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J Oral Pathol Med

doi: 10.1111/j.1600-0714.2012.01134.x ª 2012 John Wiley & Sons A/S Æ All rights reserved

wileyonlinelibrary.com/journal/jop

Recurrent aphthous stomatitis: a review


Mahesh Chavan1, Hansa Jain2, Nikhil Diwan1, Shivaji Khedkar3, Anagha Shete1, Sachin Durkar4
1
Department of Oral Medicine and Radiology, Dr. D. Y. Patil Dental College, Pune, India; 2Dr. D. Y. Patil Dental College, Pune,
India; 3Department of Oral Medicine and Radiology, Pandit Deendayal Dental College, Solapur, India; 4Department of Orthodontics
and Dentofacial Orthopedics, Dr. D. Y. Patil Dental College, Pune, India

Recurrent aphthous stomatitis (RAS) is a common clini- Activities of daily living affect the prevalence of RAS.
cal condition producing painful ulcerations in oral cavity. RAS prevalence was higher (male, 48.3%; female,
The diagnosis of RAS is based on well-defined clinical 57.2%) among professional-school students than in the
characteristics but the precise etiology and pathogenesis same subjects 12 years later when they had become
of RAS remain unclear. The present article provides a practicing professionals. This finding led some investi-
detailed review of the current concepts and knowledge of gators to theorize that stress during student life is a
the etiology, pathogenesis, and management of RAS. major factor in RAS, although the difference in age
J Oral Pathol Med (2012) groups should also be considered (4).
Epidemiologic studies have shown that the prevalence
Keywords: oral; recurrent aphthous stomatitis of RAS is influenced by the population studied, diag-
nostic criteria, and environmental factors (6). In chil-
dren, the prevalence of RAS may be as high as 39% and
is influenced by the presence of RAS in one or both
Introduction parents (6). Children with RAS-positive parents have a
Aphthae (i.e., canker sores) have plagued mankind 90% chance of developing RAS compared with 20% in
throughout recorded history and were first mentioned those with RAS-negative parents (7).
by Hippocrates (460–370 BC) who utilized the term The onset of RAS seems to peak between the ages of
aphthai’ to describe disorders of the mouth (1). 10 and 19 years before becoming less frequent with
Recurrent aphthous stomatitis (RAS, aphthae, canker advancing age (8).
sores) is a common condition that is characterized by
multiple recurrent small, round, or ovoid ulcers with Predisposing etiologic factors
circumscribed margins, erythematous haloes, and yellow The etiology of RAS lesions is unknown, but several
or gray floors typically presenting first in childhood or local, systemic, immunologic, genetic, allergic, nutri-
adolescence (2). As per large USA-based studies, RAS is tional, and microbial factors have been proposed as
the most common inflammatory ulcerative condition of causative agents (4).
the oral cavity (3). RAS is the most common ulcerative The proposed etiologic factors (4) associated with
disease of the oral mucosa making the diagnosis and RAS are as follows:
management of these recurring oral lesions common
problems in general and specialty dental practice (4).
Local trauma Smoking
Dysregulated saliva composition
Epidemiology Microbial Bacterial: Streptococci
Viral: Varicella zoster, Cytomegalovirus
Kleinman et al (5). reported that the point prevalence of Systemic Behcet’s disease
RAS was 1.23% while lifetime prevalence was 36.5% on Mouth and genital ulcers with inflamed
the basis of the results of oral mucosal examinations on cartilage (MAGIC) syndrome
Crohn’s disease
a probability sample of 40 693 USA schoolchildren Ulcerative colitis
performed as part of the National Survey of Oral Health HIV infection
in USA Schoolchildren, 1986–1987 (OHSC). Periodic fever, aphthosis, pharyngitis, and
adenitis (PFAPA) or Marshall’s syndrome
Cyclic neutropenia
Correspondence: Mahesh Chavan, Senior Lecturer, Department of Stress, psychologic imbalance, menstrual cycle
Oral Medicine and Radiology, Dr. D. Y. Patil Dental College, Pune Nutritional Gluten-sensitive enteropathy
18, India. Tel.: +91 9823623445, Fax: +91 02027423427, E-mail: Iron, folic acid, zinc deficiencies
drmahesh_1000@yahoo.co.in Vitamin B1, B2, B6, and B12 deficiencies
Accepted for publication February 2, 2012
Recurrent aphthous stomatitis
Chavan et al.

