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Recurrent Aphthous Stomatitis


S.R. Porter, C. Scully and A. Pedersen CROBM 1998 9: 306 DOI: 10.1177/10454411980090030401 The online version of this article can be found at: http://cro.sagepub.com/content/9/3/306

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RECURRENT APHTHOUS STOMATITIS


S.R. Porter* C. Scully Department of Oral Medicine, Eastman Dental Institute for Oral Health (are Sciences, University of London, 256 Gray's Inn Road, London WC1 X 8LD, United Kingdom; *corresponding author
A. Pedersen Dental Department, Bispebjerg Hospital, Copenhagen Hospital Corporation, University of Copenhagen, 23 Bispebjerg Bakke, DK-2400 (openhagen NV, Denmark
ABSTRACT: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal disorders. Nevertheless, while the clinical characteristics of RAS are well-defined, the precise etiology and pathogenesis of RAS remain unclear. The present article provides a detailed review of the current knowledge of the etiology, pathogenesis, and managment of RAS. Key words. Oral, recurrent aphthous stomatitis, Behget's syndrome.

Introduction
Recurrent aphthous stomatitis is a common oral mucosal disorder that, despite detailed investigation, has an unknown cause and poor effective management (Lehner, 1977; Rogers, 1977; Rennie et al., 1985; Scully and Porter, 1989; Porter and Scully, 1991; Eversole, 1994). This paper reviews the current etiopathogenic data on recurrent aphthous stomatitis and outlines current available therapies.

Epidemiology
Population studies have found RAS in about 2% of Swedish adults examined (Axell and Henricsson, 1985b), though a history compatible with RAS is far more common. RAS affects, in some degree, from 5 to 66% of the population, depending on the group studied. There may be a female predominance in some adult communities (Pongissawaranun and Laohapand, 1991), and there may be a female predisposition in affected children (Field et al., 1992). RAS seems to be infrequent in Bedouin Arabs (Fahmy, 1976) but is especially common in North America (Embil et al., 1975). About 1% of children in developed countries may have recurrent oral ulcers (Kleinman et al., 1994), but 40% of selected groups of children can have a history of R.AS, with ulceration beginning before 5 years of age and the frequency of affected patients rising with age (Hakemer et al., 1971; Miller et al., 1980; Peretz, 1994). Children of higher socio-economic status may be more commonly affected than those from low socio-economic groups (Crevelli et al., 1988).

Clinical Features
The clinical features of RAS consist of recurrent bouts of one or several rounded, shallow, painful oral ulcers at

