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Quintessence International is committed to presenting
evidenced-based clinical practice guidelines in collabo-
ration witti oral and noncral health care providers.
Medi ci ne
riiCTi
Clinical Practice Guidelines
Recurrent aphthous stomatitis
Jonathan A. Ship, DMDVEIisa M. Chavez, DDS^/Patricia A. Doerr, BS, MPH^/
Bradley S. Henson, BS^/Mojgan Sarmadi,
Etiology and Epidemiology: The Greek term apifia/was initially used in relation to disorders ot the
mouth and is credited to Hippocrates (460-370 BC) . Today, reourrent aphthous ulcration, or recurrent
aphthous stomatitis (RAS) , is recognized as the most common oral mucosal disease known to human he-
ings.'' Considerable research attention has been devoted to elucidating the causes of RAS; local and sys-
temic conditions, and genetic, immunologie, and infectious mierobial factors all tiave been idenfied as po-
tential etiopathogenic agents (Table 1).^-"' However, to date, no principal etiology has been discovered.
Epidemiologie studiGS indicate that the prevalence ot RAS is between 2% and 50% in the general popula-
tion; most estimates lall between 5% and 25%,^"' ' ' -^ In selected groups, such as medical and dental
students, it has been observed with a frequency as high as 50% to 60%. The peak age ot onset for RAS is
between 10 and 19 years.^^'' Atter childhood and adolescence, it may continue throughout the entire
human lifespan without geographic or age-, sex-, or race-related preference. (Quintessence Int
2000;31:95-112)
CLINICAL MANIFESTATIONS
Minor RAS
T
he most common presentation of RAS is minor
RAS. Minor RAS manifests as recurrent, round,
clearly defined, small, painful uleers with shallow
necrotic centers, raised margins, and erythematous
halos (Fig 1). They are generally smaller than 10 mm
in diameter and have a gray-white pseudomembrane.
These lesions heal within 10 to 14 days without scar-
'Protessor and Vice Chair, Department of Oral Medicine, Paltiology,
Oncology, Uni versi ty of tulichigan. School ol Dentistry, Ann Arbo^
Michigan.
' Fellow, Geri ati i c Dentistry Program, Deparl ment of Oral Medicine,
Pathology, Oncology, Universily of Michigan. School ot Denlislrv. Ann
Artjor, Michigan.
'Dental Student, University of tJlichigan, Sctiool ot Dentistry, Ann Arbor,
Michigan.
Reprint requests: Dr Jonathan A. Ship, Professor and Vice Chair, Depart-
ment of Oral tuledicine, Pathoiogy, Oncology, University of tulicfiigan.
School of Denti stry. Ann Arbor, tulichigan 48109-1078. E-mai l :
jship@umich.edu
ring. The most common loeation is on nonkeratinized
oral mueosa [the labial and buccal mucosa and floor
of the mouth). Lesions appear as single or multiple ul-
cers hut can be distinguished from other mueocuta-
neous diseases based on their history, location,
healthy appearance of adjacent tissues, and the lack of
distinguishing systemic features.*^"
fi/lajor RAS
Major RAS is occasionally referred to as Sutton's dis-
ease or periadeuitis mueosa necrolica recurrens and is
less common (approximately 10% to 15"^ of all RAS)
yet more severe than minor RAS,*= Major RAS lesions
are similar in appearance to those of minor RAS; how-
ever, they are larger than 10 mm in diarneter, are
deeper, often scar, and can last for weeks to months
(Fig 2), These lesions have a predilection for lips,
tongue, soft palate, and the palatal fauces and cause sig-
nificant pain and dysphagia. They are frequently found
in patients infected with human immunodeficiency
virus (HIV)'"'^^"''^ perhaps because of the amplification
of local immune imbalance secondary to
95
Shi p et al
TABLE 1 Possible causes of recurrent aphthous
stomatitis
Local and oral factors
Allergy to SQdium lauryl sulfate in toothpaste
Trauma
Salivary gland dysfunction
Microbiai causes
Bacterial: streptococci
Viral: human herpes 6, heipes simplex, cytomegalovirus,
Epstein-Barr, varicella zoster
Systemic conditions and laclors
Behcet's disease
Crohn's disease
Cyclic and autoimmune neutropenia
Human immunodeficiency virus infection/
acquired immunodeficiency syndrome
Mouth and genital ulcers with inflamed cartilage (MAGIC]
syndrome
Periodic fever, aphthosis, pharyngitis, adenitis (PFAPA)
syndrome
Reiter's syndrome
Stress
Systemic lupus erythematosus
Nulntionai and aliergic conditions
Toothpaste allergies
Food allergies
Folie acid, iron, selenium, and zinc deficiencies
Gluten-sensitive enteropaihy
Vitamin B,, Sj, Bj, and B, deficiencies
Genetic actors
immunologie oondltions
Localized T-cell dysfuncticn
Antibody-dependent cellular cytotoxicity
Herpetiform RAS
The least common form of KAS is herpetiform aph-
thous ulcers, which afflict 5% to 10"/b of patients with
RAS.*- Multiple small clusters of pinpoint ulcers char-
acterize this rare form of RAS, and they occur through-
out the oral cavity (Fig 3). They tend to he small (2 to 3
mm) and numerous (ranging from 10 to 100 ulcers)
but can hecome confluent to produce larger, plaque-
form, irregular lesions. Lesions last 7 to 30 days and
have the potential to scar. Although these lesions are
herpeslike or herpetiform in nature, herpes simplex
virus (HSV) cannot be cultured from these lesions.'"
Fig 1 Minor recurrent aphthous stomatitis on the inner left aspect
of the lower lip.
DIAGNOSIS
Differential diagnosis
The diagnosis of RAS is typically established from the
history and clinical presentation. However, it is im-
portant to differentiate aphthous ulcers from other
Stomatologie mucocutaneous diseases that have ulcer-
ative manifestations (Table 2). Usually these condi-
tions ean be differentiated from RAS by the location
of the lesion and/or the presence of an additional
symptom. Herpes simplex virus infections may have
similar-appearing lesions; however, primary HSV in-
fections present witb a diffuse gingival erythema and
fever preceding oral mucosal vesicles and ulcers.
