Recurrent aphthous stomatitis

17ol. 81 No. 2
February1996
REVIEW ARTICLE
Recurrent aphthous stomatitis
An update
Jonathan A. Ship, DMD, Ann Arbor, Mich.
DEPARTMENT OF ORAL MEDICINE, PATHOLOGY, SURGERY, UNIVERSITY OF MICHIGAN SCHOOL
OF DENTISTRY
Recurrent aphthous ulceration or recurrent aphthous stomatitis is the most common oral mucosal disease
known to human beings. Despite much clinical and research attention, the causes remain poorly understood, the ulcers
are not preventable, and treatment is symptomatic. The most common presentation is minor recurrent aphthous
stomatitis: recurrent, round, clearly defined, small, painful ulcers that heal in 10 to 14 days without scarring. Major
recurrent aphthous stomatitis lesions are larger (greater than 5 mm), can last for 6 weeks or longer, and frequently scar.
The third variety of recurrent aphthous stomatitis is herpetiform ulcers, which present as multiple small clusters of
pinpoint lesions that can coalesce to form large irregular ulcers and last 7 to 10 days. Diagnosis of all varieties is usually
made after clinical examination. Many local and systemic factors have been associated with these conditions, and there
is evidence that there may be a genetic and immunopathogenic basis for recurrent aphthous ulceration. Management of
this condition depends on the clinical presentation and symptoms and includes analgesic, antimicrobial, and
immunomodulatory drugs. As dental clinicians and researchers become better trained in oral medicine and stomatology,
it is anticipated that the pathophysiology, prevention, and treatment of recurrent aphthous ulceration will improve in the
future. (Oe.At SURG ORAt MED ORAL PATHOLORAl. RADIOLENDOD 1996;81:141-7)
Recurrent aphthous ulceration or recurrent aphthous
stomatitis (RAS) is the most common oral mucosal
disease known to human beings and has been the
subject of considerable clinical and research attention. The first use of the term aphthai in relation to
disorders of the mouth is credited to Hippocrates (460
to 370 BC). To date the causes remain poorly understood; RAS is not preventable and treatment is symptomatic. The most common presentation is recurrent,
round, clearly defined, small painful ulcers with
shallow necrotic centers, raised margins, and
erythematous halos. Diagnosis is usually made on the
basis of the patient's health history and clinical
examination. Many local and systemic factors have
been associated with these conditions, and there is
evidence that there may be a genetic and immunopathogenic basis for RAS. Furthermore, with the dramatic worldwide increase in patients with immunosuppression caused by medical treatments, systemic
Received for publication Apr. 17, 1995; returned for revision May
30, 1995; accepted for publication Aug. 1, 1995.
Copyright 9 1996 by Mosby-Year Book, Inc.
1079-2104/96/$5.00 + 0 718168478
diseases, or both, the prevalence of these conditions
may be increasing. There is no specific management
for RAS, and therefore analgesic, antimicrobial, and
immunomodulatory drugs have been used individually and collectively for symptomatic conditions. As
dental clinicians and researchers become better trained
in oral medicine and stomatology, it is anticipated that
the pathophysiology, prevention, and treatment of
RAS will improve in the future.
EPIDEMIOLOGIC FINDINGS
Although Hippocrates is credited with the first use
of the term aphthai in relation to disorders of the
mouth, the first valid clinical description of RAS appeared in 1888 by von Mikulicz and Kummel3, 2 RAS
is the most common oral mucosal disease observed in
human beings but its prevalence varies widely depending on the population studied. 3 In children, RAS
is the most common form of oral ulceration seen, 4 and
the peak age of onset is between 10 and 19 years. 5
After childhood and adolescence, it m a y continue
throughout the entire human lifespan. Epidemiologic
studies 2, 6-14 indicate that the prevalence is between
5% and 25% in the general population and as high as
141
142
Ship
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
February 1996
Fig. 1. Minor recurrent aphthous stomatitis ulcer.
50% to 60% in selected groups (for example, medical or dental students). Ship l~ also suggested that a
greater prevalence of the disease and severity of expression was associated with increasing social class.
