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A.Y Altenburg, MD; C.C. Zouboulis, MD

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Abstract and Introduction

Abstract

à e treatment of recurrent ap t ous stomatitis (RAS) still remains nonspecific and is based
primarily on empirical data. à e goals of t erapy include t e management of pain and functional
impairment by suppressing inflammatory responses, as well as reducing t e frequency of
recurrences or avoiding t e onset of new ap t ae. For common forms of RAS, standard topical
treatment options t at provide symptomatic relief include analgesics, anest etics, antiseptics,
anti-inflammatory agents, steroids, sucralfate, tetracycline suspension, and silver nitrate. Dietary
modifications may also support t erapeutic measures. In resistant cases of benign ap t osis or
ap t osis wit systemic involvement, appropriate systemic treatment can be selected from a
wide spectrum of immunomodulators t at include colc icine, prednisolone, cyclosporine A,
interferon-Į, tumor necrosis factor-Į antagonists, antimetabolites, and alkylating agents.

Introduction

Idiopat ic ap t ae are t e most frequently occurring inflammatory lesions of t e oral mucous

membrane. Nosologically, t e condition is clearly defined, but t e sores are often difficult to
differentiate from eterogeneously similar ap t oid ulcerations and mucosal erosions. Episodic
ap t ous attacks are c aracterized by painful lesions t at range from t e size of a pin ead up to
several centimeters. Fibrin covered ulcerations wit a yperemic alo are typically visible on t e
oral mucous membrane, but t ey rarely appear in t e genital region. Spontaneous ealing is
possible after many years.

Common simple ap t ae, wit 3-6 attacks per year, eal rapidly, are not very painful, and are
restricted to t e oral mucosa. à ey can be differentiated from complex ap t ae (less t an 5% of
ap t osis cases), w ic are recurrent, present wit few to unusual multiple lesions, are extremely
painful, eal slowly, and can also occur in t e genital region. Complex ap t osis requires t e
accurate diagnosis of a possible causal or associated condition, suc as anemia, cyclic
neutropenia, folic acid or iron deficiency, ulcus vulvae acutum, ap t ous-like ulcerations in HIV
positive patients, gastrointestinal diseases, suc as Cro n's disease and ulcerative colitis, and
Adamantiades-Be
et Disease (ABD). In ABD, w ic represents a malignant form of ap t osis,
t ere is an increase in bot t e frequency of occurrence and severity of lesions. à e diagnosis of
ABD is based on several clinical criteria sets, of w ic t e International Study Group Criteria are
t e most frequently used and t e New International Criteria are t e most recent.
àopical à
rapy

{ietary and General Measures

Certain foods s ould be avoided as t ey appear to trigger t e eruption of new ap t ae and

prolong t e course of t e lesions (e.g., foods t at are ard, acidic, salty, or spicy, as well as nuts,
c ocolate, citrus fruits, and alco olic or carbonated beverages). In addition, because surfactants
and detergents can cause irritation, dental care products containing sodium lauryl sulp ate s ould
be avoided.[4]

Ôocal Anesthetics

Pain relief can be attained using topical lidocaine 2% gel or spray, polidocanol ad esive dental
paste, or benzocaine lozenges. Available combination preparations include a pump spray wit
tetracaine and polidocanol, and a mout rinse solution t at uses benzocaine and cetylpyridinium
c loride as t e active ingredients. As well, anest etic-containing solutions, e.g., a viscous
lidocaine 2% solution, can be applied carefully on t e lesions.

Antiseptic and Anti-inflammatory Therapies

Mout was es wit ingredients known to mildly in ibit inflammation can be used, e.g.,
c amomile extract solution (Kamillosan®, MEDA P arma). Researc as s own t at t e use of
c lor exidine (CHX) mout rinses on RAS may be particularly elpful.[5] Ot er dosing forms of
CHX include dental gels or t roat sprays. àriclosan is a broad spectrum antibacterial agent t at
also ex ibits antiseptic, anti-inflammatory, and analgesic effects. Available formulations include
toot pastes and mout rinses. A randomized, double-blind study t at explored t e topical
application of diclofenac 3% in yaluronan 2.5% reported a significant reduction in pain.[6] For
adjuvant t erapy, dexpant enol, w ic acts as an umectant, emollient, and moisturizer, can be
used in different application forms and is available wit out prescription.

