Oral Maxillofacial Surg Clin N Am 15 (2003) 111 – 122
Diagnosis and treatment of recurrent aphthous stomatitis
Ellen Eisenberg, DMD
Division of Oral and Maxillofacial Pathology, University of Connecticut School of Dental Medicine,
University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
What is recurrent aphthous stomatitis (RAS)? Is it
appropriate to regard it as an infectious disease? Are
there effective measures for managing aphthous
ulcers? These are just a few of the questions that
are continually asked about this benign but highly
symptomatic oral problem.
Although it is one of the most common recurrent
oral ulcerative conditions of adults and children
recognized throughout the world, RAS is also one
of the least understood oral diseases and is among the
most vexing problems faced by affected patients and
clinicians alike [1]. The triggering factors that pre-
cipitate recurrent episodes in RAS patients seem to be
as diverse and unique as the affected individuals
themselves [2], which has posed a challenge for
scientists in their attempts to identify a specific
causation for this disease. Although the origin of
RAS remains obscure, there is growing lucidity with
regard to its pathogenesis, and that enlightenment has
influenced contemporary approaches to its manage-
ment significantly [3].
Etiology and pathogenesis
Historically, conjecture about the origin of RAS
focused on a wide spectrum of potential local and
systemic factors that encompassed microbial agents,
hematologic and hormonal disturbances, physical
injury, emotional stress, and other influences [4]. To
date, however, despite years of collective effort on the
part of many researchers, the precise cause of RAS
continues to elude disclosure. Also confounding the
search for a singular cause is the observation that
E-mail address: eeisenberg@nso2.uchc.edu
1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 0 - 5
aphthous-like oral ulcers often occur in conjunction
with diverse conditions of a systemic nature. Included
among those conditions are cyclic neutropenia [5],
selected anemias [6], inflammatory bowel diseases [7],
Behçet’s disease (see Box 1) [8,9], gluten-sensitive
enteropathy (celiac sprue) [10,11], relapsing poly-
chondritis syndromes (including the so-called
‘‘MAGIC’’ syndrome, which consists of mouth and
genital ulcers with inflamed cartilage) [12], HIV
infection [13], the purported symptom complex of
recurring fevers, aphthous stomatitis, pharyngitis, and
lymphadenopathy (FAPA syndrome) [14], and others
[2,4 – 6,15]. Given the various presentations of RAS
as either an exclusively local oral phenomenon or as a
systemically related oral condition, it is not surprising
that the search for its origin has proved frustrating.
In recent years a body of evidence has emerged to
suggest a genetic and an immunologic basis for RAS.
These revelations largely have eclipsed speculation
that RAS is caused by an infectious microorganism
or one of the other previously suspected etiologic
factors. They also have led to more rational and ef-
fective contemporary approaches to the management
of RAS [16].
Genetic factors
There is an apparent familial predisposition for
aphthous stomatitis. As compared to the general
population, the prevalence of RAS is higher when
there is a positive family history, especially when both
parents are affected [17]. There is also increased
disease correlation observed in identical twins as
compared to fraternal twins [18]. In familial cases of
RAS, the onset of disease is earlier and attacks tend to
occur more frequently than in nonfamilial cases [19].
112 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
Box 1. Behçet’s disease
A recurrent, multisystemic, immuno-
logically mediated vasculitic syndrome
Essential diagnostic component:
Oral aphthous ulcers (three or more
recurrences in one 12-month period)
accompanied by any two of the following:
Skin
 Pustular or nodular cutaneous lesions
 Positive cutaneous pathergy (ie, pus-
tule formation at injection site 24 to
48 hours after injection of sterile
solution of inert substance)
 Superficial thrombophlebitis, ery-
thema, ulcerations, acneiform lesions
Ocular
 Uveitis
 Retinal vasculitis
Genital
 Recurring ulcers of penis, scrotum,
or vulva
Less common manifestations:
Inflammatory bowel disease-related
symptoms
Arthritis
Neurologic disturbances
 Psychiatric disorders
 Meningoencephalitis
 Brain stem abnormalities
Data from International Study Group
for Behçet’s Disease. Criteria for diagnosis
of Behçet’s disease. Lancet 335:1078,
1990.
The likelihood that RAS is a genetically grounded
disease is further supported by the recognized,
although not entirely consistent, identification of
certain histocompatibility antigen (HLA) types (eg,
HLA B12, B51, Cw7), among some groups of
aphthous patients [2]. The latter type includes the
largest group of individuals whose aphthous ulcers
(‘‘canker sores’’) are isolated to the oral cavity
exclusively, without an attendant underlying systemic
disease, individuals with the mucocutaneous form of
Behcß et’s disease [8], persons with celiac disease (in
which there is immune-induced gluten sensitivity and
resultant intestinal malabsorption), and patients with
inflammatory bowel diseases (specifically Crohn’s
disease and ulcerative colitis) and oral aphthae [7,10].
Immunologic factors
Although findings have not been entirely consist-
ent and conflicting theories persist, mounting scien-
tific testimony supports immune dysregulation as a
key mechanism underlying the pathogenesis of RAS.
It is believed that the altered immune reactivity arises
perhaps in response to, or in concert with, a state of
presumably heightened antigenic stimulation [16]
exacted on a diminished mucosal barrier [2].
A constellation of cell-mediated immunologic
phenomena seems to be a consistent factor in the
disease. Serologic studies that compared RAS
patients and unaffected controls revealed diminished
ratios of circulating CD4+ helper cells to CD8+
suppressor cells in the former group [20,21]. It has
been proposed that in RAS some unspecified anti-
genic influence [2,22] is at the epicenter of an
antibody-dependent, T cell-mediated immune re-
sponse that involves a shift in local lymphocytic
subpopulations that eventuates in tissue damage
[23 – 25]. From the observations of several investiga-
tors it has been hypothesized that the entire process of
aphthous ulceration, from initiation through progres-
sion, is instigated by the expression on oral epithelial
cells of not only normally found HLA class I antigens
but also HLA class II antigens [26]. Presumably, this
renders the cells antigenically ‘‘foreign’’ and conse-
quently they become the targets of a cell-mediated
immune reaction perpetrated by lymphocytes and
Langerhans cells [26]. It has been shown that in
patients with aphthous stomatitis there is a heightened
lymphocytotoxic effect directed against oral epithelial
cells when compared to unaffected controls [25 – 27].
