcets disease is, to a
large extent, empirical.53 Ocular lesions in Behcets
disease must be vigorously treated to prevent blindness,
and therapy aims to reduce both the severity and
frequency of ocular attacks. Despite therapeutic inter-
ventions, approximately 25% of all patients with ocular
manifestations of Behcets disease will become blind.54
Systemic corticosteroids continue to be used extensively,
and may be administered as intravenous pulse therapy.
Ciclosporin is highly effective for ocular lesions, partic-
ularly in cases that have been refractory to other
therapies, but its nephrotoxity restricts usage of the
drug.54 Azathioprine is a disease-modifying drug for
Behcets disease and helps reduce recurrences; it is now
considered to be the first-line drug for this condition.
Thalidomide, despite its prescribing limitations and
neurotoxic side-effects, has proved effective for the
management of mucocutaneous lesions in Behcets
disease56 but it is not disease-modifying, and with-
drawal of the drug can lead to severe rebound of
symptoms.57 After teratogenicity, polyneuropathy is the
second most serious complication of thalidomide, and
has been reported in up to 50% of patients taking the
drug.58 Thalidomide-related polyneuropathy appears to
be dose-related and can be irreversible if not diagnosed
early. Mycophenolate mofetil does not appear to be
effective for Behcets disease.59 Colchicine is frequently
used, and recent trials have demonstrated its beneficial
effects on mucocutaneous symptoms, presumably by
inhibiting neutrophil function.60 Cyclophosphamide,
with or without corticosteroids, may be indicated for
central nervous system lesions.42, 52
Recognition of the possible pathogenetic role of TNFa
in Behcets disease has resulted in the use of anti-TNFa
therapy. Recent trials with novel anti-TNFa agents
(infliximab and etenercept)61 have indicated effective
short-term remission. Infliximab (a chimeric anti-TNFa
monoclonal antibody) has been used successfully for the
treatment of recalcitrant orogenital ulceration in Be-
hcets disease.62 These novel biological agents are,
however, expensive compared with conventional treat-
ment, and their long-term efficacy is yet to be proven in
clinical trials. Overall, the goal of management in
Behcets disease is to treat early to improve morbidity, to
avoid recurrences and irreversible damage to organs,57
and to provide symptomatic relief for patients.
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962
REVIEW: ORAL ULCERATION 957
ORAL ULCERATION AND INFLAMMATORY
BOWEL DISEASE
Oral involvement has for some time been recognized in
patients suffering from both Crohns disease and, to a
lesser extent, ulcerative colitis. Oral lesions may precede
or accompany gastrointestinal disease and can be the
only site of involvement.
Oral Crohns disease and orofacial granulatosis (OFG)
Over the last decade there has been increasing attention
paid to noninfectious granulomatous disorders of the
orofacial region, which include oral Crohns disease and
oral sarcoid, as well as clinical entities, known as the
MelkerssonRosenthal syndrome, and Miescheners
cheilitis granulomatosa (granulomatous cheilitis). The
term orofacial granulomatosis (OFG) was introduced to
encompass these disorders and to describe a clinical
syndrome presenting with swelling of the face, lips or oral
tissues in association with histological evidence of noncea-
seating granulomatous inflammation within these tis-
sues.63 Recent studies have investigated the association of
OFG with intolerance to specific foods, food additives,
flavouring and the constituents of toothpastes. Cinnamon-
aldehyde and sodium benzoates have been particularly
implicated in this respect, and in some series there was a
clinical response to specific elimination diets. It remains
unknown whether sensitivity to food additives is the
primary factor for some patients with OFG or a secondary
aggravating factor to some underlying process.64, 65
The prevalence of OFG has not been determined but
there does seem to be a geographical variation, for
example the west of Scotland, UK, appears to have a
higher number of cases.66 Oral medicine centres
throughout the UK are reporting an increased number
of cases of OFG, but this may be a result of increasing
awareness and/or reporting of this condition. One study
of 60 patients has reported that the median age of OFG
at presentation was 20 years,63 but clinical experience
indicates that many patients are older children or
teenagers. The association of OFG with Crohns disease
elsewhere in the gut has been the subject of debate, and
this inter-relationship has been fully explored in a
number of studies.67 The prevalence of symptomless
intestinal disease of Crohns in patients with OFG has
been reported as between 10% and 48% in various
studies.67 The clinical features of OFG are shown in
Table 6.
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
along the occlusal ridge, resulting in ulceration; this
can be quite deep and may become secondarily
infected. Patients may also present with RAS, but
this is not specific to OFG.
