Recurrent Aphthous Stomatitis

Etiology

The etiology of recurrent aphthous stomatitis remains imperfectly understood. The cause is believed to be multifactorial, involving a cell-mediated immunological reaction and a genetic predisposition. Histopathological changes are seen before ulceration occurs. Lymphocytes (mononuclear cells) infiltrate the oral epithelium, edema develops, and the keratinocytes (oral epithelial cells) undergo vacuolization and vasculitis. This results in localized swelling and later ulceration of the epithelium. Infiltration with neutrophils, lymphocytes, and plasma cells occurs before the epithelium heals and regenerates. The pathogenesis of RAS is a T-cell-mediated immunological reaction involving the inflammatory cytokine named tumor necrosis factor-alpha (TNF-α). TNF-α activates the chemotaxis of neutrophils, generating an acute inflammatory response and the expression of the major histocompatibility (MHC) complex.[3] Consequently, the epithelial cells are targeted for destruction by the CD8+ T cells.[6] Other cytokines, including interleukins IL-2, IL-10, IL-1b, and IL-6, may also be involved.[3]

It has also been suggested that the T-cell-mediated reaction seen in RAS is in response to Streptococcus sanguis antigens that cross-react with mitochondrial heat shock proteins, causing damage to the oral mucosa.[7]

There is a genetic predisposition to RAS; a family history of the condition is seen in 24% to 46% of patients.[2] These patients usually develop more rapid and severe ulceration.[3] A link to HLA-B51 and genes that control cytokines or heat shock proteins has been described.[8][9][10]

Predisposing Factors

Local 

Local trauma predisposes to recurrent aphthous stomatitis in susceptible individuals or those with a hereditary predisposition to the disease.[11] RAS is less common in keratinized areas of the oral mucosa, including those of tobacco smokers.[3][2][12]

Systemic

Aphthous-like ulcerations may occur in various systemic diseases, including Behçet disease, nutritional deficiencies, gastrointestinal disorders, and primary and secondary immunodeficiencies, including HIV.[3]

Recurrent aphthous stomatitis is one of the criteria to diagnose Behçet disease.[2] Behçet disease is a chronic inflammatory condition of unknown etiology, which affects the oral mucosa, genitalia, eyes, skin, and joints.[13] Mucocutaneous lesions are the hallmarks of the condition and are usually the first to appear.[13] The development of oral aphthous ulcerations in combination with ulcers in other body parts should raise suspicion of Behçet disease.

Hematinic (iron, folic acid, or vitamin B12) and zinc deficiencies have been demonstrated in some patients with recurrent aphthous stomatitis.[3][14] Hematinic deficiencies occur twice as often in patients with RAS.[3] This may be because insufficient levels of hematinics can lead to anemia and a decreased capacity of the blood to oxygenate the oral mucosa, resulting in oral epithelial atrophy.[15] However, vitamin or iron supplementation does not always resolve lesions.[3]

Aphthous-like ulcers can be a sign of bowel disease, including Chron disease, gluten-sensitive enteropathy, and ulcerative colitis. However, the ulcerations can be due to malabsorption deficiencies in hematinics.[3][2]

Women during menstruation and menopause are more susceptible to recurrent aphthous stomatitis.[14] In contrast, those who are pregnant or taking the contraceptive pill frequently experience remission of the lesions, suggesting that hormonal imbalance may play a role in the pathogenesis of RAS.[14]

HIV patients have reduced CD4 lymphocyte and elevated CD8 lymphocyte levels, predisposing them to RAS.[16]

Epidemiology

Recurrent aphthous stomatitis is a relatively common condition, affecting up to 25% of the worldwide population.[3] It usually first appears in childhood or adolescence. It may develop as an individual entity or as part of a systemic condition, like Behçet disease. Out of the 3 subtypes, minor aphthous ulcers are the most prevalent (>70% of cases), whereas major (10%) and herpetiform (10%) types are less common.[17]

History and Physical

Recurrent aphthous stomatitis is characterized by persistent painful oral ulcers lasting days to months.[3] RAS is divided into 3 subgroups: minor aphthous ulcers, major aphthous ulcers, and herpetiform aphthous ulcers.