Evidence for this pathogenetic mechanism is also
inferred from observations that tissue biopsies of
newly erupted aphthous ulcerations demonstrate
agglomeration of activated T lymphocytes at the
periphery of the lesions, whereas in well-established
aphthae the initially predominant CD4+ helper/sup-
pressor cell population is subsumed and succeeded by
cytotoxic CD8+ lymphocytes [24,25].
Additional indirect support for primary immune
dysregulation is reflected in the long-recognized cor-
relation between stress and outbreaks of aphthous
ulcers that is reported by many RAS patients, in con-
trast to the notable decrease in frequency of episodes
during periods of reduced stress [28]. This observed
 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
association is not entirely surprising, because stress is
known to affect immunologic function [2]. It also has
been observed that HIV-infected patients experience
oral aphthous-like ulcerations with relatively high
frequency. With advancing immune depletion, their
aphthous outbreaks are often dominated by larger
ulcers that run a more protracted course [13,29,30].
Attempts to explore the possibility that RAS is
fundamentally an antibody-driven disorder have dis-
closed findings that are at best inconsistent and
largely unsupportive. It seems that any previously
held conjecture that aphthous ulcers stem from a
centrally generated humoral immune mechanism
rather than from local cellular immune responses to
an antigenically modified oral mucous membrane
was predicated on assumptions that have since been
discredited [3,18,31 – 33].
Microbial factors
To date, investigations have yielded little, if any,
consistent evidence to support the hypothesis that
RAS represents an infectious disease. In particular,
from studies to determine whether there might be a
connection between previously suspect L-forms of
streptococci and RAS, or the adenoviruses, herpes
simplex virus (HSV), varicella-zoster virus, or cyto-
megalovirus and RAS, the available evidence sug-
gests that none of these microorganisms seems to be
directly culpable for RAS despite continued specu-
lation about their possible role [2,6]. One should note
that an antiviral agent, acyclovir, offers no beneficial
effect in preventing or attenuating episodic flares of
the condition [34], which serves to weaken arguments
in favor of a possible viral causation for RAS [16].
From occasional anecdotal cases in which patients
report an apparent consistent temporal relationship
between their aphthous outbreaks and an immediately
antecedent reactivated (recurrent) HSV infection, it is
tempting to postulate that in a narrow subset of
individuals who get RAS, the herpes virus may serve
as an antigenic ‘‘trigger’’ that initiates the cascade of
immunologic events that result in ulceration [2]. In a
limited subset of RAS patients, it is possible that this
is actually the case. Presumably, such patients would
benefit from appropriate therapeutic and prophylactic
antiviral therapy, coupled with treatments specifically
aimed at lessening the severity and frequency of the
RAS episodes by modulating their supposedly height-
ened immune responses to the viral ‘‘trigger’’ [6].
Such therapeutic strategies probably would be best
carried out in consultation with an infectious disease
specialist [6]. (Analogous speculation and therapeutic
113
consideration also could be applied to the other human
herpes viruses, varicella-zoster virus and cytomegalo-
virus, which are known to affect such subclinical
phenomena as asymptomatic viral shedding and ele-
vated viral titers, similar to HSV [35,36].) It must be
emphasized, however, that regarding most aphthous
patients, any suggestion of a causative nexus between
RAS and HSV seems to represent unsubstantiated
conjecture rather than proven fact [16].
Nutritional factors
Other issues explored in the quest to determine a
cause for RAS include the possible relationship of
attacks to excess or deficiency of various nutritional
factors, such as serum iron, folate, and vitamin B12,
and speculation that aphthous ulcers represent the
manifestation of an allergic reaction to certain foods
or other ingested or contacted substances. Apart from
variably favorable responses to the avoidance of
gluten products in aphthous patients with docu-
mented intestinal malabsorption disease (compared
to controls [37]) and in some aphthous stomatitis
patients with normal intestinal function [38], evi-
dence that RAS primarily represents an allergic
response or is etiologically linked to diminished
serum iron, vitamin B12, or folate levels is lacking
or, at best, equivocal [6,16,24,28,39].
For any RAS patient who exhibits physical signs
and symptoms that suggest the possibility of an
underlying malabsorption or nutritional deficiency
state or a blood dyscrasia, it is prudent to obtain a
complete blood count and assays for serum folate,
vitamin B12, and ferritin. Should any of these tests
yield findings that suggest an underlying systemic
abnormality, referral to an internist or a hematologist
is indicated [6].
Clinical features
The classic clinical features of RAS are generally
well known and usually suffice for diagnostic pur-
poses [6]. The lesions affect the oral cavity exclu-
sively and, with the occasional exception of the
dorsal aspect of the tongue, overwhelmingly favor
nonkeratinizing, freely moveable mucosal surfaces.
From the latter characteristic, one might infer that the
abridged mucosal barrier of these attenuated epithe-
lial surfaces allows for intensified antigenic stimu-
lation, which in turn launches the autoimmune
reaction that results in mucosal disruption. Involve-
ment of keratinized epithelial surfaces is distinctly
114 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

uncommon and almost always represents extension of
ulceration from its origin on an adjacent nonkeratin-
ized epithelial surface [2]. When a cluster of ulcers is
confined to a single keratinized mucosal location (eg,
hard palate, attached gingiva), the possibility that
they represent ruptured vesicles of a recurrent HSV
infection (Table 1) or are traumatic ulcers must be
considered in the differential diagnosis as more likely
than aphthous ulcers [6,40,41].
Aphthous ulcers’ preference for buccal and labial
mucosa and the lateral-ventral tongue surfaces also
lends oblique support to the condition’s immune-
related nature, because these sites are especially
susceptible to friction and prone to trauma. It is not
uncommon for some patients to report that their
aphthous ulcers typically arise on such locations
shortly after a preceding minor traumatic event, such
as an accidental self-inflicted bite, frictional irritation
or injury from tooth clenching or bruxing, or after an
inadvertent nonpenetrating ‘‘stab’’ from a utensil
during a meal [42]. These events are examples of
the so-called ‘‘Koebner phenomenon,’’ in which
lesions that are characteristic of a specific immuno-
logically mediated mucocutaneous disorder (eg,
psoriatic plaques in psoriasis) develop on sites of
recently traumatized but previously lesion-free skin
or mucosa [43]. ‘‘Koebnerization’’ also occurs in
individuals with diseases such as lichen planus [44],
various types of lupus erythematosus, and others
[45]. It seems that a subset of individuals with RAS
tends to experience a similar phenomenon with
relation to the location of at least some of their
aphthous lesions in the context of some, if not all,
of their outbreaks.