intervals of a few months to a few days. RAS has 3 main presentations-minor (MiRAS), major (MaRAS), or herpetiform (HU) ulcers (Table 1). Minor recurrent aphthous stomatitis (MiRAS) is the common variety, affecting about 80% of RAS patients, and is characterized by round or oval shallow ulcers usually less than 5 mm in diameter, with a grey-white pseudomembrane enveloped by a thin erythematous halo. MiRAS usually occurs on the labial and buccal mucosa and the floor of the mouth, but is uncommon on the gingiva, palate, or dorsum of the tongue (Figs. 1-3). These lesions heal within 10-14 days without scarring. MiRAS is the most common form of childhood RAS (Field et al., 1992). Major recurrent aphthous stomatitis (MaRAS) is a rare, severe form of RAS, also known as periadenitis mucosa necrotica recurrens. These lesions are oval and may exceed 1 cm in diameter; indeed, they may approach 3 cm. MaRAS has a predilection for the lips, soft palate, and fauces, but can affect any site. The ulcers of MaRAS persist for up to 6 weeks and often heal with scarring. MaRAS usually has its onset after puberty and is chronic, persisting for up to 20 or more years (Scully and Porter, 1989). The third and least common variety of RAS is herpetiform (HU), characterized by multiple recurrent crops of small, painful ulcers that are widespread and may be distributed throughout the oral cavity. As many as 100 ulcers may be present at a given time, each measuring 23 mm in diameter, although they tend to fuse, producing large irregular ulcers. HU may have a predisposition for women and have a later age of onset than other types of RAS (Lehner, 1977; Scully and Porter, 1989) or may represent a spectrum of oral disorders manifesting as recurring ulcers (Porter and Scully, 1991).
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erwise well. In contrast, while RAS-like ulceration can occur in Herpetiform Major Minor Behet's disease, patients with the latter have multisystem disM= F F > M (?) M=F Sex ratio ease, particularly affecting other 20-29 10-19 5-19 onset Age of (yrs) mucocutaneous surfaces, the 10-100 1-10 1-5 Number of ulcers eyes (e.g., uveitis), and the mus1-2* > 10 < 10 Size of ulcers (mm) neurological, culoskeletal, < 30 > 30 4-14 Duration (days) hematological, gastrointestinal, < monthly < monthly Rate of recurrence (mos) 1-4 and other systems. As dislips, cheeks, tongue, lips, cheeks, lips, cheeks, Sites cussed below, RAS does not tongue, floor tongue, palate, pharynx, palate, gingiva, floor of mouth of mouth pharynx have a notable geographic disuncommon uncommon common Permanent scarring tribution, has no HLA associations similar to those of *Can be larger if there is a fusion c)f ulcers. Behget's disease, and has some, but not all, of the immunological abnormalities that arise in celiac disease). These RAS patients may not always have Behget's disease. Unlike Behget's disease, RAS does not bowel symptoms or other clinical features suggestive of lead to significant morbidity or mortality (Mittal et al., GSE but usually have folate deficiency and sometimes 1985; Schreiner and lorizzo, 1987; Arbesfeld and Kurban, reticulin antibodies (Ferguson et al., 1976), particularly 1988; Jankowski et al., 1992; Stratigos et al., 1992). IgA-class reticulin and/or gliadin antibodies (Merchant et Oral ulceration similar in clinical appearance to RAS al., 1986). The haplotype of HLA-DRw1O and DQwl may Driban 1981; can arise in Sweet's Syndrome (Delke et al., predispose patients with GSE to RAS (Majorana et al., and Alvarez, 1984; Mizoguchi et al., 1988; von den Driesch 1992; Meini et al., 1993). There may also be occasional et al 1989, 1994); cyclic neutropenia (Lange and Jones, patients who have RAS with no detectable clinical or his1981; Scully et al., 1982); benign familial neutropenia tological evidence of celiac disease on jejunal biopsy, yet who may respond to dietary withdrawal of gluten (Wray, (Porter et al., 1994a); MAGIC Syndrome (Orme et al., 1990; 1981; Wright et al., 1986). However, the withdrawal of Godeau, 1993; Le Thi Huong et al., 1993), a periodic syndrome with fever and pharyngitis (Marshall et al., 1987); gluten does not often result in significant benefit (Hunter et al., 1993), is difficult to manage, and may simvarious nutritional deficiencies with or without underlyply reflect the pronounced placebo response in RAS. ing gastrointestinal disorders (Eversole, 1994; Grattan Recent data for the UK suggest that anti-endomysial and Scully, 1986); and some other primary (Porter and antibodies are extremely uncommon in RAS, thus adding Scully, 1993a,b; Scully and Porter, 1993a,b) and secondary weight to the notion that RAS is not commonly associatimmunodeficiencies (Porter et al., 1994b), including infeced with GSE. tion with human immunodeficiency virus (MacPhail et al., Hypersensitivity reactions to exogenous antigens 1992). Rarely, drugs such as non-steroidal anti-inflammaother than gluten do not have a significant etiological tories (NSAIDS) can give rise to oral ulcers similar to role in RAS. Some studies have noted an increased prevathose of RAS, along with genital ulceration (Healy and lence of atopy among RAS patients (Tuft and Ettleson, Thornhill, 1995). 1956), while others have failed to find any significant corIn several studies, hematinic (iron, folic acid, or vitarelation (Spouge and Diamond, 1963; Wray et al., 1982; min B 1 2) deficiencies have been demonstrated to be Eversole et al., 1983; Hay and Reade, 1984). Some RAS twice as common in RAS patients than in controls (Wray patients correlate the onset of ulcers with exposure to et al., 1975; Challacombe et al., 1977a, 1983; Hutcheon et certain foods, but controlled studies have failed to disal., 1978; Tyldesley, 1983; Rogers and Hutton, 1986; Field close a causal role despite the fact that certain foods et al., 1987; Porter et al., 1988). About 20% of patients with causing positive skin-prick reactions will elicit pain when RAS may have a hematinic deficiency, though one US they are topically applied to aphthous ulcers (Wilson, study did not report any hematinic problem (Olsen et al., 1980). Dietary manipulation, however, rarely improves 1982). Deficiencies of vitamins B1, B2, and B6 were RAS significantly (Spouge and Diamond, 1963; Wray et al., observed in a cohort of Scottish patients with RAS 1982; Eversole et al., 1983; Hay and Reade, 1984). (Nolan et al., 1991). Less than 5% of outpatients who iniAphthous-like ulceration has been reported in a tially present with RAS (Ferguson et al., 1976, 1980; Velso patient with zinc deficiency and immunodeficiency and Saleiro, 1987) have gluten-sensitive enteropathy (GSE:
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TABLE 1 Most patients with RAS are oth- Characteristics of the Different Types of Recurrent Aphthous Stomatitis