Also, recurrent HSV lesions are found primarily on
attached keratinized mucosa, such as the hard palate
or gingiva,^' Ulcers of RAS are not preceded by fever
or vesicles, and they occur almost exclusively on mov-
able oral mucosa, such as the huccal and labial mu-
cosa, tongue, and soft palate,'^
Recurrent aphthous lesions can he differentiated
from varieclia zoster virus (VZV) infections (shingles)
based on clinical presentation (VZV lesions have a
unilateral extraoral and intraora! distribution pattern
following the trigeminal nerve) and symptoms (VZV
infections have a prodrome of pain and hurning prior
to lesion eruption). Less common oral viral infections,
such as herpangina and band-foot-and-mouth disease,
should also be included in the differential diagnosis of
RAS when initial symptoms occur."'' However cox-
saekie virus-related oral ulcers present with other
symptoms, such as a low-grade fever or malaise, and
will resolve within 1 to 2 weeks.
96 iJumber2, 2000
Ship et al
Fig 2 Major recurrent aphthous stomatitis on the right dorsolat-
eral border of the tongue.
Fig 3 Herpetiform recurrent aphthous stomatitis on the inner as-
pect of the upper lip.
TABLE 2 Differential diagnosis of recurrent aphthous stomatitis
Difterential diagnosis
Recurrent aphthous
stomatitis
Herpes simplex virus
Vancella zoster virus
Herpangina
Hand-toot-and-mcuth
disease
Erythema multiforme
Oral lichen planus
Cicatricial pemphigoid
Pemphigus vulgaris
Oral signs
Single or multiple ulcers
on unattached mucosa
Single or multiple ulcers
on attached mucosa
Diffuse gingival erythema
Extraoral and intraorat ulcers
Unilateral distribution
i^ultiple ulcers in hard palate,
soft palate, and cropharynx
Ulcers preceded by vesicles
Lesions on attached and
unattached mucosa;
lip crusting
May be preceded by herpes
infection
Erosive and reticular lesions
on buccal mucosa, gingiva.
palate, and tongue
White (Wickham s) stnae
Vesiculobuiious lesions on
attached and unattached
mucosa
Positive Nikolsky's sign
Vesiculobuiious lesions on
attached and unattached
mucosa
Positive Nikolsky's sign
Other signs and symptoms
May be associated with
cropharyngeal or
gastrointestinal ulcers
Preceding fever and mucosal
vesicles
Prodrome of pain and burning
May cause scarring and neuralgia
Fever and malaise
Skin lesions, low-grade tever,
and malaise
Sudden onsei ct skin macules
and papules
Target lesions en skin
May be asymptomatic
Lesions may occur on skin
Can atfect eyes and genitalia
Lesions may scar
Lesions can cccur on skin
Quinte s se
97
Shi p et al
Erythema multiforme presents with painful oral ul-
cers, but, unlike RAS, erythema multiforme lesions
occur on both attached and movable mucosa and usu-
ally involve crusting of the lips with skin macules and
papules.'" Approximately two thii'ds of patients with
oral lichen planus show ulcerative lesions, which pri-
marily occur on tbe buccal mucosa.^' However, sec-
ondary sites on tbe gingiva and hard palate will distin-
guish oral lichen planus frotii RAS. In addition, oral
lichen planus is not always painful, whereas pain is
usually the cbief complaint in RAS. Vesiculobullous
oral lesions that tend to rupture within hours of occur-
rence, resulting in painful erosions or ulcrations, are
characteristic of cicatricial pemphigoid^^^^ and pem-
phigus vuigaris.'^ These lesions may occur on both at-
tached and unattached oral mucosa, and a biopsy will
reveal a characteristic histomorphometric pattern.
Qtjite often, systemic disorders will present with
oral ulcers that are similar to tbose of RAS. These in-
clude systemic lupus erythematosus,'*-'^^ ulcerative col-
itis,'' Crohn's disease,^^"-'^ Behcet's disease,^" Reiter's
syndrome,-'^ and acquired immunodeficiency syn-
drome (AIDS) or HIV nfection.^''^5-sj A detaiied med-
ical history and thorough clinical examination are re-
quired to establish an accurate diagnosis.
Hypersensitivity reactions in the oral cavity can be
induced by a variety of allergens (eg, foods, gums,
mints, dental materials, metals, and medications) but
are often difficult to diagnose. !n allergic contact
stomatitis, common manifestations are burning sensa-
tions, erythetTia, and edema"*; aphthouslike ulcers do
not usually occur. If an allergy is suspected, a more de-
tailed patient history will be required, and allergy test-
ing should be considered.
Seroiogic, chemicai, and hmatologie findings
Full hmatologie screening of patients with RAS has
been proposed to reveal deficiency states of serum
ferritin, iron, folate, and vitamin B^.^^'^' Deficient
levels of serum ferritin or iron are tbe most common
findings occurring in 11% to 36''/b of patients with
j^S.=s.s'-9s Hemoglobin levels and red blood cell in-
dexes are generally within normal range in patients
with RAS"^^' ' and are similar to levels in control
patients." However, underlying anetnic states are
sometimes discovered on screening^"''^* and replace-
ment therapy may be attempted to resolve tbe ulcers.
Hmatologie screening of children with RAS is also
recommended, because it has been reported that 21%
of patients have sume type of hmatologie abnonnality,
most notably latent iron deficiency witbout anemia.'
Histopathologic findings
A histopatbologic specimen is rarely required for the
diagnosis of RAS, because of the nonspecific nature of
the ulcer. However, if another oral nuicocutaneous
condition is suspected (see the discussion on dilferen-
tial diagnosis), tben a biopsy may be necessary. In the
preulcerative phase there is a mild infiltrate of T4
helper-inducer lymphocytes, which becomes an infil-
trate of T8 cytotoxic-suppressor cells in the ulcerative
phase.'"' Extravasation of erythrocytes occurs at and
around the centers of the ulcer. At the ulcer's margins
there is an accumulation of neutrophilic granulocytes,
and there is formation of an exdate undermining the
oral epithelium with numerous phagolysosome-rich
macrophages.'"- Polymorphonuciear neutrophils are
the predominant cell type in tbe established lesion.""
Immunofiuorescence findings
Direct and indirect immunouorescence studies are not
sensitive or specific diagnostic tests for RAS, and there-
fore sbould not be utilized except to rule out other oral
mucosal diseases (eg, pemphigus and pemphigoid).