2
techniques have demonstrated H. pylori in both affected
Genetic Ethnicity and non-affected mucosa of RAS patients and found no
HLA haplotypes association with RAS; thus, patients with stomach ulcer
Allergic ⁄ immunologic Local T-lymphocyte cytotoxicity
Abnormal CD4:CD8 ratio
may not be unusually susceptible to RAS even though
Dysregulated cytokine levels both diseases have been linked to dysregulated immune
Microbe-induced hypersensitivity functions (18). Studies conducted by Shimoyama et al.
Sodium lauryl sulfate sensitivity (19) and Mravak-Stipetic M et al. (20) showed that no
Food sensitivity raised frequency of local carriage of H. pylori has been
Other Antioxidants
Non-steroidal anti-inflammatory drugs detected in individuals with RAS.
Beta blocker Epstein–Barr virus (EBV) and lactobacillus are other
organisms that have been studied in RAS patients. A
study of the possible role of lactobacillus in RAS has
Local factors yielded no significant finding (21), but in a small study,
Local trauma is regarded as a causative agent for RAS EBV was associated with epithelial cells of pre-ulcerative
in susceptible individuals, and RAS are uncommon RAS (22).
where mucosal keratinization is present or in patients
who smoke tobacco (2). Trauma predisposes to RAS Underlying medical disease
by inducing edema, early cellular inflammation asso- Several medical disorders are associated with oral
ciated with an increased viscosity of the oral submu- ulcerations that resemble RAS (2).
cosal extracellular matrix (9). Not all oral trauma lead
to RAS, because denture wearers are usually three Behcet’s syndrome
times more susceptible to oral mucosal ulceration, but Behcet’s syndrome is a multisystem disorder resulting
RAS is not the most prevalent ulceration in this cohort from vasculitis of small- and medium-sized vessels and
(10). inflammation of epithelium. The abnormal inflamma-
Some changes in salivary composition, such as pH, tory response in Behcet’s syndrome is caused by immune
that affect the local properties of saliva and a stress- complexes induced by T lymphocytes and plasma cells.
induced rise in salivary cortisol have been correlated Behcet’s syndrome usually affects adults, but a number
with RAS (11). The various other salivary components of cases have been reported in children (23).
also have been positively associated with RAS-like Recurrent aphthous stomatitis-like ulceration is a
Tumour Necrosis Factor-alpha (12), Salivary nitric cardinal feature of Behcet’s disease. The ulceration may
oxide (13) and others. be more severe and more likely to comprise major
and ⁄ or herpetiform ulcers from RAS. Patients with
Microbial factors Behcet’s disease also have recurrent genital ulceration,
A local microbial basis for RAS might explain why only cutaneous disease (usually papulopustular lesions or
the oral mucosa is affected in patients with RAS. erythema nodosum), ocular disease (typically posterior
However, as there is no evidence of clustering of affected uveitis), and a range of other gastrointestinal, neuro-
patients (other than via vague family associations), an logical, renal, joint, and hematological abnormalities
infectious basis for RAS seems unlikely (2). (2).
Both laymen and some clinicians confuse RAS with
herpes simplex virus infection although several studies MAGIC syndrome
have demonstrated that RAS is not caused by herpes It is another variant of Behcet’s syndrome that includes
simplex virus (14). relapsing polychondritis, a disorder characterized by
Several studies have carried out to find out the mouth and genital ulcers with inflamed cartilage, has
possible involvement of Streptococci species in the been labeled MAGIC syndrome (24, 25).
etiology of RAS especially S. sanguis 2A (15). Some
studies (16) have found that there is some cross- Sweet’s syndrome
reactivity between the streptococcal 65-kDa heat shock It is also termed as acute neutrophilic dermatosis, and
protein (hsp) and the 60-kDa human mitochondrial hsp. affected patients have superficial ulceration similar to
It has thus been suggested that there is a molecular basis RAS. In addition, there is sudden onset fever, leucocy-
for earlier work suggesting a link between RAS and tosis, and well-demarcated cutaneous, plum-colored
Streptococcus sanguis, because monoclonal antibodies papules or plaques. Sweet’s syndrome usually arises in
to the part of the 65-kDa hsp of mycobacterium middle-aged females. In 50% of patients, there is an
tuberculosis react with S. sanguis (16). Thus, RAS associated malignancy (e.g., acute myeloid leukemia)
may be a T-cell-mediated response to antigens of (2).
S. sanguis that cross-react with the mitochondrial hsp
and induce oral mucosal damage (17). This theory is still PFAPA syndrome
unproven. It comprises periodic fever, aphthae-like oral mucosal
Helicobacter pylori have been proposed as a causative ulceration, pharyngitis, and cervical adenitis. Although
role in RAS because it is a common risk factor for rare, PFAPA tends to occur in young children and tends
gastric and duodenal ulcers. Studies using molecular to be self-limiting and non-recurrent (2).

