Methods. The authors reviewed publications on Medline from 1995 through 2000, the period since the last major reviews were published.

Results. RAS may have an immunogenetic background owing to cross-reactivity with Streptococcus sanguis or heat shock protein. Predisposing factors seen in a minority include haematinic (iron, folate or vitamin B12) deficiency, stress, food allergies and HIV infection. While topical corticosteroids remain the mainstay for therapy, a number of other immunomodulatory modalities now are available.

Conclusions. There is still no conclusive evidence relevant to the etiopathogenesis of RAS, and therefore therapy can attempt only to suppress symptoms rather than to address the basic issues of susceptibility and prevention.

Clinical Implications. In the majority of patients, symptomatic relief of RAS can be achieved with topical corticosteroids alone, with other immunomodulatory topical agents or by combination therapy.

	CLINICAL FEATURES OF RAS

TOP ABSTRACT CLINICAL FEATURES OF RAS ETIOPATHOGENESIS PREDISPOSING FACTORS CONDITIONS THAT MAY MIMIC... DIAGNOSIS MANAGEMENT CONCLUSION REFERENCES

 
The onset of RAS usually is during childhood, with a tendency for ulcers to diminish in frequency and severity with age.² In about 80 percent of patients with RAS, the condition develops before 30 years of age; onset in later years suggests a possibility of definable predisposing factors leading to RAS or that the ulceration is not simple RAS, but rather a part of a more complex disorder such as Behcet’s syndrome.

A prodrome of localized burning or pain for 24 to 48 hours can precede the ulcers. The lesions are painful, clearly defined, shallow, round or oval, with a shallow necrotic center covered with a yellow-grayish pseudomembrane and surrounded by raised margins and erythematous haloes. The pain lasts for three to four days, at which point early epithelialization can occur.

Clinical presentations of RAS. RAS has three clinical presentations (Table 1).

View larger version (99K): [in this window] [in a new window]   Figure 1. Minor aphthous ulceration.

View larger version (98K): [in this window] [in a new window]   Figure 2. Major aphthous ulceration.

View larger version (81K): [in this window] [in a new window]   Figure 3. Herpetiform ulceration.

Most patients have only one to three ulcers, and some have recurrences only two to four times each year (simple aphthosis). Others may have almost continuous disease activity with new lesions developing as older lesions heal, or may have ulcers associated with systemic diseases (complex aphthosis).²

	ETIOPATHOGENESIS

TOP ABSTRACT CLINICAL FEATURES OF RAS ETIOPATHOGENESIS PREDISPOSING FACTORS CONDITIONS THAT MAY MIMIC... DIAGNOSIS MANAGEMENT CONCLUSION REFERENCES

 
Family history. There often is a genetic basis for RAS. More than 42 percent of patients with RAS have first-degree relatives with RAS.⁵ The likelihood of RAS is 90 percent when both parents are affected, but only 20 percent when neither parent has RAS.⁶ It also is likely to be more severe and to start at an earlier age in patients with a positive family history than in those without.⁷

Immunopathogenesis. The pathogenesis of RAS involves a predominantly cell-mediated immune response in which tumor necrosis factor , or TNF , plays a major role. A mononuclear (lymphocytic) cell infiltrate in the epithelium in the preulcerative stage is followed by a localized papular swelling due to keratinocyte vacuolation surrounded by a reactive erythematous halo representing vasculitis. The painful papule then ulcerates and a fibrinous membrane covers the ulcer, which is infiltrated mainly by neutrophils, lymphocytes and plasma cells. Finally, there is healing with epithelial regeneration. The immunopathogenesis probably involves cell-mediated responses, involving T cells and TNF-production by these and other leukocytes (macrophages and mast cells).⁸ TNF-induces inflammation by its effect on endothelial cell adhesion and neutrophil chemotaxis.⁸ RAS can be prevented by thalidomide⁹ and pentoxifylline,⁸ which prevent the synthesis of TNF-, and these agents now have been introduced into oral medicine specialist practice to control RAS. Other cytokines such as interleukin, or IL, -2¹⁰; IL-10¹¹; and natural killer, or NK, cells activated by IL-2 play a role in RAS.¹²

	PREDISPOSING FACTORS

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Classic RAS is a localized condition representing a relatively simple disease, although a minority of patients may be predisposed to it by systemic conditions or diseases. The etiology probably is multifactorial, with various predisposing factors and immunological changes provoked by a range of factors (Box 1).

