10.

5005/jp-journals-10031-1019
Niharika Swain et al
REVIEW ARTICLE

Etiological Factors of Recurrent Aphthous Stomatitis:

A Common Perplexity
Niharika Swain, Jigna Pathak, Leela S Poonja, Yogita Penkar

ABSTRACT crateriform base surrounded by an erythematous halo of

Recurrent aphthous stomatitis (RAS) is one of the most common inflamed mucosa. For 24 to 48 hours preceding the
oral mucosal disorders. Nevertheless, while the clinical appearance of an ulcer, most patients have a pricking or
characteristics of RAS are well-defined, the precise etiology and burning sensation in the affected area. The ulcer usually
pathogenesis of RAS remain unclear. The present article
occurs on the nonkeratinized oral mucosa, including the
provides a detailed review of the current knowledge of various
etiological factors of RAS. lips, the buccal mucosa, floor of the mouth, soft palate and
the ventral surface of the tongue.
Keywords: Mouth ulcers, Recurrent aphthous stomatitis,
Etiology.
RAS is seen worldwide and may affect up to 25% of the
population.1-3 Recurrent aphthous ulceration has three
How to cite this article: Swain N, Pathak J, Poonja LS,
different variants—minor aphthous ulcers, major aphthous
Penkar Y. Etiological Factors of Recurrent Aphthous Stomatitis:
A Common Perplexity. J Contemp Dent 2012;2(3):96-100. ulcers and herpetiform ulcers, according to the classification
described by Stanley4 in 1972. Minor RAU (MiRAU) is
Source of support: Nil
the common variety, affecting about 80% of RAU patients.
Conflict of interest: None declared It is characterized by painful round or oval shallow ulcers,
regular in outline, less than 10 mm in diameter, with a gray-
INTRODUCTION white pseudomembrane surrounded by a thin erythematous
halo. MiRAU usually occurs on nonkeratinized mucosa such
Recurrent aphthous stomatitis (RAS; Aphthae; Canker
as labial mucosa, buccal mucosa and floor of the mouth.
sores), a common oral mucosal disorder that is characterized
It is uncommon on the keratinized mucosa. Minor RAU is
by multiple, recurrent, small, round or ovoid ulcers with
the most common form of childhood RAU. The lesions recur
circumscribed margins, erythematous haloes, and yellow
at varying frequencies (from every few years to almost
or gray floors that present first in childhood or adolescence.
constantly) and heal within 7 to 10 days without scarring.
Although it is one of the most common recurrent oral
Major RAU (MaRAU), also known as periadenitis mucosa
ulcerative conditions of adults and children recognized
necrotica recurrens, occurs in approximately 10% of RAU
throughout the world, RAS is also one of the least
patients. The lesions are similar in appearance to those of
understood oral diseases and is among the most vexing
minor RAU, but they are larger than 10 mm in diameter,
problems faced by affected patients and clinicians alike.1,2
single or multiple and very painful. MaRAU has a
The triggering factors that precipitate recurrent episodes in
predilection for the lips, soft palate, and fauces, but can
RAS patients seem to be as diverse and unique as the
affect any site. The ulcers of MaRAU persist for up to
affected individuals themselves, which has posed a
6 weeks or longer and often heal with scarring. Herpetiform
challenge for researchers in their attempts to identify a
aphthae accounts for 7 to 10% of all RAU cases. In
specific causation for this disease. Although the exact
herpetiform RAU there are 10 to 100 ulcers at a time, ulcer
etiology of RAS remains obscure, there is growing lucidity
size is usually 1 to 3 cm, and the ulcers form clusters that
with regard to its pathogenesis which has significantly
coalesce into widespread areas of ulceration lasting 7 to
influenced contemporary approaches toward its
10 days. These ulcers are only herpes-like in appearance;
management. This article reviews the clinical features and
herpes simplex virus has not been cultured from them.
various etiological factors of RAS.
ETIOLOGY
CLINICAL FEATURES
To date, the precise etiology of RAS has not been disclosed,
‘Aphthous’ comes from the Greek word ‘aphtha’, which despite years of collective effort on the part of many
means ulcer. Despite the redundancy, the medical literature researchers. Historically, conjecture about the origin of RAS
continues to refer to these oral lesions as aphthous ulcers. focused on a wide spectrum of potential local and systemic
‘Aphthous stomatitis’ has been used interchangeably with factors that encompassed microbial agents, hematologic and
‘aphthous ulcers’ and may be a more accurate terminology. hormonal disturbances, physical injury, emotional stress and
Aphthous ulcers are round or oval, with a grayish yellow, other influences. Also confounding the search for a singular
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Etiological Factors of Recurrent Aphthous Stomatitis: A Common Perplexity