It is possible that the actual prevalence of RAS is
greater than reported rates because of the recurrent
nature of the condition. Cross-sectional clinical surveys probably underestimate the true prevalence because active lesions m a y not be present at the time of
examination. 3
CLINICAL FEATURES OF RAS
The lesions of RAS are characterized by recurrent
ulcerations of the oral mucous membranes that occur
either singly or in multiple locations and are usually
associated with pain. RAS is divided into three varieties: minor recurrent aphthous stomatitis, major recurrent aphthous stomatitis, and herpetiform ulcers.
The more common form of RAS is the minor variety and is characterized by small round to ovoid lesions with a crateriform base, surrounded by a
distinct, raised, and erythematous halo (Fig. 1). These
lesions are generally less than 5 m m in diameter and
have a grey-white pseudomembrane. These lesions
heal within 10 to 14 days without scarfing. The most
common locations are on nonkeratinized oral mucosa
(labial and buccal mucosa and floor of the mouth)
with uncommon sites including the gingiva, palate, or
dorsal surface of the tongue. They may appear in the
form of " a t t a c k s " of single or multiple lesions but
can clearly be distinguished from primary or secondary viralinfections, bacterial infections (necrotizing
ulcerative gingivitis), dermatologic conditions (lichen planus, cicatricial pemphigoid, pemphigus), and
traumatic episodes (contusions, lacerations, burns) by
the healthy appearance of adjacent tissues and the
lack of distinguishing systemic features. 1~ Diagnosis
is generally made on the basis of history and clinical
Fig. 2. Major recurrent aphthous stomatitis ulcer.
presentation; there are no known laboratory procedures available for defnitive diagnosis, and histopathologic examination of biopsy specimens will not
provide a definitive diagnosis.
A severe but rare form of this condition is major
RAS or periadenitis mucosa necrotica recurrens and
occurs in approximately 10% of RAS patients. 15
These lesions are similar in appearance to minor RAS,
however, they are larger than 5 m m in diameter, often scar, and can last up to 6 weeks in time (Fig. 2).
Major lesions have a predilection for lips, soft palate,
and fauces and will cause significant dysphagia.
Painful ulcers resembling minor and major aphthous
lesions have been associated with human immunodeficiency virus (HIV) infection) 6,17 The major or minor
forms of RAS may be more common in HIV-infected
patients because it has been suggested that RAS represents a local breakdown in immunoregulation, a condition that could be amplified by HIV disease. 17
The third and least common form of RAS is herpetiform ulcers, which will occur in approximately
10% of patients with RAS. 15 Multiple small clusters
of pinpoint ulcers characterize this form of RAS, and
they occur throughout the oral cavity (Fig. 3). They
tend to be small (2 to 3 ram) and numerous (as many
as 100 ulcers at once), can fuse together to produce
large irregular lesions and can last 7 to 10 days. Although these lesions are herpes-like or herpetiform in
nature, herpes simplex virus cannot be cultured from
the lesions.
CAUSES OF RAS
There have been numerous proposed etiologic
mechanisms for RAS, including local, microbial,
systemic, nutritional, immunologic, and genetic factors (Table I). Nevertheless, despite much research,
the cause remains idiopathic or a result of a variety
of predisposing factors.
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ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
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Local Factors
Trauma has been often identified as a precipitating
factor, including anesthetic injections, sharp foods,
toothbrushing, and trauma from dental treatment.
However, many patients with RAS do not develop
lesions after trauma, 18 and edentulous patients are
unlikely to have lesions beneath dentures. 15 Nevertheless, minor trauma should be considered as one of
the precipitating factors in RAS. a9 Quantitative or
qualitative changes in salivary gland function have
been hypothesized to play a role in the pathogenesis
of RAS, however, most studies 21, 21 have not found a
definitive relationship.
Microbial Factors
It has been suggested that oral streptococci and
several viruses may play an etiologic role in RAS, but
overall the results are inconclusive. 22 In general, herpes simplex, varicella zoster, and Epstein-Barr viruses have not been directly isolated from RAS
lesions. 23 A recent study e4 demonstrated an association between RAS recurrences and reactivation of
varicella zoster virus and cytomegalovirus infection.