Management of orofacial granulomatosis. Patients with
OFG must be appropriately investigated, not only to
confirm the diagnosis but to identify any provoking
factors and signs and symptoms suggestive of an
underlying systemic condition, such as Crohns disease
or sarcoidosis. Biopsy of an affected site (usually the
labial or buccal mucosa and occasionally the gingivae)
Figure 3. Linear ulceration in the labial sulcus of a patient with
oral Crohns disease.
Figure 4. Pyostomatitis vegetans manifesting as snail-track
ulcers on the gingivae.
should be carried out by an experienced operator.
Histologically, noncaseating and epithelioid granulo-
mas, with or without multinucleated giant cells, are
seen in about 90% of cases. Granulomas are not always
present, and their absence does not exclude the clinical
diagnosis of OFG. Granulomata may only be present in
the underlying muscle, and it is therefore advisable to
extend the biopsy deeper beyond the superficial tissue.
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-
cated for this condition include clofazimine, hydroxy-
chloroquine, danazol, cyclosporin, sulazosulfapyridine,

2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962


thalidomide, tacrolimus and antimicrobials, such as
metronidazole and cotrimoxazole.67 Overall, results of
drug therapy for OFG and its associated oral ulceration
are disappointing and unpredictable.67
Pyostomatitis and inflammatory bowel disease
Pyostomatitis vegetans is a rare oral disorder that is
consistently associated with chronic inflammatory
bowel disease and considered to be a highly specific
marker for inflammatory bowel disease.67 The bowel
symptoms often precede oral involvement by several
months or years. Pyostomatitis vegetans has a distinct
clinical appearance with miliary abscesses and pustular
lesions affecting the oral mucosa and gingiva, which
become thickened, erythematous and may exhibit
vegetations or cobblestoning.68 Pustular lesions often
rupture, leading to erosions and ulceration, with
fissuring, in a pattern described as snail-track ulcer-
ation.69 The oral lesions predominantly affect the labial
and buccal mucosa and the labial attached gingivae
(Figure 5), although the hard and soft palate, vestibule
and tonsillar region can also be affected. The histological
features of pyostomatitis vegetans are often character-
istic, although not pathogenomonic, showing intraepit-
helial and subepithelial microabscesses containing large
numbers of eosinophils. Topical steroid therapy has been
successful for the treatment of pyostomatitis vegetans,
but in many cases systemic treatment, with or without
azathiopine or sulfamethoxypyridazine, is required.70
Management of the associated inflammatory bowel
disease may result in improvement of the oral lesions.
Figure 5. Pyostomatitis gangrenosum: ulceration on the dorsum
of the tongue.
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962
REVIEW: ORAL ULCERATION 959
Other types of oral ulceration have been described in
patients with inflammatory bowel disease; pyostomatitis
gangrenosum is rare but manifests as deep, foul-
smelling ulceration (Figure 5) with an irregular outline
and rolled margins.71, 72
DRUG-INDUCED ORAL ULCERATION
Oral ulceration is a well recognized but under-appreciated
adverse drug reaction produced by or implicated in a
number of prescribed and over-the-counter medications.73
The underlying mechanism in drug-induced oral ulcer-
ation is often unclear, but it can be due to local application
of irritant preparations, such as aspirin74 and pancreatic
supplements,75 or the effects of systemic drugs.2 Patients
with learning disabilities or the elderly may have difficulty
swallowing medication or may hold medication in the
mouth, referred to as pouching, increasing the contact
time of medication in localized areas.76
A wide spectrum of systemic drugs has been implicated
as causing oral ulceration,2 with clinical presentations
ranging from superficial, nonspecific ulceration to
aphthous-like lesions or widespread erosions of the
mucosa.2 Aphthous-like and nonspecific oral ulceration
may be caused by nicorandil (potassium channel
activator), captopril77 and some nonsteroidal anti-
inflammatory drugs,78 but the exact pathogenic mech-
anisms remain unclear.2 There are increasing reports of
nicorandil-induced oral ulceration (Figure 6),79 and in
one report of six cases from European centres, severe oral
ulceration appeared within 110 months of starting
nicorandil and mostly involved the tongue (Figure 6)
Figure 6. Non-specific oral ulceration on the tongue, in a patient
taking nicorandil.