Direct immunofluorescence tests have demonstrated
that circulating immune complexes may play a role in
tissue damage in RAS,'""*'''^"' yet findings are usually
nonspecific."*^ Once tissue destruction and degeneration
occur, it is not unusual to find nonspecific deposition of
immunoglobulin and complement components along
the basement membrane zone or in vessel walls."^
Consultations
Several systemic disorders are associated with RAS,
and they can be undiagnosed or misdiagnosed,'" lead-
ing to a delay in effective therapy. Therefore, in the
patient with recrudescent RAS lesions, or persistent
minor or major RAS, consideration must be given to
an underlying systemic disease. Consultations with 1
or tnore medical specialists are recommended, de-
pending on the signs and syrnptotns of the disease.
Dermatology. The patient with chronic minor or
rnajor RAS or lesions resistant to primary or sec-
ondary therapy may need long-term mmunosup-
pressant medications. These patients require regular
supervision to monitor hmatologie, renal, hepatic,
neurologic, and oral health, which may become im-
paired secondary to medications. Medical specialists
in dermatology as well as internal medicine, rheuma-
tology, and endocrinology can assist oral health pro-
fessionals in tbe follow-up of these patients.
Otorhinolaryngology (ear, nose, and throat). The
differential diagnosis of RAS includes infectious (eg,
herpangina), vesiculobullous (eg, pemphigus), ulcera-
98
JJumber 2. 200D
Ship et al
tive (eg, Crohn's), and autoimmune {erythema multi-
forme) diseases, whicfi may also involve the oral
pharynx, larynx, and esophagus, The patient with
symptoms of pain or partial obstruction in the throat,
dysphagia, or any other laryngeal or esophageal
problems should be referred to an otorhinolaryngolo-
gist for direct laryngoscopy.
Gastroenterology. Aphthous lesions may be as-
sociated with inflammatory bowel disease, such as
ulcerative colitis^ and Crohn' s disease."^^' ' 5
Aphthouslike ulcerative lesions often precede or co-
exist with intestinal symptoms.'"' Therefore, gas-
trointestinal endoscopie examination may be re-
quired for a definitive diagnosis.
Ophthalmology. A basic ophthalmologic exami-
nation should be conducted if Behefs disease^*'-"'"*"
or Reiter's syndrome^" is suspected. Behcet's disease
is associated with oral and genital aphthae and ocu-
lar inflammation (uveitis or iritis); however, the diag-
nosis of Behefs disease is rare without the presence
of oral ulcers.*^ The diagnosis of Behefs disease
should not be made premattirely, because the prog-
nosis may be grave and the treatment may be toxic.'^
Oral lesions, often with ulcration, occur in lOP'o of
cases of Reiter's syndrome in which arthritis, con-
junctivitis, and urethritis are classic symptoms.-"" Iritis
and uveitis may also occur in patients with inflam-
matory bowel disease.**-
Infectious disease. Oral RAS lesions are com-
mon in HIV-positive and AIDS patients,-"''^-^= and
a number of different concurrent intraoral lesions
among HIV-infectcd persons are associated with se-
vere immunosuppression and AIDS.^^ Infectious
diseases that result in oral aphthae (HIV or AIDS)
and other viral infections (HSV, VZV, coxsackie
virus) that are included in the differential diagnosis
of RAS may require concomitant therapy provided
by specialists in infectious disease.
Allergy. Oral hypersensitivity reactions [eg, foods,
gums, mints, dental materials, metals, and medica-
tions) can cause oral mucosal changes,"'^ and aller-
gic reactions such as gluten entcropathy may pro-
duce oral aphthae.^' If an allergic or hypersensitive
reaction is suspected, the patient should be referred
to an allergist.
Hematology/internal medicine. The complete
blood count of the RAS patient with signs and
symptoms of malabsorption or nutritional deficien-
cies should be monitored; serum ferritin, folate, and
vitamin B,, levels should also be evaluated for defi-
ciencies.^"" Specialists in hematology and internal
medicine can assist in the diagnosis and/or treat-
ment of these patients.
PATIENT MANAGEMENT AND TREATMENT
Goals of treatment
Treatment of RAS has 4 major goals; (Ij ulcer man-
agement (to promote healing and reduce duration),
(2) pain management (to reduce morbidity and en-
hance function), (3) nutritional management (to en-
sure adequate food and fluid intake), and (4j disease
control (to prevent recurrence or reduce frequency).
The relative importance and priority of each goal de-
pends on the severity of the condition." For example,
minor and infrequent RAS may only require brief
pain management. Alternatively, major RAS, frequent
minor RAS. and herpetiform RAS are all associated
with greater discomfort, severity, and duration of
symptoms that require intervention and nutritional
management.'^'" Furthermore, because several sys-
temic conditions are associated with RAS, possible
underlying causes must be ruled otit before a treat-
ment strategy' is selected.'"^
Evidence to support drug therapy
Evidence to support drug therapy for RAS has im-
proved recently, in part, because of the greater preva-
lence of immunocompromised patients with major
RAS.^^^^'"' In addition to drugs, several treatment
modalities for nutritional deficiencies and systemic
disorders have been evaluated for tbeir effect on RAS
and have been reported to have variable success
(these are discussed later). The best therapeutic choice
should target the primary treatment goal, based on the
severity of disease; must be supported by scientific evi-
dence; and should have a high therapeutic index with
few or tolerable side effects.
Initiation of drug therapy
Many patients with RAS experience several episodes a
year in which lesions heal within 5 to 10 days. These
patients may only require palliative therapy for pain.
However, the patient who experiences multiple
episodes each month, and/or presents with symptoms
of severe pain and difficulty in eating, drinking, chew-
ing, and swallowing, should be considered for more
extensive drug therapy.