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Chavan et al.

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Cyclic neutropenia allergy and ⁄ or hypersensitivity is a major cause of this
Cyclic neutropenia, a rare disorder that presents at disorder (4).
childhood, is also associated with recurring oral ulcers Foods such as chocolate, coffee, peanuts, cereals,
during the periods when the neutrophil count is severely almonds, strawberries, cheese, tomatoes (even the skin
depressed (4). of the tomatoes), and wheat flour (containing gluten)
There is cyclic reduction in circulating levels of may be implicated in some RAS patients (35, 36). A
neutrophils about every 21 days. Affected patients possible link between food allergy and some cases of
develop oral ulceration, fever, cutaneous abscesses, RAS has been suggested as sequential elimination of
upper respiratory tract infections, and lymphadenopa- dietary items such as milk, cheese, and wheat, has been
thy. Other oral complications include severe gingivitis found beneficial in a small subset of RAS patients
and aggressive periodontitis (2). presenting with refractory cases of RAS and known
allergy to such food items (37).
HIV disease The denaturing effect of sodium lauryl sulfate (SLS)
Aphthous-like ulceration may occasionally arise in HIV commonly found in toothpastes has also been discussed
disease. However, it remains unclear, if there is a as a cause of RAS. It was proposed that SLS may erode
significantly raised frequency of recurrent idiopathic the oral mucin layer, exposing the underlying epithe-
oral ulceration in HIV disease, RAS occurs more lium, and thereby making the individual more suscep-
frequently, lasts longer, and causes more painful symp- tible to RAS. This theory is questionable because a more
toms than in healthy individuals and is a common recent study demonstrated that use of SLS-free tooth-
finding in HIV-positive children. RAS is usually a late pastes did not affect development of new lesions in RAS
finding in AIDS patients with CD4+ lymphocyte patients (4).
counts below 100 cells ⁄ mm3, but it may occasionally
be a presenting sign of HIV infection (26, 27). Immunologic factors
For the past 30 years, much of the research on the cause
Crohn’s disease of RAS focused on detecting an abnormality in the
Aphthous-like ulceration can be a feature of inflamma- immunologic response. Early work suggested a relation-
tory bowel diseases like Crohn’s disease and ulcerative ship between several immune-mediated reactions and
colitis (4). This ulceration may reflect associated hae- development of RAS. These reactions include cytotox-
matinic deficiencies (2) while some researchers believe icity of T lymphocytes to oral epithelium, antibody-
inflammation of minor salivary glands to be the cause of dependent cell-mediated cytotoxicity, and defects in
the these oral ulcers (28). Approximately 10% of lymphocyte subpopulations (38–40).
patients with Crohn’s disease have oral mucosal ulcers, One theory is that multiple immune reactions cause
and the oral manifestations occasionally precede intes- damage induced by deposition of immune complexes
tinal symptoms (29). within the oral epithelium. More recent studies have
shown an association between RAS severity and abnor-
Hereditary and genetic factors mal proportions of CD4+ and CD8+ cells, alteration
At least 40% of RAS patients have a vague familial of the CD4+:CD8+ ratio, and elevated levels of
history of RAS (30). The role of heredity is the interleukin 2, interferon gamma, and tumor necrosing
best-defined underlying cause of RAS (6). Children factor-a (TNFa) mRNA in RAS lesions. Immunohisto-
with RAS-positive parents have a 90% chance of chemical studies of RAS biopsy tissues have demon-
developing RAS. When patients have a positive family strated numerous inflammatory cells with variable ratios
history of RAS, they tend to develop RAS at an early of CD4+:CD8+ T lymphocytes depending on the ulcer
age. Their RAS lesions appear more frequently and duration. CD4+ cells were more numerous during the
demonstrate more severe symptoms (7). Studies of pre-ulcerative and healing stages, whereas CD8+ cells
identical twins also have demonstrated the hereditary tended to be more numerous during the ulcerative state
nature of this disorder (31). of the ulcer. Similar studies on non-affected sites were
Certain genetically specific HLAs have been identified negative, making researchers focus more on the theory
in RAS patients: HLA-A2, HLA-B5, HLA-B12, HLA- that RAS may be caused by an antigen-triggering effect.
B44, HLA-B51, HLA-B52, HLA-DR2, HLA-DR7, and Because levels of serum immunoglobulins and natural
HLA-DQ series. A confounding finding is that certain killer cells are essentially within normal limits in RAS
ethnic groups have been associated with different HLA patients, the focus is still on a dysregulated, local, cell-
alleles or haplotypes (32–34), with no HLA consistently mediated immune response conducive to accumulation
associated with RAS. More studies are still needed to of subsets of T cells, mostly CD8+ cells. The local
clarify the variability of RAS in host susceptibility. immune response causes eventual tissue breakdown that
manifests as RAS (4).
Allergic factors
Allergy has been suspected as a cause of RAS, and Nutritional factors
hypersensitivity to certain food substances, oral mi- The role of nutritional deficiency as a cause of RAS has
crobes such as Streptococcus sanguis, and microbial heat been highlighted by the association of a small subset of
shock protein have been suggested as possible causative 5% to 10% of RAS patients with low serum levels of
factors, although there remains no strong evidence that iron, folate, zinc, or vitamins B1, B2, B6, and B12 (41).

