Arun Kumar M. et. al.

ETIOLOGY AND PATHOPHYSIOLOGY OF RECURRENT APHTHOUS STOMATITIS: A REVIEW

ETIOLOGY AND PATHOPHYSIOLOGY OF RECURRENT

APHTHOUS STOMATITIS: A REVIEW
IJCRR
Vol 06 issue 10 Arun Kumar M., Vasanthi Ananthakrishnan, Jaisri Goturu
Section: Healthcare
Category: Review Department of Physiology, M S Ramaiah Medical College and Teaching Hospitals,
Received on: 02/04/14
MSRIT post, MSR Nagar, Bangalore, KA, India
Revised on: 23/04/14
Accepted on: 12/05/14
E-mail of Corresponding Author: drarunkm@gmail.com

ABSTRACT
Recurrent aphthous stomatitis is the most common oral mucosal ulcer disease. It causes severe pain
and occurs repeatedly, causing discomfort in daily routine activities. The description of etiology is
varied and none of the explanations given so far are satisfactory. Clinically this condition presents itself
in three forms: major, minor and herpetiform ulcers. Causes for the ulcers could be related to host and /
or environment. Host factors include genetic, nutritional deficiency, immune dysregulation and stress
which can again be multifactorial. Environmental factors include trauma (both physical and chemical)
and infections. There are several clinical syndromes which are associated with RAS like Behcet’s
syndrome. There are several causes acting together in initiating formation of ulcer unlike a single
etiological factor as was thought previously. This means combination of host and environmental factors
are essential not only for triggering the ulcer but also for an increase in size. The severity of etiological
factors to which an individual is exposed would decide the type of ulcer. Identification of the trigger
for a particular individual seems to be important in management of the disease. Hence understanding
etiopathogenesis for recurrent aphthous stomatitis would be helpful in formulation of individualized
treatment modalities. This review is intended to understand the cause and pathogenesis of recurrent
aphthous stomatitis.
Keywords: Recurrent Aphthous Stomatitis, Oral Ulcers, RAS syndromes

INTRODUCTION in frequency and severity with age2. In about 80

Recurrent aphthous stomatitis (RAS) is a
disease of the oral mucosa which appears typically
as ulcers in the mouth and causes severe pain.
Repeated occurrence of ulcers is very debilitating.
The prevalence, clinical presentation, etiology and
pathogenesis of recurrent aphthous stomatitis will
be discussed in this review.
Prevalence of RAS (Recurrent aphthous
stomatitis)
RAS is a common oral mucosal condition and has
been reported as affecting 20% of the general
population at any given time. It reaches a peak
of50% in selected populations such as university
students1. RAS usually appears first during
childhood, with a tendency for ulcers to diminish
percent of patients with RAS, the condition
develops before 30 years of age3.
Clinical Presentation
The ulcers are typically seen on the buccal
mucosa, the labial mucosa, the floor of the mouth
or the tongue. A prodrome of localized burning or
pain for 24 to 48 hours usually precedes the ulcers.
The lesions are painful, with well defined margins
and shallow necrotic center. All ulcers have
yellow-grayish membrane at the base and are
surrounded by raised margins and erythematous
haloes. The pain is severe and gets aggravated on
eating, swallowing and speaking. The pain usually
persists for three to four days3.