960 E. A. FIELD & R. B. ALLAN
and buccal mucosa.80 Analysis of another six cases
suggested that a threshold dosage of 30 mg/day of
nicorandil might be necessary to induce the aphthous-
like lesions.81 Drugs used to suppress rheumatic dis-
eases have been reported as causing oral ulceration, and
include penicillamine,82 gold75 and methotrexate.83 A
number of chemotherapeutic agents cause severe dis-
comfort due to oral ulceration, and widespread mucosal
involvement may necessitate opioid therapy or alter-
ation to the therapeutic regimen.84 Opportunistic infec-
tions secondary to cytoxic chemotherapy can also
manifest as oral ulceration.2 Patients who develop
lichenoid-drug eruptions affecting the mouth may report
persistent or intermittent oral ulceration, and a wide
range of systemic drugs have been implicated in this
adverse reaction.2 A detailed list of current medications
is critical to identify drug-induced oral ulceration,
especially when the ulceration is resistant to therapy
and of indeterminate cause.77 It is important to ascertain
if the oral ulceration started, or became worse, at the
commencement of drug therapy or after an increased
dosage. Patients with drug-induced oral ulceration may
show improvement with topical corticosteroid treat-
ment, but definitive management is dependent on
withdrawal of the putative drug; occasionally this is
not an option. Older patients especially, but not exclu-
sively, may be taking multiple medications, a number of
which have been implicated as causing oral ulceration;
this poses difficult and challenging management.
CONCLUSION
All patients with recurrent or persistent oral ulceration
should be fully investigated to establish a definitive
diagnosis and eliminate the possibility of an underlying
systemic disorder or oral malignancy. The diagnosis of
RAS is based on the patients history and clinical
appearance of the ulcers. The majority of RAS cases
respond to topical corticosteroid and/or topical antimi-
crobial therapy, but a few will require systemic
immunomodulators. Patients with RAS may proceed
to develop Behcets disease, which is diagnosed solely on
the basis of clinical criteria. In spite of recent advances
in systemic therapy for Behcets disease the functional
prognosis of patients will remain poor until the
underlying pathogenesis of the disease is elucidated.
Clinical trials are currently being conducted to investi-
gate the efficacy of anti-TNFa. agents for Behcets
disease. Patients with undiagnosed oral ulceration
should be referred to an oral physician/surgeon for
further investigations, including biopsy if appropriate.
ACKNOWLEDGEMENT
We acknowledge the expert advice of Professor Farida
Fortune BDS, FDSRCS, MB BS, FRCP, Professor of
Medicine in relation to Oral Health, Barts and the
Royal London, Queen Marys School of Medicine and
Dentistry, concerning Behcets disease.
REFERENCES
1 Field EA, Longman LP. Tyldesleys Oral Medicine, 5th edn.
Oxford: Oxford University Press, 2003.
2 Porter SR, Scully C. Adverse drug reactions in the mouth. Clin
Dermatol 2000; 18: 52532.
3 Rennie JS, Reade PC, Hay KD, et al. Recurrent aphthous sto-
matitis. Br Dent J 1985; 159: 3617.
4 Rogers RS, 3rd. Recurrent aphthous stomatitis. Clinical
characteristics and associated systemic disorders. Semin
Cutan Med Surg 1997; 16: 27883.
5 Shohat-Zabarski R, Kalderon S, Klein T, et al. Close association
of HLA-B51 in persons with recurrent aphthous stomatitis.
Oral Surg Oral Med Oral Pathol 1992; 74: 4558.
6 Pedersen A. Psychologic stress and recurrent aphthous
ulceration. J Oral Pathol Med 1989; 18: 11922.
7 Dorsey C. More observations on relief of aphthous stomatitis
on resumption of cigarette smoking. Calif Med 1964; 101:
3778.
8 Bittoun R. Recurrent aphthous ulcers and nicotine. Med J
Aust 1991; 154: 4712.
9 Ferguson MM, McKay Hart D, et al. Progeston therapy for
menstrually related aphthae. Int J Oral Surg 1978; 7: 46370.
10 Ferguson MM, Carter J, Boyle P. An epidemiological study of
factors associated with recurrent aphthae in women. J Oral
Med 1984; 39: 2127.
11 Ferguson MM, Wray D, Carmichael HA, et al. Coeliac disease
associated with recurrent aphthae. Gut 1980; 21: 2236.
12 Soames JV, Southam JC. Oral Pathology, 3rd edn. Oxford:
Oxford University Press, 1998.
13 Freysdottir J, Lau S, Fortune F. Gammadelta T cells in Behcets
disease (BD) and recurrent aphthous stomatitis (RAS). Clin
Exp Immunol 1999; 118: 4517.