cause is the observation that aphthous-like oral ulcers often of several investigators it has been hypothesized that the
occur in conjunction with diverse conditions of a systemic entire process of aphthous ulceration, from initiation through
nature. Included among those conditions are cyclic progression, is instigated by the expression on oral epithelial
neutropenia, selected anemias, 5 inflammatory bowel cells of not only normally found HLA class I antigens but
diseases,6 Behçet’s disease,7,8 gluten-sensitive enteropathy also HLA class II antigens.25 Presumably, this renders the
(celiac sprue),9,10 relapsing polychondritis syndromes cells antigenically ‘foreign’ and consequently they become
(including the so-called ‘MAGIC’ syndrome, which consists the targets of a cell-mediated immune reaction perpetrated
of mouth and genital ulcers with inflamed cartilage),11 HIV by lymphocytes and Langerhans cells. It has been shown
infection,12 the purported symptom complex of recurring that in patients with aphthous stomatitis there is a heightened
fevers, aphthous stomatitis, pharyngitis and lymphadenopathy lymphocytotoxic effect directed against oral epithelial cells
(FAPA syndrome).13 when compared to unaffected controls.24-26
In recent years, body of evidence has emerged to suggest Evidence for this pathogenetic mechanism is also
a genetic and an immunologic basis for RAS. These inferred from observations that tissue biopsies of newly
revelations largely have eclipsed speculation that RAS is erupted aphthous ulcerations demonstrate agglomeration of
caused by an infectious microorganism or one of the other activated T lymphocytes at the periphery of the lesions,
previously suspected etiologic factors. They also have led whereas in well-established aphthae the initially
to more rational and effective contemporary approaches to predominant CD4+ helper/suppressor cell population is sub-
the management of RAS. sumed and succeeded by cytotoxic CD8+ lymphocytes.23,24
Additional indirect support for primary immune dys-
Genetic Factors regulation is reflected in the long-recognized correlation
Some people have a well-established familial basis for RAU. between stress and outbreaks of aphthous ulcers that is
As compared to the general population, the prevalence of reported by many RAS patients, in contrast to the notable
RAS is higher when there is a positive family history, decrease in frequency of episodes during periods of reduced
especially when both parents are affected. There is also stress.27 This observed association is not entirely surprising,
increased disease correlation observed in identical twins as because stress is known to affect immunologic function.
compared to fraternal twins. In familial cases of RAS, the It also has been observed that HIV-infected patients
onset of disease is earlier and attacks tend to occur more experience oral aphthous-like ulcerations with relatively
frequently than in nonfamilial cases.14-16 The likelihood that high frequency. With advancing immune depletion, their
RAS is a genetically grounded disease is further supported aphthous outbreaks are often dominated by larger ulcers
by the recognized, although not entirely consistent, that run a more protracted course.28,29 Attempts to explore
identification of certain histocompatibility antigen (HLA) the possibility that RAS is fundamentally an antibody-driven
types (e.g. HLA B12, B51, Cw7), among some groups of disorder have disclosed findings that are at best inconsistent
aphthous patients.17 and largely unsupportive. It seems that any previously held
conjecture that aphthous ulcers stem from a centrally
Immunologic Factors generated humoral immune mechanism rather than from
Despite the inconsistent finding and conflicting theories, local cellular immune responses to an antigenically modified
mounting scientific evidences support immune dys- oral mucous membrane was predicated on assumptions that
regulation as a key mechanism underlying the pathogenesis have since been discredited.17,30-32
of RAS. It is believed that the altered immune reactivity
Microbial Factors
arises perhaps in response to, or in concert with, a state of
presumably heightened antigenic stimulation18 exacted on There is little consistent evidence to support the hypothesis
a diminished mucosal barrier. A constellation of cell- that RAS represents an infectious disease. In particular, from
mediated immunologic phenomena seems to be a consistent studies to determine whether there might be a connection
factor in the disease. Serologic studies that compared RAS between previously suspect L-forms of streptococci and
patients and unaffected controls revealed diminished ratios RAS, or the adenoviruses, herpes simplex virus (HSV),
of circulating CD4+ helper cells to CD8+ suppressor cells varicella-zoster virus, or cytomegalovirus and RAS, the
in the former group.19,20 It has been proposed that in RAS available evidence suggests that none of these micro-
some unspecified antigenic influence21 is at the epicenter organisms seems to be directly culpable for RAS despite
of an antibody-dependent, T cell-mediated immune response continued speculation about their possible role. One should
that involves a shift in local lymphocytic subpopulations note that an antiviral agent, acyclovir, offers no beneficial
that eventuates in tissue damage.22-24 From the observations effect in preventing or attenuating episodic flares of the
Journal of Contemporary Dentistry, September-December 2012;2(3):96-100 97
Niharika Swain et al