Choice of drugs
Primary line of treatment. Topical gels, creams,
and ointments. The primary treatment of RAS le-
sions utilises topical anti-inflammatory agents. The
problem with topical gels, creams, and ointments,
however, is establishing effective drug delivery, be-
OuintessiTice l
99
Shi p et al
TABLE 3 Topical therapy for recurrent aphthous stomatitis
Medicafion Concentration
Geis, creams, and ointments'
Fiuocinonide
Triamoinoione
Clobetasol
Amlexanox
0,5%
0.025%
0.5%
5%
Doxymycline-cyanoacrylate
Rinses*
Sucralfafe
Tefracyoline
Lidocaine
hydro chloride
Diphenhydramine
Dyclcnine
hydrochioride
Dexamethasone
"FIjocinonide. tnamc
1 g/10 mL
2 2 mg/mL
2% VISCOUS
12.5 mg/5 mL
1 % soiution
0.5 mg/5 mL
Dosage
0,5 cm/0.25 inch
0.5 cm/0.25 inch
0.5 cm/0.25 inch
0.5 cm/0 25 inch
0.5 om/0.25 inch
5-mL rinse qid
5-mL rinse qid
5-mL rinse qid
5-mL rinse qid
5-mL rinse qid
5-mL nnse qid
Mechanism of action
Corticosferoidanti-intiammatory
Corticosteroidanti-intiammatory
Corticosteroidanti-intiammatory
Anfi-inflammatory and antialiergic
Mucosal adherent
Protective effectbinds proteins at
the tjicer surface
Antimicrobiaireducescoliagenase
activity
Analgesic
Analgesic
Analgesic
Corticosieroidanti-inflammatory
nolone, or clobetascl can be combined with Orbase to improve mucosal adher-
en ce,
'Tetracycline, lidocaine, diphenliydramire, dydonine, or dexa
nethasone maybe combined in a 1:1 mix
witli sucrairate, Kaopeclate (aiiapulgite) (Upjohn), or Maalox (aiuminurr hydranide, magnesium hydroxide)
(Rhcne-Poulerc) tot palliative relief. Other combinations of more ttian one o these, or similar agenls, can
be reviewed with a pharmacist.
cause substances applied to mucosal surfaces are
inevitably rubbed or rinsed away."' This problem is
addressed by using strong topical corticosteroids
which, when compounded with mucosal adherents
(eg, Orbase, Bristol-Myers Squihb; isobutyl cyano-
acrylate or Iso-Dent, Ellman International) are ef-
fective despite limited contact time.^' "=
The efficacy of topical agents can he increased
markedly if they are administered during the early
phase of ulcration (ie, when lymphocyte activity
is at its maximum"^). Clinicians should be cognizant
of the potential of topical glucocorticoids to cause
aeute pseudomemhranous candidiasis.'"'" However,
the use of topical glucocorticoids will diminish the
risk of suppressing the hypothalamic-pituitary-adrenal
axis system, a frequent complication of systemic gluco-
eorticoids,"''-"^
The topical glucocorticoids that have demonstrated
efficacy for RAS are fluocinonide,"' ' "' "" triam-
cinolone,'"'^" and elobetasol.**^'"^"'Triamcinolone ace-
tonide with Orbase (a mucosal adherent), however,
may not he as effective as stronger glucocorticoids,
such as fluocinonide and clobetasol. Therefore, fluoci-
nonide (see Drug Monograph, page 109} or clobetasol,
used alone or mixed with Orbase, may be preferable
for the treatment of recurrent RAS.'" Another topical
paste with anti-inflammatory and antiallergic proper-
ties is 5% amlexanox (see Drug Monograph, page 110),
which has demonstrated clinical safety and efficacy in
several vehicle-controlled multicenter clinical stud-
ies,'-'-'-'' Application of paste directly to ulcers, 4 times
daily, resulted in enhanced resolution of pain and heal-
ing of ulcers with minimal adverse experiences.
Several other topical medicaments have been used
with encouraging research results, although additional
investigations are required to establish reliable safety
and efficacy data. Topical prostaglandin E; may have
useful prophylactic activity,'^^ and oral human inter-
feron-a may assist in ulcer remission.'^^ A single topi-
cal treatment with doxymycine-cyanoacrjflate was re-
ported to relieve the intensity of pain for 6 days after a
1-day latency period.'^' Hydroxypropylcellulose film,
or Zilactin [Zila Pharmaceuticais), is a topical medica-
tion with mucosal adherence properties; it has been
demonstrated to adhere to rnucosa significantly longer
than Orbase and may protect the existing ulcer and
provide pain relief.'-*-'^"
Topical rinses. Topical rinses can also effectively pro-
vide symptomatic relief for minor aphthous ulcers
(Table 3), These rinses may be used alone or in combi-
nation with other topical drugs, A decrease in the
severity or number of ulcers may he observed during
treatment with these rinses; however, none provides
prevention or a cure, Sucralfate, which acts by locally
100
i 2, 2000
Shi p et al
hinding to proteins at the base of an ulcer, providing a
protective covering.'"*' may be useful for the relief of
pain resulting from minor RAS.'^- Dexamethasone
elixir (0.5 mg/5 mL), used as a mouthwash or gargle,
can he helpfitl for multiple minor, major, or herpetiform
ulcers that are difficult to treat with topical gels."^''''
Tetracycline ean reduce ulcer duration, size, and pain
because of its ability to reduce collagenase activity.'^-' ' "
Patients should be instructed to swish for up to 5 min-
utes and spit several times a day. Other orai rinses, such
as chlorhexidine gluconate,"*'^*-'^'' benzydamine hy-
drochloride,'^'^'^* Listerine (Warner-Lambert),"^ tri-
closan (Earnest |ohn Group),'-"' aqueous hydrocorti-
sone."' and triameinolone aqueous suspension,'-" have
been reported to provide some relief. However, further
clinical research studies are needed to establish defini-
tive results for all of these topical rinses.
Treatment ot nutritional and hmatologie deficiencies.
Several deficiencies have been reported at higher rates
among patients with RAS compared to non-RAS and
healthy controls, providing a rationale for the evalua-
tion of nutritional and hmatologie deficiencies,"''*'
Vitamin B deficiencies have been reported to be asso-
ciated with RAS and may. occasionally, be the primary
cause of RAS: deficiencies in vitamin B (tbiamine defi-
ciency"-58), vitamin B, (riboflavin deficiency^*), B^
(pyridoxine deficiency^*), and vitamin B^^ (pernicious
atiemia''''^-"'). Deficiencies in zinc," folie acid,='-^'
iron,^'-'^' and selenium-* bave also been associated
witb RAS-like ulcers. These deficiency states may all
have an adverse influence on the immune system,
which may explain, in part, tbeir possible connection
to RAS, Regardless of etiology', replacement therapy is
justified when a deficiency is identified,*''-
Avoidance of allergy-causing foods. Food sensitivity
and allergies to other suhstances should be considered
as an etiologic factor in hematologically normal pa-
tients with recurrent oral ulcration.'-*" For example,
gluten enteropathy may be a causative factor in RAS,
and withdrawal of gluten from the diet has been re-
ported to help eliminate aphthous ulcers in some stud-
ies53.109.145 but not in others,'-" One potential etiologic
tnechanism of RAS is delayed-type hiTiersensitivity, or
cell-mediated response to an antigenic stimulus.^"
Therefore, any material (food, beverage, medication,
toothpaste, chewing gum. mint, etc) that comes in con-
tact with the oral mucosa must be considered and
evaluated as a potential causative agent.
