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Current Approaches in Recurrent Aphthous Stomatitis.

The term 'aphthous' is a Greek word for burning, inflammation, fever, inflammation, was first used by Hippocrates (460-370 BC) to describe mouth wounds (1). Recurrent aphthous stomatitis (RAS) was first described scientifically by Johann von Mikulicz-Radecki, a Polish-based surgeon in 1898 (2).

RAS, the most common oral mucosal ulcerative disease, is an inflammatory condition of the oral mucosa associated with a painful, recurrent, single or multiple ulceration of unknown etiology. RAS, also known as painful ulcer, is a disease that involves one or more recurrent developments of painful ulcers. The diagnosis is based on the clinical appearance of the lesion and on the detailed anamnesis from the patient. In this study, it was aimed to inform dentists about clinical features, epidemiology, etiology, pathogenesis, differential diagnosis and current treatment approaches of 'recurrent aphthous stomatitis' which is one of the most common diseases of the oral mucosa.

CLINICAL FINDINGS

The basic mouth symptoms of RAS include weakness and pain in oral functions such as swallowing, speech and chewing (3, 4). The incidence of clinical manifestations varies according to factors such as duration of the lesion, number, and size of painful lesions. Pain is a basic clinical symptom seen in RAS and negatively affects the quality of life of patients and leads to emotional stress (5). RAS is a disease characterized by recurrent painful ulcers surrounded by erythematous areas, with a gray or white pseudo membrane-covered round or ovoid crater-shaped base (6). The edges of the ulcers are slightly raised. In ulcers, erythema is seen around the lesion with a superficial vascular inflammation and erythrocytes coming out of the veins in the superficial layers of lamina propria (1). A prodromal burning sensation may occur 2-48 hours before an ulcer occurs in RAS (7).

Epidemiology

It affects approximately 5-25% of the general population (8, 9). It is more common in childhood or adolescence. The prevalence of RAS was found to be 40% in children (10). RAS usually starts in the second decade of life and peak in the third decade. In a study from Germany in 1997, RAS was detected 1.4% of the 655 volunteers while it was 18.3% in the patient history (2). In two independent studies, the prevalence of RAS ranged from 0.89% to 1.03%. RAS is seen more in wealthier groups and women (2). Along with the increase of age, there is a reduction in the recurrence of the disease and in the severity of the lesions (11, 12).

Localization

The most frequent areas that it is seen are lip mucosa, oral cavity, and buccal mucosa, and more rarely on the soft palate (8). It is more common in the non-keratinized oral mucosa (10). It is seen less frequently in the hard palate and gingiva (13).

Etiology

The etiology of oral aphthous ulceration is not yet known and is multifactorial (8). Etiological factors are; certain chemical and microbial agents, genetic factors, hematological disorders, nutritional deficiencies, some deficiencies (vitamin B12, iron, folate, zinc), food allergies, local trauma, hormonal changes (menstrual cycle), stress and anxiety, smoking cessation (10, 14, 15).

Complete blood count, ferritin, serum folic acid, vitamin B vitamins are important parameters in a RAS patient. An examination should be performed and replacement treatments should be performed if necessary (16). The most frequent anemia is the anemia of iron deficiency. Vitamin B12 and folate deficiency may increase the incidence of megaloblastic anemia (17). Compilato et al. found that there are the pathologic values in 56% patient that are suffering from RAS. For this reason, routine hematologic screening is very important in all RAS patients. If the blood values are deficient, it is important to replace the missing substance with replacement therapy.

The amount of food-related antibodies in RAS patients was significantly higher than in the normal population. Besides, 'atopy' has been shown to be present at significantly higher levels in RAS patients. If some food is considered suspicious to trigger aphthae or prolong the healing of the lesions, they should be avoided (egg, acidic, salty, spicy foods, peanuts, chocolate, citric fruits or alcoholic drinks, etc.) (9). Several tests have been used to identify foods that cause food allergies. Specific Ig E test, skin prick test, skin patch test, and placebo-controlled food test are the most known examples. Thus, food allergies that may be associated with RAS can be detected (13). There are also studies reporting that RAS lesions may have an influence on toothpaste containing sodium lauryl sulfate (18). There are arguments that sleep disturbances and late night sleep increase the frequency of RAS (19). In many studies, the relationship between microorganisms and aphthae was found to be meaningless (20). RAS was also genetically assessed, and in 42% of patients with RAS, this condition was also found in relatives of the first degree (21). Systemic diseases such as Behcet's syndrome, hematological disorders, vitamin deficiencies, gastrointestinal diseases, cyclic neutropenia, Reiter's syndrome, Magic syndrome, PFAPA, Sweet's syndrome and immunological disorders are known to be associated with oral aphthous ulcerations (2, 3, 22).