14 Natah SS, Hayrinen-Immonen R, Hietanen J, et al. Immuno-
localisation of tumour necrosis factor-alpha expressing cells in
recurrent aphthous ulcer lesions (RAU). J Oral Pathol Med
2000; 29: 1925.
15 Sun A, Chu CT, Liu BY, et al. Expression of interleukin-2
receptor by activated peripheral blood lymphocytes upregu-
lated by the plasma level of interleukin-2 in patients with
recurrent aphthous ulcers. Proc Natl Sci Counc Repub China
B 2000; 24: 11622.
16 Porter SR, Scully C, Pedersen A. Recurrent aphthous stoma-
titis. Crit Rev Oral Biol Med 1998; 9: 30621.
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962

17 Lehner T, Lavery E, Smith R et al. Association between the
65-kilodalton heat shock protein, Streptococcus sanguis, and
the corresponding antibodies in Behcets syndrome. Infect
Immunol 1991; 59(4): 143441.
18 Hasan A, Fortune F, Wilson A, et al. Role of gamma delta
T cells in pathogenesis and diagnosis of Behcets disease.
Lancet 1996; 347: 78994.
19 Bank I, Duvdevani M, Livneh A. Expansion of gammadelta
T-cells in Behcets disease: role of disease activity and micro-
bial flora in oral ulcers. J Labor Clin Med 2003; 141: 3340.
20 Veloso FT, Carvalho J, Magro F. Immune-related systemic
manifestations of inflammatory bowel disease: a prospective
study of 792 patients. J Clin Gastroenterol 1996; 23: 2934.
21 Ferguson R, Basu MK, Asquith P, et al. Jejunal mucosal
abnormalities in patients with recurrent aphthous ulceration.
Br Med J 1976; 1: 113.
22 Veloso FT, Saleiro JV. Small-bowel changes in recurrent
ulceration of the mouth. Hepatogastroenterology 1987; 34:
367.
23 Merchant NE, Ferguson MM, Ali A, et al. The detection of IgA-
reticulin antibodies and their incidence in patients with
recurrent aphthae. J Oral Med 1986; 41: 314.
24 Sedghizadeh PP, Shuler CF, Allen CM, et al. Celiac disease
and recurrent aphthous stomatitis. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2002; 94: 4748.
25 Meini A, Pillan MN, Plebani A, et al. High prevalence of
DRW10 and DQW1 antigens in celiac disease associated with
recurrent aphthous stomatitis. Am J Gastroenterol 1993; 88:
972.
26 Scully C, Gorsky M, Lozada-Nur F. The diagnosis and man-
agement of recurrent aphthous stomatitis: a consensus
approach. J Am Dent Assoc 2003; 134: 2007.
27 Wray D. Gluten-sensitive recurrent aphthous stomatitis. Dig
Dis Sci 1981; 26: 73740.
28 Wright A, Ryan FP, Willingham SE, et al. Food allergy or
intolerance in severe recurrent aphthous ulceration of the
mouth. Br Med J (Clin Res Edn) 1986; 292: 12378.
29 Hunter IP, Ferguson MM, Scully C, et al. Effects of dietary
gluten elimination in patients with recurrent minor aphthous
stomatitis and no detectable gluten enteropathy. Oral Surg
Oral Med Oral Pathol 1993; 75: 5958.
30 Olson JA, Feinberg I, Silverman S, et al. Serum vitamin B12,
folate and iron levels in recurrent aphthous ulceration. Oral
Surg Oral Med Oral Pathol 1982; 54: 51720.
31 Porter S, Flint S, Scully C, et al. Recurrent aphthous stomatitis;
the efficacy of replacement therapy in patients with underly-
ing haematinic deficiencies. Ann Dent 1992; 51: 146.
32 Muzyka BC, Glick M. Major aphthous ulcers in patients with HIV
disease. Oral Surg Oral Med Oral Pathol 1994; 77: 11620.
33 MacPhail LA, Greenspan D, Feigal DW, et al. Recurrent aph-
thous ulcers in association with HIV infection. Description of
ulcer types and analysis of T lymphocyte subsets. Oral Surg
Oral Med Oral Pathol 1991; 71: 67883.
34 Vanderhoof JA, Rich KC, Stiehm ER, et al. Esophageal ulcers in
immunodeficiency with elevated levels of IgM and neutrope-
nia. Am J Dis Child 1977; 131: 5512.
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962
REVIEW: ORAL ULCERATION 961
35 Wright DG, Dale DC, Fauci AS, et al. Human cyclic neu-
tropenia: clinical review and long-term follow-up of patients.
