Recurrent Aphthous Stomatitis
STEPHEN R. PORTER, MD, PhD
ANNE HEGARTY, BDS, MSc
FOTINI KALIAKATSOU, BDS, MSc
TIM A. HODGSON, FDS RCS MRCP (UK)
CRISPIAN SCULLY, CBE, MD, PhD
R
ecurrent aphthous stomatitis (RAS) is a common
disorder affecting 5% to 66% of examined adult
patient groups. There may be a female predominance in some adult and child patient groups.1– 4 The
ulceration usually commences in the second decade,5
although 40% of selected groups of children can have a
history of RAS, ulceration beginning before 5 years of
age, the frequency of affected patients rising with age.
Children of higher socioeconomic status may be more
commonly affected that those from low socioeconomic
groups.6 –9
Clinical Features
The clinical features of RAS comprise recurrent bouts of
one or several rounded, shallow, painful oral ulcers at
intervals of a few months to a few days; RAS has three
main presentations: minor (MiRAS), major (MaRAS), or
herpetiform (HU) ulcers (Table 1).
Minor recurrent aphthous stomatitis (MiRAS), the
most common variety, affects about 80% of RAS adult
and child patients, and is characterized by round or
oval shallow ulcers usually less than 5 mm in diameter
with a gray-white pseudomembrane enveloped by a
thin erythematous halo. Usually, MiRAS occurs on the
nonkeratinized mobile surfaces such as the labial and
buccal mucosa and floor of the mouth and is uncommon on the gingiva, palate, or dorsum of the tongue.
These lesions heal within 1 to 2 weeks without scarring.5
Major recurrent aphthous stomatitis (MaRAS) is an
uncommon and severe form of RAS, comprising oval or
irregular ulcers that may exceed 1 cm in diameter.
These ulcers have a predilection for the lips, soft palate,
and fauces (but can affect any site), persist for up to 6
weeks, and often heal with scarring.
Herpetiform (HU) is very uncommon, being characterized by multiple recurrent crops of small, painful
ulcers that may be distributed throughout the oral cavFrom the Eastman Dental Institute for Oral Health Care Sciences,
University College London, London, England.
Address correspondence to Stephen R. Porter, M.D., Department of Oral
Medicine, University College London, University of London, 256 Gray’s Inn
Road, London WC1X 8LD UK.
© 2000 by Elsevier Science Inc. All rights reserved.
655 Avenue of the Americas, New York, NY 10010
ity. As many as 100 ulcers may be present at a given
time, although they tend to fuse, producing large irregular ulcers. It has been suggested that HU might have a
female predisposition and also a later age of onset than
other RAS types or represent a spectrum of oral disorders manifesting as recurring ulcers.10
Disorders Giving Rise to RAS-Like Disease
Similar-appearing lesions may arise in systemic disorders including Behcet’s disease,11–15 Sweet’s syndrome,16 –18 cyclic neutropenia,19 –21 benign familial
neutropenia,22,23 MAGIC syndrome,24,25 a periodic
syndrome with fever and pharyngitis,26 various
nutritional deficiencies with or without underlying
gastrointestinal disorders,27–29 some other primary
immunodeficiencies,30 –33 and infection with human immunodeficiency virus.34,35 Rarely, drugs such as nonsteroidal anti-inflammatory drugs (NSAIDS)36 or nicorandil37 can give rise to oral ulcers, similar to RAS.
Systemic Diseases Possibly Associated With RAS
The precise etiology of RAS is not known. A number of
disease associations have been proposed and are suggested to be of etiological significance; however, these
links are often tenuous and/or unlikely to be significant
to the development of the ulceration of RAS.
Hematinic Deficiency
Several studies from the UK, United States, and Spain
have demonstrated that hematinic deficiency (iron, folic
acid, or vitamin B12) are twice as common in RAS
patients than in controls.38 – 46 About 20% of patients
with RAS may have a hematinic deficiency, though one
U.S. study did not report any hematinic problem.47
Vitamin B1, B2, and/or B6 deficiency was observed in a
cohort of Scottish patients with RAS.48
Gluten-Sensitive Enteropathy
Less than 5% of outpatients who initially present with
RAS49 –51 are prone to have gluten-sensitive enteropathy
(GSE: celiac disease). These RAS patients may not always have gastrointestinal symptoms or other clinical
features suggestive of GSE but usually have folate de0738-081X/00/$–see front matter
PII S0738-081X(00)00147-4
Clinics in Dermatology
570 PORTER ET AL.
Table 1.
