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clinical practice

Aphthous Ulceration
Crispian Scully, M.D., Ph.D., M.D.S.

This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the author’s clinical recommendations.

A 20-year-old woman has had recurrent painful mouth ulcers for the past 10 years.
She is otherwise healthy and reports no genital or anal ulcers, skin lesions, gastroin-
testinal or joint problems, or fevers. Physical examination reveals several ulcers, 3 mm
in diameter, on her buccal mucosae. She has no lesions on the skin or on other muco-
sal surfaces. How should she be evaluated and treated?

The Cl inic a l Probl e m

Recurrent aphthous stomatitis (also referred to as aphthae, or canker sores) is one From the Eastman Dental Institute, Univer-
of the most common oral ailments. The disease is characterized by recurring pain- sity College London, London. Address re-
print requests to Dr. Scully at the Eastman
ful ulcers of the mouth that are round or ovoid and have inflammatory halos. The Dental Institute, University College London,
ulcers typically appear first in childhood (patients often have a family history of 256 Gray’s Inn Rd., London WC1X 8LD,
recurrent aphthous stomatitis) and tend to abate around the third decade.1,2 The United Kingdom, or at c.scully@eastman.
ucl.ac.uk.
term “recurrent aphthous stomatitis” should be reserved for recurrent ulcers con-
fined to the mouth and seen in the absence of systemic disease. However, ulcers N Engl J Med 2006;355:165-72.
that resemble recurrent aphthous stomatitis in some respects, such as their clinical Copyright © 2006 Massachusetts Medical Society.

appearance, can be found in systemic disorders such as Behçet’s syndrome, gastro-

intestinal diseases such as gluten-sensitive enteropathy or inflammatory bowel dis-
ease, and immunodeficiency syndromes such as infection with the human immu-
nodeficiency virus (HIV) or cyclic neutropenia. If these ulcers do not have all the
typical clinical characteristics or an onset in childhood, they are often termed “aph-
thous-like ulcers.” This review focuses on the evaluation of patients presenting with
recurrent oral ulcers and the management of such ulcers in the absence of sys-
temic disorders.
Approximately 80 percent of patients with recurrent aphthous stomatitis pre-
sent with minor aphthous ulcers. These are 2 to 8 mm in diameter, affect nonke-
ratinized mucosae such as the labial and buccal mucosae and the floor of mouth
or the ventral surface of the tongue (Fig. 1), are rarely seen on the dorsum of the
tongue or on the hard palate or gingiva, and heal spontaneously in 10 to 14 days.3
Much less common are major aphthous ulcers (sometimes termed “periadenitis mu-
cosa necrotica recurrens”). These ulcers are larger than minor ulcers — often 1 cm
or more in diameter (Fig. 2). A third and even less common variety is termed
“herpetiform ulceration” (unrelated to herpetic stomatitis) and comprises ulcers
that are initially multiple and pinpoint. Both major and herpetiform ulcers are
more likely than minor ulcers to lead patients to seek professional help, since these
ulcers are particularly painful, last several weeks, and can affect the dorsum of the
tongue and the hard palate, as well as the buccal and lip mucosae.
Cross-sectional studies suggest that recurrent aphthous stomatitis is more com-
mon in women, in people under the age of 40 years, in whites, in nonsmokers, and
in people of high socioeconomic status.4-6 Recurrent aphthous stomatitis affects

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 The n e w e ng l a n d j o u r na l of m e dic i n e

B
Figure 1. Minor Aphthous Ulcer on the Lateral Margin
of the Tongue.
The ulcer is small and round, with an erythematous
halo (arrowhead).