Unlike the ulcerations seen in primary or recurrent
oral HSV infections, aphthous ulcers are not preceded
by vesicles [6]. Although individual aphthae are often
categorized into one of three possible subtypes (minor,
major, and herpetiform) based primarily on their
respective size differences, this classification is purely
descriptive rather than substantive. Regardless of an
individual lesion’s dimensions, all of the subtypes
seem to represent mere superficial variations of a
single disease entity [2]. Any individual recurrence
may feature as few as one or two isolated ulcers or
upwards of virtually dozens of aphthous lesions. Any
one of the subtypes or various combinations of each of
the three subtypes can occur in the course of a single
RAS outbreak [16]. Notwithstanding size, all aphthous
ulcers are painful, and in many cases, patients also
relate histories of prodromal discomfort or other symp-
toms that routinely augur impending recurrences [40].
The frequency and severity of recurrences vary
widely among affected individuals. Some patients
experience recurrences at fairly regular intervals,
whereas for others the episodes occur with less
predictability. In many cases the attacks are precipi-
tated by a particular identifiable factor (eg, intense
stress [15] or, as reported by some women, in tem-
poral relation to their menstrual cycles [46]), whereas

Table 1
Distinctions: Recurrent aphthous ulcers and recurrent (‘‘reactivated’’) intraoral HSV lesions
Factor Recurrent aphthous ulcers Recurrent HSV
Etiology Focal immune dysregulation HSV-I (HSV-II rarely)
Antecedents Commonly stress, trauma; other factors diverse Local trauma, stress, systemic
and unique as the affected individuals immune alteration
Prodromal awareness Sporadic Typical
Location of lesions Non-keratinizing ‘‘moveable’’ mucosa and Keratinizing (‘‘bound down’’)
tongue dorsum mucosa only
Distribution Unifocal or multifocal throughout oral cavity Unifocal only
(in immunocompetent individuals)
Lesions Ulcers of varying size and number possible Unifocal cluster of vesicles
per episode that ulcerate
Symptoms Pain (regardless of lesion size) Pain
Diagnostic Confirmation History, clinical features; negative cytology for History, clinical features; positive viral
virally-modified epithelial cells; biopsy usually cytopathic changes on smear; biopsy
not necessary usually not necessary
Clinical course 7 to 14 days, no scarring (minor and herpetiform types); 7 to 14 days
greater than 14 days, scarring possible (major types) (in immunocompetent individuals)
Management Palliative agents, corticosteroids, other immune Antiviral agents
modulating agents
Modified from Regezi JA, Sciubba JJ. Vesiculo-bullous diseases: Herpes simplex infections. In: Regezi JA, Sciubba JJ, editors.
Oral pathology: Clinical-pathologic correlations. 2nd edition. Philadelphia: W.B. Saunders; 1993; p. 9; with permission.
 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
Fig. 1. Minor aphthous ulcers, lower labial mucosa.
some patients’ outbreaks arise without any identifi-
able triggering factor [16]. Episodes may occur rarely
or with some frequency, accompanied by a range of
symptomatic intensity. Most troubling for a small
subset of individuals is the experience of overlapping
recurrences for periods of time that can involve weeks
or months or, rarely, a year or more of almost
perpetual mucosal disruption from aphthous ulcer-
ations. During such periods of seemingly relentless
outbreaks, a patient’s ability to function comfortably
and even their emotional stability may be compro-
mised drastically because of protracted oral mucosal
pain [2]. Under such circumstances, patients are
occasionally suspected of having Behcß et’s disease
[8] or some other major systemic disorder. Accord-
ingly, they are often referred to appropriate medical or
dental specialists for a diagnostic consultation and
evaluation. One should note that in most cases even
the most exacting and thorough systemic evaluation
fails to reveal evidence that supports a diagnosis either
of Behcßet’s or any other identifiable systemic disease.
Instead, such evaluations only serve to confirm that
the condition is confined to the oral cavity and is
simply an extreme expression of RAS alone [2,6].
Commonly, RAS patients report sensations of
burning, tingling, or other mucosal discomfort just
before an outbreak of aphthous ulcers, similar to the
prodromal symptoms that frequently precede recur-
rent HSV infections [40]. During the prodromal phase
of RAS it may be possible to observe a transient
erythematous macule or papule at the site of mucosal
discomfort. Such lesions typically emerge onto move-
able oral mucosal surfaces or the dorsal aspect of the
tongue and can antecede the actual aphthous ulcer-
ations by at least several hours or longer. These
preulcerative lesions are succeeded by characteris-
tically painful ulcers with round, symmetrical, yel-
low-white or gray fibrinonecrotic centers surrounded
115
by slightly raised, erythematous, halo-like borders.
Several ulcers in close apposition to one another may
become confluent and result in a larger area of
mucosal disruption [2].
So-called ‘‘minor’’ (‘‘typical’’) aphthous ulcers are
smaller than 1 cm in diameter and tend to heal within
10 to 14 days (Fig. 1). Their larger counterparts, so-
called ‘‘major’’ aphthous ulcers (Mickulicz’s aphthae,
periadenitis mucosa necrotica recurrens, Sutton’s aph-
thae), are not as common. They are 1 cm in diameter or
larger, with edematous borders, and classically involve
a greater depth of submucosal tissue destruction. For
this reason, these types of aphthous ulcers tend to run a
more extended clinical course; they can take signifi-
cantly longer than 2 weeks to resolve and sometimes
heal with scar formation (Figs. 2,3). Herpetiform
aphthous ulcers, the least common type, tend to be
distributed in tight clusters of small ulcers, 1 to 3 mm
in diameter, that bear superficial resemblance to the
ruptured vesicles of oral HSV infections [2,4,6,36].
