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Aphthous Stomatitis

Aphthae

Aphthous stomatitis is a pathological condition which consists in the appearance of benign and non-contagious ulcers in the oral cavity.


Presentation

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.

Reiter's Syndrome
  • Reiter's syndrome Ulcers Conjunctivitis Keratoderma blenorrhagica Other oculomucocutaneous syndromes: ulcerative colitis, herpes simplex, syphilis, lupus erythematosus and mixed connective tissue disease. II.[stmina-monastery.org]
  • Associated diseases include Behçet syndrome; Reiter syndrome; vitamin deficiency; inflammatory bowel disease; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome[mdedge.com]
  • Systemic disorders: Disorders such as cyclic neutropenia, Reiter syndrome, Behçet disease, or HIV infection may result in aphthous ulcers (canker sores).[oralmaxillo-facialsurgery.blogspot.com]
  • syndrome; cyclic neutropenia; human immunodeficiency virus disease; inflammatory bowel disease; celiac disease; and vitamin (B 1 , B 2 , B 6 , B 12 , folate, zinc, and iron) deficiencies, must be excluded.[jamanetwork.com]
Relapsing Polychondritis
  • The name stands for "mouth and genital ulcers with inflamed cartilage" (relapsing polychondritis).PFAPA syndrome is a rare condition that tends to occur in children.[en.wikipedia.org]
  • MAGIC syndrome, mouth and genital ulcers with inflamed cartilage refers to relapsing polychondritis and is a possible variant of Behçet disease, and is associated with aphthous-like ulceration.[standardofcare.com]
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]
  • Periodic fever, aphthous stomatitis, pharyngotonsillitis, cervical adenopathy (PFAPA) syndrome, which is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and cervical adenitis, is of unknown etiology and manifests usually[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]
  • The oral lesions resemble Sutton disease, which is another form of recurrent aphthous stomatitis (RAS) that composes approximately 10 per cent of cases and is known as major aphthous stomatitis, can easily be overlooked if the other symptoms are not questioned[ncbi.nlm.nih.gov]
Aphthous Ulceration
  • 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]
  • 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.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.[oadoi.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]
  • ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be RAS; RAS is rarely associated with B12 deficiency; nevertheless, B12 treatment may be beneficial, via mechanisms that warrant further study; ([ncbi.nlm.nih.gov]
  • 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]
  • All had oral ulcerations resembling recurrent aphthous stomatitis. These cases demonstrate the heterogeneity of lesions that might be diagnosed as "canker sores."[ncbi.nlm.nih.gov]
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) was diagnosed in a 22-year-old man after a 1-year history of periodic fever, myalgia, conjunctivitis, cervical lymphadenopathy, and oral ulcers.[ncbi.nlm.nih.gov]
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]
  • 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.[oadoi.org]
  • Some suggest that screening for celiac disease should form part of the routine work up for individuals complaining of recurrent oral ulceration.[en.wikipedia.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]

Workup

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]
  • Moreover, normocytic anemia (54.0%) and iron deficiency anemia (26.4%) are the two more common types of anemia in our RAS patients.[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]
  • BACKGROUND/AIMS: The aim of the present study was to investigate whether Helicobacter pylori causes or triggers recurrent aphthous stomatitis (RAS) through cytokine gene polymorphism and/or cobalamin deficiency.[ncbi.nlm.nih.gov]
  • AIM: The aim of this study is to evaluate the association of Helicobacter pylori in recurrent aphthous stomatitis (RAS) with or without peptic ulcer.[ncbi.nlm.nih.gov]
  • OBJECTIVES: Several studies have shown the possible involvement of Helicobacter pylori infection in individuals with recurrent aphthous stomatitis (RAS), but the relationship remains controversial.[ncbi.nlm.nih.gov]
  • The effect of gastric Helicobacter pylori eradication on recurrent aphthous stomatitis . Int J Dermatol 2008; 47 : 615–617.[nature.com]
Human Herpesvirus 6
  • Detection of serum antibodies against cytomegalovirus, varicella zoster virus and human herpesvirus 6 in patients with recurrent aphthous stomatitis. J Oral Pathol Med. 1999 Jan. 28(1):12-5. [Medline]. Pedersen A, Hornsleth A.[emedicine.com]
  • Detection of serum antibodies against cytomegalovirus, varicella zoster virus and human herpesvirus 6 in patients with recurrent aphthous stomatitis. J Oral Pathol Med. 1999 Jan. 28(1):12-5. [Medline]. Lin SS, Chou MY, Ho CC, et al.[emedicine.com]