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2000;18:569 –578
Characteristics of the Different Types of Recurrent Aphthous Stomatitis
Sex ratio
Age of onset (years)
Number of ulcers
Size of ulcers (mm)
Duration (days)
Rate of recurrence (months)
Sites
Permanent scarring
Minor
Major
Herpetiform
M⫽F
5–19
1–5
⬍10
4–14
1–4
Lips, cheeks, tongue,
floor of mouth
Uncommon
M⫽F
10–19
1–10
⬎10
⬎30
⬍Monthly
Lips, cheeks, tongue,
palate, pharynx
Common
F ⬎ M(?)
20–29
10–100
1–2*
⬍30
⬍Monthly
Lips, cheeks, tongue, pharynx,
palate, gingiva, floor of mouth
Uncommon
* Can be larger if there is a fusion of ulcers.
ficiency, sometimes reticulin antibodies,50 particularly
IgA class reticulin antibodies52 and/or antigliadin antibodies.53 The haplotype of HLA-DRW 10 and DQW1
may predispose patients with GSE to RAS.54 There may
also be occasional patients who have RAS with no
detectable clinical or histological evidence of celiac disease on jejunal biopsy, yet who may respond to dietary
withdrawal of gluten.55,56 Nevertheless, the withdrawal
of gluten rarely results in significant benefit60 and may
simply reflect the pronounced placebo response in
RAS.57 Anti-endomysial antibodies are rarely present in
patients with RAS,58 thus adding weight to the evidence
that RAS is not commonly associated with GSE. Patients with Crohn’s disease can have superficial ulceration similar to that of RAS.59
Food Hypersensitivities
Some studies have noted an increased prevalence of
atopy among RAS patients,60,61 but others have failed to
find any significant correlation.62 Some patients correlate the onset of their ulcers to exposure to certain
foods, but controlled studies have failed to disclose a
causal role despite the fact that certain foods triggering
positive skin-prick reactions will elicit pain when they
are topically applied to aphthous ulcers.63,64 Dietary
manipulation significantly improves RAS in only rare
instances.65
Zinc Deficiency
Any association between RAS and zinc deficiency
seems tenuous.66
Menstrual Change
A minority of women with RAS have cyclical oral ulceration related to the luteal phase of the menstrual
cycle. Nevertheless, a detailed review of all pertinent
literature failed to find any association between RAS
and altered female sex corticosteroids.67–70 A link with
autoimmune progesterone dermatitis is most unlikely.71
Psychological Illness
Psychological illness has been proposed to initiate some
episodes of RAS, but there are sparse data to suggest a
strong link between psychological stress and RAS, or
that RAS causes significant psychological upset.72–76
Genetic Factors
Recurrent aphthous stomatitis may have a familial basis, perhaps more than 40% of RAS patients having a
vague family history of oral ulceration. Patients with a
positive family history of RAS may develop oral ulcers
at an earlier age and have more severe symptoms than
those with no such history.77,78 There is an increased
likelihood of a child developing RAS if both parents
have ulcers, and there is a high correlation of RAS in
identical twins.79,80 Nevertheless, no consistent significant association between RAS and a particular serologically determined HLA antigen or haplotype has been
demonstrated (reviewed elsewhere).5 This may reflect
inadequate patient numbers and/or variable ethnic
backgrounds of investigated patients, or most likely the
lack of any immunogenetic basis to RAS.
Possible Infectious Basis of RAS
Bacteria
An association between RAS and oral (viridans) streptoccocci has long been suggested as important in the
pathogenesis of RAS, the bacteria acting either as direct
pathogens or as antigenic stimuli culminating in an
immunologically mediated cross-reaction with keratinocyte antigenic determinants.81,82 The initial l-form isolated from RAS patients was typed as Streptococcus
sanguis,83 but later analysis disclosed that this organism
was actually a strain of S. mitis,84 or rather S. oralis,85 a
bacterium frequently present in the dental plaque of
patients with Behcet’s disease.86 In addition, although
some studies have disclosed elevated serum antibody
titers to viridans streptococci among RAS patients, others have yielded contradictory results.87,88 Lymphocyte
mitogenic responses to S. sanguis and S. mitis in RAS
patients are not significantly different from those in
control subjects.88 –90 Polymerase chain reaction (PCR)
studies have also indicated that S. oralis is not specific to
RAS, and thus unlikely to be of etiological significance.91
Clinics in Dermatology
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It has been suggested that there is a molecular basis
for the earlier work suggesting a link with S. sanguis, as
monoclonal antibodies to part of the 65-kDa heat-shock
protein (hsp) of Mycobacterium tuberculosis cross-react
with S. sanguis. Thus RAS may be a T-cell-mediated
response to antigens of S. sanguis that cross-react with
the mitochondrial hsp and induce oral mucosal damage.92–94 In the absence of data showing a high frequency of a specific streptococcal infection in RAS patients, however, this proposed etiological mechanism
seems unlikely.
