THE PATIENT WITH RECURRING ORAL ULCERS
Recurring oral ulcers are among the most common problems seen by clinicians who manage diseases of the oral mucosa. There are several diseases that should be included in the differential diagnosis of a patient who presents with a history of recurring ulcers of the mouth, including recurrent aphthous stomatitis (RAS), Behçet’s syndrome, recurrent HSV infection, recurrent erythema multiforme, and cyclic neutropenia.
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%.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.Recurring oral ulcers are among the most common problems seen by clinicians who manage diseases of the oral mucosa. There are several diseases that should be included in the differential diagnosis of a patient who presents with a history of recurring ulcers of the mouth, including recurrent aphthous stomatitis (RAS), Behçet’s syndrome, recurrent HSV infection, recurrent erythema multiforme, and cyclic neutropenia.
Recurrent Aphthous Stomatitis
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.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.
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.The best documented factor is heredity.
Miller and colleagues studied 1,303 children from 530 families and demonstrated an increased susceptibility to RAS among children of RAS-positive parents.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.
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.Hematologic deficiency, particularly of serum iron, folate, or vitamin B
,appears to be an etiologic factor in a subset of patients with RAS.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 RAS when a specific hematologic deficiency was detected and corrected with specific replacement therapy.Some cases of nutritional deficiency, such as celiac disease, are reported to be secondary to malabsorption syndrome.Most of the research into the etiology of RAS centers on immunologic abnormalities. Early work suggested either an autoimmune disorder or hypersensitivity to oral organisms such as Streptococcus sanguis.Investigations using more sophisticated immune assays have not supported the early work and suggest a role of lymphocytotoxicity,antibody-dependent cellmediated cytotoxicity, and defects in lymphocyte cell subpopulations.Burnett and Wray showed that sera and monocytes induced significantly more cytolysis in patients with RAS than in control patients.Thomas and colleagues showed that T lymphocytes from patients with RAS had increased cytotoxicity to oral epithelial cells.Work by Pedersen and colleagues and other studies demonstrated an alteration in CD4:CD8 lympho
cyte ratio, or a dysfunction of the mucocutaneous cytokine network.Further work is needed to determine if these are specific or nonspecific responses.
Other factors that have been suggested as being etiologic in RAS include trauma, psychological stress, anxiety, and allergy to foods.It is well documented that cessation of smoking increases the frequency and severity of RAS.In cases of refractory disease, Hay and Reade reported the benefit of an elimination diet in some patients with suspected or proven allergy to foods such as milk, cheese, wheat, and flour.
A detergent present in toothpaste, sodium lauryl sulfate (SLS), was suspected as an etiologic factor in RAS development,but a recent double-blind crossover study showed that use of an SLS-free toothpaste had no significant effect on ulcer development.CLINICAL MANIFESTATIONS
The first episodes of RAS most frequently begin during the second decade of life and may be precipitated by minor trauma, menstruation, upper respiratory infections, or contact with certain foods. The lesions are confined to the oral mucosa and begin with prodromal burning any time from 2 to 48 hours before an ulcer appears. During this initial period, a localized area of erythema develops. Within hours, a small white papule forms, ulcerates, and gradually enlarges over the next 48 to 72 hours. The individual lesions are round, symmetric, and shallow (similar to viral ulcers), but no tissue tags are present from ruptured vesicles (this helps to distinguish RAS from disease with irregular ulcers such as EM, pemphigus, and pemphigoid). Multiple lesions are often present, but the number, size, and frequency of them vary considerably (Figure 4-20). The buccal and labial mucosae are most commonly involved. Lesions are less common on the heavily keratinized palate or gingiva. In mild RAS, the lesions reach a size of 0.3 to 1.0 cm and begin healing within a week. Healing without scarring is usually complete in 10 to 14 days.
Most patients with RAS have between two and six lesions at each episode and experience several episodes a year. The disease is an annoyance for the majority of patients with mild RAS, but
Other factors that have been suggested as being etiologic in RAS include trauma, psychological stress, anxiety, and allergy to foods.It is well documented that cessation of smoking increases the frequency and severity of RAS.In cases of refractory disease, Hay and Reade reported the benefit of an elimination diet in some patients with suspected or proven allergy to foods such as milk, cheese, wheat, and flour.
