Epidemiology of Aphthous Stomatitis
Aphthous stomatitis, also known as aphthous ulcers, represents a potentially debilitating disorder in HIV-infected persons. When these lesions develop on a recurring basis, it is referred to as recurrent aphthous stomatitis, or recurrent aphthous ulcers. In the era prior to the widespread use of potent antiretroviral therapy, approximately 5 to 15% of HIV-infected patients developed aphthous stomatitis. In contrast to several other conditions that declined with the widespread use of potent antiretroviral therapy, the incidence use of aphthous stomatitis has not significantly changed. Immunocompetent persons can also develop painful aphthous oral lesions, but they typically have a more self-limited course than seen with HIV-infected persons, particularly those with advanced immunosuppression. Compared with immunocompetent persons, HIV-infected individuals characteristically have oral ulcers that are larger, more painful, heal more slowly, and recur more frequently. The specific cause of aphthous stomatitis remains unclear, but investigators have proposed a number of possible contributing factors, including overstimulation of tumor necrosis factor, immune cross-reactivity to infectious agents, nutritional deficiencies, stress, hormonal imbalance, food hypersensitivity, and genetic predisposition.
Aphthous lesions generally appear as round or oval ulcerations of variable depth, with a raised red border (Figure 1) and (Figure 2). The center of the ulcer is often covered by a pseudomembrane that can appear white, yellow, or gray. They most often develop on mobile non-keratinized mucosal surfaces in the mouth, though in HIV-infected patients, they may also occur in the esophagus and anogenital region. The oral lesions typically cause intense pain and can interfere with eating, speaking, and swallowing, even leading to significant anorexia and weight loss in some patients. The ulcers are generally classified as minor, major, or herpetiform. Minor aphthous ulcers, the most common form, measure less than 1 cm in diameter, are shallow, have a surrounding erythematous halo and are often covered with a pseudomembrane; aphthous minor lesions usually heal spontaneously within 1-2 weeks without scarring. Major ulcers are larger than 1 cm in diameter (often exceeding 3 cm in diameter), may develop into very large necrotic lesions, and in some instances extend to keratinized surfaces (Figure 3). Major aphthous ulcers are seen more commonly in HIV-infected than non-infected patients, especially in individuals who have a CD4 count less than 100 cells/mm3. The rare herpetiform variant is defined by multiple (up to a hundred) pinpoint lesions that may coalesce to form large, irregular ulcerations.
Diagnosis of Aphthous Stomatitis
The diagnosis of aphthous stomatitis is usually made based on clinical findings combined with an exclusion of other disorders that have a similar clinical presentation. Oral herpes simplex virus infection can manifest as ulcers that closely resemble aphthous lesions, thus the initial evaluation of an oral ulcer should include a fluorescent antibody and culture for herpes simplex virus. Other less frequently seen causes of oral ulcerations include cytomegalovirus infection, oral syphilis, systemic fungal infections, neoplasm, Behcet's syndrome, and the antiretroviral drug zalcitabine (Hivid). Although biopsy can provide a definitive diagnosis, it is infrequently performed.
Treatment of Aphthous Stomatitis
Management of aphthous stomatitis depends on the severity of the lesions (Figure 4).[,,] Minor lesions can usually be treated topically with a product that combines a mucosal binding agent and a topical steroid. Topical anesthetics play an important adjunctive role for pain control. In general, a direct application of topical therapy is adequate for mild cases with lesions that are easily reached, whereas patients with more severe aphthous stomatitis or those with relatively inaccessible lesions generally require treatment with a corticosteroid-containing oral elixir. Unfortunately, topical therapy often produces inconsistent response rates and high rates of relapse. More recently, several case reports have noted successful treatment of aphthous lesions with antiretroviral therapy.[,] Severe ulcers and those with major aphthae not responding to topical therapy may require more aggressive management consisting of systemic corticosteroids, intralesional corticosteroids, or systemic immunomodulators, such as thalidomide (Thalomid). If systemic corticosteroids are used for treatment of major aphthae, some experts recommend using oral prednisone 40 to 60 mg/day for 4 to 7 days, then tapering the dose over a 2-week period.[,] Randomized clinical trials have demonstrated the efficacy of thalidomide, an antagonist of tumor necrosis factor-alpha, for the treatment of oral and esophageal aphthous lesions in HIV-infected patients.[,,] Among HIV-infected patients with aphthous lesions, 55% of patients treated with thalidomide (200 mg/d for 4 weeks) experienced complete healing, compared with only 7% of placebo-treated patients (Figure 5). The use of thalidomide is typically reserved for the treatment of ulcers that fail to respond to systemic corticosteroid therapy, or in patients who have recurrent severe lesions, particularly when they require repeated courses of systemic corticosteroids. Because of the well-established teratogenic effects of thalidomide, the S.T.E.P.S. (System for Thalidomide Education and Prescribing Safety) program has been designed by Celgene to ensure the safe and effective dispensing of thalidomide. Physicians, pharmacists, and patients must register and agree to comply with the S.T.E.P.S. requirements related to educational, counseling, informed consent, and pregnancy testing before the patient can receive thalidomide. More detailed information and can be obtained from Celgene at 888-423-5436 or at the Celgene Thalomid Web site.