Professional Documents
Culture Documents
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
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Systemic Factors
TABLE 1
Most patients with RAS are oth- Characteristics of the Different Types of Recurrent Aphthous Stomatitis
Predissposing to RAS
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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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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
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)
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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
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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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