A detergent present in toothpaste, sodium lauryl sulfate (SLS), was suspected as an etiologic factor in RAS development,but a recent double-blind crossover study showed that use of an SLS-free toothpaste had no significant effect on ulcer development.CLINICAL MANIFESTATIONS
The first episodes of RAS most frequently begin during the second decade of life and may be precipitated by minor trauma, menstruation, upper respiratory infections, or contact with certain foods. The lesions are confined to the oral mucosa and begin with prodromal burning any time from 2 to 48 hours before an ulcer appears. During this initial period, a localized area of erythema develops. Within hours, a small white papule forms, ulcerates, and gradually enlarges over the next 48 to 72 hours. The individual lesions are round, symmetric, and shallow (similar to viral ulcers), but no tissue tags are present from ruptured vesicles (this helps to distinguish RAS from disease with irregular ulcers such as EM, pemphigus, and pemphigoid). Multiple lesions are often present, but the number, size, and frequency of them vary considerably (Figure 4-20). The buccal and labial mucosae are most commonly involved. Lesions are less common on the heavily keratinized palate or gingiva. In mild RAS, the lesions reach a size of 0.3 to 1.0 cm and begin healing within a week. Healing without scarring is usually complete in 10 to 14 days.
Most patients with RAS have between two and six lesions at each episode and experience several episodes a year. The disease is an annoyance for the majority of patients with mild RAS, but
it can be disabling for patients with severe frequent lesions, especially those classified as major aphthous ulcers. Patients with major ulcers develop deep lesions that are larger than 1 cm in diameter and may reach 5 cm (Figure 4-21, A and B). Large portions of the oral mucosa may be covered with large deep ulcers that can become confluent. The lesions are extremely painful and interfere with speech and eating. Many of these patients continually go from one clinician to another, looking for a “cure.” The lesions may last for months and sometimes be misdiagnosed as squamous cell carcinoma, chronic granulomatous disease, or pemphigoid. 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. The least common variant of RAS is the herpetiform type, which tends to occur in adults. The patient presents with small punctate ulcers scattered over large portions of the oral mucosa.
DIAGNOSIS
RAS is the most common cause of recurring oral ulcers and is essentially diagnosed by exclusion of other diseases. 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, as well as from other possible causes of recurring ulcers, such as connective tissue disease, drug reactions, and dermatologic disorders. The history should emphasize symptoms of blood dyscrasias, systemic complaints, and associated skin, eye, genital, or rectal lesions. Laboratory investigation should be used when ulcers worsen or begin past the age of 25 years. Biopsies are only indicated when it is necessary to exclude other diseases, particularly granulomatous diseases such as Crohn’s disease or sarcoidosis.
Patients with severe minor aphthae or major aphthous ulcers should have known associated factors investigated, including connective-tissue diseases and abnormal levels of serum iron, folate, vitamin B
, and ferritin (Figure 4-22). Patients with abnormalities in these values should be referred to an internist to rule out malabsorption syndromes and to initiate proper replacement therapy. The clinician may also choose to have food allergy or gluten sensitivity investigated in severe cases resistant to other forms of treatment.HIVinfected patients, particularly those with CD4 counts below 100/mmTREATMENT
,may develop major aphthous ulcers (Figure 4-23).