Medicine (Baltimore) 1981; 60: 113.
36 Orme RL, Nordlund JJ, Barich L, et al. The MAGIC syndrome
(mouth and genital ulcers with inflamed cartilage). Arch
Dermatol 1990; 126: 9404.
37 Marshall GS, Edwards KM, Butler J, et al. Syndrome of periodic
fever, pharyngitis and aphthous stomatitis. J Pediatr 1987;
110: 436.
38 Notani K, Kobayashi S, Kondoh K, et al. A case of Sweets
syndrome (acute febrile neutrophilic dermatosis) with palatal
ulceration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2000; 89: 4779.
39 Lozada-Nur F, Miranda C, Maliksi R. Double-blind clinical trial
of 0.05% clobetasol propionate ointment in orobase and
0.05% fluocinonide ointment in orobase in the treatment of
patients with oral vesiculoerosive diseases. Oral Surg Oral Med
Oral Pathol 1994; 77: 598604.
40 Katz J, Langevitz P, Shemer J, et al. Prevention of recurrent
aphthous stomatitis with colchicine: an open trial. J Am Acad
Dermatol 1994; 31: 45961.
41 Gatot A, Tovi F. Colchicine therapy in recurrent oral ulcers.
Arch Dematol 1984; 120: 994.
42 Sakane T, Takeno M, Suzuki N, et al. Behcets disease. N Engl J
Med 1999; 341: 128491.
43 International Study Group for Behcets Disease. Criteria
for diagnosis of Behcets disease. Lancet 1990; 335: 107880.
44 Main DM, Chamberlain MA. Clinical differentiation of oral
ulceration in Behcets disease. Br J Rheumatol 1992; 31: 767
70.
45 Bang D, Hur W, Lee ES, et al. Prognosis and clinical relevance
of recurrent oral ulceration in Behcets disease. J Dermatol
1995; 22: 9269.
46 Lehner T. Immunopathogenesis of Behcets disease. Ann Med
Interne (Paris) 1999; 150: 4837.
47 Lehner T. The role of heat shock protein, microbial and
autoimmune agents in the aetiology of Behcets disease. Int
Rev Immunol 1997; 14: 2132.
48 Fortune F. Can you catch Behcets disease? J Labor Clin Med
2003; 141: 56.
49 Lehner T, Fortune F, Lavery E, Studd M. Recent advances in T
cell immunoregulation and the microbial causes of Behcets
disease. In: ODuffy, JD, Kokmen, E, eds. Behcets Disease:
Basic and Clinical Aspects. New York: Marcel Dekker, 1991:
46373.
50 Ferrick DA, Schrenzel MD, Mulvania T, et al. Differential
production of interferon-gamma and interlukin-4 in response
to Th1- and Th2- stimulating pathogens by gamma delta T
cells in vivo. Nature 1995; 373: 2557.
51 Ehrlich GE. Vasculitis in Behcets disease. Int Rev Immunol
1997; 14: 818.
52 Yazici H, Barnes CG. Practical treatment recommendations for
pharmacotherapy of Behcets syndrome. Drugs 1991; 42:
796804.
53 Russell AI, Lawson WA, Haskard DO. Potential new thera-
peutic options in Behcets syndrome. Biodrugs 2001; 5: 2535.
962 E. A. FIELD & R. B. ALLAN
54 Meador R, Ehrlich G, Von Feldt JM. Behcets disease:
immunopathologic and therapeutic aspects. Current Rheu-
matol Rep 2002; 4: 4754.
55 Sakane T, Takeno M. Novel approaches to Behcets disease.
Expert Opin Invest Drugs 2000; 9: 19932005.
56 Hamuryudan V, Mat C, Saip C, et al. Thalidomide in the
treatment of the mucocutaneous lesions of the Behcets syn-
drome. A randomised double-blind, placebo-controlled trial.
Ann Intern Med 1998; 128: 44350.
57 Kaklamani VG, Kaklamanis PG. Treatment of Behcets
disease an update. Semin Arthritis Rheum 2001; 5: 299
312.
58 Gardiner-Medwin JM, Smith NJ, Powell RJ. Clinical experience
with thalidomide in the management of severe oral and
genital ulceration in conditions such as Behcets disease: use
of neurophysiological studies to detect thalidomide neuropa-
thy. Ann Rheum Dis 1994; 53: 82832.
59 Adler YD, Mansmann U, Zouboulis CC. Mycophenolate mofetil
is ineffective in the treatment of mucocutaneous Adamanti-
adesBehcets disease. Dermatology 2001; 203: 3224.
