Archives of Razi Institute, Vol. 76, No.

5 (2021) 1155-1163 Copyright © 2021 by

Razi Vaccine & Serum Research Institute
DOI: 10.22092/ari.2021.356055.1767

Review Article
Oral Aphthous: Pathophysiology, Clinical Aspects and
Medical Treatment

Gasmi Benahmed, A1, 2, Noor, S3, Menzel, A4, Gasmi, A5 *

1. Académie Internationale de Médecine Dentaire Intégrative, Paris, France

2. Université Claude Bernard, Villeurbanne, France
3. Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University Multan, Pakistan
4. Laboratoires Réunis, Junglinster, Luxembourg
5. Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France

Received 2 September 2021; Accepted 27 September 2021

Corresponding Author: [email protected]

Abstract
Oral aphthosis is a painful inflammatory process of the oral mucosa. Oral aphthous can appear alone or
secondary to numerous distinct disease processes. If recurrence occurs frequently, it is called recurrent aphthous
stomatitis. The pathophysiology of oral aphthous ulcers remains unclear but various bacteria are part of its
microbiology. Three morphological types hold great importance in literature because these types help manage
the illness properly. Google Scholar and PubMed databases were used to retrieve the relevant data and
information. Different keywords including “Aphthous”, “Aphthosis”, “Canker sores”, “Aphthous stomatitis”,
“Aphthous ulcer causes”, “Aphthous ulcer AND Microbiota” and “Aphthous ulcer AND treatment”. The causes
for oral aphthous ulcerations are widespread and ranges from localized trauma to rare syndromes, underlying
intestinal disease, or even malignant disease processes. A detailed history and thorough examination of systems
can assist the physician or dermatologist in defining whether it is related to a systemic disease process or truly
idiopathic. Management of oral aphthous ulcers is challenging. For oral aphthous or recurrent aphthous ulcers
from an underlying disease, topical medications are preferred due to their minimum side effects. Systemic
medications are necessary if the disease progresses. Within the limitation of research and literature provided, it
is safe to say that topical corticosteroids are the first line of treatment. Herein, the author discusses the
pathophysiology, types, causes, diagnosis, and appropriate treatment ladder of oral aphthous stomatitis as
described in the literature.
Keywords: Oral aphthosis, Oral aphthous, Microbiota, Corticosteroids, Recurrent aphthous ulcer, Diagnosis

1. Context throughout documented history (3). In this condition,

This article reviews current aspects of oral aphthosis the patient suffers from mouth ulcers. These ulcers
that is a typical condition characterized by numerous can appear alone or can be associated with some
tiny, spherical, or oval ulcers with confined margins, underlying disease (4). Oral ulcers are usually painful
it typically presents first in adolescence in form of an lesions that are related to numerous conditions
erythematous lesion with the yellowish-grey floor (1). developing within the oral cavity. Oral aphthous is a
Canker sores are another name for aphthae or ulcers, known disorder that has an important effect on the
these were first stated by Hippocrates who used the patients’ excellence of life, causing much pain and
term aphthae’ to describe diseases related to the difficulty with mastication and speech. It is among the
mouth (1, 2). Aphthous ulcers have afflicted mankind most common oral ulcerative condition seen in
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clinical trials and there is enough research about this 3. Results