Minor Aphthous Ulcers 

Minor aphthous ulcers are the most common type of RAS, affecting around 80% of RAS patients. They recur at 1 to 4-month intervals. The lesions are small (usually less than 5 mm in diameter), oval or round, and appear as a group of 1 to 6 ulcers at a time. The lesions are surrounded by an erythematous halo and covered by a grey-white pseudomembrane.[3]

Minor RAS mainly develops on non-keratinized mucosa, especially buccal and labial mucosa (see Image. Aphthous Ulcer) and the floor of the mouth, and heals within two weeks without scarring.[3] Oral discomfort may precede the aphthous lesions.

Major Aphthous Ulcers

Major aphthous ulcers (also known as periadenitis mucosa necrotica recurrent) are a more severe form of the disease and are seen in 10% of RAS patients.[17]

The ulcers are larger (>10 mm), last for 5 to 10 weeks, and usually leave scarring.[3] Any area of the mouth may be affected, including the oropharynx.[3]

Major aphthous ulcers are the most frequent type of RAS in patients with AIDS, and there is an increased link between these lesions and gastrointestinal and hematological disorders.[18] They do not usually follow a cyclical pattern.

Herpetiform Ulcers

Herpetiform ulceration is the least common type of RAS; it develops in around 1% to 10% of RAS patients.[3] The name derives from the resemblance to primary herpetic stomatitis; there is no connection to herpes viruses. Herpetiform ulcers have a predisposition for older females.[19]

The lesions appear as painful, small, and numerous ulcers. They may arise in numbers of up to 100 ulcers simultaneously, measuring 2 to 3 mm in diameter and lasting for one to two weeks.[3] The most frequent sites are the floor of the mouth and tongue (tip and lateral margins). They may appear on keratinized or non-keratinized mucosa. The small ulcers can sometimes fuse into a large and irregular ulcer, healing with scarring.[3]

Evaluation

Recurrent aphthous stomatitis is a clinical diagnosis.[3] However, excluding other causes of recurrent aphthous ulcers in the mouth is necessary, like Behçet disease, nutritional deficiencies, or inflammatory bowel disease, particularly when RAS develops suddenly in an adult patient.[14] Some RAS patients have anemia, hematinic, or dietary deficiencies; it is common practice to evaluate the complete blood count, red cell folate, and ferritin and vitamin B12 serum levels, which may also reveal gastrointestinal disorders.[3]

Treatment / Management

There is no specific management of recurrent aphthous stomatitis.[20] The best treatment is the one that controls the lesions for the longest time with few side effects.[21] Management is influenced by the intensity of the pain, frequency of episodes, and the patient's medical history and tolerability to medication.[4] Before initiating more directed treatment, it is essential to identify predisposing factors, if any, and control them.[4](B3)

Treatment aims to alleviate symptoms, decrease the severity of the ulcers (number and size), promote healing, and prolong disease-free periods.[2][4] In general, milder episodes of RAS are managed with NSAIDs and topical corticosteroids, like benzydamine mouthwash and chlorhexidine mouthwash, to prevent added bacterial infection. Furthermore, a combination of topical tetracycline and steroids may be of value. A short course of systemic steroids, such as prednisone, is indicated for managing a severe episode of major aphthous ulcers.[22] Long-term systemic steroids are seldom recommended due to their serious adverse effects.[22] Herpetiform ulceration is usually managed in the same way as minor aphthous ulcers.(B3)

Chlorhexidine gluconate mouthwash and topical corticosteroids have been proven to decrease the severity of aphthous ulcers and shorten their duration. However, they do not affect the frequency of the outbreaks.[23] Chlorhexidine mouthwash reduces the bacterial load, protecting from bacterial superinfection of the ulcers and promoting healing.[2] Topical corticosteroids may stop the episode of aphthous ulcers when applied in the prodromal phase (when experiencing tingling or burning).[21](A1)