Helicobacter pylori has been detected in lesional tissue
of ill-defined oral ulcers95 and by PCR in up to 72% of
examined RAS ulcers96; however, the frequency of serum IgG antibodies to H. pylori is not increased in
RAS.97
RECURRENT APHTHOUS STOMATITIS
Table 2. Some Reported Therapies of Recurrent Aphthous
Stomatitis (RAS)
Mouthrinses
Topical corticosteroids
Antibiotics
Immunomodulators
Viruses
An association of RAS with adenoviruses has been
suggested,98 –100 but adenoviruses are ubiquitous organisms. The possible association of RAS with herpesviruses-1– 6 is reviewed elsewhere.101 Herpesvirus virions
are not demonstrable in RAS,102–105 and although RNA
complimentary to herpes simplex virus (HSV) has been
detected in circulating mononuclear cells in some RAS
patients106 and in circulating immune complexes,107 serum levels of interferon are not increased,108 HSV is not
demonstrable in RAS lesions,109,110 and RAS patients are
not always HSV seropositive.111
There is contradictory serological and molecular biological data on the frequency of detection of cytomegalovirus and varicella zoster infection in patients with
RAS,112–115 and there is little substantive data to suggest
that anti-herpesvirus antivirals such as acyclovir are of
therapeutic benefit in the management of RAS.116,117
An association between Epstein-Barr virus (EBV)
and the early ulcerative lesions of RAS and Behcet’s
disease has been proposed, but the data are based upon
a very small group of patients.118 Human herpesvirus-6
(HHV-6) DNA has not been detected in 6 of 21 RAS
lesions115 and 95% of the patients had IgM antibodies to
HHV-6,114 but both HHV-6 and HHV-7 DNA are rarely
detected in peripheral blood moncytes of RAS patients
with and without ulceration.119
Local Factors Associated With RAS
Local physical trauma may initiate ulcers in people
susceptible to RAS,120,121 and RAS are uncommon on
keratinized surfaces122,123 or in patients who smoke tobacco.124 –127
Immunopathogenesis
A review of the immunology and possible pathogenesis
of RAS is beyond the scope of this clinical review. A
detailed discussion of this subject can be found elsewhere.5
571
Others
Chlorhexidine gluconate
Benzydamine hydrochloride
Carbenoxolone disodium
Betadine
Hydrocortisone hemisuccinate
Triamcinolone acetonide
Flucinonide
Betamethasone valerate
Betamethasone-17-benzoate
Flumethasone pivolate
Beclomethasone dipropionate
Sucralphate
Topical tetracyclines
Levamisole
Transfer factor
Colchicine
Gammaglobulins
Azathioprine
Dapsone
Thalidomide
Pentoxifylline
Prednisolone
Azelastine
Alpha-2-inteferon
Cyclosporine
Amlexonox
5-Aminosalicyclic acid
Systemic zinc sulphate
Monoamine-oxidase inhibitors
Sodium cromoglycate
Deglycyrrhizinated licorace
Etretinate
Low-energy laser
Management of RAS
A systematic review of the management of RAS is
available.128 Patients with oral ulceration possibly associated with systemic disease require referral to an appropriate specialist.5 All patients should be advised to
use an oral hygiene procedure that is as atraumatic as
possible, and all dental appliances should fit well and
be non-tissue-damaging.
Hematinic Replacement
The correction of any hematinic deficiency is of limited
benefit unless the cause is corrected.129 Zinc sulphate
therapy is not effective,130 and LongoVital®, a herbalbased vitamin tablet with a wide range of trace elements, seems to be of limited benefit.131
Topical Antimicrobials
Chlorhexidine used as a 0.2% w/w mouthrinse or 1%
gel can reduce the duration of ulcers and increase the
number of ulcer-free days.132–135 (Table 2) One study,
however, found little objective value of chlorhexidine
gluconate mouthrinse over placebo in the management
of RAS.136 Regular use of chlorhexidine gluconate may
Clinics in Dermatology
572 PORTER ET AL.
cause exogenous dental staining, and the bitter taste
may limit compliance.
Topical tetracyclines (eg, aureomycin, chlortetracycline, and tetracycline) may reduce healing times
and/or reduce the associated pain of RAS,137–141 but
they may cause dysgeusia, oral candidosis, and a burning-like sensation of the pharynx, and they are not
suitable for young children who might ingest them,
with resultant tooth staining.
Topical Corticosteroids
Topical corticosteroids remain the mainstay of RAS
treatment in most countries,142 although there are few
well-controlled studies of their precise efficacy.128 A
wide range of different topical corticosteroids may reduce symptoms.143–150
Topical Analgesics
Benzydamine hydrochloride mouthwash is of no more
benefit on ulcer healing than placebo194; nevertheless, it
(or lignocaine gel) can produce transient relief of pain.