60 Miyachi Y, Tangiguchi S, Ozaki M, et al. Colchicine in the
treatment of the cutaneous manifestations of Behcets disease.
Br J Dermatol 1981; 104: 679.
61 Sfikakis PP. Behcets disease: a new target for anti-tumour
necrosis factor treatment. Ann Rheum Dis 2002; 61(Suppl.
2): ii513.
62 Robertson LP, Hickling P. Treatment of recalcitrant orogenital
ulceration of Behcets syndrome with infliximab. Rheumatol-
ogy (Oxford) 2001; 40: 4734.
63 Wiesenfeld D, Ferguson MM, Mitchell DN, et al. Oro-facial
granulomatosis a clinical and pathological analysis. Q J Med
1985; 54: 10113.
64 Sweatman MC, Tasker R, Warner JO, et al. Oro-facial gra-
nulomatosis. Response to elemental diet and provocation by
food additives. Clin Allergy 1986; 16: 3318.
65 Haworth RJ, MacFadyen EE, Ferguson MM. Food intolerance
in patients with oro-facial granulomatosis. Hum Nutr Appl
Nutr 1986; 40: 44756.
66 Gibson J, Wray D, Bagg J. Oral staphylococcal mucositis.
A new clinical entity in orofacial granulomatosis and Crohns
disease. Oral Surg, Oral Med, Oral Path Oral Pathol Oral
Radiol Endod 2000; 89: 1716.
67 Field EA. Oral Lesions in IBD. Inflammatory Bowel Disease
Monitor 2001; 2: 6672.
68 Thornhill MH, Zakrzewska JM, Gilkes JJ. Pyostomatitis vege-
tans. report of three cases and review of the literature. J Oral
Pathol Med 1992; 21: 12833.
69 Forman L. Two cases of pyodermatatitis vegetans (Hallopeau):
an eosinophilic pustular and vegetating dermatitis with con-
junctival, oral and colonic involvement. Proc R Soc Med
1965; 58: 2449.
70 Healy CM, Farthing PM, Williams DM, et al. Pyostomatitis
vegetans and associated systemic disease: a review and two
case reports. Oral Surg Oral Med Oral Pathol 1994; 78: 323
8.
71 Margoles JS, Wenger J. Stomal ulceration associated with
pyoderma gangrenosum and ulcerative colitis. Gastroenter-
ology 1961; 41: 5948.
72 Asquith P, Thomson RA, Cooke WT. Oral manifestations of
Crohns disease. Gut 1975; 16: 124954.
73 McLeod RI. Drug-induced aphthous ulcers. Br J Dermatol
2000; 143: 11379.
74 Dellinger TM, Livingston HM. Aspirin burn of the oral cavity.
Ann Pharmacotherapy 1998; 32: 1107.
75 Royal Pharmaceutical Society of. Great Britain and the British
Medical Association. British National Formulary. 2003; 45:
60, 492.
76 Wakham MD, McNeal Dr Burtner AP. Pouching of medica-
tions in the mouth: a case report. Spec Care Dentist 1990;
10: 913.
77 Cohen DM, Bhattacharyya I, Lydiatt WM. Recalcitrant oral
ulcers caused by calcium channel blockers. diagnosis and
treatment considerations. J Am Dent Assoc 1999; 130: 16118.
78 Healy CM, Thornhill MH. An association between recurrent
oro-genital ulceration and non-steroidal anti-inflammatory
drugs. J Oral Pathol Med 1995; 1: 468.
79 Shotts RH, Scully C, Avery CM, et al. Nicorandil-induced
severe oral ulceration: a newly recognised drug reaction.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 87:
7067.
80 Scully C, Azul AM, Crighton A, et al. Nicorandil can induce
severe oral ulceration. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2001; 91: 18993.
81 Desruelles F, Bahadoran P, Lacour JP, et al. Giant oral aph-
thous ulcers induced by nicorandil. Br J Dermatol 1998; 138:
7123.
82 Lam PP. Severe stomatitis caused by penicillamine. Br Dent J
1980; 149: 1801.
83 Bauer J, Fartasch M, Schuler G, et al. Ulcerative stomatitis as
clinical clue to inadvertent methotrexate overdose. Hautarzt
1999; 50: 6703.
84 Singh N, Scully C, Joyston-Bechal S. Oral complications of
cancer therapies: prevention and management. Clin Oncol
1996; 8: 1524.
2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 949962