Sodium lauryl sulfate (SLS), a detergent commonly
used in toothpastes, has been reported to increase the
recurrence rate of RAS in several studies.^"-'^ This effect
may be related to destahilizafion of cell membranes by
SLS and its denaturing capacity, which increases oral
mucosal permeability and may cause epithelial desqua-
mation of oral soft tissues.'^= Patients with SLS-related
adverse reactions should use toothpastes that do not
contain SLS (eg, Biotene antibacterial dry-mouth
toothpaste, Laclede lne; Rembrandt whitening tooth-
paste for canker sore prevention, Den-Mat).
Elimination of possible allergens (eg, glutens, nuts,
strawberries, and tomatoes) may have no benefit un-
less the restricted item has been demonstrated to
cause hypersensitivity or allergic reactions. Available
data on the role of food allergies and sensitivifies in
RAS are inconsistent. Several studies have reported a
relationship,^'== while others have not established
food allergies in the etiopathogenesis of RAS.'-''''-'^
Alternatively, elimination diets, not diet diaries, have
been used successfully in identification of particular
offending foods in a small subgroup of RAS patients,'*'
Eliminafion diets require motivation and strict compli-
ance, and the offending agents found vary from pa-
tient to patient.
Other approaches to therapy. Another approach to
treatment is to convert the ulcer into a wound'" by
using chemical cautery,'-" electrocautery, or lasers,''^'^''
Ultrasound has been suggested to provide a beneficial
effect on RAS.''' Stress management, relaxation, and
imagery training are additional therapeutic approaches
that have demonstrated some clinical benefits.''^
Conversely, no associafions have heen established be-
tween RAS and the premenstrual period, pregnancy,
or menopause, and there are no consistent data to sug-
gest that ovarian hormones can be used as an effective
therapeutic modality.'''
Treatment of underlying systemic disease. Several
systemic disorders have been associated with RAS (as
already discussed), and identification and treatment of
these conditions is an important step in the treatment
of RAS. Oral aphthous ulcers may be the first clinical
sign of a systemic disorder, making clinical judgment
difficult. Treatment of numerous systemic conditions
(including Crohn's disease"-"; Behcet's disease^^"^";
cyclic neutropenia^-'"'^; a syndrome of periodic fever
that resembles human cyclic neutropenia'"; autoim-
mune neutropenia'*; pernicious anemia-*'; systemic
lupus erythematosus-'; HIV infection^*-"; periodic
fever, aphthosis, pharyngitis, and adenitis [PFAPA]
syndrome-'-'; and mouth and genital ulcers with in-
flamed cartilage [MAGIC] syndrome-'^''') has been as-
sociated with improved RAS lesions. Because resolu-
tion of oral symptoms commonly follows effective
systemic therapy, multidisciplinary care is recom-
mended for patients with oral manifestafions of these
systemic conditions.
Secondary line of treatment. For the patient whose
symptoms are not relieved by the primary line of treat-
ment or whose signs and symptoms warrant a more
aggressive treatment modahty, prednisone should be
considered for both HIV-negative3o.>->3>"4-iie and
siWTcy tfitiifnationar
101
Shi p et al
HIV-positive patients,"''''''i58 Prednisone, an anti-in-
flammatory and an immunosuppressive agent, can be
used in combination with topical geis and rinses.
Systemic prednisone therapy should be started at 1,0
mg/kg a day as a single dose in patients with severe
RAS and should be tapered after 1 to 2 weeks (see
Drug Monograph, page HI), Prednisone use has po-
tentiaily serious side effects, including insomnia, ner-
vousness, increased appetite, indigestion, diabetes mel-
litus, hirsutism, joint pain, and glaucoma. Importantly,
however, several studies have found the side effects to
be minimal, especially when prednisone is combined
with azathioprine and not used for extended periods
of time in the treatment of RAS, "-' "' ' ' ^ * ' ' ^ Most ad-
verse drug effects are related to treatment that persists
for more than 2 weeiis and can be minimized by re-
ducing drug dosages,'" When appropriate, alternate-
day therapy and prednisone intake as a single dose in
the morning will help reduce drug-related complica-
tions,"^'^^^ Alternate-day dosing allows cell-mediated
immunity, white blood cell subset levels, and potas-
sium excretion to become normalized on the off-day,
and the anti-inflammatory benefits of prednisone will
persist ionger than the hypothalamic-pituitary-adrenal
axis suppression."^
Prednisone can be combined with another immuno-
suppressive agent, azathioprine, to reduce the dosage
of prednisone required to provide effective treat-
jjjgfjj 45.i53,iso Ti^g potentially serious side effects of aza-
thioprine include thrombocytopenia, leukopenia, sec-
ondary infections, anemia, nausea, vomiting, anorexia,
diarrhea, and lymphoreticular and other malignancies
after long-term therapy,""''^ ^ Immunosupprcssive
drugs (eg, azathioprine) have been associated with the
development of cancers such as non-Hodgldns's lym-
phoma.'^^ Short- to medium-term therapy probably re-
sults in a slightly increased risk of malignancy, whereas
continuous therapy for more than 2 years is poorly
documented, and should be used cautiously,'^-
Drug-related safety and efficacy have heen demon-
strated when azathioprine is given as an initial dose of
50,0 mg per day for 1 week and then increased to no
more than 2,5 mg/kg daily with careful monitoring of
the complete blood count and platelet count,'^"^-'"'^
Azathioprine, used alone in topical form'"* or taken
systemically with topical dexamethasone,'" has also
been reported to help resolve RAS lesions. Use of
prednisone and azathioprine requires careful patient
monitoring to identify potential side effects as early as
possible as well as to evaluate the effectiveness of the
treatment. Consultation with other medical specialists
is recommended for patients who are prescribed long-
term immunosuppressive therapy.