Systemic Factors

Predissposing to RAS

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Figure 1. Typical minor aphthous stomatitis.

ulceration related to the luteal phase of the menstrual cycle, presumably modulated by changing levels of progestogens (Dolby, 1968; Segal et al., 1974; Ferguson et al., 1984) and thus defective oral mucosal epithelial turnover Nevertheless, a detailed review of all pertinent literature failed to find any association between RAS and altered female sex corticosteroids (McCartan and Sullivan, 1992). Psychological illness has been proposed to initiate some episodes of RAS (Ship et al., 1961b; Miller et al., 1977a), and there are sparse data to suggest that some patients may benefit from antidepressant therapy (Yaacob and Hamid, 1985). Nevertheless, no significant objective neurosis has been observed in two further studies (Pedersen, 1989; Buajeeb et al., 1990).

Local Factors Predisposing to RAS Local, physical trauma may initiate ulcers in susceptible people (Ross et al., 1958; Wray et al., 1981), and RAS is uncommon where mucosal keratinization is present (Sallay and Ban6czy, 1968) or in patients who smoke tobacco (Brookman, 1960; Dorsey, 1964, Shapiro et al., 1970; Axell and Henricsson, 1985a).
Genetic Basis
In some individuals, RAS may have a familial basis. Possibly more than 40% of RAS patients may have a vague familial history of oral ulceration (Sircus et al.., 1957). Patients with a positive family history of RAS may develop oral ulcers at an earlier age and have more severe symptoms than affected individuals with no family history of oral ulceration (Ship, 1965) The probability of a sibling developing RAS is influenced by the parents' RAS status (Ship, 1972), and there is a high correlation of RAS in identical twins (Miller et al., 1977b). Nevertheless, there is a clear variability in host susceptibility with a polygenic inheritance but penetrance dependent on other factors (Ship, 1965, 1972). Early studies failed to demonstrate significant associations between a particular HLA haplotype and RAS (Platz et al., 1976; Dolby et al., 1977). Later studies have reported a variety of associations or non-associations. A non-significant rise in the frequencies of HLA-A2 and Aw-29 in RAS patients (Challacombe et al., 1977b) has been suggested, and an association with HLA-B12 (Lehner et al., 1982, Malmstrom et cil., 1983) was reported but not confirmed by others (Gallina et al., 1985, Ozbakir et al., 1987). A significant association between HLA-DR2 (usually in the haplotype HLA-DR2/B12) and RAS has been observed, but the study group consisted of only 17 patients (Lehner et al., 1982) In a study of Turkish RAS patients, the frequency of HLA-B5 was raised non-significantly compared with its frequency in healthy control subjects (Ozbakir et al_, 1987). The frequency of HLA-DR4 was reduced in a cohort of Greek patients (Albanidou-

Figure 2. Minor aphthous stomatitis. Note the typical oval shape and sloughed appearance with surrounding halo.

Figure 3. Atypical aphthous ulceration of the dorsum of tongue.


(Endre, 1991). It is unlikely that an association between RAS and zinc deficiency exists, although the reported one patient did benefit from zinc supplementation. A minority of women with RAS have cyclical oral
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Farmaki et al., 1988). The frequency of HLA-B5 was reduced, but HLA-DR7 significantly increased in Sicilian RAS patients (Gallina et al., 1985). In some but not all groups, there may be a negative association of RAS with MT2 and MT3 (now the HLA-DO series) that may help differentiate RAS from Behget's syndrome (Lehner et al., 1982). The close association of both Behget's syndrome and RAS with HLA-B51 (Shohat-Zabarski et al., 1982; Albanidou-Farmaki et al., 1988) suggests a relationship in which this locus may not be the primary locus responsible-rather, some other gene close to those controlling heat shock proteins and tumor necrosis factor (Mizuki et al., 1995). No consistent, significant association between RAS and a particular serologically determined HLA antigen or haplotype has been demonstrated. This could reflect inadequate patient numbers and/or variable ethnic backgrounds of investigated patients, or most likely the lack of any immunogenetic basis for RAS. It is thus doubtful if detailed allelotypic studies would be fruitful.