up to 25 percent of the general population at

some time.
Both hereditary7 and environmental causes of
the disease have been suggested. Deficiencies of
iron, vitamin B, or folate have been reported in Figure 2. Major Aphthous Ulceration.
some patients with recurrent aphthous stomati- Panel A shows a large ulcer on the ventral surface
tis,8-12 but the data are conflicting,13 and neither of the tongue (arrowhead). Panel B shows pronounced
iron nor vitamin supplements reliably increase scarring of the fauces.
the likelihood of ulcer resolution.10,12,14 Infec-
tion with various microorganisms has been sug- identify than subsequent episodes, but a family
gested but not proven to be a contributing fac- history of the disease may suggest that diagno-
tor, although cross-reactions between a microbial sis. In addition, although most cases of recurrent
antigen and a homologous peptide within the oral aphthous stomatitis are idiopathic, a careful his-
epithelium may play a role.15 tory taking and physical examination should be
Various factors have been suggested to precipi- performed to rule out a secondary cause (Table 1).
tate outbreaks of recurrent aphthous stomatitis This step is particularly important in atypical cas-
in predisposed persons, including oral trauma, es, such as those in which the ulceration begins
the cessation of smoking 4,16 (for reasons that are after adolescence or if lesions affect sites other
unclear), anxiety or stress,17 sensitivities to food than the oral mucosa.
(e.g., to preservatives and agents such as benzoic Features such as persistent diarrhea that are
acid or cinnamaldehyde), and hormonal changes suggestive of systemic disease should raise the
related to the menstrual cycle.18 However, evidence possibility of Crohn’s disease or ulcerative coli-
to support the causative role of these factors is tis.20 Weight loss or other signs of malabsorption
scarce. may suggest gluten-sensitive enteropathy, although
this disease was present in less than 5 percent of
S t r ategie s a nd E v idence patients with recurrent aphthous stomatitis who
attended a hospital clinic.12,21 (In rare instances,
Evaluation patients with recurrent aphthous stomatitis have
The diagnosis of recurrent aphthous stomatitis no detectable histologic evidence of gluten-sen-
rests mainly on two features: a history of recur- sitive enteropathy, yet they appear to have a re-
rent ulcers since childhood (though a small num- sponse to the exclusion of gluten from the diet22;
ber of cases first appear at a later age) and the this apparent response may reflect a placebo ef-
presence of the typical multiple round or ovoid fect.) The presence of genital ulceration should
ulcers on examination. The first episode of re- raise the suspicion of Behçet’s syndrome or the
current aphthous stomatitis is more difficult to possibly related condition, complex aphthous sto-

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 clinical pr actice

Table 1. Differential Diagnosis of Recurrent Mouth Ulcers.

Cause Examples Suggestive Findings Basis of Diagnosis

Unknown Aphthae A history of recurrent round or ovoid mouth ulcers Clinical presentation and the ex-
since childhood clusion of systemic illnesses
Periodic fever, aphthae, A history of recurrent mouth ulcers since childhood; Clinical presentation and the
pharyngitis, and adenitis recurrent fever, pharyngitis, lymphadenitis exclusion of other systemic
Tumor necrosis factor recep- illnesses
tor–associated periodic
syndrome
Infections Recurrent infection with A history of recurrent localized ulcers, sometimes Clinical presentation and viro-
herpesvirus* aphthous-like, usually on the palate or tongue, logic studies
generally at the same site in each episode, often
appearing after oral trauma; may be evidence of
immunocompromised state
HIV infection Intraoral infections (candidiasis, hairy leukoplakia) Clinical presentation and HIV
or neoplasms (Kaposi’s sarcoma, lymphoma); testing
other clinical evidence of or risk factors for HIV
infection
Rheumatic Behçet’s syndrome Aphthous-like ulcers occurring on genital or other mu- Clinical presentation and sero-
diseases cosae; skin pustules, erythema nodosum, or other logic testing to rule out other
lesions; uveitis; joint involvement; central nervous conditions
system manifestations
Reactive arthritis (Reiter’s Urethritis; colitis; keratoderma blennorrhagicum; Serologic testing to rule out
syndrome) conjunctivitis; balanitis; joint and other involve- other conditions
ment; usually found in men
Sweet’s syndrome Red plaques on skin; fever; aphthous-like ulcers on Serologic testing to rule out
genital or other mucosae; often associated with other conditions
other conditions (e.g., inflammatory bowel dis-
ease, leukemia)
Cutaneous Erythema multiforme Lesions on mucosae other than oral or on skin or Clinical presentation and biopsy
diseases† eyes; lip swelling of perilesional tissue
Hematologic Cyclic neutropenia Recurrent fevers; associated intraoral and other Clinical presentation and com-
diseases recurrent infections; onset in childhood or plete blood count
adolescence
Leukemias Infections; anemia; petechiae or purpura Complete blood count
Gastrointestinal Gluten-sensitive enteropathy Dental defects; malabsorption; bloating; diarrhea; Clinical presentation; presence
diseases weight loss of antigliadin and transglu-
taminase antibodies; biopsy
of small intestine
Inflammatory bowel disease Labial or facial swelling; bloody diarrhea; weight loss; Clinical presentation and colo-
(ulcerative colitis, Crohn’s occasionally, joint manifestations; hepatobiliary noscopy or biopsy of ulcer
disease) disease tissue
Drugs Nonsteroidal antiinflamma- Rash History and response to drug
tory drugs withdrawal
Beta-blockers
Nicorandil (Ikorel)
Alendronate (Fosamax)

