Download Pediatr Infect Dis J 2007 Aug 26(8) 728 32

REVIEW ARTICLE
Guidelines for Diagnosis and Management of Aphthous
Stomatitis
Felice Femiano, MD, PhD, Alessandro Lanza, DD, Curzio Buonaiuto, MD, Fernando Gombos, MD,
Monica Nunziata, DD, Silvia Piccolo, DD, and Nicola Cirillo, DD
Abstract: Aphthous ulcers are the most common oral mucosal
lesions in the general population. These often are recurrent and
periodic lesions that cause clinically significant morbidity. Many
suggestions have been proposed but the etiology of recurrent aphthous stomatitis (RAS) is unknown. Several precipitating factors for
aphthous ulcers appear to operate in subjects with genetic predisposition. An autoimmune or hypersensitivity mechanism is widely considered possible. Sometimes aphthous ulcers can be the sign of systemic
diseases, so it is essential to establish a correct diagnosis to determine
suitable therapy. Before initiating medications for aphthous lesions,
clinicians should determine whether well-recognized causes are contributing to the disease and these factors should be corrected.
Various treatment modalities are used, but no therapy is definitive.
Topical medications, such as antimicrobial mouth-washes and topical
corticosteroids (dexamethasone, triamcinolone, fluocinonide, or clobetasol), can achieve the primary goal to reduce pain and to improve
healing time but do not improve recurrence or remission rates. Systemic
medications can be tried if topical therapy is ineffective.
during childhood, particularly in adolescences, with the ulcers showing a tendency to diminish in severity and frequency with age. The onset of aphthous lesions in later years
suggests these lesions may have an underlying systemic
cause.4 The ulcers are painful, clearly defined, shallow, round
or oval, with a necrotic center covered by yellowish-tan
pseudomembranes and surrounded by an erythematous halo.
The ulcerations may lead to difficulty in speaking, eating, and
swallowing, thus may negatively affect patients’ quality of
life.5 There is often a genetic basis for RAS. The probability
of developing aphthous lesions is approximately 90% in
subjects with both parents affected, whereas it is reduced to
20% when neither parent has RAS. There is also a greater
severity and an earlier onset of aphthous lesions in people
with a positive family history for RAS tan in those without a
family history. The probability of a sibling developing RAS
may be influenced by the parents’ RAS status and there is a
high correlation of RAS in monozygotic but not dizygotic
twins.6,7
Key Words: aphthae, oral ulcer, stomatitis, RAS
CLASSIFICATION
(Pediatr Infect Dis J 2007;26: 728 –732)
T
he term “aphthous” originated with Hippocrates as far
back as 460 –370 BC in reference to disorders of the
mouth. In general usage, the word “aphthae” refers to the
presence of an otherwise undefined ulcer.1
Aphthous ulcers are a common disease of the oral
mucosa affecting 20% of the general population. The term
“aphthous stomatitis” has been used interchangeably with
“aphthous ulcers,” but at present, the term aphthous stomatitis is preferred.2 A higher prevalence has been found
in the higher socioeconomic groups, in females, and
among individuals with stress, such as students at the time
of examinations.3
Aphthous lesions are rarely documented as a single
episode in the clinical history of patients; generally, the ulcers
have a periodic course and are described as recurrent aphthous stomatitis or RAS. The onset of RAS usually occurs
Accepted for publication March 23, 2007.
From the Stomatology Department, II University of Medicines and Surgery,
Naples, Italy.
Address for correspondence: Dr. Felice Femiano, Via Francesco Girardi 2, S.
Antimo, NA 80029, Italy. E-mail: [email protected].