Immunopathogenesis
Patients with RAS may have increased levels of peripheral blood CD8+ T-lymphocytes and/or decreased CD4+ Tlymphocytes (Sun et al., 1987; Pedersen et al., 1989, 1991; Landesberg et al., 1990; Ratis et al., 1991; Savage and Seymour, 1994). There may be a reduced percentage of CD4+ICD5+(2H4T)l "virgin" T-cells and an increased percentage of CD4+1CD29+(4B4+)l "memory" T-lymphocytes (Pedersen et al., 1989). Patients with active RAS have an increased proportion of y8 cells compared with healthy control subjects and RAS patients with inactive disease (Pedersen and Ryder, 1994). The y8 T-cells may play a role in antibody-dependent cell-mediated cytotoxicity (ADCC); however, the exact stimulus for the increased generation of y8 T-cells in RAS is unclear. Interestingly, a rise in -y T-cells may occur in Behcet's disease (Suzuki et al., 1990), and it is believed that the yb T-cells play a role in immunological damage (Hasan et al., 1996). There is an elevation of serum levels of IL-6, IL-2R, and soluble intercellular adhesion molecules compared with controls; however, these changes do not correlate with disease activity, and their pathogenic significance remains unclear (Yamamoto et al., 1994). Perhaps surprisingly, there is a decrease in the number of mononuclear cells, including CD4+ and CD8+ Tlymphocytes, in the affected and non-affected oral mucosa of RAS patients (Hayrinen-Immonen et al., 1991; Pedersen et al, 1992). In the pre-ulcerative phase of RAS, there is a local mononuclear infiltrate consisting initially of large granular lymphocytes (LGL) and T4 (CD4+) helper-induced lymphocytes (Hayrinen-Immonen et al., 1991). The ulcerative phase is associated with the appearance of CD4+ cytotoxic suppressor cells, but these are replaced by CD4+ cells during healing (Savage et al.,
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1985). Polymorphonuclear lymphocytes (PMNL) also appear in the lesion, but in contrast to Behcet's syndrome, where they appear to be hyperactive, their chemotactic function is normal in RAS (Abdulla and Lehner, 1979; Dagalis et al., 1987). Indeed, PMNL phagocytic function is also not significantly defective (Ueta et al., 1993). The aggregation of lymphocytes is probably mediated by the adhesion molecules-intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-antigen-3 (LFA-3)-binding to their counterpart ligands LFA-1 and CD-2 on lymphocytes (Hayrinen-Immonen et al., 1992; Verdickt et al., 1992). ICAM-1 is expressed on the submucosal capillaries and venules, suggesting that it may control the trafficking of leukocytes into the submucosa (Savage et al., 1986; Eversole, 1994), while LFA-3 and its counterpart ligand CD-2 are likely to be involved in T-cell activation in RAS. HLA class I and 11 antigens appear on basal epithelial and then perilesional cells in all layers of the epithelium in the early phases of ulceration (Savage et al., 1986), presumably mediated by gamma interferon released by T-cells. Such MHC antigens may target these cells for attack by cytotoxic cells: Indeed, activated mononuclear cells infiltrate the epithelium, especially the prickle cell layer (Honma, 1976), and are in close contact with apoptotic prickle cells, which they and PMNL sometimes phagocytose (Honma et al., 1985). Nevertheless, despite earlier studies purporting to implicate cell-mediated immune responses in RAS, these results have not been confirmed (Peavy et al., 1982; Gadol et al., 1985; Greenspan et al., 1985). It seems more likely that a B-lymphocyte-mediated mechanism involving antibody-dependent cellular cytotoxicity and, possibly, immune complexes is involved. Circulating immune complexes have not been reliably demonstrated in RAS (Levinsky and Lehner, 1978; Lehner et al., 1979; BurtonKee et al., 1981; Bagg et al., 1987). Immune deposits do occur in lesional biopsy specimens (Ullman and Gorlin, 1978), especially in the stratum spinosum (Schroeder et al., 1984), and there can be evidence of leukocytoclastic or immune complex vasculitis (Lunderschmidt, 1982; Schroeder et al., 1984), leading to the non-specific deposition of immunoglobulins and complement. Nevertheless, it seems probable that immune-complexmediated tissue damage is of secondary importance in the etiopathogenesis of RAS. Serum immunoglobulin levels are generally normal, though increases in serum IgA, IgG, IgD, and IgE have all been reported in different groups of RAS patients (Lehner, 1969; Ben-Aryeh et al., 1976; Scully et al., 1983). Normal or reduced immunoglobulin levels have been observed in other groups of RAS patients (Brady and Silverman, 1969). Serum levels of C9 have been reported to be raised in some patients (Adinolfi and Lehner, 1976;