Frequently, close crops of these ulcers coalesce to
involve a broad surface area (Figs. 4,5). Although
their small size allows for resolution of herpetiform
aphthae within a 7- to 10-day period, some patients
experience recurrences that flare at relatively close
intervals. Although herpetiform aphthae also exhibit a
strong predilection for nonkeratinized epithelium,
unlike their minor and major counterparts they
coalesce readily and can occur on any oral mucosal
surfaces, including those that are keratinized [2].
Histopathology
Once an aphthous ulcer has emerged onto the oral
mucosa, biopsy is usually not required for diagnostic
Fig. 2. Major aphthous ulcer of longer than 8 weeks’
duration. Located on anterior buccal-labial mucosa, the
lesion had been secondarily traumatized.
116 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
Fig. 3. Hyperplastic scar tissue from healed major
aphthous ulcer, lower right vestibular mucosa adjacent to
mandibular canine and first premolar tooth. Scar resembles
epulis fissuratum.
confirmation because there are no defined pathogno-
monic microscopic features of this disorder. At the
tissue level, the clearly nonvesicular nature of the
ulcerative lesion and the absence of virally modified
epithelial cells may serve to distinguish an early
aphthous ulcer from an herpetic lesion in cases in
which there is clinical diagnostic ambiguity [4,40].
Relatively early in their course, aphthous lesions
demonstrate an ulcer base covered by a fibrinopuru-
lent pseudomembrane. The marginal epithelium may
appear spongiotic with attendant lymphocytosis,
especially in the basal-most strata. At the marginal
epithelial-stromal interface, ‘‘tagging’’ of lympho-
cytes is prominent, and throughout the superficial
stroma polymorphonuclear leukocytes and chronic
inflammatory infiltrates dominated by lymphocytes
and histiocytes prevail. Within the deeper submucosa,
perivascular infiltrates of lymphocytes and histiocytes
Fig. 4. Minor, major, and herpetiform aphthae occurring
synchronously on right soft palatal mucosa.
Fig. 5. Herpetiform aphthous ulcers on the soft palate and
uvula. These clusters of small ulcerations have coalesced to
form extensive lesions that resemble major aphthae.
may be seen [2]. As an aphthous ulcer ‘‘ages,’’ the
histopathologic findings become increasingly non-
specific [16]. Biopsy of any long-standing, nonheal-
ing oral ulcer may be indicated, however, to determine
whether the lesion is benign or malignant or repres-
entative of some unsuspected unusual diagnostic
entity, such as a granulomatous infection or inflam-
matory disease.
Management of recurrent aphthous stomatitis
General considerations
Conventional wisdom and clinical experience
strongly suggest that most cases of RAS are isolated
to the oral cavity and are neither attributable to nor
associated with an underlying systemic disease or
some other generalized pathologic condition. If the
medical history is positive for or suggestive of any of
the systemic conditions known to be linked to oral
aphthae, however, and the patient experiences severe
bouts or unusually frequent recurrences of aphthous
stomatitis, it may be prudent to rule out the possibility
that the oral flare up reflects an exacerbation of the
systemic disease. Should that suspicion be confirmed
through an appropriately focused evaluation in con-
sultation with the patient’s primary care provider or
an appropriate medical specialist, the apparent incit-
ing condition must be addressed and treated accord-
ingly. The expectation is that once the underlying
systemic problem is brought under control, at least
temporary remission or regression of the RAS can be
achieved [2,6,16].
Whether it is of value to include complete hem-
atologic screening of RAS patients as part of the
 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
standard diagnostic and treatment planning evalu-
ation is debatable. Although low serum iron and
ferritin levels have been documented in some
patients by some investigators [47,48], others have
found that RAS patients generally have normal
erythrocyte counts and hemoglobin levels, similar
to those of controls [49,50]. Some researchers recom-
mend that children with RAS be screened hemato-
logically because in approximately 20% of children
who get aphthous ulcers, dormant serum iron defi-
ciencies unaccompanied by anemia have been dis-
closed [51]. Regardless of the patient’s age, if
hematologic testing reveals a deficiency state or
other abnormality, management of the blood dyscra-
sia also may constitute a key strategy for managing
the oral lesions.
Objectives, principles, and caveats
Treatment is targeted at reducing the duration
and expediting the resolution of ulcers, alleviating
pain, lessening the frequency of attacks, and fore-
stalling recurrences. Management decisions should
be dictated by each patient’s perceptions of the
severity of the oral lesions, the frequency of recur-
rences, and the degree of debilitation that attends the
outbreaks. All treatment efforts must be applied in
balance with the safest, most judicious use of
therapeutic agents available.
In patients with strictly oral manifestations of
RAS and no concomitant systemic abnormality, a
broad scope of possible treatment options is avail-
able. At the extremes, choices range from doing
essentially nothing other than to confirm the diag-
nosis to prescribing major therapeutic agents aimed at
prevention and control of the immunologic mecha-
nisms that produce aphthous ulcers. In between these
extremes several relatively conservative strategies are
available for alleviating symptoms exclusively, cur-
tailing the duration and pain of a single episode,
attenuating an active outbreak that may be part of a
series of overlapping or frequent outbreaks of RAS,
and preventing future episodes (see Box 2). It is
vitally important for the patient and the clinician to
bear in mind that any and all interventions for RAS,
regardless of severity, are neither curative nor intend-
ed for persistent use [16]. Rather, they are prescribed
to effect temporary respite from a disease with a
proclivity for recurrences [1 – 4,6,16,28,40].
Because aphthous stomatitis is an immunologi-
cally mediated disease, therapies centered in
immunomodulation are most appropriate. They can
be applied successfully for managing individual epis-
117
Box 2. Recurrent aphthous stomatitis:
treatment options
No treatment
Palliative approach
 Topical agents: home remedies, over-
the-counter medications, prescribed
analgesics, cauterizing agents
Antiinflammatory and antimicrobial
agents
Immunomodulation*
 Topical: corticosteroid creams, oint-
ments, gels, rinses; ‘‘intralesional’’
(perilesional) corticosteroid injections
 Systemic: corticosteroids, nonsteroi-
dal immunosuppressive agents, anti-
inflammatory agents
Combined therapy: topical and sys-
temic agents, systemic agents in com-
bination
* Most efficacious approaches.
odic flares and can be used on an intermittent basis as
a preemptive strategy for attenuating an incipient
attack or they can be used to abort an imminent
aphthous outbreak in its prodromal stage. The unre-
mitting use of immunomodulating agents for this
essentially benign disease, whether topical, systemic,
or combined, is contraindicated, given these agents’
recognized potential for pernicious side effects
[2,3,6].