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Some of these nutritional deficiencies may be second- burning any time from 2 to 48 h before an ulcer appears.
ary to other diseases such as malabsorption syndrome or During this initial period, a localized area of erythema
gluten sensitivity associated with or without enteropathy develops. Within hours, a small white papule forms,
(42). Hematologic screening of RAS patients for anemia ulcerates, and gradually enlarges over the next 48–72 h.
or deficiency of iron, foliate, and B vitamins is appro- Individual lesions are usually round, symmetric, and
priate for patients with major RAS or cases of minor shallow (similar to viral ulcers), but no tissue tags are
RAS (MiRAS) that worsen during adult life (43, 44). A present, and this helps to distinguish RAS from disease
deficiency of calcium and vitamin C has also been with irregular ulcers such as EM, pemphigus, and
recently proposed in patients with RAS, but these pemphigoid (4).
findings were in association with vitamin B1 deficiency, Recurrent aphthous stomatitis has three main pre-
supporting the idea of combined nutritional deficiency sentations (4, 17) as summarized in Table 1.
in RAS patients (44).
• Minor (MiRAS),
• Major (MaRAS), or
Psychologic stress
• Herpetiform (HU) ulcers.
Stress and psychologic imbalance have been associated
with RAS (11, 45). In women, appearance of RAS may
coincide with menses (46). Stress of student life may be Minor RAS
the precipitating factor for the higher prevalence of RAS It is the most common presentation affecting about 80%
in a cohort of professional students (47). of patients with RAS: ulcers are round or oval usually
< 5 mm in diameter with a gray–white pseudomem-
Other factors brane and an erythematous halo. MiRAS usually occur
The role of antioxidants in RAS is currently attracting on the labial and buccal mucosa and floor of mouth, but
attention because blood levels of antioxidants such as are uncommon on the gingiva, palate, or dorsum of
erythrocyte superoxide dismutase and catalase seem to the tongue. The ulcers heal within 10–14 days without
be higher in patients with RAS and Behcet’s syndrome scarring.
than in normal controls, but their causative roles in
RAS are yet to be clearly defined (4). Major RAS (MaRAS)
There also have been several reported cases of It is a rare, severe form of RAS, sometimes termed
drug-induced RAS. A recent case–control study periadenitis mucosa necrotica recurrens (picture). These
associated a higher risk of RAS with drug exposure ulcers are oval and may exceed 1 cm in diameter and
and found significant association with non-steroidal have a predilection for the lips, soft palate, and fauces.
anti-inflammatory drugs and b-blockers. The medica- The ulcers persist for up to 6 weeks and often heal with
tion history and current medications of RAS patients scarring. MaRAS usually has its onset after puberty and
should be closely scrutinized to identify any pattern is chronic, persisting for up to 20 or more years.
associated with the frequency and duration of RAS
lesions (4). Herpetiform ulceration (HAU)
It is the least common variety and is characterized by
multiple recurrent crops of widespread, small, painful
Clinical features
ulcers. As many as 100 ulcers may be present at a given
Recurrent aphthous stomatitis comprises recurrent time, each measuring 2–3 mm in diameter (picture),
bouts of one or several rounded, shallow, painful ulcers although they tend to fuse producing large irregular
at intervals of a few months to a few days. All forms of ulcers. HU may have a predisposition for women and
RAS are painful recurrent ulcers. Patients occasionally have a later age of onset than other types of RAS.
have prodromal symptoms of tingling or burning before Minor RAU (MiAU) has a tendency to appear on the
the appearance of the lesions (3). movable, lining, and non-keratinized mucosae, predom-
First episode of RAS most frequently begin during inately buccal and lip mucosa, ventral tongue, soft
the second decade of life and may be precipitated by palate, and in the vestibule. Major RAU (MaAU) is
minor trauma, menstruation, upper respiratory tract seen on the soft palate and fauces, tongue, and buccal
infection, or contact with certain foods. Lesions are and labial mucosae while herpetiform aphthous ulcer-
confined to oral mucosa and begin with prodromal ation (HAU) involve the anterior part of the mouth, tip,