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Lehner and Adinolfi, 1980) and, together with elevated serum levels of I 2 microglobulin (Scully, 1982), may represent a non-specific acute phase response. Patients with RAS do not have IgG subclass deficiencies (Porter et al., 1992). As noted above, there can be an increase in y8 Tcells, important in antibody-dependent cell-mediated cytotoxicity. In vitro studies have indicated that peripheral blood leukocytes of patients with RAS may demonstrate increased cytotoxicity toward oral mucosal epithelium (Lehner, 1967; Dolby, 1969; Rogers et al., 1974, 1976; Greenspan et al., 1981; Burnett and Wray, 1985), and it is thus possible that RAS may represent an ADCC-type reaction to the oral mucosa. This concept is supported by the knowledge that peripheral blood mononuclear cells of patients with RAS (but no active disease) cause lysis of oral mucosal cells expressing classes I and II MHC antigens. More importantly, peripheral blood CD4+ T-cells from RAS patients can also cause epithelial lysis (Savage and Seymour, 1994). It is thus feasible that CD4+ and CD8+ T-cell-mediated cytotoxic reactions occur in RAS. Natural killer (NK) cells do not seem to play a central role in the pathogenesis of RAS. In RAS, levels of peripheral blood NK cells may be increased (Thomas et al., 1990) or, similar to those of control subjects and NK subsets (e.g., CD16+, CD56+, and CD14+), are not altered in RAS (Pedersen and Pedersen, 1993). Likewise, baseline NK cell function is not notably altered in RAS (Pedersen and Pedersen, 1993; Ueta et al., 1993), although it may be reduced during exacerbation of MaRAS or the late ulcerative stage of MiRAS (Sun et al., 1991). It is thus evident that there is no unifying theory of the immunopathogenesis of RAS. It would seem that the ulceration is due to the cytotoxic action of lymphocytes and monocytes upon the oral epithelium, but the trigger for these responses remains unclear.

Microbial Aspects of RAS


Oral streptoccocci were previously suggested as important in the pathogenesis of RAS, either as direct pathogens or as an antigenic stimulus culminating in the genesis of antibodies that may conceivably cross-react with keratinocyte antigenic determinants (Martin et al., 1979; Lindemann et al., 1985). The initial L-form isolate from RAS patients was typed as S. sanguis (Barile et al., 1963), but later analysis disclosed that this organism was actually a strain of S. mitis (Hoover and Greenspan, 1983). While some studies have disclosed elevated serum antibody titers to viridans streptococci among RAS patients, other investigations have yielded contradictory results (Barile et al., 1968; Donatsky, 1976). Furthermore, lymphocyte mitogenic responses to S. sanguis and S. mitis in RAS patients are not significantly different from those in
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control subjects (Barile et al., 1968; Gadol et al., 1985; Greenspan et al., 1985). More recently, cross-reactivity between a streptococcal 60-65-kDa heat shock protein (hsp) and the oral mucosa has been demonstrated and significantly elevated levels of serum antibodies to hsp observed in RAS (Lehner et al., 1991). While lymphocytes of patients with Behget's disease have reactivity to 3 of 4 T-cell epitopes of the 65kDa hsp of Mycobacterium tuberculosis (Pervin et al., 1993), the lymphocytes of RAS patients have reactivity to another peptide, peptide 9 1-105 (Hasan et al., 1995). Of particular relevance was a significantly increased lymphoproliferative response to this peptide in the ulcerative