Although there are theories that there is a relationship between the time that the lesions occur and the menstrual cycle. It has been found that remission occurs in aphthous lesions in people using oral contraceptives and in pregnancies. In addition, it has been observed that ulcers exacerbated after birth (15).

Studies have shown that cigarette smoking has a preventive effect on RAS (23). It is argued that this inhibitory effect is related to the increase of keratinization in the oral mucosa. The increased keratin layer acts as a local mechanical defense shield for the mucosa against many factors including microbial penetration and trauma.

Pathogenesis

When the mechanism of RAS is examined, the immunological response that is formed by the activation of proinflammatory cytokines is seen. Histological examination reveals increased leukocyte infiltration over time. Monocytes, lymphocytes (mainly T-type), mast, and plasmatic cells accumulate under the basal layer before ulceration occurs in the initial phase. Polymorphonuclear leukocytes concentrate at the center of the ulcer while mononuclear cells surround in the progressive phase (24). Interstitial collagenases (MMP-1 and MMP-8) are effective in destructive events (25). It can be argued that TNF-[alpha] (Tumor Necrosis Factor) plays an important role because RAS lesions are 2-5 times more common in the saliva of affected individuals (26). Changes in enzymes such as Superoxide Dismutase (SOD) in the saliva defense system also play a role in the inflammatory response process of RAS (10).

Classification

Stanley divides the oral aphthae into minor, major, and herpetiform (1). RAS patients usually only have one of these types. Less frequently, the two types may coexist or the clinical presentation may change over time. RAS is seen in three different clinical types. Small ulcers (minor type) (Mikulicz) are smaller than 1 cm in diameter (usually 2-5 mm) and can heal rapidly within 4-14 days. This group accounts for 80-90% of all RAS lesions. The probability of scar tissue formation is very low. Major type ulcers (Sutton ulcers) are usually 1-3 cm in size, deeper and can be seen for up to 10 days to 6 weeks. It constitutes 10% of all RAS ulcers. Approximately 64% of major type ulcers heal by scarring. Herpetiform types are usually small that are 1-2 mm and are seen as small groups. These aphthous lesions are seen in 5% of the population and last 7-10 days (8). Another classification is based on the duration of lesions in the mouth (5). Simple RAS are painful ulcers that are small and rapidly healing in a limited number and recurring 3-6 times a year. A few or many slowly healing intense painful aphthous lesions are called as complex RAS. These are seen in oral and even in genital mucosa. In complex lesions, short, non-lesioned periods and frequent recurrent ulcers, systemic effects related to pain and nutrition can be seen (27).

Histopathology

If the lesions are serious, the patient is over 25 years old and it is necessary to exclude other diseases, a biopsy may be taken. As result of biopsies, superficial ulceration with fibrinous exudate containing granulation tissue and chronic inflammatory infiltration. Early RAS lesions include large granular lymphocytes and CD4 lymphocytes with focal degeneration of basal cells and small intraepithelial vesicle formation (28).

Differential Diagnosis

It is important to distinguish between the following diseases during diagnosis (9)

Gastrointestinal diseases: Ulcerative colitis, Crohn's disease, Celiac Disease

Infections: Herpes Simplex and Zoster, Infectious Mononucleosis, Hand, Foot and Mouth Disease, Herpangina, AIDS, Syphilis, ANUG, Candidiasis.

Reactive changes: Morsicatio buccarum, Traumatic ulcer. Malignant diseases: Oral carcinoma, Non-Hodgkin's lymphoma.

Mucocutaneous rheumatic diseases: Lupus erythematosus, Sweet syndrome, Reactive arthritis, MAGIC syndrome, Sarcoidosis.

Bullous and lichenoid dermatoses: Erythema multiforme and its types, Bullous diseases, Lichen Planus.

Other oral diseases: Allergic contact stomatitis, Geographic Language, PFAPA syndrome.

Clinical and Research Consequentions

The main purpose of the RAS treatment is to shorten the duration of lesions, to help the patient to eat, and to reduce the incidence of lesions (13, 27). The treatment protocol may vary depending on various factors such as medical history, predisposing factors, the frequency of recurrences, severity of pain, and patient's tolerance to drugs. Possible preliminary factors should be considered carefully before treatment (3, 28, 29). Corticosteroids and antimicrobial agents are being used commonly as a treatment option (13, 30). These drugs can be used in a local or systemic way.