Treatment

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:

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.

Prognosis

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.

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

  1. Kozlak ST, Walsh SJ, Lalla RV. Reduced dietary intake of vitamin B12 and folate in patients with recurrent aphthous stomatitis. J Oral Pathol Med. 2010 Feb 7.
  2. Miller MF, Garfunkel AA, Ram C, Ship II. Inheritance patterns in recurrent aphthous ulcers: twin and pedigree data. Oral Surg Oral Med Oral Pathol. 1977 Jun. 43(6):886-91.
  3. Axéll T, Henricsson V. The occurrence of recurrent aphthous ulcers in an adult Swedish population. Acta Odontol Scand. 1985 May. 43(2):121-5.
  4. Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol. 1992 Jul;74(1):79-86.
  5. Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Sharkey KA, Häyrinen-Immonen R. Recurrent aphthous ulcers today: a review of the growing knowledge. Int J Oral Maxillofac Surg. 2004 Apr;33(3):221-34.
  6. Kleinman DV, Swango PA, Niessen LC. Epidemiologic studies of oral mucosal conditions--methodologic issues. Community Dent Oral Epidemiol. 1991 Jun;19(3):129-40.
  7. Reichart PA. Oral mucosal lesions in a representative cross-sectional study ofaging Germans. Community Dent Oral Epidemiol. 2000 Oct;28(5):390-8.
  8. Rogers RS 3rd, Hutton KP. Screening for haematinic deficiencies in patients with recurrent aphthous stomatitis. Australas J Dermatol. 1986 Dec. 27(3):98-103.
  9. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. 2003 Feb;134(2):200-7.
  10. Alidaee MR, Taheri A, Mansoori P, Ghodsi SZ. Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial. Br J Dermatol. 2005 Sep. 153(3):521-5.
  11. Brice SL. Clinical evaluation of the use of low-intensity ultrasound in the treatment of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Jan. 83(1):14-20.
  12. Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N. Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Mar. 109(3):402-7.
  13. de Abreu MA, Hirata CH, Pimentel DR, Weckx LL. Treatment of recurrent aphthous stomatitis with clofazimine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Nov. 108(5):714-21.
  14. Arikan OK, Birol A, Tuncez F, Erkek E, Koc C. A prospective randomized controlled trial to determine if cryotherapy can reduce the pain of patients with minor form of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Jan. 101(1):e1-5.
  15. Eversole LR, Shopper TP, Chambers DW. Effects of suspected foodstuff challenging agents in the etiology of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol. 1982 Jul. 54(1):33-8.
  16. Hay KD, Reade PC. The use of an elimination diet in the treatment of recurrent aphthous ulceration of the oral cavity. Oral Surg Oral Med Oral Pathol. 1984 May. 57(5):504-7.
  17. Wright A, Ryan FP, Willingham SE, et al. Food allergy or intolerance in severe recurrent aphthous ulceration of the mouth. Br Med J (Clin Res Ed). 1986 May 10. 292(6530):1237-8.
  18. Axell T, Henricsson V. Association between recurrent aphthous ulcers and tobacco habits. Scand J Dent Res. 1985 Jun. 93(3):239-42.
  19. Bittoun R. Recurrent aphthous ulcers and nicotine. Med J Aust. 1991 Apr 1. 154(7):471-2.

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Last updated: 2019-06-28 11:19