Toothpastes
Toothpastes that enhance the salivary peroxidase system are not effective.141,151,152 It has been suggested that
elimination of sodium lauryl sulphate (SLS) can reduce
or prevent RAS,153 but although one later study confirmed this,154 another did not.155
Other Topical Agents
Sodium cromoglycate lozenges may provide mild
symptomatic relief,156,157 but cromoglycate-containing
toothpaste is of no benefit.158 Carbenoxolone sodium
mouthwash reduced the severity of RAS in one
study.159
Topical immunomodulatory agents that have been
suggested to be of some benefit in the management of
RAS include azelastine,160 human alpha-2-interferon in
cream,161,162 topical cyclosporine,163 deglycyrrhizinated
licorice,164 topical 5-aminosalicylic acid (5-ASA),165 and
prostaglandin E2 (PGE2) gel.166 There have been several
studies of the efficacy of amlexanox in the management
of RAS,167–169 including one detailed randomized controlled study168 suggesting that the 5% paste may significantly reduce the pain and time of healing of RAS
ulceration.
A cross-over study found that sucralfate reduced the
duration of symptoms and improved duration of remission of RAS.170 A previous study did not report sucralfate to be clinically useful,171 although a recent investigation of Italian patients suggested that 20% sucralfate
is of some benefit in reducing the symptoms of RAS.172
Cimetidine has found favor with some workers128.
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Physical Therapies
Surgical removal, debridement, or laser ablation of ulcers is not practical and is of very limited practical
benefit.173–175 The efficacy of a chemical cautery agent
(Debacterol) is unclear.176
Systemic Therapies
Systemic immunosuppression is sometimes warranted
in view of the limited efficacy of topical agents, and the
sometimes profound pain and/or long-standing ulceration; however, whereas many such agents have been
proposed to be clinically useful, there is little evidence
base.
Prednisolone and/or Azathioprine
Systemic prednisolone177 and azathioprine178 have been
suggested to be effective, but there are no detailed
published studies on their precise clinical benefits.
Levamisole
Levamisole rarely causes objective clinical improvement,179 and the associated adverse effects (nausea, hyperosmia, dysgeusia, and agranulocytosis) discourage
its use.180 –186
Colchicine
Colchicine has proved clinically beneficial when investigated in small groups of patients with RAS,187,188 and
in an open study of 20 patients, colchicine (1.5 mg/day
for 2 months) caused a significant reduction in pain
scores and frequency of self-reported ulcers.189 Unfortunately, not all patients benefit from colchicine therapy, and at least 20% can have painful gastrointestinal
symptoms or diarrhea.189 Long-term use can induce
infertility in young men. Combined colchicine and thalidomide therapy may occasionally benefit recalcitrant
RAS.190
Pentoxifylline
Results of limited open studies suggest that pentoxifylline (400 mg three times daily) may significantly reduce
the number of RAS for up to 9 months after a month of
therapy.191–195 The results of a recent study, however,
did not confirm that pentoxifylline reduces the recurrence of RAS when therapy is stopped.196 About 10% of
patients will have some degree of gastrointestinal upset
with pentoxifylline therapy.
Dapsone
Dapsone has been reported to reduce the oral lesions in
a few patients with RAS-like lesions, but the clinical
features of this group of patients were poorly described.197
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RECURRENT APHTHOUS STOMATITIS
Thalidomide
Thalidomide remains the most effective agent for the
management of RAS, producing a remission in almost
50% of treated patients in one randomized controlled
trial.198 Open and double-blind studies of patients with
HIV-related oral ulceration199,200 and in non-HIV-related RAS,201 and in several case studies, all confirm
that thalidomide is of clinical benefit.202–204 Thalidomide gives rise to mild adverse side effects (eg, intolerance, loss of libido) in up to 75% of treated patients,
and polyneuropathy can arise in about 5% of cases.
Clearly the risk of teratogenicity also limits the clinical
application of thalidomide in the management of RAS.
Other Agents
Transfer factor205 and gammaglobulin therapy206 have
been suggested to be beneficial, but more detailed studies are needed to confirm these preliminary observations.
The reported clinical benefit of monoamine oxidase
inhibitor therapy in the treatment of three patients with
RAS207,208 was probably due to accompanying dietary
modifications rather than any alteration in psychological status.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Conclusions
Recurrent aphthous stomatitis remains a common oral
mucosal disorder in most communities of the world;
however, as its precise etiology (or etiologies) remains
unknown, therapy is nonspecific and often of limited
efficacy. Fortuitously, patients with RAS are generally
otherwise quite well.
17.
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