Regardless of the clinical form, ulcers always appear in the same location inside the mouth of the affected individual: the non-keratinized area of the mucosa. Therefore, parts such as tongue dorsum, gums, and hard palate mucosa, all keratinized structures, are never touched by ulceration.

As previously stated, AS tends to affect healthy individuals who are present by no particular clinical condition. The ulcers generally appear during childhood or early adulthood, with 80% of the patients being younger than 30 years, and its frequency and severity tend to decrease with the passing of years. The condition might consist in isolated episodes which usually develop 2-4 times a year, but it might also show a continuous pattern that involves the constant formation of new lesions from older ones soon after healing. Lesions are generally characterized by a disproportionate pain lasting for 4-7 days. The appearance of ulcers is usually preceded by a prodrome of pain and burning which generally lasts for 1-2 days with no previous vesicles. Ulcers present as shallow and well-demarcated bodies with an oval or round shape at the center of which can be seen a yellow-gray pseudo-membrane associated with a red halo and a slightly raised margins of red color.

The most common clinical form is the minor aphthous ulcer which accounts for around 80-85% of cases. The lesions tend to appear on the buccal mucosa and pharynx, on the floor of the mouth or the lateral and ventral positions of the tongue, with a diameter smaller than 1 cm. They heal within 10 days leaving no sign of scarring.

Major aphthous ulcers, on the other hand, represents 10% of the cases of AS and generally sets in after puberty. The main aspect of this form is the tendency of presenting with marked clinical features, with a more intense prodrome and a longer appearance period that usually lasts for several weeks or months. Their size is greater than seen in the minor form, with a diameter generally larger than 1 cm. Major ulcers tend to appear on the soft palate, lips, and throat and might be associated with fever, malaise, dysphagia, and scars.

Lastly, herpetiform aphthous ulcers represent the least common clinical form that accounts for around 5% of the cases of AS. The lesions are much smaller, with a diameter generally ranging between 1 and 3 mm, and they tend to appear in multiple clusters of small and painful ulcers throughout the inside of the month. After a while they tend to coalesce, to turn into lager ulcers which generally disappear after 2 weeks. For this last clinical form a gender-related predisposition has been observed, with lesions more frequently occurring in women than men, usually at a later stage than the one observed in the other forms.

• Fever of Unknown Origin

  Clinicians, not only pediatricians, should take into account this clinical entity in every patient of whatever age suffering from recurrent fevers of unknown origin. [ncbi.nlm.nih.gov]

  A roadmap for fever of unknown origin in children. Int J Immunopathol Pharmacol. 2013;26:315–326 8. Brown KL, Wekell P, Karlsson A, et al. On the road to discovery in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. [journals.lww.com]

• Intestinal Perforation

  One patient with atypical PFAPA, who received low-dose steroids for over 1 year, developed intestinal perforation after an increment of the 7-day steroid dose. [ncbi.nlm.nih.gov]

• Aphthous Stomatitis

  It is thought that oxidative stress caused by systemic inflammation plays a basic role in the etiopathogenesis of recurrent aphthous stomatitis. The aim of this study is to review oxidative status and DNA damage in recurrent aphthous stomatitis. [ncbi.nlm.nih.gov]

  Lalla, Validation of anamnestic diagnostic criteria for recurrent aphthous stomatitis, Journal of Oral Pathology & Medicine, 42, 4, (290-294), (2012). [doi.org]

  […] recurrent aphthous stomatitis (MaRAS). [en.wikipedia.org]

• Aphthous Ulceration

  ulcer is higher in women and girls than in men or boys. [4] Age Recurrent aphthous ulcer minor is the most common form of childhood recurrent aphthous ulcer. [emedicine.medscape.com]

  Thanks to the clinical data gathered so far, it is now possible to categorize aphthous ulcers into three main clinical forms: recurrent aphthous ulcer minor, recurrent aphthous ulcer major, and herpetiform recurrent aphthous ulcer. [symptoma.com]

  Puram, Chennai 600 028 India Source of Support: None, Conflict of Interest: None DOI: 10.4103/0973-029X.86669 Abstract Recurrent aphthous ulcers are common painful mucosal conditions affecting the oral cavity. [doi.org]

• Oral Ulcers

  Recurrent aphthous stomatitis consists on recurring oral ulcers of unknown etiology. Oral ulcers may be different in number and size depending on the clinical presentation, which also determines the time needed for healing. [ncbi.nlm.nih.gov]

  ulceration.[8] Many of the systemic diseases cause other symptoms apart from oral ulceration, which is in contrast to aphthous stomatitis where there is isolated oral ulceration. [en.wikipedia.org]