Stress. Stress can provoke episodes of RAS, but the association is not invariable.¹³

Foods. Foods such as chocolate, coffee, peanuts, cereals, almonds, strawberries, cheese, tomatoes (even the skin of the tomatoes) and wheat flour (containing gluten) may be implicated in some patients.^14,15 In one study of patients with RAS who previously were diagnosed in patch tests as reactive to agents such as benzoic acid and/or cinnamaldehyde, 50 percent showed clinical improvement when certain foods were excluded from the diet.¹⁶

Hormonal imbalance. There are a few patients whose RAS remits with oral contraceptives or during pregnancy.¹⁷

Tobacco smoking. Patients suffering from RAS usually are nonsmokers,¹⁸ and there is a lower prevalence and severity of RAS among heavy smokers as opposed to moderate smokers.¹⁹ Some patients report an onset of RAS after smoking cessation,²⁰ while others report control on reinitiation of smoking.²⁰ The use of smokeless tobacco also is associated with a significantly lower prevalence of RAS.²¹ Nicotine-containing tablets also appear to control the frequency of RAS.²²

	CONDITIONS THAT MAY MIMIC CLASSIC APHTHAE

TOP ABSTRACT CLINICAL FEATURES OF RAS ETIOPATHOGENESIS PREDISPOSING FACTORS CONDITIONS THAT MAY MIMIC... DIAGNOSIS MANAGEMENT CONCLUSION REFERENCES

 
Aphthaelike ulcers—usually in adult-onset RAS rather than childhood-onset—may be seen in association with exposure to certain drugs or with some immune or other defects (Box 2).

Immune disturbances. Large aphthouslike ulcers may be seen where CD4 T lymphocyte counts are lower than 100 cells per milliliter,²⁷ in HIV-positive patients²⁸ and in non–HIV-infected patients with other immunodeficiencies,²⁹ myelodysplastic syndromes,³⁰ benign neutropenia³¹ and other forms of neutropenia such as cyclical neutropenia.³²

Hematinic deficiency states. Though some studies deny an etiologic relationship between RAS and deficiencies of folic acid or iron,³³ deficiencies of vitamin B₁, B₂, B₆ or B₁₂, folic acid or iron have been found in 18 to 28 percent of cases of classical RAS compared with about 8 percent in healthy people.^34,16 Replacement of the deficiency improves RAS in some patients.³⁵

Gastrointestinal diseases. Celiac disease, or gluten-sensitive enteropathy, is seen in more than 4 percent of patients whose initial presentation was classical RAS,³⁶ and RAS in patients with celiac disease remits completely on a gluten-free diet. One uncontrolled study reported that dietary gluten withdrawal produced a favorable response in patients with RAS without celiac disease,³⁷ but another study conducted on these otherwise healthy RAS patients showed no significant response to gluten withdrawal above that with placebo.³⁸ Crohn’s disease and ulcerative colitis also may occasionally be accompanied by RAS or other mouth ulcers.³⁹

Behcet’s syndrome. Behcet’s syndrome manifests with classical RAS and a range of systemic complications, notably affecting the eyes, joints, neurological system and skin.⁴⁰

Periodic fever, aphthae, pharyngitis and adenitis syndrome. Periodic fever, aphthae, pharyngitis and adenitis, or PFAPA, syndrome is a syndrome occasionally seen in young children who have classical RAS.⁴¹

Sweet’s syndrome. Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is characterized by fever, neutrophil leukocytosis, erythematous skin plaques or nodules and, often, classical RAS.⁴² It may occur in conjunction with malignant conditions, such as leukemia.⁴³

	DIAGNOSIS

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The diagnosis of RAS is made on the basis of history and clinical criteria, since there are no specific laboratory tests available.

A medical history should be taken to rule out other ulcerative disorders and conditions such as Crohn’s disease, celiac disease, neutropenia, HIV infection and Behcet’s syndrome (Figure 4).

View larger version (18K): [in this window] [in a new window]   Figure 4. Differentiation of causes of oral ulceration. RAS: Recurrent aphthous stomatitis. PFAPA: Periodic fever, aphthae, pharyngitis and adenitis syndrome.

	MANAGEMENT

TOP ABSTRACT CLINICAL FEATURES OF RAS ETIOPATHOGENESIS PREDISPOSING FACTORS CONDITIONS THAT MAY MIMIC... DIAGNOSIS MANAGEMENT CONCLUSION REFERENCES

 
Since the etiology of RAS remains unknown, and the cyclic nature of the disease makes it difficult to conduct well-designed prospective double-blind controlled clinical studies, there is no definitive treatment. Although a miscellany of supposed therapies have been tried, few have been subjected to double-blind randomized controlled trials (Box 3). Misclassification bias may explain the inconsistency of results found in the vast literature on treatment outcomes.^45,46 Some patients have mild outbreaks, whereas others have severe and longer episodes. Some present with a few small ulcers, while others present with larger ulcers or a combination of small and large.⁴⁷ In some patients, the severity and frequency of outbreaks ease with the passing of years; in others, severity and frequency worsen. Thus, therapy should be tailored to each patient individually.

– decrease symptoms;

– reduce ulcer number and size;

– increase disease-free periods.

The best treatment is that which will control ulcers for the longest period with minimal adverse side effects. The treatment approach should be determined by disease severity (pain), the patient’s medical history, the frequency of flare-ups and the patient’s ability to tolerate the medication. In all patients with RAS, it is important to rule out predisposing factors and treat any such factors, where possible, before introducing more specific therapy.