First-line therapeutic choices
When a recurrent episode consists of a relatively
limited number of aphthous lesions that are either
small or large, closely apposed to one another, and
distributed on readily accessible oral surfaces such
as the labial or vestibular mucosa or the anterior
portion of the tongue, first-line therapeutic manage-
ment should involve regimens based on conserva-
tive topical therapy [2 – 4,6,16]. Among the options
available are any of the over-the-counter nonsteroi-
dal occlusive preparations, such as Orabase, with or
without topical analgesic (usually benzocaine) that
may be applied primarily for symptomatic relief or
nonsteroidal antiinflammatory preparations, such
as amlexanox 5% paste (Aphthasol oral paste).
Applied directly to active lesions, amlexanox pro-
motes pain reduction by inhibiting release of his-
118 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
tamine and leukotrienes. It has been shown that
aphthous ulcers treated with amlexanox resolve in
less time (by 1 day) than their untreated counter-
parts [2 – 4,6].
Topical corticosteroid gels, creams, or ointments
that are selectively prescribed and judiciously applied
to active lesions constitute an effective conservative
modality for managing RAS. The cream or ointment
preparations are preferred, because some patients
report stinging or burning with the use of cortico-
steroid gels [3,40].
Some patients who wish to use topical cortico-
steroid gels, creams, or ointments are reluctant to do
so or fail to comply because of the fear that attends
reading the warning on prescription packaging inserts
or receiving pharmacists’ admonishments that topical
corticosteroid preparations are for external use only.
Clinicians should reassure their patients that the use
of these topical agents strictly as prescribed for
limited periods of time is not likely to produce
untoward effects and is safe [3,40,52].
Over the course of several days, starting as early
as possible from the onset of the outbreak, direct
application of a thin film of the corticosteroid agent
three to five times daily and at bedtime after gentle
drying of the affected area alleviates discomfort and
reduces the duration of ulcers so that they heal within
several days, rather than linger for a week or more, as
is typical of untreated lesions [6]. Among the recog-
nized vagaries inherent in using creams or ointments
on oral mucous membranes is the likelihood that they
rapidly wash away from the site of application and
thereby diminish the therapeutic efficacy of the
medication. This problem can be addressed either
by prescribing a topical corticosteroid compounded
with tissue adhesive (eg, 0.1% or 0.5% triamcinolone
acetonide [Aristocort A, Kenalog] in Orabase) or,
as an alternative, by prescribing more potent topical
corticosteroids, such as 0.05% betamethasone dipro-
pionate cream or ointment (Diprolene; Lotrisone),
0.05% fluocinonide cream or ointment (Lidex),
or 0.05% clobetasol propionate ointment or cream
(Temovate) alone, without tissue adhesive [2 – 4,6].
The latter three topical agents seem to provide greater
therapeutic efficacy than those compounded in an
occlusive or adherent base, despite their limited time
in contact with active lesions [3]. There seems to be
no appreciable therapeutic advantage to applying
corticosteroid in a base preparation (ie, compounded
in Orabase or some other inert mucous membrane
dressing) as compared to applying a base preparation
alone (ie, without corticosteroid) [53]. Regardless of
whether a base preparation or corticosteroid alone or
a compound of both is applied, avoidance of food and
drink for 30 minutes after application is advised to
promote adherence of the preparation to the ulcer-
ations. To prevent or address corticosteroid-induced
candidiasis, an antifungal medication can be com-
pounded into the corticosteroid cream or ointment,
with or without a tissue adhesive base when indi-
cated [40].
For aphthous ulcers that are difficult to reach with
a finger—predominantly ulcers that involve the most
posterior oral regions—or are so numerous and widely
distributed as to render the direct application of
creams or ointments impractical, corticosteroid rinses
are an excellent topical therapeutic alternative [2 – 4,
6,16,28,40]. Rinsing over a period of several days
with betamethasone (Celestone) syrup 0.6 mg/5 mL,
dexamethasone (Decadron) elixir 0.5 mg/5 mL, or a
specially compounded aqueous suspension of 0.1% or
0.2% triamcinolone acetonide accelerates resolution
of the ulcers and alleviates discomfort. Three to four
times daily and before retiring for the night, 1 tea-
spoonful of the liquid is held and swished in the
mouth for 2 to 3 minutes and then expectorated. The
rinse regimen is followed by avoidance of food and
drink for 30 to 60 minutes afterward. This is not only
an effective method for addressing active RAS out-
breaks but also may be useful for aborting an immi-
nent attack in its prodromal phase [16]. The author
also has found that ‘‘customized’’ prophylactic corti-
costeroid rinse regimens can be adapted to an indi-
vidual patient’s needs, particularly in cases in which it
is necessary to intercept and prevent episodes known
to occur with some regularity or frequency. Triamcin-
olone acetonide suspension can be compounded with
nystatin (Nystatin oral suspension USP) for individu-
als predisposed to oral candidiasis or with 2% lido-
caine (Xylocaine 2% viscous solution) if there is a
need for expedient pain relief (Karen A. Baker, MS
Pharm, personal communication, 2001).
Another method for applying topical corticoste-
roid medication to active lesions (particularly major
aphthous ulcers or other types of aphthae located
primarily in intertriginous-like regions of the oral
mucosa, such as the upper or lower buccal or labial
vestibules or the sublingual vestibule) involves
using a gauze sponge either soaked in corticosteroid
rinse preparation or on which a small amount of
corticosteroid cream or ointment has been applied
for delivery. By laying the gauze sponge directly
onto the lesion or lesions and holding it in place for
15 to 20 minutes two or three times daily during
waking hours, the concentrated contact method for
delivery of the medication requires fewer applica-
tions and promotes more expeditious healing of
ulcers [3,4].
 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
Perilesional injection
Perilesional injection of corticosteroid medication
is another therapeutic alternative. Such injections can
be highly efficacious for treating major aphthous
ulcers that have been resistant to other more conserv-
ative topical approaches or are unresponsive to sys-
temic treatment [2]. The author has found that this
route of corticosteroid administration can reduce
significantly the diameter of either a newly erupted
or a long-standing major aphthous lesion within the
24- to 48-hour postinjection period and dramatically
shorten healing time.