condition,33 which serves to weaken arguments in favor of level but, within the normal range, and serum copper levels
a possible viral causation for RAS. From occasional were also normal.43 So far no information exists on the
anecdotal cases in which patients report an apparent associations between RAU and other trace elements.
consistent temporal relationship between their aphthous
outbreaks and an immediately antecedent reactivated Environmental Factors
(recurrent) HSV infection, it is tempting to postulate that in Stress
a narrow subset of individuals who get RAS, the herpes
Earlier studies have documented an association between
virus may serve as an antigenic ‘trigger’ that initiates the
RAU and a variety of psychological factors including
cascade of immunologic events that result in ulceration.
anxiety, repressed hostility, as well as job-related and other
In a limited subset of RAS patients, it is possible that this is
stress factors. Conversely, other studies have failed to reveal
actually the case. Presumably, such patients would benefit
any association between anxiety, depression, psychological
from appropriate therapeutic and prophylactic antiviral
life stress and recurrences of RAU. In one study, in which a
therapy, coupled with treatments specifically aimed at
relaxation/imagery treatment program was used,
lessening the severity and frequency of the RAS episodes
a significant decrease in the frequency of ulcer recurrence
by modulating their supposedly heightened immune
among all treated subjects was noted.44 Although the
responses to the viral ‘trigger’. Such therapeutic strategies
majority of investigators have been unable to validate the
probably would be best carried out in consultation with an
concept that stress plays an important role in the
infectious disease specialist. It must be emphasized,
development of RAU, the literature continues to indicate
however, that regarding most aphthous patients, any
that stress may play a role in precipitating RAU.
suggestion of a causative nexus between RAS and HSV
seems to represent unsubstantiated conjecture rather than Local Trauma
proven fact.34,35
A subset of patients with RAU is predisposed to develop
Nutritional Factors aphthae at sites of trauma. The reason why local trauma,
Other issues explored in the quest to determine a cause for such as anesthetic injections, sharp foods, tooth-brushing
RAS include the possible relationship of attacks to excess and dental treatment, can trigger aphthous ulceration in these
or deficiency of various nutritional factors, such as serum patients is still unknown.45
iron, folate and vitamin B12, and speculation that aphthous
Tobacco
ulcers represent the manifestation of an allergic reaction to
certain foods or other ingested or contacted substances. Several investigators have documented a negative
Apart from variably favorable responses to the avoidance association between smoking and the occurrence of RAU.46
of gluten products in aphthous patients with documented Such a negative association has also been documented as
intestinal malabsorption disease (compared to controls36 and regards the use of smokeless tobacco (chewing tobacco and
in some aphthous stomatitis patients with normal intestinal snuff), as well as in patients who are smokers.47 Para-
function,37 evidence that RAS primarily represents an doxically, the majority of patients with RAU are non-
allergic response or is etiologically linked to diminished smokers, and in a recent study only 9% of RAU patients
serum iron, vitamin B12 or folate levels is lacking or, at were found to be active smokers, compared with 25% among
best, equivocal.23,27,38 For any RAS patient who exhibits the control subjects.48
physical signs and symptoms that suggest the possibility of Nicotine has been reported to be beneficial in RAU and
an underlying malabsorption or nutritional deficiency state in inflammatory bowel disease, and its effects may result
or a blood dyscrasia, it is prudent to obtain a complete blood from influences on nerve function, although these may also
count and assays for serum folate, vitamin B12 and ferritin. exert direct anti-inflammatory effects. However, the
Should any of these tests yield findings that suggest an mechanism by which cigarette smoking protects against
underlying systemic abnormality, referral to an internist or RAU is still unknown.
a hematologist is indicated.
The improvement of RAU with zinc sulfate Food Hypersensitivity
supplementation has been described in an open trial39 and Some investigators have correlated the onset of ulcers to
in a case report of aphthous ulcers with zinc deficiency and exposure to certain foods, such as cows’ milk, gluten,
immunodeficiency,40 but such improvement was not been chocolate, nuts, cheese, azo dyes, flavoring agents and
confirmed in later studies.41,42 In a Chinese study the level preservatives. Eversole et al (1982) found no significant
of serum zinc in 75 cases of RAU was found to be at a low association between RAU and three specific food items
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Etiological Factors of Recurrent Aphthous Stomatitis: A Common Perplexity