  Lalla, Recurrent oral ulceration: Etiology, classification, management, and diagnostic algorithm, Periodontology 2000, 80, 1, (49-60), (2019). [doi.org]

• Recurrent Oral Ulceration

  Hypofunction of the sympathetic nervous system should be considered as a possible etiologic factor in patients with recurrent oral ulcers when not associated with known systemic diseases. [ncbi.nlm.nih.gov]

  Abstract Recurrent oral ulceration is common and may present in childhood. Causes of recurrent oral ulceration are numerous and there may be an association with underlying systemic disease. [magonlinelibrary.com]

  Pharmacist. 2013; 38(6) 14 Hypervariable Region Polymorphism of mtDNA of Recurrent Oral Ulceration in Chinese Sun, M. and Fu, S.-M. and Wang, L.-F. and Dong, G.-Y. and Wu, D. and Wang, G.-X. and Wu, Y. [doi.org]

• Tongue Ulcer

  The following are the most common symptoms: ulcers in the mouth, usually inside the lips, on the cheeks, or on the tongue ulcers that are covered with a yellow layer and have a red base no fever present (in most cases) lesions usually heal between seven [childrenshospital.org]

  Signs and symptoms may include: Ulcers in the mouth, usually inside the lips, on the cheeks, or on the tongue Ulcers that are covered with a yellow layer and have a red base No fever present (in most cases) Lesions usually heal in seven to 14 days Lesions [chop.edu]

  Symptoms may include: Ulcers in the mouth, usually inside the lips, on the cheeks, or on the tongue Ulcers that are covered with a yellow layer and have a red base No fever present (in most cases) Lesions usually heal in seven to 14 days Lesions tend [nyhq.org]

• Microscopic Hematuria

  Microscopic hematuria, first detected at age 8 years, worsened during episodes of PFAPA-related fever; since 10 years of age, the hematuria was accompanied by sustained proteinuria. Examination of a kidney biopsy specimen led to a diagnosis of IgAN. [ncbi.nlm.nih.gov]

The diagnosis of AS can generally be performed by using the following laboratory studies:

• Complete blood cell count, usually employed to determine hemoglobin concentration and the levels of glucose-6-phosphate dehydrogenase and glycemia. 
• Measurement of the levels of iron, folate, ferritin, and vitamins B-6 and B-12 [8]
• Measurement of erythrocyte sedimentation rate
• Laboratory tests like Tzanck test, viral culture, or skin biopsy. These tests are necessary to rule out the presence of simplex virus infection, especially in immunocompromised individuals diagnosed with HIV. 

Because of the lack of definitive histological features and tests, diagnosis is invariably made by an exclusion process based on the clinical history and lesion presentation [9].

• Normocytic Anemia

  Of 69 anemia AG /RAS patients, 30 (43.5%) had normocytic anemia and 23 (33.3%) had iron deficiency anemia. Of 38 anemia AG-/RAS patients, 26 (68.4%) had normocytic anemia and 5 (13.2%) had iron deficiency anemia. [ncbi.nlm.nih.gov]

• Helicobacter Pylori

  Helicobacter pylori (H. pylori) is a gram-negative, microaerophile bacteria, that colonizes the gastric mucosa and it was previously suggested to be involved in RAS development. [ncbi.nlm.nih.gov]

• HLA-B5

  There is an association with HLA-B5 and HLA-B51. Clinical Manifestations: I. Major criteria: Recurrent aphthous stomatitis (RAS): in 90%-100% of cases. Recurrent painful genital ulcers that tend to heal with scars: in 64%-88% of cases. [stmina-monastery.org]

  […] lead to ulceration.[5] RAS etiopathogenesis may also include genetic factors, and RAS patients have an increased prevalence of HLA-B12 and Behcet's disease, which is a disorder characterized by recurrent aphthous ulcers and is associated with increased HLA-B5 [ijds.in]

  In patients with RAS, a higher incidence of HLA-A33, HLA-B35 and HLA-B81 (Wilhelmsen et al. 2009 ), HLA-B12 (Lehner et al. 1982 ), HLA-B51 (Özdemir et al. 2009 ), HLA-DR7 and HLA-DR5 and lower incidence of HLA-B5 and HLA-DR4 (Albanidou-Farmaki et al. [dx.doi.org]

• HLA-DR4

  On the other hand, the HLA-DR4 frequency was reduced. Sun et al.24 stated that the HLA-DRw9 frequency can be considered a genetic marker for RAS in the Chinese population. Their study was made up of 80 Chinese patients with RAS. [scielo.br]

  In patients with RAS, a higher incidence of HLA-A33, HLA-B35 and HLA-B81 (Wilhelmsen et al. 2009 ), HLA-B12 (Lehner et al. 1982 ), HLA-B51 (Özdemir et al. 2009 ), HLA-DR7 and HLA-DR5 and lower incidence of HLA-B5 and HLA-DR4 (Albanidou-Farmaki et al. [dx.doi.org]