Table 1 Clinical types and treatment of recurrent aphthous stomatitis (RAS)

Minor Major Herpetiform


Size < 0.5 cm > 0.5 cm < 0.5 cm
Shape Oval Ragged oval, Crateriform Oval
Number 1–5 1–10 10–100
Location Non-keratinised mucosa Non-keratinised mucosa Any intra-oral site
Treatment Topical Corticosteroids, Tetracycline Topical ⁄ Systemic ⁄ Intralesional Corticosteroids, Topical ⁄ Systemic Corticosteroids,
mouth rinse Immunosuppressives Tetracycline mouth rinse

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lateral and ventral tongue, and the floor of the mouth Type B
but rarely appear on the lips (48). Painful RAS each month, lasting between three and
The three forms of aphthous ulcers minor, major, and 10 days, is type B (52). In this scenario, the patient may
herpetiform can be briefly studied under the following have changed diet and oral hygiene habits because of the
table (4). pain. If a precipitating factor can be identified – for
example, oral hygiene, stress, trauma, or diet – alterna-
tives or remedies should be discussed with the patient. It
Management
is imperative to identify patients who experience pro-
The diagnosis of RAS is invariably based upon the dromal symptoms, such as tingling or swelling, because
history and clinical findings. It is essential however to the patient can use corticosteroids (if they are indicated
always consider a possible systemic cause, especially for him or her) at the prodromal stage to abort the
when adult patients suddenly develop what appears to attacks. Treatment often includes the use of a chlorh-
be RAS (49, 50). exidine mouthwash (without alcohol base) and a short
course of topical corticosteroids as soon as the ulcers
• Porter et al., 1993: It is common practice to assess
appear. Because of the consistent recurrent pattern,
the full blood cell count, red cell folate, and serum
these patients may need a maintenance treatment
levels of ferritin (or equivalents) and vitamin B12 (2,
protocol. Alternative regimens include dexamethasone
49)
0.05 mg ⁄ 5 ml (rinse and spit three times per day) or a
• Sedghizadeh et al., 2002: These investigations may
high-potency topical corticosteroid such as clobetasol
also reveal potential gastrointestinal causes of oral
ointment 0.05% in Orabase (1:1) (Colgate Oral Phar-
ulceration but, in the absence of other manifesta-
maceuticals, Canton, Mass.) or fluocinonide ointment
tions, screening of patients with RAS for GSE is
0.05% in Orabase (1:1) if the ulcer(s) recurs on the same
usually fruitless (50).
site, used three times daily. If corticosteroids are used,
The proper treatment of RAS depends on the patients should be monitored for yeast superinfection.
frequency, size, and number of the ulcers (51). The best In patients with poor oral hygiene, professional help
treatment is that which will control ulcers for the longest from a dental hygienist should be considered once ulcers
period with minimal adverse side effects. The treatment heal. In patients with recalcitrant RAS, a short course of