The procedure the author uses is based on a
modification of the adjuvant intralesional cortico-
steroid injection regimen described for use in treat-
ing recalcitrant pemphigus lesions [54]. After
administration of local anesthesia (with vasocon-
strictor), 10 to 40 mg of sterile triamcinolone
acetonide injectable suspension, USP (Kenalog-40)
40 mg/mL diluted to 10 mg/mL strength, is injected
into the perilesional tissue immediately adjacent to
the ulcer border. The lesion is clinically evaluated
48 hours after injection to determine whether the
treatment was adequate. If there seems to be neither
improvement in symptoms nor evidence of progres-
sion toward healing, it may be necessary to repeat
the procedure. Usually a single administration of
corticosteroid is sufficiently therapeutic, however,
so that even large, painful, or stubbornly recalcitrant
major aphthous lesions that were present for many
weeks before the injection resolve within 5 to
7 days.
Indications for second-line therapy
Prednisolone (Prelone) or betamethasone (Celes-
tone) syrup preparations can be used exclusively as
rinses or as several times daily rinse-and-swallow
regimens for cases that are recalcitrant to the topical
approach alone. The latter combined route of admin-
istration can be helpful for treating major aphthae and
is especially effective in cases in which the aphthous
ulcers are concentrated in the posterior oral cavity, soft
palate, and tonsillar fauces and are attended by con-
siderable pain. Used in this manner, the corticosteroid
agent provides topical and systemic immunomodula-
tory benefits and is considered to be a second-line type
of therapy [2].
For the occasional patient plagued by frequent
or overlapping RAS attacks over a protracted
period of time and whose quality of life has been
eroded as a result, the goal of treatment is two-
119
fold. The first goal is to remedy the current attack.
The second goal is to attempt to break the apparent
cycle of recurrence to achieve at least a temporary
period of remission or an interim in which recur-
rences are less frequent, ulcerations are fewer, and
symptoms are less intense. Achieving this goal may
require an approach that briefly couples systemic
corticosteroid ‘‘burst therapy’’ with topical cortico-
steroid therapy initially, followed by a ‘‘prophy-
lactic maintenance’’ regimen with continuance of
the topical corticosteroid alone. The author has
found that individual case-centered modifications
of the therapeutic approach reported by Vincent
and Lilly [16] can be effective in most cases for
accomplishing these goals. They recommend using
a ‘‘burst’’ therapeutic regimen of prednisone (40
mg taken 1 hour after rising in the morning for
5 days, followed by 20 mg every other day for an
additional week) along with oral rinses with com-
pounded 0.1% triamcinolone acetonide aqueous
suspension (5 mL of liquid swished four times
daily for 2 to 3 minutes and expectorated ; NPO
for 1 hour afterward). If the triamcinolone suspen-
sion is not available, dexamethasone elixir used
similarly three to four times daily at outset also
can be effective.
In the author’s experience, ‘‘burst therapy’’ also
can be used safely over a 3-week period if necessary
(eg, 40 mg prednisone every morning for 7 days
followed by 20 mg every morning for 7 additional
days followed by 20 mg every other morning for
another 7 days) and does not require any further
tapered doses [16]. Coupled with the initial four-
times-daily corticosteroid rinse regimen, burst ther-
apy is more effective than 5 to 7 days of abbreviated
systemic corticosteroid (dosepak) therapy alone for
obtaining control of an active outbreak and intercept-
ing and preventing subsequent recurrences [16].
Once the systemic corticosteroid regimen is com-
pleted, a prophylactic rinse regimen (eg, either one to
three times daily or one to three times on alternate
days as needed; NPO for 30 minutes to 1 hour after
rinsing) can provide long-term preventive mainte-
nance. Although systemic complications from using
attenuated corticosteroid rinse regimens over ex-
tended periods of time do not seem to be a significant
problem [16], oral candidiasis can be a potential
problem for some individuals on this therapy, par-
ticularly individuals whose cell-mediated immune
responses are compromised by an underlying medical
condition, such as diabetes. In such cases, inter-
vention with ketoconazole (Fluconazole, Nizoral)
tablets or clotrimazole (Mycelex) troches may be
indicated [2,3].
120 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
Other medications
Various other medications and methods too numer-
ous to mention in this article and of highly variable
efficacy have been used for managing aphthous sto-
matitis. These medications include inert and more
active prescribed preparations (antimicrobial agents,
cauterizing solutions, monoamine oxidase inhib-
itors, tissue films, and others) and myriad home
remedies [2,4]. When cases are resistant to cortico-
steroid-based immunomodulatory regimens exclu-
sively, other nonsteroidal immunosuppressive agents,
such as cyclosporine (Sandimmune, Neoral), dapsone,
or azathioprine (Imuran) given systemically in com-
bination with adrenal-sparing doses of prednisone and
other agents with antiinflammatory, immunomodula-
tory properties alone (eg, pentoxyphylline [Trental] or
colchicine) may or may not prove useful as alternative
second- or third-line therapies [2 – 4,6,16,28,40]. Their
potential for producing serious side effects does limit
case selection for their use.
Recently, thalidomide (Thalomid), a potent immu-
nosuppressive medication, was found to be effective
for treating HIV-infected patients with severe RAS
when prescribed at daily doses of 100 to 200 mg [55]
and for managing oral aphthae in immunocompetent
individuals with Crohn’s disease [56] and Behcßet’s
disease [8,57]. Because of thalidomide’s recognized
potential for profound side effects, however, its use
must be reserved only for patients whose aphthous
ulcers have been so unrelenting and sufficiently
symptomatic as to significantly compromise quality
of life and who, after exhaustive efforts, also have
failed to respond to other, more conservative thera-
peutic measures. Use of this systemic agent requires
strict adherence to guidelines for patient selection.
Patients who take thalidomide must be monitored
frequently to intercept and prevent its potential toxic
effects [2,6].