Perhaps surprisingly, few randomized controlled clinical trials have been conducted to determine the best treatments for RAS. Those that exist showed that chlorhexidine gluconate mouthwashes and topical corticosteroids both can reduce the severity and duration of RAS ulcers, but that neither significantly influences the frequency of RAS episodes.⁴⁸

To help determine management strategies, the practitioner may find it useful to classify RAS in three clinical presentations: type A, type B and type C.

Type A. RAS episodes lasting for only a few days, occurring only a few times a year, are classified as "type A."

In this scenario, pain is tolerable. The clinician should try to identify what precipitates the ulcers, what the patient uses to treat them, and how effective that treatment is. If it is effective and safe, the health care provider, or HCP, should encourage the patient to continue it. If a precipitating factor(s) is identified, the HCP should try eliminating it first. For example, if trauma-induced RAS is suspected, the HCP can suggest a softer toothbrush and gentler brushing. Medication may not be indicated.

Type B. Painful RAS each month, lasting between three and 10 days, is type B. In this scenario, the patient may have changed diet and oral hygiene habits because of the pain. If a precipitating factor can be identified—for example, oral hygiene, stress, trauma or diet—alternatives or remedies should be discussed with the patient. It is imperative to identify patients who experience prodromal symptoms, such as tingling or swelling, because the patient can use corticosteroids (if they are indicated for him or her) at the prodromal stage to abort the attacks.

Treatment often includes the use of a chlorhexidine mouthwash (without alcohol base), and a short course of topical corticosteroids as soon as the ulcers appear. Because of the consistent recurrent pattern, these patients may need a maintenance treatment protocol.

Alternative regimens include dexamethasone 0.05 milligrams/ 5 mL (rinse and spit three times per day) or a high-potency topical corticosteroid such as clobetasol ointment 0.05 percent in Orabase (1:1) (Colgate Oral Pharmaceuticals, Canton, Mass.) or fluocinonide ointment 0.05 percent in Orabase (1:1) if the ulcer(s) recur on the same site, used three times daily (Figure 5). If corticosteroids are used, patients should be monitored for yeast superinfection.⁴⁹ In patients with poor oral hygiene, professional help from a dental hygienist should be considered once ulcers heal.

View larger version (54K): [in this window] [in a new window]   Figure 5. The case of a 14-year-old patient with recurrent aphthous stomatitis. A. Baseline photo. Note the erythema around the base of the ulcer. B. The patient after one week of treatment with clobetasol ointment in adhesive paste.

Type C. Type C RAS involves painful, chronic courses of RAS in which by the time one ulcer heals, another develops.

These patients are best treated by an oral medicine specialist, who often will use potent topical corticosteroids (such as betamethasone, beclomethasone, clobetasol, fluticasone or fluocinonide), systemic corticosteroids, azathioprine or other immunosuppressants such as dapsone, pentoxifylline and sometimes thalidomide.⁵⁰ Table 2 shows the potential adverse effects of these agents.

	CONCLUSION

TOP ABSTRACT CLINICAL FEATURES OF RAS ETIOPATHOGENESIS PREDISPOSING FACTORS CONDITIONS THAT MAY MIMIC... DIAGNOSIS MANAGEMENT CONCLUSION REFERENCES

 
RAS is a common oral disorder of uncertain etiopathogenesis for which symptomatic therapy only is available. Its ethiopathogenesis remains unknown, and there are no diagnostic tests available. Diagnosis, therefore, is made on clinical grounds alone. Several factors—such as trauma, diet and stress—are known to trigger the disease. The most important role of the HCP is to identify underlying precipitating factors and try to eliminate them. Furthermore, it is essential to educate the patient regarding the nature of this condition, especially the fact that RAS is not a contagious condition, as often is thought, and that it is not caused by the herpes simplex virus.

Given its painful presentation and inflammatory nature, RAS responds quite well to the use of topical or systemic anti-inflammatory drugs, particularly corticosteroids. Since the advent of high-potency topical steroids, most patients with RAS can be managed this way. However, early intervention is the key. Topical steroids, when used for a short period, have a very safe profile and should be the first line of treatment for recurrent oral stomatitis.

View larger version (123K): [in this window] [in a new window]   Dr. Scully is the dean, Eastman Dental Institute for Oral Health Care Sciences, University of London, 256 Gray’s Inn Road, London WCIX 8LD, England, e-mail "c.scully{at}Eastman.ucl. ac.uk". Address reprint requests to Dr. Scully.

View larger version (130K): [in this window] [in a new window]   Dr. Gorsky is a professor in oral medicine, Department of Oral Pathology and Oral Medicine, The Maurice and Gabriela Gold-schleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.

View larger version (121K): [in this window] [in a new window]   Dr. Lozada-Nur is a professor of clinical oral medicine and the director, Graduate Program in Oral Medicine, Department of Stomatology, University of California, San Francisco.