* In rare instances, cytomegalovirus infection may have a similar presentation in immunocompromised patients.
† The early phages of pemphigus may be characterized by recurring ulcers.19

matitis; it is rare for patients apparently present- or manifestations of HIV infection.27 Table 1 lists
ing with recurrent aphthous stomatitis subse- several systemic conditions that may result in
quently to be found to have Behçet’s syndrome.23-26 aphthous-like ulcers and features that suggest
Joint pain or swelling or urethritis suggests the them.19-33
possibility of a syndrome of reactive arthritis (for- Medications should also be reviewed. A case–
merly known as Reiter’s syndrome), which is an control study has shown that aphthous-like ul-
associated condition. The history taking and ex- ceration is associated with nonsteroidal antiin-
amination should also focus on risk factors for flammatory agents and various beta-blockers.31

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Other drugs linked in observational studies to ulcers caused by conditions other than aphthous
aphthous ulceration include those that damage stomatitis.
neutrophils (such as cytotoxic agents), as well as
nicorandil32 and alendronate.33 Sodium lauryl Investigations
sulfate, a component of many toothpastes and If the results of the history taking and examina-
other products, may also occasionally predispose tion are characteristic of recurrent aphthous sto-
people to aphthous ulceration; although some matitis, routine laboratory testing is probably not
data have suggested a reduced incidence of ulcer- warranted, since such testing is ineffective for
ation when the patient stops using the product, identifying treatable disorders of this type. Some
a double-blind crossover trial showed no signifi- experts advocate the performance of a complete
cant effect of excluding toothpaste containing blood count and measurement of the levels of red-
sodium lauryl sulfate on the incidence or pattern cell folate, serum vitamin B12, and serum ferritin,
of aphthous ulceration.34 although data in support of routine testing are
Any ulcer that persists for three or more weeks, lacking. This approach is more likely to be useful
whether painful or not, requires further evalua- if other findings suggest a nutritional deficiency
tion to rule out cancer, infection (e.g., with herpes or a hematologic disorder.
simplex virus or cytomegalovirus, particularly in A biopsy should be considered for solitary or
immunocompromised patients, and syphilis, tu- multiple ulcers that last more than three weeks.
berculosis, a deep mycosis, or leishmaniasis), and Immunostaining is mandatory if a mucocutane-
other serious disorders, such as vasculitis. Clini- ous disorder is suspected. The need for additional
cal signs suggestive of cancer include associated analyses, such as serologic tests for rheumato-
swelling or induration and a red or white lesion logic disease, cultures or other specific tests for
such as leukoplakia, especially if there is ipsilat- infectious agents (such as herpes simplex virus,
eral cervical lymphadenopathy.35 Chronic ulcer- cytomegalovirus, or HIV), and evaluation for gas-
ation may also indicate an underlying mucocuta- trointestinal disease, should be guided by the pres-
neous disease such as lichen planus, pemphigus, ence of features suggestive of these disorders.
or pemphigoid; on examination, these can gen-
erally be distinguished from recurrent aphthous Treatment
stomatitis, since the ulcers tend not to have the The treatment choices should be guided by the
characteristic ovoid or round shape or clearly de- severity of the disease (the amount of pain), the
fined outlines. Figure 3 shows examples of oral frequency of ulceration, and the potential adverse

A B C

D E

Figure 3. Oral Ulcers Caused by Conditions Other Than Aphthous Stomatitis.