Copyright © 2007 by Lippincott Williams & Wilkins
ISSN: 0891-3668/07/2608-0728
DOI: 10.1097/INF.0b013e31806215f9
728
Aphthous stomatitis is divided, on morphologic criterion, into 3 clinical presentations. It is unclear whether these
presentations are manifestations of a specific disease or they
represent other oral disorders characterized by recurrent ulcer. The clinical presentations of RAS include minor, major,
and herpetiform aphthae.3
Minor aphthae represent the most common variety
accounting for 80 – 85% of RAS. These ulcers vary between
3 and 10 mm. Minor ulcers typically involve movable and
nonkeratinized oral mucosa, principally the mucosa of the
cheek, lip, floor of mouth, ventral and lateral surface of
tongue. The prodromal stage of ulceration is variable, but
there is usually a sensation described as “burning” or “prickling” for a short period before the ulcers appear. During an
attack of minor aphthae, single lesions or up to 5 concurrent
ulcers may occur. Each lesion lasts 10 –14 days and heals
without scarring. The variability in times of recovery can
depend on the area affected or on whether superinfection
occurred.8,9
Major aphthae, formerly known as periadenitis mucosa
necrotica recurrentis or Sutton disease, represent about 10%
of RAS. Major ulcers have an irregular border and a size
exceeding 10 mm. These lesions are deeper and larger and
they last longer than minor aphthae. As a result of the long
periods involved, there is a greater tendency for the production of a heaped-up margin which, when a single ulcer is
seen, may lead to the suspicion that the lesion is malig-
The Pediatric Infectious Disease Journal • Volume 26, Number 8, August 2007
The Pediatric Infectious Disease Journal • Volume 26, Number 8, August 2007
nant.5,10 They persist longer than minor aphthae and can last
for weeks or months and often leave a scar after healing.
These lesions cause substantial pain associated with fever,
dysphagia, and malaise. They have a predilection for the
posterior part of the month, particularly the soft palate and
pharyngeal wall or tonsillar fauces.
Major aphthae can be associated with human immunodeficiency virus (HIV) infection; clinicians should consider
HIV testing when aphthae are large and slow to heal.11
Herpetiform aphthae are the least common type comprising about 10% of occurrences. This variety is characterized by multiple recurrent crops of 10 or more (as many as a
hundred ulcers may be present at the same time) small ulcers
of 2–3 mm in diameter, although they may fuse producing
large irregular ulcers. This tendency to coalesce is similar to
what is seen in viral infections, thus, the term herpetiform and
the subsequent confusion. The herpetiform type, like the
other forms of RAS, occurs usually on mobile mucosa and
not on attached mucosa like a true herpes infection. The age
of onset of herpetiform aphthae is later than the other types
with initial episode usually presenting in the second or third
decade of life.12
Currently classification of aphthous lesions is based on
severity and they are associated with systemic factors. Simple
aphthosis is described when ulcer recurrences are few and not
associated with systemic factors and occur only 2– 4 times
each year. Complex aphthosis is a disorder in which patients
develop recurrent oral and genital aphthous ulcers or when
there is a continuous disease activity with new lesions developing as older lesions heal, or when ulcers are associate with
systemic diseases.13–15
These complex ulcers can mimic aphthous lesions
occurring in RAS and for this reason they are named
“aphthous-like lesions.” Diseases associated with aphthae
include Behcet disease, Crohn disease, ulcerative colitis,
malabsorption syndromes, gluten-sensitive enteropathy,
nutritional deficiencies, PFAPA syndrome (periodic fever,
aphthae, pharyngitis and adenitis), Sweet syndrome, HIV
infection, and cyclic neutropenia.9
IMMUNOPATHOGENESIS
Although the clinical characteristics of RAS are well
defined, the precise etiology remains unclear, and therefore
the term “idiopathic” is widely used. RAS may be the
common manifestation of a group of disorders of different
etiology, rather than a single entity.16
Immune mechanisms appear to play an essential role
for onset of oral ulceration.17 A genetic background is found
for some RAS patients and those having positive family
history for oral ulcerations have shown an increased frequency of HLA types A2, A11, B12, and DR2. At present, no
unifying theories on the immunopathogenesis of RAS exist.
