Burket’s Oral Medicine Diagnosis and Treatment Tenth edition

Recurrent Aphthous Stomatitis
RAS is a disorder characterized by recurring ulcers confined to the oral mucosa in patients with no other signs of disease. Many specialists and investigators in oral medicine no longer consider RAS to be a single disease but, rather, several pathologic states with similar clinical manifestations. Immunologic disorders, hematologic deficiencies, and allergic or psychological abnormalities have all been implicated in cases of RAS. RAS affects approximately 20% of the general population, but when specific ethnic or socioeconomic groups are studied, the incidence ranges from 5 to 50%.78 RAS is classified according to clinical characteristics: minor ulcers, major ulcers (Sutton’s disease, periadenitis mucosa necrotica recurrens), and herpetiform ulcers. Minor ulcers, which comprise over 80% of RAS cases, are less than 1 cm in diameter and heal without scars. Major ulcers, are over 1 cm in diameter and take longer to heal and often scar.Herpetiform ulcers are considered a distinct clinical entity that manifests as recurrent crops of dozens of small ulcers throughout the oral mucosa.
ETIOLOGY

It was once assumed that RAS was a form of recurrent HSV infection, and there are still clinicians who mistakenly call RAS “herpes.” Many studies done during the past 40 years have confirmed that RAS is not caused by HSV.79,80 This distinction is particularly important at a time when there is specific effective antiviral therapy available for HSV that is useless for RAS. “Herpes” is an anxiety-producing word, suggesting a sexually transmitted disease among many laypersons, and its use should be avoided when it does not apply. There continue to be investigations studying the relationship of RAS to other herpesviruses such as varicella-zoster virus or Cytomegalovirus, but the results of these studies continue to be inconclusive.81,82 The current concept is that RAS is a clinical syndrome with several possible causes. The major factors identified include heredity, hematologic deficiencies, and immunologic abnormalities. 83,84 The best documented factor is heredity.85 Miller and colleagues studied 1,303 children from 530 families and demonstrated an increased susceptibility to RAS among children of RAS-positive parents.86 A study by Ship and associates showed that patients with RAS-positive parents had a 90% chance of developing RAS, whereas patients with no RAS-positive parents had a 20% chance of developing the lesions.85 Further evidence for the inherited nature of this disorder results from studies in which genetically specific HLAs have been identified in patients with RAS, particularly in certain ethnic groups.87,88 Hematologic deficiency, particularly of serum iron, folate, or vitamin B12, appears to be an etiologic factor in a subset of patients with RAS.84 The size of the subset is controversial, but most estimates range from 5 to 15%. A study by Rogers and Hutton reported clinical improvement in 75% of patients with

wheat.102 A detergent present in toothpaste.92Work by Pedersen and colleagues and other studies demonstrated an alteration in CD4:CD8 lymphocyte ratio. such as celiac disease. and pemphigoid). During this initial period.91 Investigations using more sophisticated immune assays have not supported the early work and suggest a role of lymphocytotoxicity.The disease is an annoyance for the majority of patients with mild RAS. and flour.96 Thomas and colleagues showed that T lymphocytes from patients with RAS had increased cytotoxicity to oral epithelial cells. In mild RAS. and defects in lymphocyte cell subpopulations. sodium lauryl sulfate (SLS). size. but the number. Other factors that have been suggested as being etiologic in RAS include trauma. and shallow (similar to viral ulcers).0 cm and begin healing within a week. The buccal and labial mucosae are most commonly involved. or a dysfunction of the mucocutaneous cytokine network.Within hours. anxiety. and allergy to foods. 97–99 Further work is needed to determine if these are specific or nonspecific responses. Multiple lesions are often present. was suspected as an etiologic factor in RAS development. and gradually enlarges over the next 48 to 72 hours. Lesions are less common on the heavily keratinized palate or gingiva. the lesions reach a size of 0.104 CLINICAL MANIFESTATIONS The first episodes of RAS most frequently begin during the second decade of life and may be precipitated by minor trauma. cheese. Healing without scarring is usually complete in 10 to 14 days. psychological stress. The individual lesions are round. 103 but a recent double-blind crossover study showed that use of an SLS-free toothpaste had no significant effect on ulcer development. Hay and Reade reported the benefit of an elimination diet in some patients with suspected or proven allergy to foods such as milk. menstruation. Early work suggested either an autoimmune disorder or hypersensitivity to oral organisms such as Streptococcus sanguis.92 antibody-dependent cellmediated cytotoxicity. and frequency of them vary considerably (Figure 4-20). The lesions are confined to the oral mucosa and begin with prodromal burning any time from 2 to 48 hours before an ulcer appears. a small white papule forms. Most patients with RAS have between two and six lesions at each episode and experience several episodes a year. upper respiratory infections.89 Some cases of nutritional deficiency.100 It is well documented that cessation of smoking increases the frequency and severity of RAS. but . or contact with certain foods.101 In cases of refractory disease. symmetric. ulcerates. pemphigus. a localized area of erythema develops.90 Most of the research into the etiology of RAS centers on immunologic abnormalities.RAS when a specific hematologic deficiency was detected and corrected with specific replacement therapy. 93–95 Burnett and Wray showed that sera and monocytes induced significantly more cytolysis in patients with RAS than in control patients.3 to 1. but no tissue tags are present from ruptured vesicles (this helps to distinguish RAS from disease with irregular ulcers such as EM. are reported to be secondary to malabsorption syndrome.