Tertiary line of treatment. Tbaiidomide {see Drug
Monograph, page 112), an inhibitor of tumor necrosis
factor-K, has been sbown to be an effective treatment
for severe RAS, despite the potential for significant
side effects.-'"'"-''' Use of tbaiidomide in children has
been documented with some success, but iotig-term ef-
fects have not been established.'" Thalidomide therapy
has been more tboroughly researched in HIV-positive
patients,-*"'""^ One study I'eported that HIV-infected
patients with RAS experienced significant improve-
ment, diminished pain, and an increased ability to eat
after a 4-week course of 200 mg of thalidomide daily
when compared to a placebo.''" However, tbe dose was
reduced or completely terminated in approximately
2O0/0 of patients because of toxicity (eg, rash, somno-
lence, or peripherai sensory neuropathy).
Initial treatment in either HIV-positive or HlV-neg-
ative patients should be 100 to 200 mg of thalidomide
daily, depending on the severity of iesions and the pa-
tient's tolerance. Once remission has been accom-
plished, tberapy may be stopped until ulcers recur. If
there is recurrence, the initial regimen should be re-
peated until remission, and then a maintenance
dosage of 50 to 100 mg daily or 50 mg every other day
should be attempted. The maintenance dosage should
be tapered as much as possible to minimize side ef-
fects. Because of the established teratogenic capacity
of thalidomide, strict precautions must be talien in
women of child-bearing ages (see Drug Monograph),
Levamisole [150 mg daily), an immunotherapeutic
drug, may also be an effective treatment for RAS. A re-
cent open iabel study'" and several randomized, dou-
bie-blind studies'"""'"" reported significant reduction in
pain, number, and duration of aphthae and frequency
of episodes after a course of levamisole. However, at
least 3 similar studies did not report any signiflcant
differences in symptoms between treatment and
placebo groups,'^'-'"^
Several other immunomodulating and anti-inflam-
matory drugs, including colchicine,'*'-'** cyclo-
sporine,'*"^'** pentoxyfylhne,''^"''*' azelastine,'^- and
dapsone,"-''"'' have shown some effectiveness for treat-
ment of RAS in case studies and open trials. Lysine,
an amino acid required for protein synthesis, was re-
ported to have effective prophylactic and bealing char-
acteristics."' '''' Most of these drugs require further
research to demonstrate safe and effective use in pa-
tients with RAS,
Adjunctive therapy
Supportive therapy for persistent and painful RAS le-
sions includes topical analgesics, fluids, and protein,
vitamin, and minerai supplements. For many individu-
is, painful aphthous lesions impair mastication and
deglutition, and therefore patients should he encour-
aged to maintain fluid and nutritional intake. Dietary
102
Volume 3-] Niimha. 2, 2000
Shi p et al
supplements, such as Ensure (Abbott Laboratories) or
Sustacal (Mead Johnson Nutritionals), may be indi-
cated for severe cases. Foods and beverages that exac-
erbate pain sbouid be avoided: acidic foods; crusty,
hard, and difticult to chew foods; spicy or salty foods;
citrus fruits and liquids; and alcoholic beverages.
Patients should be encouraged to maintain daily
oral hygiene. If dentifrices or mouthwashes precipitate
or exacerbate RAS lesions, patients should use less ir-
ritating agents and those that do not contain sodium
lauryl sulfate (eg, Biotene antihacterial dry-mouth
toothpaste or Rembrandt whitening toothpaste for
canker sore prevention). Topical anesthetics are
widely used to treat the painful symptoms of RAS.
Oral discomfort may be relieved witb topical anesthet-
ics, such as 2'^k viscous lidocaine hydrochloride (Xylo-
caine, Astra), diphenhydramine elixir (Benadryl,
Parke-Davis), dyclonine hydrochloride (Dyclone,
Astra), and sucralfate (Carafate, Hoechst Marion
Roussel) (see Table 5).
SUMMARY
RAS is the most common oral mucosal disorder found
in men and women of all ages, races, and geographic
regions. The 3 classic forms of lesion are minor, major,
and herpetiform. Considerable research attention has
been devoted to elucidating the causes of RAS; local
and systemic conditions, genetic, immunologie, and
infectious microbial factors all bave been identified as
potential etiopathogenic agents. However, to date, no
principal etiology has been discovered.
The goals of current treatments are to quickly pro-
mote ulcer healing, to reduce ulcer duration and pain,
to allow the patient to maintain nutritional intake, and
to prevent recurrence or to diminish frequency of oc-
currence. Therapies range from topical anti-inflamma-
tory and analgesic preparations to systemic glucocorti-
coids and immunomoduiatory drugs.
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RECURRENT APHTHOUS STOMATITIS: R^ FLUOCINONIDE
Fluocinonide. a high-polency topical corlicosteroid. has anii-intlammalory and vasoconslnctive ac-
tions. The mechanism of action is not weii defined; however. I is believed to result trom a combina-
tion of 3 properties: anti-inflammatory, immunosuppressive, and antiproiiferative- Drug upfate is by
absorption following topical application. The extent ot absorption is dependent on the amount ap-
plied, the vehicle, the mucosai integrity, and the use of occlusive dressings. Foiiowing absorption,
the drug is protein bound, metaboiized in the liver, and then removed by the kidneys. Pregnancy risk
factor C.
Ship el al
1 . Indications
2. Contraindications
3. Drug interactions
4. Administration
(route and dosage)
5. Monitored efficacy
and tovicity
6. Length of
treatment
7. Cessation of
treatment
8. Instructions to
the patient
Drug ot choice for Ihe management of minor aphthous ulcers and as an adjunct to prednisone
and other systemic immunosuppressive therapy tor major recurrent aphthous stomatitis.
History of adverse reaction to lluocinonide.
Infections (virai, fungai, or bacleriai): In the presence of infecfion, appropriate adjunctive treat-
ment should be insfituted.
Low doses should be used in patients witn glaucoma, osteoporosis, diabetes meiiifus. or psy-
choses.
diateiy
None is known.
0.5 cm (V; inch) of gei is appiied topically to the affected area, up to 5 times daily, imme
following meais and orai hygiene and at bedtime.
Dosage form: 0.05% gei in 15-, 30-, 60-, and 120-g tubes.
Apply as soon as symptoms of ulcer are noticed.