Immune dysregulation may play a role.18
A strong correlation was observed in the inheritance of
an allele of interleukin-1 (IL-1 b 51). In addition, the allele of
IL-6-174 was strongly associated with RAS, this being greatest with a/a homozygosity. Such strong associations with
these genotypes of IL-1 b and IL-6 suggest that RAS may
© 2007 Lippincott Williams & Wilkins
Management of Aphthous Stomatitis
indeed have some sort of genetic basis. It may be that an
unopposed or excessive production of IL-1 b or IL-6 (eg,
response to local trauma) may be instrumental in the development of RAS.17,19 The HLA class I and II antigens occur
on basal epithelial and then perilesional cells in all layers of
the epithelium in the early phases of ulceration presumably
mediated by interferon gamma (IFN-g).20,21
Cell-mediated and immune complex mechanisms are
probably involved in RAS pathogenesis. The involvement of
cell-mediated mechanisms is corroborated by an increase in
RAS patients compared with that in healthy controls, of
gamma– delta T cells, which may be involved in antibodydependent cell-mediated cytotoxicity. These cells produce
tumor necrosis factor a (TNF-a), which can be responsible
for keratinocyte vacuolation.22
Although there are cell-mediated immune changes within
RAS, a B lymphocyte-mediated mechanism involving antibodydependent cell-mediated cytotoxicity and, possibly, formation of
immune complexes have also been observed. Although circulating immune complexes have not reliably been demonstrated
in RAS, immune deposits occur in lesional biopsy specimens,
especially in the stratum spinosum, and there can be evidence of
leucocytoclastic or immune complex vasculitis leading to the
nonspecific deposition of immunoglobulins and complement.23,24 TNF-a, a major inflammatory mediator, induces initiation of the inflammatory process by its effect on endothelial
cell adhesion and a chemotactic action on neutrophils.
Studies have shown that RAS can be prevented by
treatments that inhibit the synthesis of endogenous TNF-a
such as thalidomide and pentoxifylline.11,25–27 In the preulcerative stage, many neutrophils have been shown to surround small vessels. This infiltrate of neutrophils represents
the effect of a vasculitis by immune complex and could be
responsible of appearance of ulcer lesion for tissue necrosis
through a vascular obstruction and activation of lysosomial
enzymes.28,29
Cross-reactivity between a streptococcal 60 – 65-kd
heat shock protein and the oral mucosa, demonstrated in RAS
patients, might play a pathogenetic role. RAS thus may be a
T-cell mediated response to antigens of Streptococcus sanguis, which cross-react with the mitochondrial heat shock
protein and induce oral mucosal damage.
Different cytokines can contribute to the pathogenesis of
oral lesions in RAS such as IL (interleukin)-2, IL-6 and IL-10.20
Elevated IL-2 and TNF-a, and lower concentrations of IL-10
have been reported in lesional mucosa of RAS patients. IL-10
usually stimulates epithelial proliferation in a healing process;
therefore, its low levels in RAS patients may delay epithelization
and prolong the duration of the ulcers.26,29 A markedly increased
plasma IL-2 has been recorded in the active stage of RAS.
Also, natural killer cells activated by IL-2 may play a
role in disease pathogenesis. An increased activity of these
cells has been noted in active lesions, diminishing during
periods of remission. Salivary prostaglandin E2 and epidermal growth factor may potentially aid mucosal healing. Both
are reduced in the early stages of RAS ulcer and then rise in
the healing phase.30
Patients with RAS may be subject to uncontrolled or
excessive release of locally active inflammatory mediators,
729
Femiano et al
The Pediatric Infectious Disease Journal • Volume 26, Number 8, August 2007
perhaps in response to local trauma. Amounts of IL-2, IFN-g,
and TNF-a mRNA are raised in lesional tissue of RAS,
whereas concentrations of IL-10 mRNA are reduced in the
normal mucosa of RAS patients when compared with that of
control subjects. Local amounts of IFN-g are higher in the
mucosa of RAS patients than in controls; whereas in contrast
IL-10 values remain low in the former but not the latter.