looking for a “cure. betamethasone or clobetasol. use of a protective emollient such as Orabase (Bristol-Myers Squibb. may develop major aphthous ulcers (Figure 4-23). placed directly on the lesion shortens healing time and reduces the size of the ulcers. In mild cases with two or three small lesions. Patients with abnormalities in these values should be referred to an internist to rule out malabsorption syndromes and to initiate proper replacement therapy. systemic complaints. folate. Patients with major ulcers develop deep lesions that are larger than 1 cm in diameter and may reach 5 cm (Figure 4-21. eye. genital. The gel can be carefully . Laboratory investigation should be used when ulcers worsen or begin past the age of 25 years. and ferritin (Figure 4-22). A detailed history and examination by a knowledgeable clinician should distinguish RAS from primary acute lesions such as viral stomatitis or from chronic multiple lesions such as pemphigoid. DIAGNOSIS RAS is the most common cause of recurring oral ulcers and is essentially diagnosed by exclusion of other diseases. Patients with severe minor aphthae or major aphthous ulcers should have known associated factors investigated. A and B). The effectiveness of the topical steroid is partially based upon good instruction and patient compliance regarding proper use. Many of these patients continually go from one clinician to another.”The lesions may last for months and sometimes be misdiagnosed as squamous cell carcinoma.102 HIVinfected patients. The lesions are extremely painful and interfere with speech and eating. The patient presents with small punctate ulcers scattered over large portions of the oral mucosa. Princeton. The lesions heal slowly and leave scars that may result in decreased mobility of the uvula and tongue and destruction of portions of the oral mucosa. an NSAID frequently used topically after eye surgery. including connective-tissue diseases and abnormal levels of serum iron.it can be disabling for patients with severe frequent lesions. and associated skin.105 In more severe cases. particularly those with CD4 counts below 100/mm3. drug reactions. such as connective tissue disease. vitamin B12. Phoenix. The history should emphasize symptoms of blood dyscrasias. especially those classified as major aphthous ulcers. chronic granulomatous disease. or rectal lesions. which tends to occur in adults. Biopsies are only indicated when it is necessary to exclude other diseases. The clinician may also choose to have food allergy or gluten sensitivity investigated in severe cases resistant to other forms of treatment. the use of a high-potency topical steroid preparation. particularly granulomatous diseases such as Crohn’s disease or sarcoidosis. such as fluocinonide. Large portions of the oral mucosa may be covered with large deep ulcers that can become confluent. or pemphigoid. as well as from other possible causes of recurring ulcers. and dermatologic disorders.AZ) is all that is necessary. NJ) or Zilactin (Zila Pharmaceutions. Pain relief of minor lesions can be obtained with use of a topical anesthetic agent or topical diclofenac. The least common variant of RAS is the herpetiform type. TREATMENT Medication prescribed should relate to the severity of the disease.

applied directly to the lesion after meals and at bedtime two to three times a day. Intralesional steroids can be used to treat large indolent major RAS lesions. and the patient must have a pregnancy test monthly. which can be used either as a mouth rinse or applied on gauze sponges. Other side effects of thalidomide include peripheral neuropathy. and the clinician must weigh the potential benefits versus the risks. For example. Thalidomide has been shown to reduce both the incidence and severity of major RAS in both HIV-positive and HIV-negative patients. but this drug must be used with extreme caution in women during childbearing years owing to the potential for severe life-threatening and deforming birth defects. Drugs that have been reported to reduce the number of ulcers in selected cases of major aphthae include colchicine. and drowsiness. or mixed with an adhesive such as Orabase prior to application.109 All clinicians prescribing thalidomide in the United States must be registered in the STEPS (System for Thalidomide Education and Prescribing Safety) program. gastrointestinal complaints. In patients with major aphthae or severe cases of multiple minor aphthae not responsive to topical therapy. two methods of birth control must be used. It should be emphasized that no available topical therapy decreases the onset of new lesions. .106–108 Each of these drugs has the potential for side effects. and thalidomide. Other topical preparations that have been shown to decrease the healing time of RAS lesions include amlexanox paste and topical tetracycline. Larger lesions can be treated by placing a gauze sponge containing the topical steroid on the ulcer and leaving it in place for 15 to 30 minutes to allow for longer contact of the medication. pentoxifylline. dapsone. and patients receiving the drug must be thoroughly counseled regarding effective birth control methods that must be used whenever thalidomide is prescribed. use of systemic therapy should be considered. short bursts of systemic steroids.

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