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 Arun Kumar M. et. al. ETIOLOGY AND PATHOPHYSIOLOGY OF RECURRENT APHTHOUS STOMATITIS: A REVIEW
Three clinical presentations of RAS are: Minor
aphthous stomatitis (Minor or Mikulicz’saphthea
or mild aphthous ulcers), Major aphthous
stomatitis (MjRAS or periadenitis
mucosanecrotica recurrence or Sutton’s disease)
and Herpetiform ulcers.
Minor RAS: This is the commonest type of RAS
and 75-85% of RAS are of this type. They
typically measure 5-10 mm in size, last for 10-14
days and heal without scarring. Followingthe
healing of the ulcers, there is a variable ulcer free
intervalof about 3–4 weeks.
Major RAS: They typically measure more than 10
mm in size, last for more than two weeks to
months and generally heal by scarring. 10-15% of
RAS are of this type. MjRAS may produce lesions
Host Factors: Environmental factors:
 Genetic factors
 Food allergy
 Vitamin deficiency
 Immune dysregulations
 Physical or emotional stress
1. Genetic Factors: Field and Allan in 2003
described that there is a genetic predisposition
for RAS and more than 40% of affected
individuals have first degree relatives with
RAS2. Scully et al 2004 found that the
likelihood of RAS is 90% when both parents
are affected, but only 20 % when neither parent
has RAS. A family history of recurrent
aphthous ulcers is evident in some patients. A
familial connection includes a young age of
onset and symptoms of increased severity.
Recurrent aphthous ulcers are highly correlated
in identical twins4. HLA subtypes like HLA
B-515, HLA-B52, HLA-B446, HLA-DRW10
and DQW17 antigens were found to be closely
associated with RAS.
2. Nutrition: Foods such as chocolate, coffee,
peanuts, cereals, almonds, strawberries, cheese,
tomatoes (even the skin of the tomatoes) and
wheat flour (containing gluten) may be
implicated in some patients. In one study of
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Page 17
throughout the entire oral cavity, including the soft
palate, tonsillar areas, and oropharynx. The longer
duration simulates the malignant ulcer.
Herpetiformulcers: They typically occur as crops
of multiple ulcers measuring less than 5mm which
may coalesce to form larger confluent areas of
ulceration, usually with marked erythema. They
last for 10-14 days but severity of pain is more
than other forms. 5-10% of RAS are of this type.
They resemble ulcers of primary Herpes simplex
virus (HSV) infection. The recurrence period may
be variable1,2.
Etiology ofRecurrent aphthous stomatitis:
There are many hypotheses that are put forth for
the etiology of RAS. There is no conclusive
evidence regarding the etiopathogenesis of RAS.
 Microtrauma.
 Local trauma
 Chemicalinjury or physical trauma.
 Infections
 Smoking
patients with RAS who previously were
diagnosed in patch tests as reactive to agents
such as benzoic acid, 50% showed clinical
improvement when certain foods were
excluded from the diet8.
3. Vitamin Deficiency: Hematinic (iron, folic
acid, vitamins B-6 and B-12) deficiencies were
twice as common in patients with RAS9. As
many as 20% patients with RAS had a
hematinic deficiency. Lower dietary intake of
folate and vitamin B-12 is more common
among persons with aphthous ulcers and
treatment with 1000 mcg/d has shown benefit
in individuals regardless of serum vitamin B-
12 levels10. A small group of adolescents were
shown to have reduced incidence and pain
from RAS when given 2000 mg/d of ascorbic
acid11.
4. Immune Dysregulations: Immune
dysregulations may play a significant role but
no conclusive evidence has been noted.
 Arun Kumar M. et. al. ETIOLOGY AND PATHOPHYSIOLOGY OF RECURRENT APHTHOUS STOMATITIS: A REVIEW
Cytotoxic action of lymphocytes and
monocytes on the oral epithelium seems to
cause the ulceration, but the trigger remains
unclear. Upon histologic analysis, RAS
consists of mucosal ulcerations with mixed
inflammatory cell infiltrates. T-helper cells
predominate in the pre-ulcerative and healing
phases, whereas T-suppressor cells
12
predominate in the ulcerative phase .
There is reduced response of patients'
lymphocytes to mitogens. There may be
alterations in the activity of natural killer cells
in various stages of disease13. Increased
adherence of neutrophils and reduced
quantities and functionality of regulatory T
cells in tissue with lesions and release of tumor
necrosis factor-alpha (TNF-alpha) is seen14.
There is significant involvement of mast cells
in the pathogenesis of RAS. Reduced cellular
expression of heat shock protein 27 and
interleukin 10is seen15 in aphthous lesions16.
There is an increase in the Toll-like receptor
activity in RAS17. Oxidative stress markers
(glutathione and malondialdehyde) show
altered levels and impaired balance18. Serum
IgE levels were found to be increased in RAS
patients by several investigators. Scully et al
reported that increased IgE concentrations
might be related to cell-mediated phenomena
in the immunopathogenesis of RAS.
The expression of protein C, protein S and D-
dimer were increased, while t-PA (tissue
plasminogen activator) was reduced in patients
with RAS and Behcet‘s disease. Remarkably,
the expression of PAI-1(Platelet activator
inhibitor-1) was significantly elevated in both
Behcet’s Disease and RAS patients compared
with that in healthy controls19. The results
suggest the abnormal fibrinolytic activity is
due to increased inhibition of tissue
plasminogen activator20.
5. Trauma: Local trauma may play a role in
initiating the mucosal injury which leads to
ulcers in patients with RAS. This study was
Int J Cur Res Rev, May 2014/ Vol 06 (10)
Page 18
initiated to determine whether standardized
mechanical injury would lead to ulcers in
patients prone to aphthous stomatitis when
compared with normal controls. In this study
experimental biopsies failed to disclose any
histological differences between mechanically
induced and spontaneous ulcers21.
6. Physical or Psychological stress:
Psychological stress may play a role in the
manifestation of recurrent aphthous stomatitis
as a trigger or a modifying factor22. No studies
have conclusively proved stress as a causative
or precipitating factor for RAS.
7. Infections: The possible immunopathological