illness (4). Developed countries have the highest 3.1. Pathophysiology of Oral Aphthous
prevalence of aphthous ulceration, and women are at a The pathogenesis of recurrent aphthosis stomatitis
slightly greater risk than men. Usually, men and (RAS) remains poorly defined. It likely involves a
women are equally affected but in a special type predominantly cell-mediated inflammation involving
called herpetiform ulcers, women are at a slightly high T-cells and TNF-α (tumor necrosis factor-alpha)
incidence, etiology of this remains unknown. production. Light and electron-microscope examination
Aphthous ulcers affect between 20-25% of the of oral aphthous ulcers showed a penetrating, early,
population and are one of the most common oral lympho-monocyte infiltration of the epithelium.
lesions in the overall population (3). It can reoccur According to a study by Lehner (6), under light
any time in life with a frequency that varies up to 3 microscopy, oral ulcer epithelium showed considerable
months and the recurrence rates are as high as 50%. intercellular edema and degenerative changes. There
These ulcers, most commonly appear on the non- was epithelial hyperplasia and only the basement
keratinized oral mucosa, they can cause substantial membrane adjacent to the ulcer was affected, the rest of
pain, and may cause difficulty with chewing, eating, the basement membrane appeared intact. Mononuclear
and speaking. Oral aphthous occurs worldwide cells normally infiltrate the basal-cell and prickle-cell
although it appears most common in the developed layers of the epidermis and they are most commonly
countries. Most ulcers are benign and self-resolving lymphocytes and monocytes, but superficial to and
but a small percentage of them are malignant. The immediately adjacent to the ulcer neutrophil
incidence and prevalence of oral cancers vary across polymorphs were also found. According to Lehner (6),
the world. A significant minority of oral ulcers are the Intra-nuclear inclusion bodies were found in 3 out
malignant. Patients with an ulcer that persists for more of the 25 biopsies examined by electron microscopy.
than three weeks should be suspected of malignancy The affected nuclei were slightly larger and the nucleoli
and it requires urgent referral to a specialist (5). were uneven in shape. Inclusion bodies were not seen
Patients with oral aphthosis especially complex in the cytoplasm. Herpetiform ulcers differ from
aphthosis must be monitored for the development of recurrent aphthous ulcers in that they showed epithelial
any other skin lesions, this will help rule out other vesicles and intra-nuclear inclusion bodies, suggesting
systemic conditions and make the diagnosis quite a virus etiology. The immuno-fluorescent studies
easy. showed predominantly IgG and IgM binding only in
This review aims to provide a clinically oriented autologous tissues from patients with aphthous ulcers
overview of pathophysiology, clinical aspects, causes, (7). This reaction could indicate blood group antigens,
diagnosis, and treatment of aphthous ulcers in the light trapped globulins due to the inflammatory reaction,
of scientific knowledge. non-immunological physicochemical binding of the
fluorescent conjugate, or normal immunoglobulin
2. Evidence Acquisition
transport through the oral mucosa. An
For the retrieval of the relevant review articles and immunofluorescent examination couldn’t detect
information databases such as Google Scholar, Scopus specific globulin binding to salivary gland tissue in the
and PubMed were used. Different keywords including oral aphthous lesion. Major aphthous ulcers do not
“Aphthous”, “Aphthosis”, “Canker sores”, “Aphthous differ much from minor aphthous ulcers, but they have
stomatitis”, “Aphthous ulcer causes”, “Oral Aphthous an increase in the degree of severity of the pathological
Pathophysiology”, “Aphthous ulcer AND Microbiota” changes. There were no vascular abnormalities and
and “Aphthous ulcer AND treatment” were used. fibrinous necrosis noticed in recurrent oral ulcers. A
 Gasmi Benahmed et al / Archives of Razi Institute, Vol. 76, No. 5 (2021) 1155-1163 1157