Ôocal Cauterization

Applications of ydrogen peroxide 0.5% solution, silver nitrate 1%-2% solution, or a silver
nitrate caustic stick represent several older t erapeutic met ods t at can reduce t e duration of
solitary ap t ae. Cauterizing c emical treatments must be administered by a dentist or p ysician
to avoid burning ealt y tissues.

Tetracycline

Localized t erapy wit tetracycline can effectively reduce t e duration and pain of oral
ap t ae.[7] ào avoid difficulties related to t e c emical stability of tetracycline w en it is
formulated in an aqueous solution, a prescription for compounding and preparation, as s own in
àable 1 , as been proposed.[8] Due to acidic pH values, patients may experience a brief burning
sensation, but contact sensitization as not been reported in t e context of intra-oral topical
tetracycline applications. Marked improvement as been described wit t e use of a dental paste
containing c lortetracycline 3%.[9]
uucralfate

àopical sucralfate is effective in treating RAS ulcerations w en administered at 5mL, 4

times/day. Sucralfate exerts a soot ing effect on lesions by ad ering to mucous membrane
tissues and forming a protective barrier on t e affected site. à is drug is commonly used to treat
peptic ulcers.

Topical uteroids

àopical steroids, suc as triamcinolone acetonide and prednisolone (2 times/day), are formulated
as oral pastes, and are commonly used in t e management of RAS. Additionally, t erapeutic
benefit can be derived from a mout was containing betamet asone. Of concern is t e fact t at
t e long-term use of steroids may predispose patients to developing local candidiasis.
Combination t erapy wit a topical anest etic during t e day and a steroid paste at nig t is
widely accepted as t e optimal treatment regimen. An intralesional injection of triamcinolone
(0.1-0.5mL per lesion) can be considered for painful single ap t ae. For t e treatment of genital
ap t ous ulcers, a combination of fluorinated steroids and antiseptics t at are formulated in a
cream base can be effective (e.g., dexamet asone 0.1% + c lor exidine 1% or flumetasone
0.02% + clioquinol 3%).

New Findings

Application of 5-aminosalicylic acid 5% cream (applying a small amount to cover t e ap t ae 3

times/day), or a toot paste containing amyloglucosidase and glucose oxidase can reduce pain
and lessen t e duration of oral ap t ae.[10] A topical prostaglandin E2 gel prevented t e
appearance of new ap t ae in a s ort-term study involving a small number of patients.[11]
According to t e experience of several patients, raw egg w ite may partially soften oral pain in
RAS. Interestingly, t e number of ap t ae and frequency of recurrence are reduced during
p ases of smoking compared wit p ases of abstinence; experimental data confirmed t e anti-
inflammatory effect of nicotine and bioc anin A on keratinocytes.[12,13] Also, a small study
s owed t e remission of ap t osis during t erapy wit c ewable nicotine tablets

uyst
ic à
rapy

Colchicine

Colc icine as been s own to reduce t e number and duration of lesions in up to 63% of patients
wit RAS.[15] àreatment over 6 weeks, followed by long-term (years) t erapy (1-2mg/day) is
recommended. However, relapse following treatment discontinuation is common. P ysicians
must ensure t at appropriate contraceptive met ods are practiced by patients before initiating
treatment. From our experience, combination t erapy wit colc icine and pentoxifylline,
benzat ine penicillin, immunosuppressants, or interferon-alp a (IFN-Į) is possible.
×entoxifylline

In uncontrolled studies, pentoxifylline (300mg, 1-3 times/day) was s own to be effective against
orogenital ap t ae. à e response rates in c ildren ranged between 36% and 63%.[16]

Corticosteroids

Systemic corticosteroids are used as rescue treatment in patients wit acute exacerbation and in
t ose w o inadequately responded to t erapy wit colc icine and pentoxifylline. Oral
prednisolone, or its equivalent, at 10-30mg/day for up to 1 mont can be administered during an
outbreak. From our experience, intravenous (IV) pulse t erapy at 100mg/day for 3 days results in
quick improvement for severe cases of RAS wit out t e side-effects t at are associated wit
long-term prednisolone use. Patient surveillance during t erapy is advisable.