Pedersen 23 has suggested that the systemic and local
cellular immunosuppression associated with RAS is
consistent with a viral reactivation or is a result of a
latent viral infection of oral mucosa. Nevertheless,
further research is needed to definitively establish a
viral cause.
Systemic factors
RAS has been observed in several systemic disorders, including Beh~et's disease, 25 cyclic neutropenia, 26 mouth and genital ulcers with inflamed cartilage syndrome, 27 nutritional deficiencies with and
without underlying gastrointestinal disorders, 28 and
immunocompromised conditions including HIV infection. 29 Aphthous-like ulcers have been detected in
patients with Crohn's disease and ulcerative colitis
and other small bowel changes. 3~ The lesions in these
patients may occur at any time during the course of
the disease, can be present before any intestinal
symptoms occur, and may occur more frequently
when the intestinal problems become active. 31 These
ulcers are histologically similar to the intestinal
lesions of the disease. Deficiencies in iron, folic acid,
zinc, and vitamins B1, B2, B6, B12 32 have been detected in patients with RAS. Hematologic deficiencies in patients with RAS 33 may be related to abnormalities of the small intestine, including coeliac disease (gluten-sensitive enteropathy), although these
patients may not always have symptoms of bowel
disease. Food sensitivities and allergies to other substances can also cause ulcers in hematologically normal patients with recurrent lesions. 34
Fig. 3. Herpetiform recurrent aphthous stomatitis ulcers.
Some studies 7, 9 have associated stress with RAS,
however, a more recent investigation 35 revealed no
association between psychological life stress and recurrences of RAS. Nevertheless, the literature continues to report that stress may play a role in precipitating RAS, and severe emotional or environmental
stress should be contemplated in the clinical assessment o f RAS. No associations have been established
between RAS and the premenstrual period, pregnancy, or menopause. Furthermore, no properly
designed study has shown a therapeutic effect of
ovarian hormones on RAS, which suggests that the
lesions of RAS are not caused by changes in female
hormones. 36 In summary, systemic causes should be
considered in the evaluation of a patient with RAS,
although it is important to know that most lesions occur in patients who are otherwise healthy.
Genetic factors
Earlier studies by Ship et al.37 found that RAS had
a definite tendency to occur along family lines and
that the probability of a sibling developing RAS was
influenced by the parents' RAS status. 1~ A high correlation of RAS has been detected in identical twins
but not in nonidentical twins. 38 Nevertheless, there is
a clear variability in host susceptibility with a polygenic inheritance but a penetrance dependent on other
factors. 22 More recent investigations 22 have detected
associations between RAS and specific HLA subtypes, which indicates that RAS in certain persons
may have a genetic basis.
Immunopathogenesis
RAS may have primary immunologic abnormalities that result in altered immunoregulatory balances. 39 For example, there are increases in antibodydependent cell cytotoxicity4~ 41 and greater levels of
serum immunoglobulins 42 in patients with RAS.
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Ship
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
February 1996
Table I. Suggested causes of recurrent aphthous
stomatitis.
Local/oral factors
Trauma
Salivary gland dysfunction
Microbial
Bacterial: streptococci
Viral: varicella zoster, cytomegalovims
Systemic factors
Behqet's disease
Crohn's disease
Ulcerative colitis
Cyclic neutropenia
Mouth and genital ulcers with inflamed cartilage syndrome
HIV infection
Stress
Nutritional
Gluten sensitive enteropathy
Iron, folic acid, zinc deficiencies
Vitamin B1, B2, B6, B12 deficiencies
Genetic
Immunologic
Localized T-cell dysfunction
Antibody-dependent cellular cytotoxicity
Lymphocytes from patients with severe RAS demonstrate increased numbers of T-helper/inducer cells, 39
decreased numbers of T-suppressor/inducer cells, 39
and depressed responses to mitogens. 43 Activated Tlymphocytes aggregate in the periphery of RAS
lesions confirming the hypothesis that RAS represents an activated cell-mediated immune response. 44
Immunohistochemical studies of lymphocyte subsets
in aphthous ulcers of HIV-seronegative patients 45 and
HIV-seropositive patients 46 have yielded similar findings, which strongly indicates that these ulcers represent a cell-mediated immunologic dysfunction in
which infiltrating T-lymphocytes play a primary role.