Monitor the patient for reiief of symptoms, remission, or resoiution of lesions.
Extended use may increase the risk of developing oral fungai infections.
In some patients, topicai corticosteroids have been absorbed in amounts adequate to produce
reversible hypothalamic-pituitary-adrenai axis suppression, manifestations of Cushing's syn-
drome, and hyperglycemia as a function of dosage, duration ot treatment, and the surface area
covered An attempt should be made to reduce the frequency of applicalicn, to substitute less
potent topicai corticosteroids, or to withdraw the drug. Chiidren may absorb larger amounts of
topicai corticosteroids and are therefore more susceptibie to systemic toxicity.
Continue Ireatment untii there is significant improvement, and then begin to laper the number of
applications.
If significant reduction in pain and healing have not occurred in 10 days, consider additicnai pri-
mary and/or secondary lines of treatment.
Taper siowiy and watch for exacerbation of disease.
As soon as symptoms of ulcers are noticed, apply 0.5 cm {'A inch) of gel direcfly to Ihe uicers,
up to 5 times daily, immediately following meais and oral hygiene and at bedtime.
Avoid contact wifh eyes. If contact occurs and irritation ensues, immediately tiush with a large
volume of water.
Report any signs of iocal adverse reaction.
Inform aii your health care providers that you are using fiuocinonide.
For additional information, please review the manufacturer's recommendations.
Qu iitessadce international
109
Ship et ai
RECURRENT APHTHOUS STOMATITIS: R^ AMLEXANOX
Amlexanox is a toploai anti-inflammatory and antialiergic drug. It inhibits chemical mediatory
release of the slow-reacting substance of anaphyiaxis and may have antagonist effects on in-
terleukin-3: however, the mechanism by which amlexanox accelerates the healing of aphthous
ulcers is unknown. Most systemic absorption probabiy occurs in the gastrointestinal tract after
swallowing the 5% amlexanox paste rather than directly through the ulcer. Amlexanox is me-
tabolized to a hydroxylated and conjugated product, and 17% is excreted unchanged.
Pregnancy risk factor B.
1 . Indications
2. Contraindications
3. Drug interactions
4. Administration
(route and dosage)
5. Monitored efficacy
and toxicity
6. Length of
treatment
7. Cessation of
treatment
8. Instructions to
the patient
Drug of ohoice for the management ot minor aphthous ulcers and as an adjunot to prednisone
and other systemic immunosuppressive therapy for major recurrent aphthous stomatitis.
History of adverse reaotion to amlexanox.
Infections (viral, fungal, or bacterial). In the presence ot infection, appropriate adjunctive treat-
ment shouid be instituled.
None is known.
0.5 cm (% inch) of paste is appiied topically to the aflected area. 4 times daily, immediateiy fol-
lowing meals and orai hygiene and at bedtime.
Dosage form: 5% paste in 5-g tube.
Appiy as soon as symptoms of ulcer are noticed.
Monitor the patient for relief of symptoms, remission, or resolution ot lesions.
Ingestion overdose may cause gastrointestinal upset (diarrhea and vomiting).
Continue treatment until there is significant improvement, and then begin to taper the number ot
appiications.
If significant reduction in pain and heaiing have not occurred in 10 days, consider additional pri-
mary and/or secondary lines ct treatment.
Taper slowly and watch tor exacerbation of disease.
As soon as symptoms of ulcers are noticed, apply 0.5 cm {'A inch) of paste directly to the ulcer,
4 times daily, immediateiy foilowing meals and oral hygiene and at bedtime.
Avoid contact with eyes, it contact occurs and irritation ensues, immediately flush with a iarge
volume of water.
Report any signs of locai adverse reaction.
- Inform ali your health care providers that you are using amlexanox.
For additional information, please review the manufacturer's recommendations.
110
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ShiD et al
RECURRENT APHTHOUS STOMATITIS: R^ PREDNISONE
Prednisane. a glucocorticosteroid. decreases inflammation by suppressing ciiemotaxis ol polymor-
phonuelear neutrophil leukocytes and reducing capillary permeability. It is an immunosuppressant
that reduces lymphocytic activity and suppresses adrenal function. It is tiigtiy protein bound after
absorption into the vascular compartment. Prednisone is rapidly metabolized in the iiver (pred-
nisoione is the active metabolite) and eliminatod in the kidneys (tiaif-tife: 18 to 36 hours). Pregnancy
risk factor B.
1 . Indications
2. Contraindications
3. Drug interactions
4. Administration
(route and dosage)
5. Monitored efficacy
and toxicity
6. Length of
treatment
7. Cessation of
treatment
e. Instructions to the
patient
When the lirst line of treatment has been ineffective, or when signs and symptoms are more se-
vere and prolonged (eg, major aphthous ulcers or herpetiform aphthae).
History of adverse reaction to prednisone.
Infections (viral, fungal, or bacterial): In the presence of infection, appropriate adjunctive treat-
ment should be instituted.
Concurrent administration witn a vaccine.
Use witfi caution in patients witfi gastrointestinai uicerations, diabetes, glaucoma, psychoses,
renal disease, osteoporosis, seizures, congesti^ie heart failure, and hypertension,
Decreases effects of anticoagulants.
Increases metabolism ot isoniazid and salioyiates,
Causes hyperglyoemia, resulting in a need to adjust doses of insulin or otfier hypoglycmie
agents,
Increases risi< of gastrointestinal irritation with concomitant use of uicerogenic agents, suoh as
nonsteroidal anti-intlammatory drugs,
Oraily, taken with food or milk.
Dosage forms: 1.0-, 2.5-, 5.0-, 10.0-, 20.0-, 25.0-, and 50,0-mg tablets: 5-mg/5-mL syrup.
Dose is individually titrated in accordance with the patient s response.
initially, give 1.0 to 1.5 mg/kg a day for 1-2 weeks, monitor the patient's response.
If there is no response, the dosage should be increased in 0,25-mg/kg increments a day until
the lesions respond, compiications anse, or a dosage of 2.0 to 2.5 mg/i<g is reached.
2.0 mg/kg of azathioprine can be used in combination with prednisone and during the pred-
nisone taper (azathioprine also requires strict monitonng and precautions, see text).
Monitor the patient for relief of symptoms, remission, or resolution of lesions.
Early signs and symptoms of toxicity
Fluid and eiectroiyte disturbances: hypertension.
