Treatment Strategies for Recurrent Oral Aphthous Ulcers

Disclosures

Am J Health Syst Pharm. 2001;58(1) 

In This Article

Etiology

The most likely factors precipitating aphthous ulcers are local trauma and stress. Injury to the oral mucosa may result from accidental self-biting, dental procedures, toothbrush bristles, and sharp-edged foods (e.g., potato chips). In a trial involving 128 patients, 16% claimed that a traumatic incident was associated with their RAU.[5] Emotional and environmental stress may precede 60% of first-time aphthous ulcer cases and involve 21% of recurrent episodes.[5] A frequency of RAU of 31-66% has been reported among medical and dental students, compared with 10-20% in the general population.[5]

Systemic diseases involving immune and nutritional deficiencies have been associated with aphthous ulcers.[5] Oral ulcers have been reported in patients with cyclic neutropenia and agranulocytosis and are common in patients with HIV disease. Nutritional deficiencies involving iron, folic acid, zinc, and vitamins B 1 , B 2 , B 6 , and B 12 are twice as common in patients with RAU as in healthy persons, occurring in up to 20% of patients. RAU has been associated with gastrointestinal problems, including Crohn's disease, ulcerative colitis, and celiac disease; whether the link is related to immunologic mechanisms or nutritional deficiencies resulting from malabsorption is unknown.

Antibodies to cow's milk and wheat protein (celiac disease) have been demonstrated in patients with RAU.[6] Strict elimination diets involving cow's milk or glutens (wheat, barley, and oats) have resulted in resolution of or improvement in persistent aphthae in greater than 25% of patients.[6,7] However, many foods that are commonly allergenic (e.g., strawberries, tomatoes, and nuts) have not been causally associated with RAU.[6]

A bacterial or viral cause of RAU has been suggested, but bacterial antibody titer association with RAU has been inconclusive. Antibodies to herpes simplex virus and cytomegalovirus have not been consistently demonstrated in the serum or lesional tissue of patients with RAU. The precipitation of RAU after viral infections may result from the systemic and local immunosuppression associated with viral reactivation rather than from the virus itself.[5,6]

Some people have a well-established familial basis for RAU. However, evidence for a genetic predisposition is not strong.[1] Patients with a family history of RAU may develop the disease earlier and more severely than those with no family history.[5] Forty to fifty percent of first-degree relatives of patients with RAU may have the condition.[5,6] RAU has been found more commonly in identical twins than in nonidentical twins. Elevations in human leukocyte antigen markers have been observed in Israelis with RAU and in patients with Behçet's syndrome.[5] However, what appears to be a familial association may reflect the effects of personality and stressors in the domestic and work environments that collectively activate RAU.[1]

RAU may be more common and more severe in patients with immune disorders, including cyclic neutropenia, inflammatory bowel disease, Behçet's disease, and HIV disease.[8] Patients with RAU have evidence of antibody-dependent cytotoxicity and elevated serum immunoglobulins.[1] Immunopathogenesis of RAU may involve an imbalance in T-helper/inducer cells and T-suppressor/inducer cells.[8] Patients with severe RAU have increased numbers of T-helper/inducer cells and fewer T-suppressor/inducer cells.[9] The presence of activated T lymphocytes in the periphery of ulcers indicates that RAU may result from an activated cell-mediated response.[10] Similarities in immunohistologic findings in HIV-seronegative and HIV-seropositive individuals with RAU further confirm the hypothesis of a cell-mediated immunologic dysfunction involving primarily T lymphocytes.[1,11] The antigen precipitating this reaction is unknown but may include many of the factors discussed previously, including trauma, microorganisms, and food allergies.[10]

Antineoplastic medications cause ulcerative stomatitis in up to 37% of patients receiving therapy for acute or chronic leukemia.[12] The likely mechanism is accelerated detachment of oral epithelial cells. Antineoplastic drugs associated with stomatitis include methotrexate, daunorubicin, doxorubicin, and hydroxyurea. Predicting which patients are most likely to manifest stomatitis is not possible. However, patients sensitive to one stomatotoxic drug are often sensitive to others.[12] Burning and reddening of the oral mucosa occur within hours of drug administration. The painful erosions and ulcerations involve both keratinized and nonkeratinized epithelium. Chemotherapy-induced stomatitis should alert the clinician to the possibility of gastroenterocolitis, which often follows a parallel course.[12] Precautionary oral hygiene measures may avoid superimposed infections.

Contact stomatitis with ulceration may occur after prolonged exposure to uncoated potassium chloride, aspirin, and pancreatic enzyme preparations. Cases of "scalded mouth" have been reported with angiotensin-converting- enzyme inhibitors, especially captopril.[13] Patients should be instructed to swallow the tablets as quickly as possible. Stomatitis associated with systemic effects of medications is rare, and objective methods for associating a drug with an event are lacking.

Other medications observed to cause stomatitis include antimicrobials, auranofin, barbiturates, didanosine, foscarnet, griseofulvin, non-steroidal anti-inflammatory drugs, penicillamine, quinidine, and sulfonamides.[13]

The frequency of aphthous ulcers is similar in persons seronegative and persons seropositive for HIV. However, HIV-seropositive patients with CD4+ lymphocyte counts below 100 cells/mm 3 are more likely to have major recurrent aphthae, which may lead to difficulty eating.[2] Therefore, early diagnosis and treatment are important. The same causes of RAU in HIV-seronegative patients must be considered in HIV-seropositive patients.[14] However, the presence of HIV infection may suggest other causes of oral ulcers -- neoplasms, infections, and medications -- that should be excluded before the lesions are diagnosed as aphthous ulcers.[15]

Kaposi's sarcoma is the most common cause of oral tumors in AIDS patients, while tumors in non-Hodgkin's lymphoma may be primarily located in the oral cavity. Herpes simplex virus reactivation and associated lesions are frequent in HIV-infected individuals at any level of immunocompetence.[15] Oral ulcers attributable to Histoplasma capsulatum and Crytococcus neoformans are uncommon but may occur in the setting of disseminated disease. Candida albicans may cause oral ulcers in advanced stages of AIDS.[15] Oral and esophageal ulcers are found in acute HIV infection, together with malaise, fever, myalgia, rash, acute myelitis, and encephalitis.[15]

Accurate diagnosis of oral lesions in HIV-seropositive patients may require biopsy in combination with a clinical examination and patient history. Lesions located on keratinized mucosa are probably not aphthous ulcers. Any ulcer located on keratinized oral mucosa, major aphthous ulcer, or ulcer not responding to topical corticosteroid treatment should be biopsied. Diagnostic protocols addressing the role of cultures, biopsies, and cytology studies have been developed to help the clinician.[14,15]

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