The severity of the lesions and the frequency of episodes vary in each patient; treatment must be adjusted to the patient's needs. Classifying patients into 3 categories, each with a different treatment strategy (A, B, or C), is helpful.[4](B3)

Type A

Patients in the type A category experience RAS episodes a few times a year, with outbreaks lasting only a few days and with mild pain.[4] As with all RAS cases, it is essential to identify precipitating factors and eliminate them, such as trauma-induced RAS, where a softer toothbrush can be recommended.[4] Medication may not be required.[4](B3)

Type B

Patients in this category experience painful episodes of RAS monthly, lasting for 3 to 10 days.[4] Patients may have difficulty eating or toothbrushing due to pain.[4](B3)

Treatment includes chlorhexidine mouthwash and a short course of topical corticosteroids immediately after the ulcers appear.[4] These patients usually require maintenance due to the recurrent pattern of the lesions.[4](B3)

Alternative treatments include dexamethasone 0.05 milligrams/5 mL (rinse and spit 3 times daily) or a high-potency topical corticosteroid. For example, clobetasol ointment 0.05% in Orabase (1:1) or fluocinonide ointment 0.05% in Orabase (1:1) if the lesions recur on the same area, applied 3 times per day.[4](B3)

If oral hygiene is deficient, professional cleaning by a dental hygienist must be considered after the ulcers have healed.[4](B3)

In major aphthous ulcers, systemic corticosteroids may be indicated, but never exceeding more than 50 mg daily for 5 days.[4](B3)

Type C

This category includes severely painful RAS lesions. There is no period without ulcers - a new one develops when one aphthous ulcer heals.[4] These patients are managed with topical and systemic corticosteroids and immunosuppressants like pentoxifylline, dapsone, and thalidomide.[4] Immunosuppressants are indicated to prevent the formation of new RAS lesions and decrease the prevalence of adverse effects experienced with systemic steroids.[5](B3)

Differential Diagnosis

Systemic diseases resembling recurrent aphthous stomatitis include:[3]

Behçet disease: patients also have recurrent ulcerations in the genitalia, skin disorders (usually erythema nodosum or papulopustular lesions), ocular disease (usually posterior uveitis), and a variety of neurological, gastrointestinal, renal, hematological, or joint disorders.

MAGIC syndrome (Sweet syndrome): patients experience a sudden onset of fever, leucocytosis, and cutaneous lesions (well-demarcated plum-colored papules or plaques). Associated malignancy is seen in half of the patients.

PFAPA syndrome: includes periodic fever, pharyngitis, aphthae, and cervical adenitis. It occurs in young children; around two-thirds of cases improve with tonsillectomy.

Cyclic neutropenia: Patients develop fever, skin abscesses, lymphadenopathy, and respiratory tract infections. Besides oral ulceration, further oral complications may be seen, including severe gingivitis and aggressive periodontitis.

HIV disease

Prognosis

Recurrent aphthous stomatitis is a chronic condition that usually follows a cyclical pattern. The severity of the disease is typically related to the type of RAS. Minor RAS lesions tend to resolve in up to 2 weeks without scarring, whereas major RAS lesions are more persistent, healing with scarring after 6 weeks.[24] Herpetiform ulcers resolve in up to a month, and scarring is infrequent.[24]

Complications

The intensity of pain associated with the lesions is variable. Severe pain complicates drinking and eating, possibly leading to dehydration and nutritional deficiencies. Oral hygiene may also be impaired due to pain. There is a risk of bacterial superinfection of the aphthous ulcers, which is prevented with chlorhexidine mouthwash. Long-term maintenance with topical corticosteroids may lead to opportunistic fungal infections in the oral mucosa; therefore, a topical antifungal medication must be indicated for at least 2 weeks.[2]