Local production of TNF-a is higher in RAS lesions than
traumatic ulcers and unstimulated peripheral blood leukocytes of patients with RAS produce greater amounts of
TNF-a than healthy controls.27,29
Precipitating factors can act on genetic predisposition to
cause simple aphthous lesions. Most patients appear to be
otherwise well, but a minority has etiologic factors that can be
identified by the history. These factors may include the following: toothpastes containing sodium-lauryl-sulfate, trauma, stress,
cessation of smoking, hormonal state, and food hypersensitivity.
Patients affected by RAS usually are nonsmokers. Some patients
reveal an onset of RAS after smoking cessation and disappearance on reinitiation of smoking. This is likely to be due to the
positive effect of nicotine on keratinization of oral mucosa.16,31
Emotional and environmental stress may precede 60% of firsttime aphthous ulcer cases and involve approximately 20% of
recurrent episodes. Food allergy such as that for chocolate,
cheese, wheat flour, tomatoes, peanuts and strawberries might be
responsible for the onset of oral ulcers. In a small percent of
patients removing indicted food can lead to recovery from
disease. A minority of women with RAS have cyclical oral
ulceration related to the luteal phase of the menstrual cycle,
presumed to be progestogen-driven defective oral mucosal epithelial turnover.32 It has been suggested in some studies that
sodium-lauryl-sulfate, a detergent in some oral healthcare products may give rise to ulceration akin to that of RAS.16
A small number of aphthous ulcers are associated
with other disease processes or disorders. These ulcers,
also called aphthous-like ulcers, can mimic classic aphthae
and their onset generally coincides with underlying disease. The onset, length, and severity of aphthous-like
ulcers is determined by the conditions or defects that have
caused them. The correction of responsible factors may
cause healing and prevent relapses.
Several kinds of drugs can cause aphthous-like lesions.
In some predisposed patients, aphthous-like lesions appear
after use of nonsteroidal anti-inflammatory drugs, activator of
ATP-sensitive potassium (nicorandil), ace inhibitor, and antiarrhythmics drugs.33–38 The pathogenesis of these oral adverse reactions related to the intake of medications is not
well-understood, and the prevalence is not known. Aphthae
usually commence in the second decade of life as recurrent
oral ulcerations and usually wane during the fourth decade. In
contrast, drug-induced ulcerations present mostly in older age
groups and not always as a recurrent pattern. The interruption
and the substitution of the responsible drug coincides with
resolution of oral ulcers. Immunodeficiency diseases, myelodysplastic syndromes, cyclical neutropenia (RAS appearing
on a regular 3-week cycle may indicate a neutropenia),
immunodeficiency in HIV-positive patients with CD4 T lymphocyte counts less than 100 cells per milliliter can cause
large aphtha-like ulcers.11,24
730
Recurrent aphthous-like ulcers are seen as oral manifestations of hematinic deficiencies of vitamin B1, B2, B6,
B12, of folic acid or iron. Correction of the deficiency can
improve oral ulcers in some patients. Recurrent aphthous-like
ulcers are seen in patients affected by celiac disease or
gluten-sensitive enterophathy. These RAS like lesions remit
on a gluten-free diet.
Behcet syndrome is characterized by classic oral RAS
and recurrent ulcers that affect the genital areas, eyes, and are
associated with a range of systemic complications including
joints, neurologic system, and skin; for these reasons Behcet
syndrome belongs to the complex aphthosis subtype. Patients
with inflammatory bowel disease, in particular Crohn disease
and ulcerative colitis, may present with recurrent oral ulcer
lesions like aphtha.18,39 – 41
Among the conditions that may mimic classic aphthae, it is necessary to remember some syndromes such as
PFAPA syndrome also known as Marshall syndrome (periodic fever, aphthae, pharyngitis, and adenitis) and Sweet
syndrome, also known as acute febrile neutrophilic dermatosis characterized by fever, neutrophil leukocytosis, well
demarcated cutaneous, plum-colored papules or plaques,
recurrent oral ulcers and, in 50% of patients, an associated
malignancy (eg, acute myeloid leukemia). Oral ulcers can
be found in Reiter syndrome associated with uveitis, conjunctivitis, and HLA B27-positive arthritis, following nongonococcal urethritis or bacillary dysentery.42– 44
MANAGEMENT
The diagnosis of RAS is invariably based on the history
and clinical findings. It is essential, however, to consider a
possible systemic cause, especially when adult patients suddenly develop what appears to be RAS.8 Ulcers are selflimiting and they can be recurrent, but because the etiology is
unknown, definitive treatment is difficult to determine. Treatment of RAS depends on the number of lesions, size and
duration, and particularly on the frequency of recurrences.