• HLA-DR5

  The HLA-DR5 frequency, differently from our findings, was predominant in these patients. On the other hand, the HLA-DR4 frequency was reduced. [scielo.br]

  In patients with RAS, a higher incidence of HLA-A33, HLA-B35 and HLA-B81 (Wilhelmsen et al. 2009 ), HLA-B12 (Lehner et al. 1982 ), HLA-B51 (Özdemir et al. 2009 ), HLA-DR7 and HLA-DR5 and lower incidence of HLA-B5 and HLA-DR4 (Albanidou-Farmaki et al. [dx.doi.org]

• HLA-DR7

  Gallina et al.12, with a sample of 26 Sicilian patients with RAS, found a statistically increased value for HLA-DR7 frequency. [scielo.br]

  In patients with RAS, a higher incidence of HLA-A33, HLA-B35 and HLA-B81 (Wilhelmsen et al. 2009 ), HLA-B12 (Lehner et al. 1982 ), HLA-B51 (Özdemir et al. 2009 ), HLA-DR7 and HLA-DR5 and lower incidence of HLA-B5 and HLA-DR4 (Albanidou-Farmaki et al. [dx.doi.org]

There is a variety of agents that are used to treat recurrent aphthous ulcers. These range from agents with palliative effects to those which shorten the healing time [10] [11] and prevent recurrence. Topical agents include:

• Anti-inflammatory and immunomodulatory agents: These are used immediately, at the beginning of the treatment, and generally include a variety of different products such as topical gels, creams, ointments, and sprays. 
• Adjuvant rinses: These have proven to reduce the presence of pathogens inside the mouth, and are thought to lower inflammatory levels and healing time. The most important products include chlorhexidine gluconate and diluted hydrogen peroxide.
• Oral bioadherents: They are generally used to reduce pain, which sometimes might be very severe and disproportionate compared to the size of lesions. The mucoadhesives form a protective coating which alleviates pain. 

Systemic agents include:

• Colchicine: This medication is commonly used to treat gout and was originally extracted from the plants of the genus Colchicum.
• Prednisone: This is a corticosteroid used as an alternative for Colchicine. 
• Azathioprine: This is an immunosuppressive drug used in organ transplantation and autoimmune diseases.
• Montelukast sodium: This is an active leukotriene receptor antagonist which has been reported having few adverse effects, especially when compared to steroids [12]. 
• Thalidomide: This is an immunomodulatory drug especially used to treat individuals affected by HIV infection. 
• Clofazimine: This is a fat-soluble iminophenazine dye used in multidrug therapy to treat leprosy. This drug is especially indicated in those showing the tendency of continuously experiencing the appearance of new lesions [13].

There is no surgical approach to treat recurrent aphthous ulcers [14]. Diet modifications are strongly suggested, as outbreaks of AS might be caused by allergic stimuli whose frequency can be drastically reduced, for not saying eliminated at all, with finely chosen food changes [15] [16] [17].

The mainstay for the treatment for AS is undoubtedly represented by the use of chlorhexidine gluconate mouthwashes and topical corticosteroids. These should be applied during prodrome, so that clinical signs can be reduced before their development. The corticosteroid dexamethasone 0.5 mg/5 mL is particularly effective in rinses, generally followed by the use of ointments like clobetasol ointment 0.05% or fluocinonide ointment 0.05% in mucosal protective paste. If topical corticosteroids turn out to be ineffective to treat ulcers, they may be replaced by prednisone which is usually administered in doses of 40 mg once a day in a 5 days treatment. Severe cases are best treated with systemic corticosteroids and immunosuppressants. Some agents can even be administered intralesionally, especially with betamethasone, dexamethasone, or triamcinolone.

AS frequently tends to appear in healthy individuals, with no particular clinical consequences. However, in some cases it might be associated with a systemic disease like Behcet's syndrome or inflammatory bowel disease, in a clinical situation which might easily result into a significant morbidity or mortality.

Unfortunately, despite the clear clinical characterization that has been defined over the course of the years, the etiology of AS is still unknown, and no precise cause responsible for its appearance can be suggested. However, the most commonly accepted theory among experts is that AS must be a multifactorial condition which originates from immune-related events that cause the self-destruction of the oral epithelium. The destruction is mostly cell-mediated, with the intervention of cytokines like IL-2, IL-10, and in particular TNF-α, all well known inflammatory mediators playing a pivotal role in the functioning of the immune system.