three-fold rise in mast cells was found in recurrent oral mucosa, whereas all Helicobacter pylori DNA-positive
aphthous, in contrast to a decreased count in non- ulcers were present on the buccal mucosa. The results
specific ulcers. Mast cell count was present in all three indicated that Cytomegalovirus and Helicobacter pylori
groups of oral ulcers when it was compared with that in (HP) DNA can be found in isolated oral mucosal ulcers
other oral lesions and normal tissue. Leukocytes have a in normal healthy adults with a competent immune
normal chemotactic function in oral aphthosis but in system. The possible causal role of CMV or HP
Behcet’s disease, they showed hyperactive function (6). remains unclear. However, further studies are now in
There’s a chance that a few immunologically arbitrated progress regarding the presence of CMV and HP in oral
mechanisms are playing an important role in the mucosal lesions (13, 14).
pathogenesis of oral aphthosis. It may be due to an Pure cultures of a transitional L form of bacteria were
unopposed or excessive production of IL (interleukin)- isolated from numerous lesions in RAS patients, their
1 or IL-6, which is essential for its development, a examination suggested that an association exists between
concept that may explain why ulceration worsens after the L form of bacteria and the pathogenesis of RAS (15).
local injury, or cessation of smoking, or both (8). By DNA sequencing, plasmid DNA purification, and by
3.2. Microbiota of Aphthous Ulcers sequencing the 16S ribosomal RNA gene, the presence
Several different bacterial species have been of many previously unidentified bacteria was revealed in
associated with an aphthous ulcer. There have been a the gingival sulcus. Prevotella is a genus that
few studies to know about the association of bacteria consistently appears only in RAS samples and
with these ulcers (9-11). These studies aimed to corresponds to 16% of all lesion-derived clones (9).
estimate the bacterial diversity in oral lesions using a There has been a vast diversity of bacteria in oral
culture-independent molecular approach. These studies aphthous, it is confirmed that the healthy oral flora is
have supported a possible relationship between replaced by rare species of bacteria. There’s no
Streptococcus sanguinis (S. sanguinis) and this association of the herpes simplex virus with oral
condition. Amongst the bacterial infections, the role of aphthous. The only virus that has been found in the
a Streptococcus strain which was first identified as S. patient of oral aphthous is cytomegalovirus.
sanguinis but now reclassified as S. oralis has been 3.3. Types of Oral Aphthosis and Clinical Aspects
extensively studied since its isolation from a recurrent Aphthous ulcer is one or several rounded, superficial,
aphthous stomatitis lesion (12). Other streptococcal painful ulcers that remain between a few days to a few
species, such as S. mitis and S. oralis, have also been months. Before the actual ulcer appears, patients will
suspected to provoke the development of a recurrent infrequently have on and off symptoms of an itchy or
aphthous ulcer (9). burning sensation (4). Oral aphthous most often begin
Pyrosequencing analysis can be successfully after 10 years of life and may be caused by minor
employed to compare the oral microbiota of RAS strain, menstruation or stress, or contact with certain
patients with healthy controls. The mucosal microbiota hot or spicy foods. During this initial phase, erythema
of RAS lesions is characterized as a decrease in the develops, and it is localized to a specific part. Within
members of healthy core microbiota (normal oral flora) hours, small white papules form which later ulcerates,
but an increase of rare species, also a decrease in S. and slowly enlarges over the next 48–72 hours (2).
salivarius, and an increase in Acinetobacter johnsonii There are three morphological types of aphthous ulcers.
are related with RAS. Two of the ulcers containing 3.3.1. Minor Aphthous Ulcer
Cytomegalovirus (CMV) DNA were found on the It affects about 70-80% of patients. Ulcers are tiny
mucosa of the lips and one on the posterior palatal less than 4 mm in diameter, spherical, usually with a
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yellowish or grey-white false membrane and erythema The number of ulcers is usually 10-100 and the size is
is also present. It usually occurs on non-keratinized greater than 10 mm. Scarring can occur following the
surfaces particularly the mucosa of lips and mucosa of fusion of ulcers. If recurrence occurs, it will occur in
the mouth, and floor of the mouth (8). If we talk about less than a month. Despite the name, there is no
the sex ratio, we can safely say men and women are association with herpes viruses (9).
equally affected. The age of onset for minor aphthae is 3.4. Causes of Oral Aphthous
approximately between 10-19 years. The number of Oral ulcers may have a lot of causes, although in
ulcers is usually 1-5 and the size is less than 10 mm. some patients no cause is identified. If oral ulcers
Scarring does not occur, and the ulcer heals within 10- persist for less than three weeks’ duration, they are
14 days. If recurrence occurs, it will occur between 4- called ‘acute’ and if they persist for longer than three
14 months (16). weeks, they are called chronic. Oral ulcers may be
3.3.2. Major Aphthous Ulcer recurrent. The majority of patients with a complaint of
Major RAS is a severe form of RAS also known as aphthous ulcers do not have a related underlying