Panel A shows lichen planus with a superficial irregular erosion on the lip (arrowhead). Panel B shows pemphigus
on the buccal mucosa, with irregular ulceration (arrowhead). Panel C shows pemphigoid on the gingiva (arrowhead), caus-
ing erosion. Panel D shows lupus erythematosus with irregular ulceration on the buccal mucosa (arrowhead). Panel E
shows squamous-cell carcinoma on the buccal mucosa in the form of a mass that has ulcerated (arrowhead).

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 clinical pr actice

effects of the medications. In the absence of a trial demonstrated a significant reduction in the
clearly defined cause, the treatment is aimed pri- duration of multiple ulcers with the use of be-
marily at pain relief and the reduction of inflam- tamethasone aerosol four times daily for 4 to
mation. If an underlying disorder is present, effec- 8 weeks (means, 8.5 days in the active group vs.
tive treatment of the condition may result in the 15.0 days in the placebo group).41 However, these
remission or amelioration of the ulcers, but the and other, more potent topical corticosteroids are
interventions discussed below may help in the in- not readily available in oral pastes (and thus are
terim before diagnosis. Referral to a specialist unlikely to remain on the oral mucosa). A risk of
is indicated if cancer is suspected, if there is evi- any of these therapies is oral candidiasis, and a
dence of an associated systemic disease, or if ul- concern is the systemic absorption of the drug
ceration is severe (particularly painful, frequent, through ulcerated oral mucosa.
or disabling). Antimicrobial mouthwashes may also bene-
fit patients with recurrent aphthous stomatitis.
Minor Ulcers Mouthwashes containing chlorhexidine gluco-
For the management of minor aphthous ulcers, nate (Peridex, Periogard, Corsodyl) or triclosan
patients should avoid oral trauma (for example, (Plax, Total) inhibit the accumulation of bacterial
from hard toothbrushes or foods such as toast) plaque on teeth and improve oral hygiene; they are
and acidic foods or drinks that may exacerbate approved for use in the treatment of periodontal
pain or perhaps precipitate ulcers.1 Although nico- disease but not for aphthous stomatitis. The data
tine-replacement therapy may help people whose from some, but not all, randomized trials support
ulcers arise on smoking cessation, only a small the benefit of such mouthwashes. In one trial, for
open-label trial showed a benefit.36 Clinical ex- example, patients using a 0.2 percent chlorhex-
perience suggests that topical analgesics (such as idine gluconate mouthwash three times daily
benzydamine or lidocaine) and protective bioad- for 6 weeks had significantly longer ulcer-free
hesives (such as carmellose or cyanoacrylate37) periods (mean, 22.9 days) than patients who
can help relieve pain,1 although data from clini- received a placebo (mean, 17.5 days).42 Chlorhex-
cal trials are limited. idine gluconate mouthwashes interact with tan-
Randomized clinical trials support the use of nins to stain the teeth brown, although patients
some topical treatments to speed healing and re- can reduce this staining by brushing their teeth
duce pain38 (Table 2). These therapies are main- before using the mouthwash and by minimizing
ly used for aphthae that recur more often than their intake of tea, coffee, and red wine. In a dou-
monthly and for any ulcers that are bothersome. ble-blind crossover trial, 0.15 percent triclosan
However, much of the evidence in support of mouthwashes (three preparations differing in
these interventions is from small and incompletely the solubilizing agent) used twice daily over a
blinded trials, and the efficacies of the interven- period of six weeks resulted in significantly fewer
tions are generally modest. new ulcers (166 to 211 total) in the three triclosan
Topical corticosteroids may speed the healing groups than in the placebo group (290 total).43
of ulcers and reduce pain. The Food and Drug One double-blind trial also suggested that the use
Administration (FDA) has approved 1 percent tri- of Listerine mouthwash reduced the duration of
amcinolone dental paste (Adcortyl or Kenalog in lesions and associated pain.44 Tetracycline mouth
Orabase) for the relief of symptoms of any in- rinse (for example, the contents of a 100-mg dox-
flammatory condition in the mouth. Other, more ycycline capsule dissolved in 10 ml of water by
potent topical corticosteroids or other related the patient and used as a rinse four times daily)
preparations (such as a 2.5-mg lozenge of hydro- may also benefit patients; its adverse effects may
cortisone, taken four times daily for two weeks1,39) include tooth discoloration — if swallowed by a
may be useful, although they are not specifically child — or local discomfort from candidiasis,
approved for this indication. In a single-blind tri- particularly with prolonged use.
al, patients with recurrent aphthous stomatitis Five percent amlexanox paste (Aphthasol,
who were randomly assigned to receive topical Aphtheal) is a topical antiinflammatory treatment
0.05 percent fluocinonide in Orabase up to five that is approved by the FDA for aphthous ulcer-
times daily for 6 weeks had a mean ulcer dura- ation. In one small placebo-controlled, double-
tion of 4.9 days, as compared with 7.8 days in blind trial, patients receiving amlexanox (applied
the placebo group.40 A randomized, double-blind by the investigators twice daily for three days)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Therapies to Consider for Recurrent Aphthous Stomatitis.