Topical Treatment

Topical anesthetics

Oral rinses containing lidocaine HCl 1% cream, lidocaine 2% gel or spray, benzocaine pastille, benzocaine and cetylpyridinium chloride are effective topically to reduce pain (31). Mouthwashes containing tetracycline reduce the size of the ulcers, the duration of the lesion and pain. It has also been shown that tetracycline-containing rinse is effective in preventing secondary infections and concomitantly inhibit collagenase activity (3). Tetracycline group drugs are effective by local inhibition of collagenases and metalloproteinases by inhibiting processes leading to inflammatory and cell destruction, ulcer formation (10). It was showed that doxycycline administered in a mucoadhesive gel form is more effective. 2.5% chlortetracycline oral rinse reduces the pain and prolongs the ulcer-free period. It has been reported that minocycline 0.2% rinse is more successful than tetracycline 0.25% rinse for reducing pain (31).

Doxycycline is the best inhibitor of metalloproteinases in the tetracycline group (32). In a study, 100 mg of doxycycline powder and denture adhesive were mixed with 1-2 drops of saline and it is applied to the ulcer area. It is suggested not to eat or drink for 2 hours after the application. A significant reduction in pain scores was seen after 10 days of evaluation. A significant decrease in the pain score was also seen in the placebo group where only the dental adhesive was applied without the drug. This can be explained by the mechanical protection of the applied adhesive and the acceleration of healing. Pain reduction in the doxycycline group was more rapid, which could be explained by the therapeutic effect of doxycycline (33). Mouthwashes which are containing 0.15% triclosan, ethanol, and zinc sulfate have been reported to reduce pain intensity by 45% and prolong the duration of the ulcer (34). 3% diclofenac and 2.5% hyaluronic acid gel has been found to be more effective in reducing pain compared to 3% lidocaine gel (35). Chlorhexidine-containing rinse reduces the frequency of RAS and accelerates healing (36). It also affects the sense of taste and causing coloration of teeth. Benzydamine hydrochloride also temporarily relieves the pain (37).

Topical corticosteroids

Topical corticosteroids should be initiated when topical anesthetics and anti-inflammatory agents are not adequate. The use of topical anesthetics and topical corticosteroids together during the treatment was also found effective (38). However, long-term use of topical corticosteroids may cause candida infections. Intralesional triamcinolone suspension of 0.1-0.5 ml/lesion may be used especially for very painful and deep ulcerations (38). Topical corticosteroids suppress the inflammatory process of the lesion. Corticosteroids act on T-lymphocytes and suppress the immunological response against factors such as allergy, trauma, and microorganisms. It is important to be careful using topical corticosteroid that it may lead to superinfections and candidiasis. During the treatment period, oral hygiene should be kept at a maximum level to reduce the risk of additional infections. If the topical gel is not available or ulcers are too large, corticosteroids can also be used as a mouthwash (1). The application of local corticosteroids may be administered in order according to the severity of the lesions (37). From mild to severe type of lesion; triamcinolone acetonide, fluocinolone acetonide, and clobetasol propionate can be used.

Na'mah et al. compared dexamethasone with triamcinolone acetonide pomade and they found that both are similarly effective (39). Dexamethasone topical application is equal to triamcinolone in reducing pain but dexamethasone is more effective than triamcinolone in terms of recovery speed (30).

Triamcinolone acetonide is a medium-high-level corticosteroid and is a fluorinated prednisolone derivative (4). The duration of this drug in the mucosa is important. For example, the duration of contact with mucosa in mouthwashes is very short. However, this time is extended in mucoadhesive polymers (40).

Additional topical treatments

In a double-blind, placebo-controlled study, 5-aminosalicylic acid was found to reduce pain and provide fast recovery in 5% cream form (41, 42).

Amlexanox is a drug that has been studied in the last few years and has been found to be effective in the prodromal period and as a short-term effect. Its mechanics are not exactly known, but it is a topical agent with anti-inflammatory and antiallergic effects. Amlexanox 5% paste or 2 mg tablet was found to decrease the number of aphthous ulcers and pain when used in the prodromal period (43, 44).

The recurrence of oral aphthous ulcers has been found to decrease with smoking. In the study conducted, it was found that nicotine has an anti-inflammatory effect on keratinocytes (36). Dexpanthenol has also been found to be useful as an adjunct to treatment (9).