(tomatoes, strawberries and walnuts).49 Some investigators 8. International Study Group for Behçet’s Disease. Criteria for
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39. Merchant HW, Gangarosa LP, Glassman AB, Sobel RE. Zinc ABOUT THE AUTHORS
sulphate supplementation for the treatment of recurring oral
ulcers. South Med J 1977;70:559-61. Niharika Swain (Corresponding Author)
40. Endre L. Recurrent aphthous ulceration with zinc deficiency Lecturer, Department of Oral Pathology, MGM Dental
and cellular immune deficiency. Oral Surg Oral Med Oral Pathol College and Hospital, Navi Mumbai, Maharashtra, India
Oral Radiol Endod 1991;72:559-61. e-mail: [email protected]
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Baisden CR. Zinc sulphate as a preventive of recurrent aphthous
ulcers. J Dent Res 1981;60A:609. Jigna Pathak
42. Wray D. A double-blind trial of systemic zinc sulfate in recurrent Professor, Department of Oral Pathology, MGM Dental College and
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Endod 1982;53:469-72.
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Leela S Poonja
medicine for recurrent aphthous ulcer and human zinc and
copper. Zhongguo Zhong Xi Yi Jie He Za Zhi 1992;12:280-82. Professor, Department of Oral Pathology, MGM Dental College and
44. Andrews VH, Hall HR. The effect of relaxation/imagery training Hospital, Navi Mumbai, Maharashtra, India
on recurrent aphthous stomatitis: A preliminary study.
Psychosom Med 1990;52:526-35. Yogita Penkar
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in initiating recurrent aphthous ulceration. Br Med J Lecturer, Department of Oral Pathology, MGM Dental College and
1981;283:1569-70. Hospital, Navi Mumbai, Maharashtra, India

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