approach should be determined by disease severity systemic corticosteroid therapy may be required, never
(pain), the patient’s medical history, the frequency of exceeding more than 50 mg per day (preferably in the
flare-ups, and the patient’s ability to tolerate the morning) for 5 days. This course of treatment is best left
medication (52). to a physician or oral medicine specialist.
Patients who experience the occasional episodes of
minor aphthous ulcers experience significant relief with Type C
appropriate topical therapy. Symptoms resulting from Type C RAS involves painful, chronic courses of RAS in
occasional small lesions are often adequately controlled which by the time one ulcer heals, another develops (52).
with use of a protective emollient such as Zilactin (Zila These patients are best treated by an oral medicine
Pharmaceuticals, Phoenix, Arizona) or Orabase (Bristol specialist, who often will use potent topical corticoster-
Myers Squib, Princeton, New Jersey), used either alone oids (such as betamethasone, beclomethasone, clobetasol,
or mixed with a topical anesthetic such as benzocaine. fluticasone, or fluocinonide), systemic corticosteroids,
Other topical agents that can minimize patient discom- azathioprine, or other immunosuppressants such as
fort include diclofenac, a non-steroidal anti-inflamma- dapsone, pentoxifylline, and sometimes thalidomide. In
tory drug, or amlexanox paste, which has also been addition, oral medicine specialists may administer
shown to decrease the healing time of minor aphthae (51). intralesional injections of a corticosteroid such as beta-
To help determine the management strategies, the methasone, dexamethasone, or triamcinolone to enhance
practitioner may find it useful to classify RAS in three or boost the local response, thus allowing for shorter
clinical presentations: type A, type B, and type C (52). systemic treatment. In patients with poor oral hygiene,
professional help from a dental hygienist should be
Type A considered.
Recurrent aphthous stomatitis episodes lasting for only Various treatment modalities are described for the
a few days, occurring only a few times a year, are treatment of RAS in the literature, some of the
classified as type A’ (52). In this scenario, pain is treatments are not currently used as they are ineffective
tolerable. The clinician should try to identify what but all these treatment modalities can be summarized in
precipitates the ulcers, what the patient uses to treat the following classification:
them, and how effective that treatment is. If it is effective Some reported therapies for RAS (2, 17).
and safe, the health care provider (HCP) should
encourage the patient to continue it. If a precipitating
factor(s) is identified, the HCP should try eliminating it Local physical treatment Surgical removal
first. For example, if trauma-induced RAS is suspected, Debridement
Laser ablation
the HCP can suggest a softer toothbrush and gentler Low dense ultrasound
brushing. Medication may not be indicated.

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