Summary
Currently, RAS is recognized as an immunologi-
cally mediated, inflammatory oral condition rather
than an infectious disease. Contemporary approaches
to its management are focused on modulating the
aberrant immune responses that underlie its pathogen-
esis. Immunomodulation has been applied with great
success for managing existing episodes and prevent-
ing recurrences of RAS. Safe, effective, and reliable
therapies for actually curing this disease remain elu-
sive at this time. It is reasonable to suggest that for the
future, anticipated new insights into the condition’s
origin and pathogenesis, combined with ongoing
research directed toward the development of safer,
more effective immunomodulating agents, render the
prospect of a cure for RAS increasingly plausible.
Acknowledgment
The author wishes to express sincere gratitude to
Marilyn R. Holt, MS, for her technical expertise and
invaluable assistance in preparing the manuscript.
References
[1] Ship JA. Recurrent aphthous stomatitis: an update. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:
141 – 7.
[2] Neville BW, Damm DD, Allen CM, Bouquot JE. Al-
lergies and immunologic diseases: recurrent aphthous
stomatitis. In: Oral and maxillofacial pathology.
2 nd edition. Philadelphia: W.B. Saunders; 2002.
p. 285 – 90.
[3] Eisen D, Lynch DP. Selecting topical and systemic
agents for recurrent aphthous stomatitis. Cutis 2001;
68:201 – 6.
[4] Reich RF, Kerpel SM, Freedman PD. Differential diag-
nosis and treatment of ulcerative, erosive, and vesicu-
lobullous lesions of the oral mucosa. Oral Maxillofac
Surg Clin N Am 1998;10:95 – 129.
[5] Wright DG, Dale DC, Fauci AC. Human cyclic neu-
tropenia: clinical review and long-term follow-up of
patients. Medicine (Baltimore) 1981;60:1 – 13.
[6] Ship JA, Chavez EM, Doerr PA, et al. Recurrent aph-
thous stomatitis. Quintessence International 2000;31:
95 – 112.
[7] Glickman RM. Inflammatory bowel disease: ulcerative
colitis and Crohn’s disease. In: Fauci AS, Braunwald
E, Isselbacher KJ, et al, editors. Harrison’s principles
of internal medicine. 14th edition. New York: McGraw-
Hill; 1998. p. 1633 – 45.
[8] Ghate JV, Jorizzo JL. Behcßet’s disease and complex
aphthosis. J Am Acad Dermatol 1999;40:1 – 18.
[9] International Study Group for Behcßet’s Disease. Criteria
for diagnosis of Behcß et’s disease. Lancet 1990;335:
1078 – 80.
[10] Magro C, Crowson AN, Mihm M. Cutaneous manifes-
tations of nutritional deficiency states and gastrointes-
tinal disease: Behcßet’s disease, inflammatory bowel
diseases (Crohn’s disease, ulcerative colitis, celiac dis-
ease). In: Elder D, Elenitsas R, Jaworsky C, Johnson B,
editors. Lever’s histopathology of the skin. 8th edition.
Philadelphia: Lippincott-Raven; 1997. p. 359 – 63.
[11] Rizzi R, Bruno S, Dammacco R. Behcß et’s disease: an
immune-mediated vasculitis involving vessels of all
sizes [review]. Int J Clin Lab Res 1997;27:225 – 32.
[12] Orme RL, Nordlund JJ, Barich L, et al. The MAGIC
 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
syndrome (mouth and genital ulcers with inflamed car-
tilage). Arch Dermatol 1990;126:940 – 4.
[13] Ficarra G. Oral ulcers in HIV-infected patients: an up-
date on epidemiology and diagnosis [review]. Oral
Diseases 1997;3(Suppl 1):S183 – 9.
[14] Marshall GS, Edwards KM, Butler J, et al. Syndrome
of periodic fever, pharyngitis and aphthous stomatitis.
J Pediatr 1987;110:43 – 6.
[15] Rogers III RS. Recurrent aphthous stomatitis: clinical
characteristics and associated systemic disorders.
Semin Cutan Med Surg 1997;16:278 – 83.
[16] Vincent SD, Lilly GE. Clinical, historic, and therapeu-
tic features of aphthous stomatitis: literature review and
open clinical trial employing steroids. Oral Surg Oral
Med Oral Pathol 1992;74:79 – 86.
[17] Ship JA. Inheritance of aphthous ulcers of the mouth.
J Dent Res 1965;44:837 – 44.
[18] Miller MF, Garfunkel AA, Ram CA, et al. Inheritance
patterns in recurrent aphthous ulcers: twin and pedi-
gree data. Oral Surg Oral Med Oral Pathol 1977;43:
886 – 91.
[19] Miller MF, Garfunkel AA, Ram CA, et al. The inher-
itance of recurrent aphthous stomatitis. Oral Surg Oral
Med Oral Pathol 1980;49:409 – 12.
[20] Landesberg R, Fallon M, Insel R. Alterations of
T-helper/inducer and T-suppressor/inducer cells in pa-
tients with aphthous ulcers. Oral Surg Oral Med Oral
Pathol 1990;69:205 – 8.
[21] Savage NW, Mananonda R, Seymour GJ, et al. The
proportion of suppressor-inducer T-lymphocytes is re-
duced in recurrent aphthous stomatitis. J Oral Pathol
Med 1988;17:293 – 7.
[22] Schroeder HE, Muller-Glauser W, Sallay K. Stereolog-
ical analysis of leukocyte infiltration in oral ulcers of
developing Mickulicz aphthae. Oral Surg Oral Med
Oral Pathol 1983;56:629 – 40.
[23] Greenspan JS, Gadol N, Olson JA, et al. Antibody-
dependent cellular cytotoxicity in recurrent aphthous
ulceration. Clin Exp Immunol 1981;44:603 – 10.
[24] Pedersen A, Hougen P, Kenrad B. T-lymphocyte sub-
sets in oral mucosa of patients with recurrent aphthous
ulceration. J Oral Pathol Med 1992;21:176 – 80.
[25] Savage NW, Seymour GJ, Kruger BJ. T-lymphocyte
subset changes in recurrent aphthous stomatitis. Oral
Surg Oral Med Oral Pathol 1985;60:175 – 80.
[26] Savage NW, Seymour GJ, Kruger BJ. Expression of
class I and class II major histocompatibility complex
antigens on epithelial cells in recurrent aphthous sto-
matitis. J Oral Pathol Med 1986;15:191 – 5.
