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 arti-
cle 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 pre-
dominance in some adult communities (Pongissawaranun
and Laohapand, 1991), and there may be a female predispo-
sition 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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intervals of a few months to a few days. RAS has 3 main
presentations-minor (MiRAS), major (MaRAS), or her-
petiform (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 usu-
ally 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 her-
petiform (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 2-
3 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 repre-
sent a spectrum of oral disorders manifesting as recur-
ring ulcers (Porter and Scully, 1991).
9(3):306-32 1 ( 1998)
 Systemic Factors
Predissposing to RAS TABLE 1
Most patients with RAS are oth- Characteristics of the Different Types of Recurrent Aphthous Stomatitis
erwise well. In contrast, while
RAS-like ulceration can occur in
Beh§et's disease, patients with
the latter have multisystem dis-
ease, particularly affecting other Sex ratio
mucocutaneous surfaces, the Age of onset (yrs)
Number of ulcers
eyes (e.g., uveitis), and the mus- Size of ulcers (mm)
culoskeletal, neurological, Duration (days)
hematological, gastrointestinal, Rate of recurrence (mos) 1-4
and other systems. As dis- Sites
cussed below, RAS does not
have a notable geographic dis-
tribution, has no HLA associa- Permanent scarring
tions 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 immunologi-
cal abnormalities that arise in
Behget's disease. Unlike Behget's disease, RAS does not
lead to significant morbidity or mortality (Mittal et al.,
1985; Schreiner and lorizzo, 1987; Arbesfeld and Kurban,
1988; Jankowski et al., 1992; Stratigos et al., 1992).
Oral ulceration similar in clinical appearance to RAS
can arise in Sweet's Syndrome (Delke et al., 1981; Driban
and Alvarez, 1984; Mizoguchi et al., 1988; von den Driesch
et al 1989, 1994); cyclic neutropenia (Lange and Jones,
1981; Scully et al., 1982); benign familial neutropenia
(Porter et al., 1994a); MAGIC Syndrome (Orme et al., 1990;
Godeau, 1993; Le Thi Huong et al., 1993), a periodic syn-
drome with fever and pharyngitis (Marshall et al., 1987);
various nutritional deficiencies with or without underly-
ing gastrointestinal disorders (Eversole, 1994; Grattan
and Scully, 1986); and some other primary (Porter and
Scully, 1993a,b; Scully and Porter, 1993a,b) and secondary
immunodeficiencies (Porter et al., 1994b), including infec-
tion with human immunodeficiency virus (MacPhail et al.,
1992). Rarely, drugs such as non-steroidal anti-inflamma-
tories (NSAIDS) can give rise to oral ulcers similar to
those of RAS, along with genital ulceration (Healy and
Thornhill, 1995).
In several studies, hematinic (iron, folic acid, or vita-
min B 1 2) deficiencies have been demonstrated to be
twice as common in RAS patients than in controls (Wray
et al., 1975; Challacombe et al., 1977a, 1983; Hutcheon et
al., 1978; Tyldesley, 1983; Rogers and Hutton, 1986; Field
et al., 1987; Porter et al., 1988). About 20% of patients with
RAS may have a hematinic deficiency, though one US
study did not report any hematinic problem (Olsen et al.,
1982). Deficiencies of vitamins B1, B2, and B6 were
observed in a cohort of Scottish patients with RAS
(Nolan et al., 1991). Less than 5% of outpatients who ini-
tially present with RAS (Ferguson et al., 1976, 1980; Velso
and Saleiro, 1987) have gluten-sensitive enteropathy (GSE:
9(3) 306 321 (1998)
9(3)-.306-321 Crit Rev Oral Biol Med
Crit RevOral
Minor Major Herpetiform
M= F M=F F > M (?)
5-19 10-19 20-29
1-5 1-10 10-100
< 10 > 10 1-2*
4-14 > 30 < 30
< monthly < monthly
lips, cheeks, lips, cheeks, lips, cheeks, tongue,
tongue, floor tongue, palate, pharynx, palate, gingiva,
of mouth pharynx floor of mouth
uncommon common uncommon
celiac disease). These RAS patients may not always have
bowel symptoms or other clinical features suggestive of
GSE but usually have folate deficiency and sometimes
reticulin antibodies (Ferguson et al., 1976), particularly
IgA-class reticulin and/or gliadin antibodies (Merchant et
al., 1986). The haplotype of HLA-DRw1O and DQwl may
predispose patients with GSE to RAS (Majorana et al.,
1992; Meini et al., 1993). There may also be occasional
patients who have RAS with no detectable clinical or his-
tological evidence of celiac disease on jejunal biopsy, yet
who may respond to dietary withdrawal of gluten (Wray,
1981; Wright et al., 1986). However, the withdrawal of
gluten does not often result in significant benefit
(Hunter et al., 1993), is difficult to manage, and may sim-
ply reflect the pronounced placebo response in RAS.
Recent data for the UK suggest that anti-endomysial
antibodies are extremely uncommon in RAS, thus adding
weight to the notion that RAS is not commonly associat-
ed with GSE.