{apsone

Dapsone (100mg/day) can be used for oral and genital ap t ae, owever, rapid relapses can
occur after discontinuation of treatment. Intermittent administration of ascorbic acid and t e
reduction of smoking are useful in averting ematologic side-effects.[17]

Thalidomide

Under standard (100-300mg/day) or low (50mg/day) dosing levels of t alidomide, a dose-

dependent effect against orogenital ulcerations emerges wit in 7-10 weeks following treatment.
Due to teratogenicity and ot er potentially severe side-effects, t erapy s ould be reserved for
exceptional cases, suc as in patients wit persistent perip eral neuropat y.

Antimetabolites (Azathioprine and Methotrexate)

Azat ioprine (Imuran®, GlaxoSmit Kline) at 50-150mg/day can reduce t e frequency and extent
of severe orogenital ap t osis in ABD, as demonstrated in placebo-controlled studies.[18] It is
contraindicated for women w o are pregnant or breastfeeding, and it is not recommended for use
in pediatric patients. During treatment, blood cell count and liver function s ould be monitored.
Met otrexate (7.5-20mg/week) as been proven to be effective in severe orogenital ap t osis.
W ile on t erapy, folic acid s ould be administered intermittently.

Cyclosporine A

Cyclosporine A, at a dosage of 3-6mg/kg, was s own to be effective in about 50% of ABD

patients wit respect to ap t osis.[19] However, abrupt wit drawal of t erapy may lead to a
rebound p enomenon. Due to t e potential for severe side-effects from t erapy, clinical and
serologic vigilance must be observed.
Interferon-alpha (IFN-Ƚ)

Recombinant IFN-Į preparations, IFN-Į 2a and 2b, ave not been tried for RAS; owever, t ey
ave successfully treated ABD. A study evaluating t e efficacy and safety of systemic IFN-Į in
patients wit ABD reported complete or partial remission of mucocutaneous lesions.[20]
Intermediate or ig doses of IFN-Į 2a (6-9 x 106 units, 3 times/week) seemed to be more
effective t an t e low dose (3 x 106 units 3 times/week). à e low dose may be recommended for
maintenance t erapy if t e treatment is s own to be effective wit in 1-4 mont s. Disease
recurrences after stopping IFN t erapy were common, but reinstatement of t erapy also elicited a
rapid response.

Biologics

Infliximab (Remicade®, Centocor) at 5mg/kg IV can be administered at different time intervals.

As early as several days following t e first dose, rapid ealing can occur, even in patients wit
refractory recurrent disease w o ex ibit bot oral and genital ulcers. It is possible t at relapses
may not occur wit in t e first 6 weeks of starting t erapy. Etanercept (Enbrel®, Amgen-Wyet )
at 25mg, twice weekly, given subcutaneously) appears to be effective on oral, but not on genital
ap t ae.[21]

Alkylating Agents

Monot erapy wit c lorambucil on orogenital ulcerations in ABD demonstrated a good response
w en administered at an initial dose of 0.1mg/kg, followed by a low maintenance dose of
2mg/day.[22] Orogenital ap t ae in ABD patients also improved w en using pulse t erapy
combined wit cyclop osp amide. àreatment wit alkylating agents s ould be limited
exclusively to patients wit severe forms of systemic ap t osis

ât
r uyst
ic à
rapi
s

In a study involving 13 patients, minocycline (100mg/day) was found to be effective in genital

ap t osis, but it was ineffective against oral ap t osis.[23] For t e immunomodulator, levamisole,
treatment at 150mg/day on 3 consecutive days/week during attacks as been occasionally
reported to be effective against orogenital ap t ae.[24,25] Subcutaneous testosterone, administered
once yearly, was s own to be effective in individual female patients w o developed ap t ae
premenses.[26] Also, oral contraceptives containing ig levels of estrogen can be used
successfully; improvement may be expected after 3-6 mont s.

Conclusion

Localized topical regimens are considered to be t e standard treatment in mild cases of RAS. In
more severe cases, topical t erapies are likewise very useful in reducing t e ealing time, but
t ey are often ineffective at prolonging disease-free intervals. For most patients wit RAS,
monot erapy wit colc icine, or in combination wit eit er pentoxifylline or t e s ort-term use
of prednisolone, is satisfactory. Furt ermore, ig ly efficacious drugs from a wide spectrum of
immunomodulatory agents are available. However, t ey s ould not be utilized wit out first
cautiously weig ing t e risks and t e benefits for eac patient.