peri adenitis mucosa necrotica recurrent in the USA. systemic disease, but aphthous-like ulcers may occur in
10% of the affected patients present with this association with systemic diseases such as Crohn’s
complaint. These ulcers usually occur on the lips, disease or MAGIC (mouth and genital ulcers
cheeks. tongue, palate, and pharynx. Just like a minor with inflamed cartilage) syndrome, or they can occur
aphthous ulcer, the sex ratio in men and women is due to the use of medication such as non-steroidal anti-
equal. The age of onset for major aphthae is inflammatory drugs (5).
approximately between 10-19 years. The number of 3.4.1. Local Causes
ulcers is usually 1-10 and the size is greater than 10 One of the most common causes of oral ulceration is
mm. If recurrence occurs, it will occur in less than a local trauma (19). It is most frequently caused by tooth
month. They persist for up to 6 weeks and scarring may procedures, braces, or sharp/broken teeth. It can also be
or may not occur. Large ulcers may take a longer time due to accidental tongue or cheek biting, scratching of
to resolve and mostly heal without scarring. The major the tongue with fingernails, or eating rough/hot foods.
ulcer will rarely leave a scar. They can be mistaken as These ulcers generally start to heal within 10 days after
malignant lesions due to their clinical appearance (17). removal of the cause. Persistence after the presumed
The major aphthous ulcer usually appears after puberty, cause has been removed should lead to urgent further
it is chronic, and persists for up to 30 years (18). investigation (19). Dr. Harding stated that ulcers can
3.3.3. Herpetiform Aphthous Ulcer arise due to chemical injury from direct contact of oral
Herpetiform ulceration (HU), is a rare form of mucosa with aspirin or Bisphosphonates (20).
aphthous ulcer, only 1-10% of patients are affected. It 3.4.2. Malignant Causes
is characterized by multiple recurrent picks of Malignant causes of oral ulcers include oral
extensive, minor, painful ulcers (8). This ulcer usually squamous cell carcinoma (most common) lymphoma,
occurs on the lips, cheeks, tongue. pharynx, palate. minor salivary gland tumors, tumor extension from the
gingiva, the floor of the mouth. In herpetiform maxillary sinus, Odontogenic tumors, metastatic
aphthous ulcers, females are more affected than males, neoplasms, neoplasms of bone, neoplasms of
cause and reason for this are maybe it is stress connective tissue, neoplasms of melanocytes, and
associated. During stress situations and menses, some vascular neoplasms (20). Unusually, smoking may be
women might develop these ulcerative lesions. The age protective of oral aphthous, even though smoking
of onset for herpetiform ulcers is almost mid-twenties. makes many oral ulcers and skin conditions worse. It
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has been recommended that cigarette smoking should be performed to examine the mucosa of the oral
improves keratinization of the oral mucosa thus it stops cavity. This process requires a good light source and
aphthous ulcers to grow in the oral cavity (21, 22). preferably two dental mirrors. Tissues of the oral cavity
3.4.3. Systemic Causes can be held back with tongue depressors, and it will
There are a few systemic diseases that also contain help with a clear visualization of the whole cavity.
oral ulcers and can be a leading cause of oral aphthous There are seven regions in the oral cavity, these must
ulcers. One of these systemic illnesses is MAGIC be examined thoroughly to avoid missing a lesion,
syndrome (23), the other one is Sweet Syndrome also these sites include lips, cheek mucosa, the floor of the
known as acute febrile neutrophilic dermatosis (8). mouth (mainly the posterior floor of the mouth between
Oral ulceration is the most common indicator of the tongue and the mandible), teeth and gums, hard
Behcet’s disease and can occur in up to 99% to 100% palate, oral tongue, and the retro-molar trigone (27, 28).
of patients with the disease that is why Behcet’s disease If an ulcer is present assess whether it is localized or
is a major cause of RAS. Inflammatory bowel diseases inflamed. The shape and margins of the ulcer should be
(IBDs) affect the intestinal tract, but it has been noted. Induration of the ulcer should be felt along with
recently suggested that it also has extra-intestinal the surrounding tissue and ensure that there is no
involvement within the oral cavity (24). Oral ulcers are fixation of moveable tissues such as the tongue. Note
seen along with intestinal symptoms of Crohn’s disease the relation of any prosthesis, sharp or broken teeth, or
in about 60% of these patients (25, 26). dental repairs to an ulcer if present. An extra-oral
3.5. Diagnosis of Oral Aphthous examination to look for swelling or lymphadenopathy
The diagnosis of oral aphthous is pretty critical should always be performed (27).
because there is no specific diagnostic test currently Patients with RAS show signs of immune
available. And in this situation diagnosis is based on dysregulation. Oral aphthous ulcers are mucosal
history and clinical findings. There is a need to exclude ulcerations with a varied inflammatory infiltrate and
other possible causes of recurrent oral ulceration, such large granular lymphocytes. These cells and
as Behcet’s disease, PFAPA (Periodic Fever, Aphthous inflammatory infiltrate predominate in the pre
Stomatitis, Pharyngitis, Adenitis) syndrome, and ulcerative and healing phases, keeping this in mind
possible infection by HIV. It is necessary to histology can be performed to make a diagnosis.