stage as opposed to the period of remission. There is some crossreactivity between the 65-kDa hsp and the 60-kDa human mitochondrial hsp. It has thus been suggested that there is a molecular basis for earlier work suggesting a link between RAS and Streptococcus sanguis, since monoclonal antibodies to part of the 65-kDa hsp of Mycobacterium tuberculosis react with S. sanguis (Lehner et al., 1991). Thus, RAS may be a T-cell-mediated response to antigens of S. sanguis that cross-react with the mitochondrial hsp and induce oral mucosal damage (Hasan et al., 1995). Together with the known changes in y8 T-cell numbers, and perhaps the presence of immune complexes in lesional tissue, this suggests a pathogenic mechanism common with that of Behcet's disease. Nevertheless, the evidence is still incomplete, and reasons for the limited oral involvement of RAS in comparison with the multisystemic nature of Behcet's disease remain unclear. Helicobacter pylori has been detected in lesional tissue of ill-defined oral ulcers, but the frequency of serum IgG antibodies to H. pylori is not increased in RAS (Porter et al., in press). It has also been suggested that viruses may play a role in RAS and Behcet's syndrome (Hooks, 1978). An association of RAS with adenoviruses (Sallay et al., 1971, 1973) has been suggested, but adenoviruses are ubiquitous organisms, and these results need confirmation. The possible association of RAS with herpesviruses 1-6 has recently been reviewed (Pedersen, 1993). Herpesvirus virions and antigens are not demonstrable in RAS (Dodd and Ruchman, 1950; Driscoll et al., 1961; Ship et al., 196 1a; Griffin, 1963). RNA complementary to herpes simplex virus (HSV) has been detected in circulating mononuclear cells in some RAS patients (Eglin et al., 1982) and HSV-1 in circulating immune complexes (Hussain et al., 1986). However, serum levels of interferon are not increased in RAS (Hooks et al., 1979). Virus-like particles have been seen in some tissues in Behcet's syndrome but not in oral mucosa and have not been reliably demonstrated in RAS. Herpes simplex virus has not been successfully isolated from lesional material (Donatsky et al., 1977; Rothe et al., 1978). Only about a third of RAS patients are HSV-seropositive (Ship et al., 1967), and HSV
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is rarely detected in lesional tissue by the polymerase chain-reaction (PCR) (Studd et al., 1991). IgM and IgG antibodies to varicella zoster virus (VZV) may be elevated in some RAS patients (Pedersen and Hornsleth, 1993), suggesting an association between reactivation of VZV and RAS. Furthermore, VZV DNA can be detected in lesional tissue by the polymerase chain-reaction (Pedersen et al., 1993); however, contamination is possible and may underlie these observations (Pedersen etal., 1993). Antibodies to cytomegalovirus (CMV) may be significantly elevated in some RAS patients (Pedersen and Hornsleth, 1993), and CMV DNA has been detected in illdefined oral ulcerations in non-HIV-infected persons (Leimola-Virtanen et al., 1995). DNA from human herpesvirus 6 (HHV-6) and HHV-7 has not been demonstrated in RAS, but HHV-8 DNA is present in HIV-related oral ulcers (Di Alberti et al., 1997a,b). The role of viruses in RAS is reviewed elsewhere (Scully, 1993). There are thus no definitive epidemiological data to support an infectious etiology to RAS. Likewise, a viral cause seems unlikely, and current evidence suggests that some cross-reactivity between bacterial heat shock proteins and epithelial components may play a role in the development of RAS.