Hypersensitivity reactions to exogenous antigens
other than gluten do not have a significant etiological
role in RAS. Some studies have noted an increased preva-
lence of atopy among RAS patients (Tuft and Ettleson,
1956), while others have failed to find any significant cor-
relation (Spouge and Diamond, 1963; Wray et al., 1982;
Eversole et al., 1983; Hay and Reade, 1984). Some RAS
patients correlate the onset of ulcers with exposure to
certain foods, but controlled studies have failed to dis-
close a causal role despite the fact that certain foods
causing positive skin-prick reactions will elicit pain when
they are topically applied to aphthous ulcers (Wilson,
1980). Dietary manipulation, however, rarely improves
RAS significantly (Spouge and Diamond, 1963; Wray et al.,
1982; Eversole et al., 1983; Hay and Reade, 1984).
Aphthous-like ulceration has been reported in a
patient with zinc deficiency and immunodeficiency
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Figure 1. Typical minor aphthous stomatitis.
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
308 Crit Rev Oral Biot Med
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 fami-
ly 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 asso-
ciations 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-signif-
icantly 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-
9(3):306-321 (1998)
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 dif-
ferentiate 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 responsi-
ble-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 back-
grounds 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 peripher-
al blood CD8+ T-lymphocytes and/or decreased CD4+ T-
lymphocytes (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 per-
centage 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 con-
trols; however, these changes do not correlate with dis-
ease activity, and their pathogenic significance remains
unclear (Yamamoto et al., 1994).
Perhaps surprisingly, there is a decrease in the num-
ber of mononuclear cells, including CD4+ and CD8+ T-
lymphocytes, 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 syn-
drome, where they appear to be hyperactive, their
chemotactic function is normal in RAS (Abdulla and
Lehner, 1979; Dagalis et al., 1987). Indeed, PMNL phago-
cytic function is also not significantly defective (Ueta et
al., 1993).
The aggregation of lymphocytes is probably mediat-
ed 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 submu-
cosal capillaries and venules, suggesting that it may con-
trol 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 epithe-
lial and then perilesional cells in all layers of the epithe-
lium 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 con-
tact with apoptotic prickle cells, which they and PMNL
sometimes phagocytose (Honma et al., 1985).
Nevertheless, despite earlier studies purporting to impli-
cate 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; Burton-
Kee 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 depo-
sition of immunoglobulins and complement.
Nevertheless, it seems probable that immune-complex-
mediated 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;
Oral Biol Med
Biol Med 309
Lehner and Adinolfi, 1980) and, together with elevated
serum levels of I 2 microglobulin (Scully, 1982), may rep-
resent 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 T-
cells, important in antibody-dependent cell-mediated
cytotoxicity. In vitro studies have indicated that peripher-
al blood leukocytes of patients with RAS may demon-
strate increased cytotoxicity toward oral mucosal epithe-
lium (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 periph-
eral 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 ulcera-
tive 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 impor-
tant 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 anti-
body titers to viridans streptococci among RAS patients,
other investigations have yielded contradictory results
(Barile et al., 1968; Donatsky, 1976). Furthermore, lym-
phocyte mitogenic responses to S. sanguis and S. mitis in
RAS patients are not significantly different from those in
310 Grit Rev Oral Biol
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Crit
control subjects (Barile et al., 1968; Gadol et al., 1985;
Greenspan et al., 1985).
More recently, cross-reactivity between a streptococ-
cal 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 65-
kDa 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 lymphoprolifera-
tive response to this peptide in the ulcerative stage as
opposed to the period of remission. There is some cross-
reactivity 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 tuber-
culosis 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 num-
bers, 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 multi-
systemic 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 ubiqui-
tous 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 circu-
lating 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 syn-
drome 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 re-
activation of VZV and RAS. Furthermore, VZV DNA can be
detected in lesional tissue by the polymerase chain-reac-
tion (Pedersen et al., 1993); however, contamination is
possible and may underlie these observations (Pedersen
etal., 1993).
Antibodies to cytomegalovirus (CMV) may be signif-
icantly elevated in some RAS patients (Pedersen and
Hornsleth, 1993), and CMV DNA has been detected in ill-
defined 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 else-
where (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 pro-
teins 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 some-
times 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 diag-
nostic benefit, since the histopathological features are
non-specific. Hematological and serological investiga-
tions 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 pre-
vent 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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garnet (Nd:YAG) laser] can provide short-term sympto-
matic relief and ulcer healing (Convissar and Massoumi-
Sourey, 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 spe-
cialist for detailed evaluation and suitable therapy
(Bagan, 1995). Individuals with RAS possibly related to
foodstuffs may occasionally benefit from dietary alter-
ations (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 vita-
min 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 hema-
tinic deficiencies (Pedersen et al., 1990a,b). The preven-
tive effects of this therapy may be due to the contempo-
rary 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 glu-
conate 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, benzy-
damine hydrochloride mouthwash (or lignocaine gel)
can produce transient relief of pain in severe RAS. In clin-
ical practice, both chlorhexidine and benzydamine
appear to be useful in the management of RAS. Topical
tetracyclines used alone or in combination with ampho-
tericin 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 evi-
dence 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
Oral Biol Med
311
TABLE 2 and there have been several studies of its efficacy.