In a study conducted, it was stated that both ozonated oil and sesame oil have a positive effect on the recovery of RAS lesions. Ozonated oil reduces ulcer pain and ulcer size significantly (15).

Systemic treatment

Systemic treatments can be performed when the RAS is severe and local treatment does not provide the desired result.

Systemic corticosteroids

The use of systemic corticosteroids should be considered when they respond negatively to other topical options (9). Prednisolone is the most commonly used drug. In a study, prednisolone 5mg tablet was used once a day for 3 months and there was a significant decrease in pain, number of lesions and lesion size (14). Prednisolone can also be prescribed with topical application to shorten the systemic administration period.

Dapson (Dapsone, GlaxoSmithKline, India): An aniline derivative of the synthetic dapsone group. Given the mechanism of action, it appears to be both antibacterial and anti-inflammatory. It inhibits neutrophil activation and chemotaxis. It reduces the number and size of oral and genital ulcers seen in Behcet's disease. The most common side effects are methemoglobinemia and hemolysis, but usually, the drug is well tolerated (45).

Sucralfate: Sucralfate is commonly used as an antacid in the treatment of stomach and duodenal ulcers. It forms a protective barrier in the ulcer zone (9). There is local or systemic use for oral mucosa. Sucralfate suspension has been shown to cause rapid healing and pain reduction in oral and genital aphthous ulcers (46).

Azathioprine and methotrexate (Antimetabolites): It has positive effects in the treatment of orogenic aphthous ulcer (5). However, given the huge systemic side effects, use of these drugs may be limited in very limited cases (47).

Cyclosporins: Cyclosporins are powerful immunosuppressive drugs commonly used to prevent organ rejection after organ transplantation. This drug is used in the treatment of many diseases. These drugs suppress T cell-mediated immunity. In a study, patients diagnosed with Behcet's disease, a reduction in aphthous ulcers was observed in 70% of patients who received cyclosporine at various doses (36). Side effects are more common than colchicine. These side effects may include hirsutism, fever, fatigue and gastrointestinal symptoms (48).

Thalidomide: It can be used in the orogenital aphtha but its teratogenicity and other side effects limit its use (9).

Interferon-[alpha]: Interferons are mainly seen as molecules that regulate the immune system and are released against the stress. It has antiviral, proapoptotic, antiproliferative, and antiangiogenic effects. It regulates cell growth and differentiation. It reduces orogenital lesions in Behcet's disease (49).

CONCLUSION

The etiology of RAS is not yet fully explained. It maintains its importance as a disease that is frequently seen in the general population and adversely affects the quality of life of patients. After a careful assessment of predisposing factors in treatment, the main goal is to relieve pain, to shorten the duration of lesion, to help the patient fed properly and to reduce the frequency of recurrence. Firstly, after detailed anamnesis, there are number of treatment options including local, systemic or local-systemic treatments in relation to the frequency of lesions and the severity of the lesions. These options should be well known by the doctor. Depending on the type and severity of the lesions, analgesics, corticosteroids, and antimicrobial agents are mostly used. If necessary, it is also possible to use systemic or local-systemic effective medicines together, less frequently.

In conclusion, dentists and medical doctors play a critical role in the diagnosis and treatment process, guiding the patient. It is important to refer the patient to the necessary units if it is thought to be related to a systemic disease. For this reason, it is crucial to be up to date about this common disease.

Peer-review: Externally peer-reviewed.

Author contributions: Concept - G.K., M.U.; Design - G.K., M.U.; Supervision - G.K., M.U.; Resource -G.K., M.U.; Materials - G.K., M.U.; Data Collection and/or Processing - G.K., M.U.; Analysis and/or Interpretation - G.K., M.U.; Literature Search - G.K., M.U.; Writing - G.K., M.U.; Critical Reviews - G.K., M.U.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

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Gokay Karapinar, Meral Unur

Department of Oral and Maxillofacial Surgery, Istanbul University School of Dentistry, Istanbul, Turkey

Cite this article as: Karapinar G, Unur M. Current Approaches in Recurrent Aphthous Stomatitis. Clin Exp Health Sci 2018; 8: 62-6.

Correspondence Author: Gokay Karapinar E-mail: gokaykarapinar@gmail.com

Received: 06.08.2017 Accepted: 17.10.2017

DOI: 10.5152/clinexphealthsci.2017.649
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