Hyperglycemia, poiydypsia, poiyphagia, orpolyurea.
Increased susceptibility to infectionTreat infections aggressively,
Acute psychosisParticularly in patients with psychoiogic disorders receiving more than 40,0
mg of prednisone daily.
Peptic ulcer diseaseEspecially in patients taking nonsteroidal anti-inflammatory drugs, con-
sider an Hj blocking agent for prophyiaxis.
Late signs and symptoms of toxicity:
Gushing's syndrome: moon tacies, buffalo hump, hirsutism, obesity.
Hypothalamic, pituitary, and adrenal axis suppressionUsuaily occurs after 3 weeks of treat-
ment: taper dosage as soon as possibie. -,. , ^
Osteoporosis and osteo nee ros isPatients should be instructed to supplement diet with 1.0
q/day of elemental caicium and to report any joint pain or discomfort.
CataractsIt a 15,0-mg dosage of prednisone is maintained for more than 1 year, instruct the
patient to schedule annual ophthalmoiogic examinations.
Continue treatment untii there is significant improvement, and then begin to taper dosage.
Aiways taper dosage. . , _, ^ ,
Siow taper aiiows for close monitoring for evidence ot exacerbation of disease and symptoms
. l l pe^ by To mg per week until 10 mg is reached, then taper by 2.5-mg increments untii discon-
tinued or the iowest effective dose is reached.
If withdrawal occurs, raise the dosage again and taper by 1 mg weekly.
Do not stop taking prednisone all at once.
Keep a good supply readiiy available.
If a dose is forgotten, resume taking the medication as soon as possible.
. Report any adverse etfects, such as joint pain, excessive thirst or urination, black, tarry stoois,
vision changes, etc. , . ^ . ,. . j
intorm all your health care providers that you are taking prednisone and at what dosage.
For additional information, please review the manufacturer's recommendations.
Ship et ai
RECURRENT APHTHOUS STOMATITIS: Rv THALIDOMIDE
Thalidomide. a derivative o glutamic acid, was first prescribed in he 1950s as a sedative and lo
prevent morning sickness in pregnancy, but was withdrawn from the world market in 1961 beoause
of severe teratcgenic effects. Recently, it iias been demonstrated that thalidomids is an immune-
modulator and is effective for the symptomatic treatment of certain cutaneous and mucooutaneous
disorders. The mechanism of action of the nonsedative effects is unofear; t^owever. it has been
shown to decrease the production of tumor necrosis factor a and inhibit leukocyte chemotaxis.
Pregnancy risk factor X.
1 . Indications
2. Contraindications
3. Drug interactions
4. Administration
(route and dosage)
5. Monitored efficacy
and toxicity
6. Length of
treatment
7. Cessation oi
treatment
8. Instructions to the
patient
Treatment ol severe recurrent aphthous stomatitis that is not controlied by topical or oral steroids,
iHuman immunodeiicienoy virus-positive patients with recurrent aphthous stomatitis.
Women who are pregnant or who oould beoome pregnant whiie taking the drug.
Women who are nursing a baby.
individuals with preexisting human immunodeficiency virus-reiated peripheral neuropathy or
enoephaiopathy.
Enhances the activity c( barbiturates, alcohol, ohiorprcmazine, and reserpine,
May antagonize the action cf histamine, serotonin, acetylcholine, and prostag land ins,
Dosage forms: 50-mg tablets,
initiai treatment: taken oraiiy, 100 to 200 mg daily, tor 2 months.
Maintenance: tai<en oraiiy, 50 tc 100 mg daiiy, or 50 mg every other day (taper ctcse as neces-
sary to maintain remission),
Monitor the patient tor reiiet of symptoms, remission, or resoiution of lesions,
- The neurologic status of the patient must be carefuily obsen^ed,
- May oause drowsiness, dizziness, si<in rash, mood changes, saiivary hypofunotion, headache,
nausea, constipation, increased appefite, facial and peripheral edema, thyroid dysfunction, dry
skin, pruritus, irreguiar menstrual period, neutropenia, changes in heart rate, altered blood
sugar levis, brittie tingernails, and decreased libidc.
Continue treatment until signiiioant improvement or remission is observed or the patient cannot
tolerate side eifeots, and then toliow maintenance therapy.
May be stopped abruptly,
Femaie patients
' Even 1 dose ol thalidomide, early in pregnancy, can produce signilicant birth deleots, including
stunted growth ot arms and legs and severe defects of vitai organs,
You must have a negative biood or urine pregnancy test to begin treatment and the test shouid
he repeated at least every month while you are tailing thalidomide and 4 weeks after your last
dose
You must abstain from sexual intercourse or use 2 highly effective and medicaliy approved birth
controi metnods beginning 1 month before and continuing 1 month after treatment,
Stop taking thalidomide immediateiy and report to your doctor if any of the foiiowing occurs: you
have a late or an irregular menstrual period, you stop practicing sexual abstinence, you stop
using birth control methods, you think that you are pregnant, or you become pregnant.
Male patients
Abstain from sexuai intercourse cr use a condom during intercourse while, and fcr 1 month
after, taking thalidomide, it is not known if thaiidomide is present m semen.
For ali patients
Do not give fhalidomide tc anyone fcr use because it can be extremely harmfui if used by
others
Thaiidomide often causes drowsiness; avoid drinking alcohol and taking other sedatives, it may
affect your ability to drive or operate machinery.
Thaiidomide may cause nerve damage: report to your doctor if you experience burning, numb-
ness, or tingiing of your arms, hands, iegs, cr feet.
Check with your doctor before taking any other medications,
If you develop a skin rash with or without a fever, changes in your heart rate, or icw blood pres-
sure, stop taking thaiidomide and contact your doctor,
Repcrt any side effects to your doctor. These inciude mood changes, dry mouth, headache,
nausea, constipation, increased appetite, puffiness of the face and iimbs, dry skin, itching, irreg-
uiar menstrual period, iow white biood celi count, thyroid problems, blood sugar that is too high
or too iow, brittie fingernaiis, decreased iibido, dizziness, and red palms.
For additionai information, please review the manufacturer's recommendations or visit the
web site of the manufacturer at http://www,celgene.com/thalomid.htm or the web site of
the US Food and Drug Administration at http://www.rda.gov/cder/news/thalinfo/default,htm