Route of Possible Adverse Effects,

Drug Administration Examples Contraindications, or Comments
Preparation Application or Dose
Mild disease*
Topical Topical 0.15% Benzydamine oral rinse Applied to ulcers 4 times Occasional numbness or stinging;
anesthetics† (Difflam, Tantum) daily for 2 wk or until rare hypersensitivity reactions
5% Lidocaine gel or viscous ulcers heal
Xylocaine
Protective Topical Carmellose (Orabase: pectin Applied to ulcers 4 times Possible religious objections to the
bioadhesives plus gelatin) daily for 2 wk or until use of gelatin in carmellose
ulcers heal
CorticosteroidsठTopical, in ad- 1% Triamcinolone dental paste Applied to ulcers 4 times Oral candidiasis (addition of anti-
hesive base (Adcortyl or Kenalog in daily for 2 wk or until fungal agents to more potent
(carmellose), Orabase) ulcers heal corticosteroids recommended
or as spray, Hydrocortisone, 2.5 mg pellets because of this possible risk)
cream, or (Corlan) Possible religious objections to the
pellet 0.05% Fluocinonide cream use of gelatin in carmellose
(Metosyn)
Antimicrobial Topical 0.12% or 0.2% Chlorhexidine 4 times daily for a vari- Superficial tooth staining (mitigated
mouth rinsesঠgluconate aqueous mouth- able duration (2 wk by reducing intake of coffee, tea,
wash (e.g., Peridex) or 1% to months or longer) and red wine)
chlorhexidine gluconate gel
Amlexanox Topical A 5% preparation in an Applied to ulcers 4 times Stinging
(Aphthasol)‡ adhesive base daily for 2 wk or until
ulcers heal
Severe disease*
Corticosteroids Systemic Tablet or capsule Orally 30 to 60 mg for Increased blood pressure; hypergly-
1 wk, followed by cemia; other effects of cortico-
a 1-wk taper steroid excess
Thalidomide Systemic Tablet Orally 50 to 200 mg daily Teratogenesis (contraindicated in
(Thalomid)‡∥ for 4 to 8 wk pregnancy); neuropathy (moni-
toring of sensory-nerve action
potentials every 3 mo recom-
mended); drowsiness

* Mild disease refers to minor aphthous ulcers recurring frequently or considered sufficiently bothersome to warrant intervention. Severe dis-
ease refers to painful persistent ulcers — typically major ulcers.
† Alternatives include Maalox (a suspension containing aluminum hydroxide, simethicone, and magnesium hydroxide) used as swish and spit.
‡ The value of this agent is supported by data from randomized trials.
§ Triamcinolone dental paste can be effective if applied to a dried ulcer, but it rarely adheres to ulcers on the tongue; in the latter cases, another
formulation should be used, such as hydrocortisone pellets. More potent corticosteroids — such as 500 μg of betamethasone (Betnesol) in
a soluble tablet dissolved in 10 ml of water and used as a mouthwash four times daily — are alternatives but are not approved for this use.
¶ An alternative in more refractory cases is tetracycline–doxycycline mouthwash (e.g., the contents of a 250-mg capsule of tetracycline or a
100-mg capsule of doxycycline dissolved into 10 ml of water and used as a rinse four times daily for three days). The risks include tooth
discoloration, if swallowed by a child, and candidiasis. This alternative should not be used by children under eight years of age, pregnant
women, or women who are breast-feeding.
∥ This drug is not approved by the FDA for this use and should be considered only in extreme cases of recurrent aphthous stomatitis or aph-
thous-like ulcers (particularly in association with HIV infection or Behçet’s syndrome).