It seems likely that in genetically predisposed persons, antibody-dependent cellular cytotoxicity mad
local immune complex-related reactions are involved
in the immunopathogenesis of RAS, but the precipitating factors are unknown. Unfortunately, to date no
consistent theory of immunopathogenesis has been
accepted. This information will be useful in the future
so that more effective treatment and preventive modalities can be identified.
TREATMENT A N D MANAGEMENT OF RAS
There is no specific treatment for RAS, and management strategies depend on the symptoms, duration,, severity, and when applicable, associated systemic conditions (Table II). The value of physical debridement of these lesions i s unknown. 47 Surgical
removal of ulcers has traditionally been ineffectual,
yet recently carbon dioxide laser therapy was shown
to be useful for RAS. 48
Table II. Currently recommended treatments of
recurrent aphthous stomatitis
Topical therapies*
Glucocorticoid creams/ointments
Triamcinolone acetonide (Kenalog 0.1% or 0.5%, or Kenalog in
orabase)
Fluocinonide 0.05% gel or ointment (Lidex)
Betamethasone valerate 0.1% (Valisone)
Clobetasol propionale 0.05% cream or ointment (Temovate)
Glucocorticoid elixirs
Dexamethasone elixir 0.5 mg/5 ml (Decadron)
Glucocorticoid injections
Triamcinolone diacetate 25 mg/ml (Aristocort-Intralesional)
Betamethasone sodium phosphatefoetamethasone acetate 6
mg/ml (Celestone Soluspan)
Antimicrobials
Chlorhexidine gluconate 0.12% (Peridex)
Analgesics
Dexamethasone elixir 0.5 rag/5 ml (Decadron)
Diphenhydramine HCI elixir 12.5 mg/5 ml (Benadryl)
Dyclonine HCI 0.5% or 1.0% (Dyclone)
Lidocaine HCI viscous 2% (Xylocaine)
All can be combined in a 50% elixir with sucralfate, Kaopectate,
or Maalox
Systemic therapiest
Medications
Glucocorticoids
Prednisone: 60 mg qd or qod for two doses decreasing to 40
mg, 30 mg, 20 mg, 10 rag, 5 mg (each qd or qod for two
doses)
lmmunomodulators
Azathioprine 50 mg bid (Imuran)
Nutritional replacements
Avoidance of allergens
Stress reduction
*Should be used before systemic therapy unless a systemic cause has been
identified.
]'May require coordination with physicians.
Patients with RAS as a result of systemic conditions should be referred to the appropriate health care
provider to treat the underlying disease. If stress is felt
to be a strong cofactor, consultation with behavioral
medicine, psychology/psychiatry, or both is warranted. For example, relaxation and imagery training
in patients with RAS produced a significant decrease
in ulcer recurrence and influenced patients' reports of
their overall psychological distress. 49 Concomitant
topical treatment with many agents may help diminish pain, hasten healing, and improve oral-pharyngeal
function. If there is a nutritional or vitamin deficiency, replacement therapy can be useful. 3a When a
food sensitivity is demonstrated from patch testing,
avoidance of the allergen can improve oral symptoms. 34 A gluten-free diet has been suggested for patients with RAS and gluten sensitive enteropathy,
however, a recent report 5~ indicated that it is not superior to placebo for RAS patients without gluten enteropathy.
Topical therapies include antimicrobial and anal-
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
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gesic mouth rinses, topical glucocorticoids, immunomodulators, and hormones. 22, 23, 51 The most common
topical therapy uses glucocorticoids, including hydrocortisone, triamcinolone, fluocinonide, betamethasone, and flumethasone. 22 These medications
can reduce symptoms and will not cause hypothalamic-pituitary-adrenal axis suppression when used
for less than 3 weeks. 52 Topically, greater efficacy
can be achieved w i t h stronger glucocorticoids that
should be administered for long-lasting, nonhealing,
or major RAS lesions. For example, clobetasol propionate ointment 0.05% in adhesive paste was used two
to three times dally in patients with persistent major
RAS, and five of seven patients experienced complete
remission with no major side effects. 53 This potent topical corticosteroid can be used if lesions are refractory
to weaker medications, and if effective, it may alleviate
the need to administer systemic glucocorticoids.