The choice of a specific treatment modality should be based
on the patient’s needs and balancing the potential side effects
of drugs with the benefits.5,18,34
Once a diagnosis of RAS is reached, the clinician
must decide whether to provide more than palliative care.9
As part of informed consent, the patient should receive
instruction about the condition, treatment options, and the
expected outcome from each of the various treatment plans
offered. Patients with frequent or severe outbreaks of
aphthae should be counseled, regarding the advisability of
a medical screening for various forms of anemia, gastrointestinal disease, food “allergies,” and other diseases
potentially affecting the immune system. It may also be
wise to rule out Behcet’s disease through questioning
about the presence of lesions of the genital mucosa. Suggested supportive care includes rest, increased fluid intake,
adequate nutritional intake, multivitamin and mineral therapy, and reassurance that aphthae are not communicable.45
It is common practice to assess the full blood-cell
count, red-cell folate, serum ferritin (or equivalents), glucose,
vitamin B12, and IgE. If there is any suspicion of celiac
© 2007 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 26, Number 8, August 2007
disease, either due to the patient’s history or evidence of
malabsorption on routine testing, then serologic testing for
antiendomysial antibody and other appropriate investigations
should be undertaken: it is debatable whether all RAS patients should undergo screening for celiac disease.
Some patients present with infrequent small ulcers and
do not require any treatment. In some subjects, the severity
and frequency of episodes decrease with the passing of years,
whereas in others, severity and frequency worsen. For this
reason, the therapy for oral ulcer cannot be standardized but
it is different for each patient. There is no curative treatment
available for aphthous ulcers, but symptomatic improvement
is possible.46
Goals in the management of RAS reflect that it is generally mild and self-limiting, and that, currently, there is no
treatment widely believed to be curative. Treatments that reduce
pain during attacks or reduce ulcer number and size, promote
healing of existing ulceration, frequency of recurrent attacks
with minimal adverse side effects are considered successful.
Treatments used for this generally benign disease should not be
associated with more morbidity that the disease itself.47
The first step towards effective management of RAS is to
identify and appropriately treat any modifiable predisposing
factor before introducing therapy. It is warranted to reassure
RAS patients on the benign nature of this ulcer, reduce stress,
eliminate trauma or bad habit (eg, cheek bite); any iron or
vitamin deficiency should be corrected once the cause of that
deficiency has been established. If an obvious relationship to
certain foods is established, these should be excluded from the
diet. Possible causal drugs should be excluded.48
In case aphthous ulcers are the expression of systemic
disease, treatment should be first directed to the underlying
conditions. The treatment choice of RAS should consider
severity of pain, time required to heal, ulcer number for each
episode, frequency of episodes, and ability to tolerate the
treatment of each patients. The American Academy of Oral
Medicine has recommended topical treatments for RAS.
Topical medications include anesthetics, antihistamines, antimicrobials, and anti-inflammatory agents. Evidence of successful use of these agents for aphthous ulcers is primarily
anecdotal.49 –52
For correct control of recurrent aphthae, the clinician
would have to perform an exhaustive medical history to
recognize precipitating factors eliminating bad habit, changing oral hygiene habit, and correcting or to modify diet, and
then to consider the therapy suggesting topical use of corticosteroids in mouthwash or in oral gel (dexamethasone,
fluocinonide, and triamcinolone). These treatments work best
if started at prodrome when the reaction is beginning. For
severe RAS cases, one can resort to use of a high-potency
steroid like clobetasol in ointment and to systemic therapy
with corticosteroids, disodium cromoglycate, azathioprine,
pentoxifylline, colchicine, or sometimes thalidomide.52–54
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