Management
(A) DIAGNOSIS
The diagnosis of RAS is almost always based upon the history of the patient's complaint and clinical findings. Typically, patients report a history of recurrent bouts of ulceration of the mobile oral mucosal surfaces. Each bout of ulceration lasts a few weeks, healing being sometimes accompanied by the development of new ulcers. Patients are typically well despite the oral ulceration. Histopathological examination, including direct immunofluorescence of lesional tissue, is rarely of diagnostic benefit, since the histopathological features are non-specific. Hematological and serological investigations may reveal an accompanying hematinic deficiency, particularly ferritin, but rarely are any other significant abnormalities likely to be detected. Detailed virological investigations of lesional tissue or serum are usually not warranted unless to exclude atypical herpetic infection.

(B) THERAPY
There is no specific therapy reliably effective for RAS. The symptoms can be reduced, but it is not possible to prevent recurrences reliably. Surgical removal of ulcers is inappropriate, and the value of physical debridement of ulcers is unknown (Potoky, 1981). Laser ablation Ifor example, with a pulsed neodymium:yttrium-aluminum(1998) 9(3) 306 321 (1998) 9(3):306-321
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garnet (Nd:YAG) laser] can provide short-term symptomatic relief and ulcer healing (Convissar and MassoumiSourey, 1992) but is of very limited practical benefit (Howell et al., 1988). Patients with RAS, which is possibly secondary to systemic disease, require referral to an appropriate specialist for detailed evaluation and suitable therapy (Bagan, 1995). Individuals with RAS possibly related to foodstuffs may occasionally benefit from dietary alterations (Spouge and Diamond, 1963; Eversole et al., 1983; Hay and Reade, 1984), while hematinic replacement can be of value in patients with hematinic deficiency of unknown cause (Wray et al., 1975; Rogers and Hutton, 1986; Porter et al., 1992a). Zinc sulphate therapy is not effective (Wray, 1982). LongoVital, a herbal-based vitamin tablet with a wide range of trace elements, has proven superior to placebos in the prevention of RAS after two months' daily intake in patients without hematinic deficiencies (Pedersen et al., 1990a,b). The preventive effects of this therapy may be due to the contemporary increase in the fraction of peripheral CD4+ T-cells (Pedersen et al., 1990b). Chlorhexidine gluconate aqueous mouthrinse may be of some benefit in the management of RAS. Chlorhexidine can reduce the number of ulcer days and increase ulcer-free days and the interval between bouts of ulceration, but cannot prevent the recurrence of ulcers. Chlorhexidine is generally used as a 0.2% w/w mouthrinse, but the 0.10% w/w mouthwash or I% gel can also be beneficial (Addy et al., 1974, 1976; Addy, 1977; Hunter and Addy, 1987). However, one recent study found little objective value of chlorhexidine gluconate mouthrinse over a placebo in the management of RAS (Matthews et al., 1987). In addition, chlorhexidine gluconate must be used almost daily for long periods and may cause exogenous dental staining. Benzydamine hydrochloride mouthwash is of no more benefit than a placebo (Matthews et al., 1987). Nevertheless, benzydamine hydrochloride mouthwash (or lignocaine gel) can produce transient relief of pain in severe RAS. In clinical practice, both chlorhexidine and benzydamine appear to be useful in the management of RAS. Topical tetracyclines used alone or in combination with amphotericin can reduce the severity of ulceration, but do not alter the recurrence rate of RAS (Guggenheimer et al., 1968; Graykowski and Kingman, 1978; Denman and Schiff, 1979; Hayrinen-Immonen et al., 1994). The evidence on the therapeutic benefits of acyclovir requires further investigation (Wormser et al., 1988; Pedersen, 1992). Therapeutic approaches involving the enhancement of the salivary peroxidase system are not effective (Donatsky et al., 1983; Henricsson and Axell, 1985), although a modified mouthrinse is under investigation (Hoogendoorn and Piessens, 1987). Of interest, the
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TABLE 2 Some Reported Therapies of Recurrent Aphthous Stomatitis (RAS)


Mouthrinses

Topical corticosteroids

Antibiotics Immunomodulators

Others

Chlorhexidine gluconate Benzydamine hydrochloride Carbenoxolone disodium Betadine Hydrocortisone hemisuccinate (pellets) Triamcinolone acetonide (in adhesive paste) Flucinonide (cream) Betamethasone valerate (mouthrinse) Betamethasone- 1 7-benzoate (mouthrinse) Flumethasone pivolate (spray) Beclomethasone dipropionate (spray) Topical tetracyclines Levamisole Transfer factor Colchicine Gammaglobulins Azathioprine Dapsone Thalidomide Pentoxifylline Prednisolone Azelastine Alpha-2-inteferon Cyclosporin Amlexanox 5-amino salicyclic acid Systemic zinc sulphate Monoamine-oxidase inhibitors Sodium cromoglycate Deglycirrhizinated liquorice Sucralphate
Etretinate Low-enerqy laser

and there have been several studies of its efficacy. Subjective improvement is possible, but rarely is there objective clinical improvement, and the possible adverse effects of nausea, hyperosmia, dysgeusia, and agranulocytosis have discouraged its use (Lehner et al., 1976; De Meyer et al., 1977; Drinnan and Fischman, 1978; Gier et al., 1978; Kaplan et al., 1978; Miller et al., 1978; Olsen and Silverman, 1978). Recently, however, a group of Taiwanese patients was reported to have had significant clinical improvement (i.e., reduced pain, number, frequency, and duration of ulcers) with levamisole therapy (100-150 mg daily for 2-3 months). However, these patients are perhaps unusual, since they often had slightly reduced CD4+ and increased CD8+ peripheral blood T-lymphocytes, the presence of anti-nuclear antibodies, and anti-basement membrane antibodies (Sun et al., 1994). The frequency of side-effects of levamisole was not reported in this study. Transfer factor (Schulkind et al., 1984) and gammaglobulin therapy (Kaloyannides, 1971) have been suggested to be beneficial, but more detailed studies are needed to confirm these preliminary observations.