differentiate between the lesions in Behcet’s disease Normal CBC (complete blood count) and hematinic
and those in oral aphthosis to make a proper diagnosis can be done along with another serological testing (29).
(8). Also, special attention should be focused on 3.6. Treatment of Oral Aphthous
detailed history. Medical specialists should ask about Treatment of oral aphthous consists of both topical
dental procedures before the emergence of the ulcer, and systemic agents. There is a multitude of therapies
and any recent local or chemical injury. Also, ask about for oral aphthous ulcers. The goals of therapy include
the current use of drugs and the history of tobacco and analgesia which means control of the pain of an ulcer,
alcohol use. As it is discussed above the causes of oral ulcer healing, and prevention of recurrence.
aphthous so, there is a need to prevent all those causes. 3.6.1. Topical Treatments
Information about any other systemic illnesses or the 3.6.1.1. Corticosteroids
use of drugs like NSAIDS or bisphosphonates should Topical corticosteroids are the mainstay of therapy in
also be questioned. After the history, the next important the case of oral aphthous ulcers. Triamcinolone
step is the examination of the oral cavity. According to acetonide is used as an ointment or emollient paste and
Paleri, Staines (5), a complete intraoral examination it is applied to the ulcer site 4 times a day. To make
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sure it stays in place, additional applications may be clinical trial, doxycycline 100 mg in 10 ml water used
necessary. Improved adhesion of triamcinolone in for 2–3 minutes, 4 times daily for 3 days as a
ointment or emollient paste can be obtained by drying mouthwash has provided some good results for the
the ulcer before drug application. Food and fluid intake treatment of ulcers (8, 40).
should be restricted for at least 30 minutes before the 3.6.2. Systemic Treatment
use of ointment (30, 31). Recurrent aphthous ulceration is often known as an
3.6.1.2. Amlexanox “orphan” disease. Patients are often seen by a range of
Amlexanox has already been used in Japan for the medical specialties including dermatologists, dental
treatment of asthma but according to recent clinical surgeons, and otolaryngologists, with no certain
trials 5%, Amlexanox paste is effective in the treatment medical specialty assuming particular interest in the
of a type of aphthous ulcer. An overall excellent safety management of these patients. Dermatologists are often
profile for 5% Amlexanox paste is supported by the faced with referrals of patients suffering from oral
following very low reported incidence of side effects in aphthosis, many of these patients are transferred from
subjects treated for aphthous ulcers (32-34). dentists or Orthodontists. It is therefore important that
3.6.1.3. Triclosan we can treat such patients with the specialized care that
Tricoslan is an antibacterial agent used in toothpaste they require. No doubt that topical treatment is
and mouth rinses. A cross-over study was performed to effective in such patients but in severe cases, systemic
examine the effect of triclosan on the incidence of oral treatment is important as well.
aphthous when administered in mouth rinses. The 3.6.2.1. Systemic Corticosteroids
results showed that the patients experienced a Dexamethasone is an adrenocortical steroid and
significant decrease in the number of oral ulcers during azathioprine an immunosuppressant if both of these
the experimental period when the mouth rinses drugs are combined, they’re effective in the treatment
contained triclosan (30, 35). of oral aphthous ulcers. In a double-blinded, controlled
3.6.1.4. Levamisole clinical trial, the efficacy and safety of topical
A double-blinded study was performed by De Cree, dexamethasone and placebo in patients with recurrent
Verhaegen (36) to check the effectiveness of aphthous ulcerations were studied. Patients were asked
levamisole in the treatment of aphthous ulcers. to apply dexamethasone five times a day on ulcers and
According to the results and statistical evaluation of size, pain level, healing ratio, and safety of
this study, patients who were treated with levamisole dexamethasone were observed. Results of this study
showed a reduction in the number of lesions and revealed the effective healing of ulcers and safety as
reduced pain of lesions. These results have been compared to placebo (41). Studies have also shown that
confirmed by subsequent follow-up in an open trial oral prednisolone (31) and tetracycline hydrochloride
(37). (42) are also effective in the treatment of severe cases
3.6.1.5. Benzydamine of oral aphthous.
Benzydamine mouthwash has been found to have a In patients with HIV (human immunodeficiency
transient local anesthetic effect, which gave pain relief virus)-positive patients, there are several adverse effects
for oral ulcers (38), but it doesn’t aid healing (39). of corticosteroid therapy, and such adverse events place
3.6.1.6. Tetracycline oral corticosteroids among the last treatment options for
A double‐blind trial of a tetracycline suspension was RAS in HIV-seropositive patients (43).
carried out in patients with aphthous oral ulcerations, 3.6.2.2. Thalidomide
the tetracycline group showed significant reductions in In patients with immunocompromised systems or
ulcer duration, size, and pain. In the UK according to a those with advanced HIV infection, aphthous ulcers can
 Gasmi Benahmed et al / Archives of Razi Institute, Vol. 76, No. 5 (2021) 1155-1163 1161