Topical glucocorticoids may also be helpful in patients with ulcers who are immunocompromised.
HIV-infected patients with minor and herpetiforrn
ulcers as well as some major lesions can experience
resolution from topical glucocorticoids without notable side effects. 29 Alternatively, severe cases of major RAS may require systemic prednisone. 29 When
systemic prednisone is used for severe recalcitrant
RAS in HIV-seronegative and HIV-seropositive patients, a 2-week tapering dose is recommended starting with 60 mg. Administration of glucocorticoids in
single dally doses compared with multiple daily doses
and on alternate-day regimens will help minimize
hypothalamic-pituitary-adrenocortical suppression. 54
Furthermore, the use of a combination of immunosuppressant (for example, azathioprine) and glucocorticoid may be effective in these patients. 55
Other immunosuppressive drugs including colchicine, which blocks the ability of serum to enhance
neutrophil migration, 56 cyclosporin, which suppresses
lymphocyte-dependent antibody response, 57 and thalidomide, which inhibits histamine-induced circulating immune-complex mediated damage 58 have been
used for patients with RAS; all require more extensive testing before clinical recommendations can be
made. An 8-week trial of topical cyclosporin mouth
rinses was helpful in eight patients with severe
RAS. 57 Another multicenter crossover randomized
trial used 100 mg/day thalidomide versus placebo for
2 months in patients with severe RAS. 58 Complete
remission was obtained in 32 of 67 patients, and thalidomide patients experienced a diminution in number of ulcers despite significant side effects (drowsiness, constipation, headache, and xerostomia).
Immunopotentiating agents such as levamisole,
which enhances cell- and humoral-mediated immunity, may be beneficial in patients with RAS. 59 Sire-
Ship 145
ilar drugs include transfer factor (extract of immunocytes6~ gammaglobulin, 61 and LongoVital (food
supplement that m a y increase T-lymphocytes62), but
all require comprehensive clinical testing before routine use in patients with RAS.
It has been postulated that RAS may be due to reactivation of one or more members of the herpesvirus f a m i l y Y and several immunomodulatory drugs
that also have nonspecific antiviral activities have
been tested in patients with RAS. Low-dose human
interferon alpha treatment (1200 IU/day, 1 minute
rinse + swallow) was used in a double-blind study in
19 patients with chronic minor RAS, and within 2
weeks all patients achieved total remission. 63 After
drug withdrawal, 11 of 19 patients did not experience
any recurrence during a 6-month observation period.
Interferon has been shown to have potent activity
against several infectious agents and possesses significant immune regulatory functions, which could
explain its potential usefulness with RAS.
Acyclovir (400 mg twice a day for 1 year) was used
in a double-blind study in 25 patients with RAS
without any benefit in the prevention of ulcers. 64 Alternatively, higher dosages (800 mg twice a day for
8 weeks) of acyclovir were used in one study of eight
patients with recurrent RAS, and six patients experienced either total regression of existing ulcers or relief of symptoms within 2 days of therapy. 65 As with
other immunomodulatory and antimicrobial medications, further investigations are required to identify
reliable and safe drug treatment strategies before treatment recommendations can be supported.