had a significantly greater reduction in ulcer size an ulcer was evident. The likelihood of having an
on day 5 than did patients receiving placebo (me- ulcer by day 3 was significantly lower in the early-
dian reduction, 76 percent vs. 40 percent) and use group (35 percent) than in the late-use group
their ulcers were more likely to be rated by the (97 percent). Early treatment with amlexanox also
investigators as having improved, although chang- reduced the size, associated pain, and duration of
es in pain ratings did not differ significantly be- the ulcers, as compared with late therapy or with
tween the two groups. Another randomized trial a no-treatment run-in phase. However, the study
compared the use of amlexanox (applied four was limited by the lack of a placebo group.45,46
times daily to the affected area) during the pro- Head-to-head comparisons of different agents
dromal phase of ulcer symptoms with its use once are limited38 and have failed to demonstrate the

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 clinical pr actice

superiority of a particular agent over others. For the interventions are limited. Other medications
example, one small study comparing topical cya- (such as levamisole, colchicine, and pentoxifyl-
noacrylate alone and cyanoacrylate applied over line) have been suggested for the treatment of
0.025 percent triamcinolone acetonide or 0.012 more refractory cases, but limited data are avail-
percent chlorhexidine gluconate showed no dif- able to support their effectiveness. Further study
ferences in ulcer duration among the treatment is needed to guide the management of this dis-
groups.47 These agents have not been well stud- ease better.
ied in combination.
Guidel ine s
Severe Aphthous Stomatitis
For patients with severe recurrent aphthous sto- Recommendations for the management of recur-
matitis, possible therapies include systemic cor- rent aphthous stomatitis are available from Prod-
ticosteroids or thalidomide.26 A one-week course igy Guidance of the U.K. Department of Health
of 30 to 60 mg of oral prednisone or oral pred- (www.prodigy.nhs.uk/aphthous_ulcer) and from
nisolone (tapered over a second week) has been the U.S. National Guideline Clearinghouse (www.
used in practice, although data that demonstrate ngc.gov). The recommendations in this review
a greater efficacy than with topical corticoste- are consistent with these guidelines.
roids are lacking and there is an increased risk of
adverse effects. In a randomized trial of patients Sum m a r y a nd R ec om mendat ions
with severe recurrent aphthous stomatitis, 45 per-
cent of those treated with 100 mg of thalidomide The presentation of the patient in the vignette is
daily for two months had fewer ulcers or none at consistent with recurrent aphthous stomatitis,
all (but only while taking the medication), as based on the history of recurrent ulcers since child-
compared with 3 percent of patients given pla- hood, the examination showing typical round or
cebo.48 Thalidomide (200 mg daily) was likewise ovoid ulcers, and the lack of clinical evidence of
effective in a randomized trial of patients with any drug-related or systemic cause. I would rec-
HIV infection who had aphthous-like ulcers.49 ommend the avoidance of oral trauma and acidic
Open-label studies suggest that thalidomide may foods and drinks. Topical therapy such as lidocaine
also be effective at a lower dose (50 mg daily).50 or protective bioadhesives might be helpful. On
Serious adverse effects — including neuropathy the basis of the data available from randomized,
and teratogenesis — are possible, however, and controlled trials, I would also recommend treat-
thalidomide is not approved by the FDA for the ment with topical corticosteroids in a paste, or
treatment of aphthous ulcers, so it should be used 5 percent amlexanox paste (typically for two weeks
cautiously and only in extreme cases. or until the ulcers heal), or treatment with a mouth
rinse such as chlorhexidine gluconate, since these
A r e a s of Uncer ta in t y may speed healing and reduce pain. I would re-
peat this treatment as needed if the ulcers recur.
The cause of recurrent aphthous stomatitis re- No potential conflict of interest relevant to this article was
mains unclear. Randomized, controlled trials of reported.

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