Subjective improvement is possible, but rarely is
Some Reported Therapies of there objective clinical improvement, and the pos-
Recurrent Aphthous Stomatitis (RAS) sible adverse effects of nausea, hyperosmia, dys-
geusia, and agranulocytosis have discouraged its
Mouthrinses Chlorhexidine gluconate use (Lehner et al., 1976; De Meyer et al., 1977;
Benzydamine hydrochloride Drinnan and Fischman, 1978; Gier et al., 1978;
Carbenoxolone disodium Kaplan et al., 1978; Miller et al., 1978; Olsen and
Betadine Silverman, 1978). Recently, however, a group of
Topical corticosteroids Hydrocortisone hemisuccinate (pellets) Taiwanese patients was reported to have had signif-
Triamcinolone acetonide (in adhesive paste) icant clinical improvement (i.e., reduced pain, num-
Flucinonide (cream) ber, frequency, and duration of ulcers) with lev-
Betamethasone valerate (mouthrinse) amisole therapy (100-150 mg daily for 2-3 months).
Betamethasone- 1 7-benzoate (mouthrinse) However, these patients are perhaps unusual, since
Flumethasone pivolate (spray) they often had slightly reduced CD4+ and increased
Beclomethasone dipropionate (spray) CD8+ peripheral blood T-lymphocytes, the presence
Antibiotics Topical tetracyclines of anti-nuclear antibodies, and anti-basement
membrane antibodies (Sun et al., 1994). The fre-
Immunomodulators Levamisole quency of side-effects of levamisole was not report-
Transfer factor ed in this study.
Colchicine Transfer factor (Schulkind et al., 1984) and gam-
Gammaglobulins maglobulin therapy (Kaloyannides, 1971) have been
Azathioprine suggested to be beneficial, but more detailed stud-
Dapsone
Thalidomide ies are needed to confirm these preliminary obser-
Pentoxifylline vations.
Prednisolone Sodium cromoglycate lozenges may provide
Azelastine mild symptomatic relief (Dolby and Walker, 1975;
Alpha-2-inteferon Kowolik et al., 1978), but cromoglycate-containing
Cyclosporin toothpaste is not beneficial (Potts et al., 1984).
Amlexanox Carbenoxolone sodium mouthwash reduced the
5-amino salicyclic acid severity of RAS in one study (Poswillo and Partridge,
Others Systemic zinc sulphate 1984).
Monoamine-oxidase inhibitors Dapsone has been reported to reduce the oral
Sodium cromoglycate lesions in a few patients with RAS-like lesions, but
Deglycirrhizinated liquorice the clinical features of this group of patients were
Sucralphate poorly described (Handfield-Jones et al., 1985).
Etretinate Thalidomide may produce remission or reduction in
Low-enerqy laser 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,
absence of sodium lauryl sulphate from a dentifrice may 1992); however, this treatment is not without its
lessen the liability to RAS (Herlofson and Karkvoll, 1994). dangers. Thalidomide therapy should be considered
Topical corticosteroids remain the mainstay of RAS when patients have episodes of profound ulceration, and
treatment. A spectrum of different topical corticosteroids perhaps limited to persons with HIV-related ulceration,
can be used (Table 2): All can reduce symptoms, and nei- although thalidomide hypersensitivity can occur in HIV
ther hydrocortisone nor triamcinolone preparations disease (Williams et al., 1991). Aside from teratogenicity,
cause adrenal suppression, but ulcers still recur (Cooke thalidomide can give rise to several other serious (e.g.,
and Armitage, 1960; Zegarelli et al., 1960; Merchant et al., irreversible polyneuropathy) side-effects.
1978; Yeoman et al., 1978; Fisher, 1979; Pimlott and Possibly by virtue of its action on the microtubular
Walker, 1983; Scaglione et al., 1985). Perhaps, at best, top- function of polymorphonuclear leukocytes and interface
ical corticosteroids and chlorhexidine may reduce in adhesion molecule expression, colchicine may be of
painful symptoms but not the rate of recurrence of ulcers clinical benefit in Behget's disease. Colchicine was ini-
(Miles et al., 1993). tially reported to have a favorable outcome in small
Levamisole was proposed as a possible treatment groups of patients with RAS (Gatot and Tovi, 1984; Ruah
for RAS by virtue of its wide immunostimulatory effects, et al., 1988), and, in a more recent open study of 20

Rev Oral
Grit Rev Oral Biol Med
Biol Med 9(3):306-321

312 Crit 9(3):306-321 (1998)

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 diar-
rhea (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 lim-
ited 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 thera-
py; 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 improve-
ment may have been due to accompanying dietary mod-
ifications 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.
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 immunolog-
ically mediated cytotoxicity of epithelial cells. There
remains no safe therapy to ensure no recurrence of
9(3) 306-321 (1998)
9(3):306-321 Crit Rev
Grit
Rev Oral
ulcers; indeed, there have been few studies that conclu-
sively 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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