A variety of other medications may have direct
beneficial effects on the ulcers of RAS and should
receive further research attention. Tetracyclines have
recently been demonstrated to inhibit collagenase activity, and oral rinses were effective in alleviating the
discomfort caused by lesions. 21 Sucralfate is believed
to act primarily at ulcer craters to form a protective
coat that shields the lesion and promotes healing. A
prospective randomized, double-blind placebo-controlled, cross-over clinical trial with 21 patients reported
that after 2 years of follow-up, sucralfate was superior
to both placebo and antacid with respect to duration of
pain, reduction o f healing period, and duration of
remission. 66 Azelastine hydrochloride helps stabilize
cell membranes and suppresses reactive oxygen generation; 1 mg oral administration twice daily for 3 weeks
significantly diminished the frequency of occurrence,
the ulcer duration, and oral irritation in 43 patients. 67
There has also been interest in developing hormonal
medications for inflammatory conditions. Patients who
used prostaglandin E-2 gel (0.3 mg twice a day for 10
days) over a 10-day trial experienced significantly fewer
new lesions compared with placebo in one study. 68 A1-
146
Ship
tematively, no differences were observed in the duration
of healing and the pain o f lesions. 68
A n t i m i c r o b i a l rinses h a v e s o m e clinical e f f i c a c y
for the treatment o f R A S . In addition to tetracycline,
a c o m m o n l y used m e d i c a t i o n is c h lo r h e x i d i n e gluconate. S e v e r a l studies h a v e reported that this rinse
reduces the n u m b e r o f ulcer days, increases ulcer-free
days and the interval b e t w e e n bouts o f ulceration, but
does not p r e v e n t recurrence. 22 T o p i c a l tetracyclines
can also r e d u c e the severity o f ulceration 2t but do not
alter the r e c u r r e n c e rate o f R A S . 22 A n o t h e r potential
oral rinse is Listerine ( W a r n e r L a m b e r t Co., M o r r i s
Plains, N.J.). T w i c e - d a i l y rinsing with Listerine o v e r
a 6 - m o n t h p e r i o d r e d u c e d the duration and severity o f
R A S in o n e study. 69 Interestingly, both the Listerine
and the h y d r o a l c o h o l i c control m o u t h rinse significantly r e d u c e d the i n c i d e n c e o f R A S o c c u r r e n ces
f r o m baseline. 69
Finally, oral analgesic rinses can be prescribed if
patients h a v e c o n s i d e r a b l e pain. B e c a u s e protracted
R A S - a s s o c i a t e d pain can cause d y s p h a g ia and ev en tual nutritional i m p a i r m e n t , especially in y o u n g patients and i m m u n o c o m p r o m i s e d persons, these rinses
m a y p r e v e n t systemic sequelae. D e x a m e t h a s o n e elixir
(0.5 mg/5 ml), diphenhydramine elixir (12.5 rag/5 ml),
and dyclonine hydrochloride 0.5% or 1.0% can be used
3 to 4 times daily. They can be combined with sucralfate, Kaopectate (Upjohn, Kalamazoo, Mich.), Or
Maalox (Rhone-Poulenc Rorer, Ft. Washington, Pa.) to
improve drug adhesion to ulcers. Patients should be instructed that these rinses m a y reduce the gag reflex, and
therefore caution should be exercised during eating and
drinking to avoid possible airway compromise.
SUMMARY A N D CONCLUSIONS
M u c h progress has b e e n m a d e o v e r the last three
decades on the e p i d e m i o l o g i c information, c o m p l e t e
description, causes, and t r e a tm e n t o f recurrent aphthous ulcers. R A S r e m a in s the m o s t c o m m o n oral
m u c o s a l disorder and is f o u n d in m e n and w o m e n o f
all ages, races, and g e o g r a p h i c region. T h e three
classic f o rm s o f the lesions are minor, herpetiform,
and major. C o n s i d e r a b l e research attention has been
d e v o t e d to elucidating the causes o f these conditions,
and local and s y s t e m i c conditions, genetic, i m m u n o logic, and m i c r o b i a l factors all m a y play a role in the
pathogenesis o f R A S . H o w e v e r , to date, no principal
cause has b e e n discovered. T r e a t m e n t o f R A S includes the use o f topical and systemic glucocorticoids, topical analgesics, and antimicrobial drugs, and
i m m u n o m o d u l a t o r y and h o r m o n a l medications.
I greatly appreciate the careful review of the manuscript
by Professor Crispian Scully, of the Eastman Dental Institute, London, U.K.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
February 1996
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Reprint requests:
Jonathan A. Ship, DMD
Vice Chair, Associate Professor and Section Head
Oral Medicine/Hospital Dentistry
Department of Oral Medicine/Pathology/Surgery
University of Michigan School of Dentistry
Director, Hospital Dentistry
University of Michigan Medical Center
1011 N. University, Room 2010
Ann Arbor, MI 48109-1078