[27] Rogers RS, Sams WM, Shorter RG. Lymphocytotox-
icity in recurrent aphthous stomatitis. Arch Dermatol
1974;109:361 – 3.
[28] Woo S-B, Sonis ST. Recurrent aphthous ulcers: a re-
view of diagnosis and treatment. J Am Dent Assoc
1996;127:1202 – 13.
[29] MacPhail LA, Greenspan JS. Oral ulceration in HIV-
infection: investigation and pathogenesis. Oral Dis-
eases 1997;3(Suppl 1):S190 – 3.
[30] Phelan JA, Eisig S, Freedman PD, et al. Major aph-
121
thous-like ulcers in patients with AIDS. Oral Surg Oral
Med Oral Pathol 1991;71:68 – 72.
[31] Cohen L. Etiology, pathogenesis and classification of
aphthous stomatitis and Behcßet’s syndrome. J Oral Path-
ol 1978;7:347 – 52.
[32] Lehner T. Immunologic aspects of recurrent oral ul-
cers. Oral Surg Oral Med Oral Pathol 1972;33:80 – 5.
[33] Ben Aryeh H, Malberger E, Gutman D, et al. Salivary
IgA and serum IgG and IgA in recurrent aphthous
stomatitis. Oral Surg Oral Med Oral Pathol 1976;42:
746 – 52.
[34] Wormser GP, Mack L, Lenox T, et al. Lack of effect of
oral acyclovir on prevention of aphthous stomatitis.
Otolaryngol Head Neck Surg 1988;98:14 – 7.
[35] Kameyama T, Sujaku C, Yamamoto S, et al. Shedding
of herpes simplex virus type I into saliva. J Oral Pathol
1988;17:478 – 81.
[36] Neville BW, Damm DD, Allen CM, Bouquot JE. Viral
infections: HSV, VZV, CMV. In: Oral and maxillofa-
cial pathology. 2nd edition. Philadelphia: W.B. Saun-
ders; 2002. p. 213 – 24.
[37] Veloso FT, Saleiro JV. Small-bowel changes in recur-
rent ulceration of the mouth. Hepatogastroenterology
1987;34:36 – 7.
[38] Wray D. Gluten-sensitive recurrent aphthous stomati-
tis. Dig Dis Sci 1981;26:737 – 40.
[39] Olson JA, Feinberg I, Silverman Jr S, et al. Serum
vitamin B12, folate and iron levels in recurrent aph-
thous stomatitis. Oral Surg Oral Med Oral Pathol
1982;54:517 – 20.
[40] Regezi JA, Sciubba JJ. Ulcerative conditions: condi-
tions associated with immunologic dysfunction. Aph-
thous ulcers. In: Regezi JA, Sciubba JJ, editors. Oral
pathology: clinical-pathological correlations. 2nd edi-
tion. Philadelphia: W.B. Saunders; 1993. p. 52 – 60.
[41] Rodu B, Mattingly G. Differential diagnosis of oral
mucosal ulcerations. J Am Dent Assoc 1992;123:
83 – 6.
[42] Wray D, Graykowski EA, Notkins AL. Role of mu-
cosal injury in initiating recurrent aphthous stomatitis.
BMJ 1981;283:1569 – 70.
[43] Murphy GF, Mihm Jr MC. The skin: chronic inflamma-
tory dermatoses. In: Cotran RS, Kumar V, Robbins SL,
editors. Robbins pathologic basis of disease. 5th edition.
Philadelphia: W.B. Saunders; 1994. p. 1198.
[44] Boyd AS, Neldner KH. The isomorphic response to
Koebner. Int J Dermatol 1990;29:401 – 10.
[45] Domonokos AN. Cutaneous symptoms, signs and di-
agnosis: Koebner’s phenomenon. In: Domonokos AN,
editor. Andrews’ diseases of the skin: clinical derma-
tology. 6th edition. Philadelphia: W.B. Saunders; 1971.
p. 26.
[46] Ferguson MM, Carter J, Boyle P. An epidemiological
study of factors associated with recurrent aphthae in
women. J Oral Med 1984;39:212 – 7.
[47] Porter SR, Scully C, Flint S. Hematologic status in
recurrent aphthous stomatitis as compared with other
oral disease. J Oral Pathol 1978;7:418 – 23.
[48] Rogers III RS . Screening for hematinic deficiencies in
122 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122
patients with recurrent aphthous stomatitis. Australas J
Dermatol 1986;27:98 – 103.
[49] Challacombe SJ, Barkhan P, Lehner T. Hematological
features and differentiation of recurrent oral ulceration.
Br J Oral Surg 1977;15:37 – 48.
[50] Porter SR, Kingsmill V, Scully C. Audit of diagnosis
and investigations in patients with recurrent aphthous
stomatitis. Oral Surg Oral Med Oral Pathol 1993;76:
446 – 52.
[51] Field EA, Rotter E, Speechley JA, et al. Clinical and
hematological assessment of children with recurrent
aphthous ulceration. Br Dent J 1987;163:19 – 22.
[52] MacPhail L. Topical and systemic therapy for recurrent
aphthous stomatitis. Semin Cutan Med Surg 1997;16:
301 – 7.
[53] Voute AB, Schulten EA, Langendijk PN, et al. Fluocin-
onide in an adhesive base for treatment of oral lichen
planus: a double-blind, placebo-controlled clinical
study. Oral Surg Oral Med Oral Pathol 1993;75:
181 – 5.
[54] Bystryn J-C, Steinman NM. The adjuvant therapy
of pemphigus: an update. Arch Dermatol 1996;132:
203 – 12.
[55] Jacobson JM, Greenspan JS, Spritzler J, et al, for the
National Institute of Allergy and Infectious Diseases
AIDS Clinical Trials Group. Thalidomide for the treat-
ment of aphthous ulcers in patients with human immu-
nodeficient virus infection. N Engl J Med 1997;336:
1487 – 93.
[56] Weinstein TA, Sciubba JJ, Levine J. Thalidomide for
the treatment of oral aphthous ulcers in Crohn’s dis-
ease. J Pediatr Gastroenterol Nutr 1999;28:214 – 6.
[57] Eisenbud L, Horowitz I, Kay B. Recurrent aphthous
stomatitis of the Behcßet’s type: successful treatment
with thalidomide. Oral Surg Oral Med Oral Pathol
1987;64:289 – 92.