destruction of oral mucosa by viridian
streptococci was under consideration until
1986 but was disproved23.Streptococcus
sanguisor its L-form has been implicated, as
has autoimmunity to the oral mucosal
homogenate. A common or cross-reactive
antigen between streptococci and oral
epithelium has been suggested and
demonstrated between the streptococcal 60–65
kD heat shock protein (HSP) and oral mucosal
tissue. Significant increase in serum antibodies
to HSP has been detected in patients with
RAS24. Helicobacter pylori has been detected
in lesional tissue of oral ulcers, but the
frequency of serum immunoglobulin G
antibodies to H pylori is not increased in
recurrent aphthous ulcers, and the organisms
have never proven causative25,26.
8. Tobacco smoking: Patients suffering from
RAS usually are nonsmokers, and there is a
lower prevalence and severity of RAS among
heavy smokers as opposed to moderate
smokers. Some patients report an onset of RAS
after smoking cessation, while others report
control on re-initiation of smoking. The use of
smokeless tobacco is associated with a
significantly lower prevalence of RAS.
Nicotine-containing tablets also appear to
control the frequency of RAS27.
 Arun Kumar M. et. al. ETIOLOGY AND PATHOPHYSIOLOGY OF RECURRENT APHTHOUS STOMATITIS: A REVIEW
 Recurrent aphthous stomatitis Associated
Syndromes
i. Behcet’s disease (BD) is a multisystemic,
chronic, relapsing vasculitis that affects nearly
all organs and systems. It is associated with
multiple oral, genital ulcers, arthritis,
hematemesis, melena, and epigastric pain as
predominant manifestations. Seung-Ho Rhee et
al 2005 in their study described that RAS and
BD had similar presenting symptoms like oral
lesions and abdominal pain. There was no
clinical, endoscopical, histopathologicalor
serological difference between patients with
intestinal BD, RAS and healthy volunteers in
Anti-Neutrophil Cytoplasmic Antibodies
28
(pANCA) .
ii. RAS is a part of PFAPA syndrome which
includes the Periodic Fever, Aphthous
stomatitis, Pharyngitis and cervical Adenitis.
PFAPA syndrome is regarded as a non-
hereditary disease of unknown etiology
although the clinical observation is that, in a
small proportion of cases, one of the parents or
a more distant relative had similar symptoms
in childhood29.
iii. MAGIC syndrome: Mouth And Genital
ulcers with Inflamed Cartilage syndrome (also
known as "MAGIC syndrome") is a cutaneous
condition2.
iv. Imerslund-Grasbeck syndrome (IGS) is
characterized by Juvenile megaloblastic
anemia due to vitamin B12 deficiency and
proteinuria. All the three cases of Imerslund-
Grasbeck syndrome described in the study
ArnonBroides et al 2006 were associated with
RAS. Though it was described that defective
neutrophil phagocytosis and neutropenia
caused by the Vitamin B12 deficiency may be
the possible mechanism for the causation of
stomatitis, none of the patients had
neutropenia. The cause of RAS in IGS was
inconclusive30.
v. Sweet’s syndrome, also known as acute
febrile neutrophilicdermatosis, is characterized
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Page 19
by fever, neutrophil leukocytosis,
erythematous skin plaques or nodules and,
often, classical RAS. It may occur in
conjunction with malignant conditions, such as
leukemia2.
vi. Celiac disease (CD) is caused by gluten
sensitivity of the small intestines. According to
study by SelimAydemir et al 2004 the CD
prevalence (40%) in patients with RAS is
higher than in the normal population. It is also
described that RAS may be the presenting sign
of the disease and may be used as a marker for
the CD31.
vii. Crohn’s disease: The intraoral involvement
in Crohn’s disease (CD) is observed in
approximately 9% of cases and oral
inflammation precedes intestinal symptoms in
about 60% of these patients. Hence it is
important to consider the differential diagnosis
of Crohn’s disease in subjects with intestinal
symptoms and RAS32.
Pathophysiology of Recurrent aphthous
stomatitis:
The complex interactions of various etiological
factors together can trigger ulcer formation.
Etiological factors can be classified into
predisposing factors and precipitating /
triggering factors. The factors like HLA
associations, immune dysregulation, nutritional
deficiency, personality type A are the
predisposing factors. Microtrauma, infections,
stress could be the initiating or triggering
factor for ulcer formation.
Those individuals who are susceptible when
exposed to the triggering factors for certain
duration tend to develop ulcers. Based on the
intensity and duration of the triggering factors,
ulcer starts growing till the factors are
removed. Pain suffered by the patients is
directly proportional to the size of the ulcer
and severity of the triggering factors. For
example the serum cortisol level: which is a
biomarker of the stress was increased in the
 Arun Kumar M. et. al. ETIOLOGY AND PATHOPHYSIOLOGY OF RECURRENT APHTHOUS STOMATITIS: A REVIEW
subjects with RAS and the increase was
directly proportional to the ulcer size33.
CONCLUSION
Recurrent aphthous stomatitis or aphthous
ulcers are more common in younger adults.
There are several causes that have been
explained for ulcer formation but no single
cause is definitive. The cause is still non-
specific. There are multiple factors which may
be acting together in a complex manner in
initiating the formation of ulcer unlike a single
etiological factor as was thought previously.
This means a combination of host and
environmental factors are essential not only for
triggering the ulcer but also for an increase in
size. The severity of etiological factors to
which an individual is exposed would decide
the type of ulcer. Underlying mechanisms
relating to pathogenesis need to be explored
inorder to establish the treatment protocol.
ACKNOWLEDGEMENT
Authors acknowledge the immense help
received from the scholars whose articles
are cited and included in references of this
manuscript. The authors are also grateful to
authors / editors / publishers of all those
articles, journals and books from where the
literature for this article has been reviewed
and discussed.
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