become extensive and unbearable. Certain reports may present with skin lesions or as a manifestation of
advise that thalidomide may promote the recuperation systemic disease. Confusion exists on how oral
of oral aphthous ulcers. According to a double-blinded, aphthosis is classified. Therefore, all patients with oral
study of thalidomide as therapy oral aphthous ulcers in aphthous should be evaluated with these conditions in
HIV-infected patients, of the 29 patients in the mind, via careful history-taking and examination.
thalidomide group, 26 (90 percent) had complete or Diagnosis can be made through selective hematologic
partial responses at the end of week 4 (44, 45). and serologic testing. Once the diagnosis is made the
Thalidomide is effective in treating oral aphthous ulcers management of the predisposing medical condition
but, because of its toxicity, side effects, and expensive often leads to the resolution of the ulcers. A more
cost, it should be used only when oral corticosteroids standardized assessment of oral aphthosis involving
cannot be used (46). proper characterization of the ulcers together with a
3.6.2.3. Pentoxifylline structured management algorithm and follow-up
This anti-TNF agent (400 mg thrice daily) duration may improve patient outcomes and treatment
considerably reduced the amount of RAS when used results. It may require various systemic therapies;
one month for treatment purposes in a study (47), dermatologists are in a good position to offer primary
however concerning 100% of patients developed duct care for these patients. Symptomatic and definitive
symptoms, and therefore the positive impact wasn't treatment ranges from mouthwash rinses to systemic
confirmed in an exceedingly newer study. It inhibits agents. In particular, topical corticosteroids are very
TNF-α production and presumably the assembly of important in the treatment of ulcers. Thalidomide is
another Helper T-cell one and pro-inflammatory beneficial in patients who have associated HIV
cytokines, like IL-1β, that area unit thought to be infection. Several Anti-TNF agents have also been
necessary within the RAS malady method. Those proved efficient in the treatment of aphthous ulcers.
patients who were treated with pentoxifylline had less
pain and their ulcers were reduced in size (47). Authors' Contribution
3.6.2.4. Adalimumab Study concept and design: A. G. B.
Adalimumab is an anti-TNF-α monoclonal antibody Analysis and interpretation of data: A. G. B and S. N.
that has been used to treat severe, recalcitrant, major Drafting of the manuscript: A. G. B., S. N. and A. M
aphthous ulcersi but due to the increased risk of serious Critical revision of the manuscript for important
side effects, it should be used carefully and only in intellectual content: A. M.
severe conditions (48). Administrative, technical, and material support: A. G.

4. Conclusion Conflict of Interest

In conclusion, oral aphthosis is a relatively common The authors declare that they have no conflict of
oral mucosal condition. Although its pathogenesis interest.
remains unclear, however, it likely involves a
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