Medication prescribed should relate to the severity of the disease. In mild cases with two or three small lesions, use of a protective emollient such as Orabase (Bristol-Myers Squibb, Princeton, NJ) or Zilactin (Zila Pharmaceutions, Phoenix, AZ) is all that is necessary. Pain relief of minor lesions can be obtained with use of a topical anesthetic agent or topical diclofenac, an NSAID frequently used topically after eye surgery.In more severe cases, the use of a high-potency topical steroid preparation, such as fluocinonide, betamethasone or clobetasol, placed directly on the lesion shortens healing time and reduces the size of the ulcers. The effectiveness of the topical steroid is partially based upon good instruction and patient compliance regarding proper use. The gel can be carefully applied directly to the lesion after meals and at bedtime two to three times a day, or mixed with an adhesive such as Orabase prior to application. 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. Other topical preparations that have been shown to decrease the healing time of RAS lesions include amlexanox paste and topical tetracycline, which can be used either as a mouth rinse or applied on gauze sponges. Intralesional steroids can be used to treat large indolent major RAS lesions. It should be emphasized that no available topical therapy decreases the onset of new lesions. In patients with major aphthae or severe cases of multiple minor aphthae not responsive to topical therapy, use of systemic therapy should be considered. Drugs that have been reported to reduce the number of ulcers in selected cases of major aphthae include colchicine, pentoxifylline, dapsone, short bursts of systemic steroids, and thalidomide.Each of these drugs has the potential for side effects, and the clinician must weigh the potential benefits versus the risks. 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.All clinicians prescribing thalidomide in the United States must be registered in the STEPS (System for Thalidomide Education and Prescribing Safety) program, and patients receiving the drug must be thoroughly counseled regarding effective birth control methods that must be used whenever thalidomide is prescribed. For example, two methods of birth control must be used, and the patient must have a pregnancy test monthly. Other side effects of thalidomide include peripheral neuropathy, gastrointestinal complaints, and drowsiness.
DIAGNOSIS
RAS is the most common cause of recurring oral ulcers and is essentially diagnosed by exclusion of other diseases. 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, as well as from other possible causes of recurring ulcers, such as connective tissue disease, drug reactions, and dermatologic disorders. The history should emphasize symptoms of blood dyscrasias, systemic complaints, and associated skin, eye, genital, or rectal lesions. Laboratory investigation should be used when ulcers worsen or begin past the age of 25 years. Biopsies are only indicated when it is necessary to exclude other diseases, particularly granulomatous diseases such as Crohn’s disease or sarcoidosis.
Patients with severe minor aphthae or major aphthous ulcers should have known associated factors investigated, including connective-tissue diseases and abnormal levels of serum iron, folate, vitamin B
, and ferritin (Figure 4-22). Patients with abnormalities in these values should be referred to an internist to rule out malabsorption syndromes and to initiate proper replacement therapy. The clinician may also choose to have food allergy or gluten sensitivity investigated in severe cases resistant to other forms of treatment.HIVinfected patients, particularly those with CD4 counts below 100/mmTREATMENT
,may develop major aphthous ulcers (Figure 4-23).
Medication prescribed should relate to the severity of the disease. In mild cases with two or three small lesions, use of a protective emollient such as Orabase (Bristol-Myers Squibb, Princeton, NJ) or Zilactin (Zila Pharmaceutions, Phoenix, AZ) is all that is necessary. Pain relief of minor lesions can be obtained with use of a topical anesthetic agent or topical diclofenac, an NSAID frequently used topically after eye surgery.In more severe cases, the use of a high-potency topical steroid preparation, such as fluocinonide, betamethasone or clobetasol, placed directly on the lesion shortens healing time and reduces the size of the ulcers. The effectiveness of the topical steroid is partially based upon good instruction and patient compliance regarding proper use. The gel can be carefully applied directly to the lesion after meals and at bedtime two to three times a day, or mixed with an adhesive such as Orabase prior to application. 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. Other topical preparations that have been shown to decrease the healing time of RAS lesions include amlexanox paste and topical tetracycline, which can be used either as a mouth rinse or applied on gauze sponges. Intralesional steroids can be used to treat large indolent major RAS lesions. It should be emphasized that no available topical therapy decreases the onset of new lesions. In patients with major aphthae or severe cases of multiple minor aphthae not responsive to topical therapy, use of systemic therapy should be considered. Drugs that have been reported to reduce the number of ulcers in selected cases of major aphthae include colchicine, pentoxifylline, dapsone, short bursts of systemic steroids, and thalidomide.Each of these drugs has the potential for side effects, and the clinician must weigh the potential benefits versus the risks. 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.All clinicians prescribing thalidomide in the United States must be registered in the STEPS (System for Thalidomide Education and Prescribing Safety) program, and patients receiving the drug must be thoroughly counseled regarding effective birth control methods that must be used whenever thalidomide is prescribed. For example, two methods of birth control must be used, and the patient must have a pregnancy test monthly. Other side effects of thalidomide include peripheral neuropathy, gastrointestinal complaints, and drowsiness.