Of note, many individuals affected by AS show hematinic deficiencies, especially in terms of low levels of iron, folic acid, and vitamins B-6 and B-12 [1], which appear twice as frequently as in healthy individuals. Furthermore, the pathological condition seems to run in certain families, as suggested by the high appearance frequency in identical twins [2], and this tendency might underline the involvements of genetic factors in the etiology of AS.

In America, AS appears to affect around 20% of the population, even though it seems to be particularly frequent in certain social groups, such as the students of professional schools. Strangely enough, the condition is more common among children with a high socioeconomic background [6]. Internationally, AP affects all populations in every continent, with an international frequency that ranges from 2 to 66% according to the particular country considered [3]. There is no evident gender-related predisposition, even though in particular social groups the pathology might be much more common in females than males. In America, around 1% of the children can be affected by recurrent AS, with an early onset which generally appears before the age of 5 years. The percentage of affected individuals tends to decrease after reaching the age of 30. In other individuals, the onset of AS might take place after puberty and generally tends to persist for the rest of their life, although less frequently. To sum up, AP primarily affects young individuals, but its incidence and severity tends to decrease over the years [4] [5] [6] [7].

Thanks to the clinical data gathered so far, it is now possible to categorize aphthous ulcers into three main clinical forms: recurrent aphthous ulcer minor, recurrent aphthous ulcer major, and herpetiform recurrent aphthous ulcer.

The most common of these forms is recurrent aphthous ulcer minor, which appears as a discrete, shallow, and painful lesion usually smaller than 1 cm in diameter. There might be just one minor ulcer present in the mouth at a time, but frequently more than one is observed. This clinical form accounts for more than 80% of the AS cases.

Recurrent aphthous ulcer major, on the other hand, is much less common than the minor form. It presents in an oval shape and its diameter is usually greater than 1 cm. In this form, there might be many lesions in the mouth at a time. These are large and deep ulcers with irregular borders that may coalesce after a while.

Herpetiform recurrent aphthous ulcer is the least common form, with a frequency of around 5-10%. It is characterized by a reduced size that is usually no larger than 1 mm in diameter. For this reason, sometimes it is possible to observe the appearance of this clinical form with the development of tiny ulcers in clusters of tens or hundreds of units which might be localized in certain points or be spread throughout the oral soft mucosa.

Outbreak of aphthae might be prevented with a gluten-free diet in celiac patients. Those who already have lesions in their mouth are advised to avoid hard and sharp foods, to prevent worsening the conditions of the already existing ulcers or the formation of new ones. Furthermore, affected individuals should also evade salt and hot spices, which might increase the already severe pain that  characterizes AS. In this regards, it is worth noting that the appearance of aphthae has been reported after the ingestion of cinnamon, nuts, and pineapples, which might act as inciting agents.

According to some studies, there is an association between smoking and the occurrence of AS, which might be reduced by using tobacco. For example, the incidence of recurrent aphthous ulcer is significantly lower in smoking people than the incidence observed in non smokers [18] [19]. This tendency is explained with the capacity of tobacco to increase keratinization in the mucosa, which as a consequence might remain much less exposed to ulceration. In other words, nicotine that is locally absorbed, might work as a preventing agent against the formation of lesions.

Aphthous stomatitis (AS) is also referred to as recurrent aphthous ulcers (RAU) or canker sores. This type of ulceration represents one of the most common mucosal lesions, usually found even in healthy individuals affected by no other pathological condition. Although AS is characterized by a clinically significant morbidity, its etiology remains generally unknown. The lesions consist of ulcers which appear on the mucous membranes inside the oral cavity for 7 to 10 days. Some lesions might even last for several weeks, leaving scars after the completion of the healing process.

Generally speaking, the activity for idiopathic recurrent aphthous ulcers is self-limiting, but in some cases it might appear as a continuous process. Furthermore, similar lesions can be seen in the genital region. As previously stated, AS frequently affects healthy individuals, even though in some cases it might be associated with other pathological conditions such as Behcet's syndrome or systemic lupus erythematosus.

Aphthous stomatitis (canker sores, or aphthous ulcers) is a pathological condition characterized by the presence of small and painful ulcers inside the mouth which usually appears in childhood and tends to recur over the course of the years. This condition is common, but its origin is still unknown, even though it tends to run in families. However, many experts believe that this is a multifactorial pathology which might be favored or triggered by several factors such as oral injuries, stress and certain foods. Symptoms include pain and burning in the initial stage, that is then followed by a ulcer after a few days. Pain is disproportionally severe and usually lasts from 4 to 7 days. The lesions present as soft and loose formations, usually less than 1 cm in diameter, and frequently gather in clusters of two or more units. Ulcers tend to disappear by themselves within 7-10 days leaving no scar on the oral tissue affected. Treatment is palliative and based on general measures such as the use of corticosteroid combined with frequent rinses.

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