Sodium cromoglycate lozenges may provide mild symptomatic relief (Dolby and Walker, 1975; Kowolik et al., 1978), but cromoglycate-containing toothpaste is not beneficial (Potts et al., 1984). Carbenoxolone sodium mouthwash reduced the severity of RAS in one study (Poswillo and Partridge,
1984).

absence of sodium lauryl sulphate from a dentifrice may lessen the liability to RAS (Herlofson and Karkvoll, 1994). Topical corticosteroids remain the mainstay of RAS treatment. A spectrum of different topical corticosteroids can be used (Table 2): All can reduce symptoms, and neither hydrocortisone nor triamcinolone preparations cause adrenal suppression, but ulcers still recur (Cooke and Armitage, 1960; Zegarelli et al., 1960; Merchant et al., 1978; Yeoman et al., 1978; Fisher, 1979; Pimlott and Walker, 1983; Scaglione et al., 1985). Perhaps, at best, topical corticosteroids and chlorhexidine may reduce painful symptoms but not the rate of recurrence of ulcers (Miles et al., 1993). Levamisole was proposed as a possible treatment for RAS by virtue of its wide immunostimulatory effects,
312

Dapsone has been reported to reduce the oral lesions in a few patients with RAS-like lesions, but the clinical features of this group of patients were poorly described (Handfield-Jones et al., 1985). Thalidomide may produce remission or reduction in symptoms of RAS (Mascaro et al., 1979; Grinspan, 1985; Eisenbud et al., 1987; Grinspan et al., 1989; Nicolau and West, 1990; Revuz et al., 1990; Gunzler, 1992); however, this treatment is not without its dangers. Thalidomide therapy should be considered when patients have episodes of profound ulceration, and perhaps limited to persons with HIV-related ulceration, although thalidomide hypersensitivity can occur in HIV disease (Williams et al., 1991). Aside from teratogenicity, thalidomide can give rise to several other serious (e.g., irreversible polyneuropathy) side-effects. Possibly by virtue of its action on the microtubular function of polymorphonuclear leukocytes and interface in adhesion molecule expression, colchicine may be of clinical benefit in Behget's disease. Colchicine was initially reported to have a favorable outcome in small groups of patients with RAS (Gatot and Tovi, 1984; Ruah et al., 1988), and, in a more recent open study of 20
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patients, colchicine (1.5 mg/day for 2 months) produced a significant reduction in pain scores and frequency of self-reported ulcers (Katz et al., 1994). Unfortunately, not all patients benefit from colchicine therapy, and at least 20% can have painful gastrointestinal symptoms or diarrhea (Katz et al., 1994), and it can produce infertility in young males. Combined colchicine and thalidomide therapy may occasionally benefit recalcitrant RAS (Genvo et al., 1984). Pentoxifylline is an agent with minimal adverse effects but one that has immunosuppressive actions (e.g., interference in neutrophil adherence, inhibition of T- and B-lymphocyte activation and NK cell activity). It has been of clinical benefit in the management of vasculitides (Ely, 1988) and Behcet's syndrome (Yasim et al., 1996). In limited open studies, pentoxifylline (400 mg three times daily) for one month caused a notable reduction in the number of RAS episodes for up to 9 months after therapy; no side-effects were reported (Pizarro et al., 1995, 1996; Wahba-Yahav, 1995a,b). This seems the most promising agent currently available. Other immunomodulatory agents that have been suggested to be of some benefit in the management of RAS include azathioprine (Brown and Bottomley, 1990), systemic prednisolone (Yel et al., 1994), azelastine (Ueta et al., 1994), human alpha-2-interferon in cream (Hamuryudan et al., 1990, 1991), topical cyclosporin (Eisen and Ellis, 1990), deglycirrhizinated liquorice (Das et al., 1989), topical 5-aminosalicylic acid (Collier et al., 1992), amlexanox (Greer et al., 1993), and prostaglandin E2 (PGE2) gel (Taylor et al., 1993). Sucralfate in at least one cross-over study of RAS reduced the duration of symptoms and improved the duration of remission (Rattan et al., 1994). Monoamine oxidase inhibitor therapy caused the remission of RAS in three patients (Rosenthal, 1984; Lejonc and Fourestie, 1985), although clinical improvement may have been due to accompanying dietary modifications rather than to any alteration in psychologic status. In several of the aforementioned studies, some patients reported clinical improvement with a placebo. This placebo effect, combined with the often-limited nature of RAS, ensures that most patients ultimately have a reduction in symptoms.

ulcers; indeed, there have been few studies that conclusively prove that any agent, apart from anti-inflammatory agents, can reduce the frequency or severity of recurrent aphthous stomatitis more than can placebo.

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Conclusions
While recurrent aphthous stomatitis remains a common oral mucosal disorder in most communities of the world, its precise etiology remains unclear. No precise trigger has ever been demonstrated, and there is no conclusive evidence for a genetic predisposition to RAS in most patients. Lesions arise as a consequence of immunologically mediated cytotoxicity of epithelial cells. There remains no safe therapy to ensure no recurrence of
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