A. Altenburg, MD; C. C. Zouboulis, MD
Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany
The treatment of recurrent aphthous stomatitis (RAS) still remains nonspecific and is based primarily on empirical data. The goals of therapy include the management of pain and functional impairment by suppressing inflammatory responses, as well as reducing the frequency of recurrences or avoiding the onset of new aphthae. For common forms of RAS, standard topical treatment options that provide symptomatic relief include analgesics, anesthetics, antiseptics, anti-inflammatory agents, steroids, sucralfate, tetracycline suspension, and silver nitrate. Dietary modifications may also support therapeutic measures. In resistant cases of benign aphthosis or aphthosis with systemic involvement, appropriate systemic treatment can be selected from a wide spectrum of immunomodulators that include colchicine, prednisolone, cyclosporine A, interferon-á, tumor necrosis factor-a antagonists, antimetabolites, and alkylating agents.
Recurrent aphthous stomatitis, RAS
Idiopathic aphthae are the most frequently occurring inflammatory lesions of the oral mucous membrane. Nosologically, the condition is clearly defined, but the sores are often difficult to differentiate from heterogeneously similar aphthoid ulcerations and mucosal erosions. Episodic aphthous attacks are characterized by painful lesions that range from the size of a pinhead up to several centimeters. Fibrin covered ulcerations with a hyperemic halo are typically visible on the oral mucous membrane, but they rarely appear in the genital region. Spontaneous healing is possible after many years.
Common simple aphthae, with 3-6 attacks per year, heal rapidly, are not very painful, and are restricted to the oral mucosa. They can be differentiated from complex aphthae (less than 5% of aphthosis cases), which are recurrent, present with few to unusual multiple lesions, are extremely painful, heal slowly, and can also occur in the genital region.1 Complex aphthosis requires the accurate diagnosis of a possible causal or associated condition, such as anemia, cyclic neutropenia, folic acid or iron deficiency, ulcus vulvae acutum, aphthous-like ulcerations in HIV positive patients, gastrointestinal diseases, such as Crohn’s disease and ulcerative colitis, and Adamantiades-Behçet Disease (ABD). In ABD, which represents a malignant form of aphthosis, there is an increase in both the frequency of occurrence and severity of lesions. The diagnosis of ABD is based on several clinical criteria sets, of which the International Study Group Criteria2 are the most frequently used and the New International Criteria are the most recent.3
Dietary and General Measures
Certain foods should be avoided as they appear to trigger the eruption of new aphthae and prolong the course of the lesions (e.g., foods that are hard, acidic, salty, or spicy, as well as nuts, chocolate, citrus fruits, and alcoholic or carbonated beverages). In addition, because surfactants and detergents can cause irritation, dental care products containing sodium lauryl sulphate should be avoided.4
Pain relief can be attained using topical lidocaine 2% gel or spray, polidocanol adhesive dental paste, or benzocaine lozenges. Available combination preparations include a pump spray with tetracaine and polidocanol, and a mouth rinse solution that uses benzocaine and cetylpyridinium chloride as the active ingredients. As well, anesthetic-containing solutions, e.g., a viscous lidocaine 2% solution, can be applied carefully on the lesions.
Antiseptic and Anti-inflammatory Therapies
Mouth washes with ingredients known to mildly inhibit inflammation can be used, e.g., chamomile extract solution (Kamillosan®, MEDA Pharma). Research has shown that the use of chlorhexidine (CHX) mouth rinses on RAS may be particularly helpful.5 Other dosing forms of CHX include dental gels or throat sprays. Triclosan is a broad spectrum antibacterial agent that also exhibits antiseptic, anti-inflammatory, and analgesic effects. Available formulations include toothpastes and mouthrinses. A randomized, double-blind study that explored the topical application of diclofenac 3% in hyaluronan 2.5% reported a significant reduction in pain.6 For adjuvant therapy, dexpanthenol, which acts as an humectant, emollient, and moisturizer, can be used in different application forms and is available without prescription.
Applications of hydrogen peroxide 0.5% solution, silver nitrate 1%-2% solution, or a silver nitrate caustic stick represent several older therapeutic methods that can reduce the duration of solitary aphthae. Cauterizing chemical treatments must be administered by a dentist or physician to avoid burning healthy tissues.
Localized therapy with tetracycline can effectively reduce the duration and pain of oral aphthae.7 To avoid difficulties related to the chemical stability of tetracycline when it is formulated in an aqueous solution, a prescription for compounding and preparation, as shown in Table 1, has been proposed.8 Due to acidic pH values, patients may experience a brief burning sensation, but contact sensitization has not been reported in the context of intra-oral topical tetracycline applications. Marked improvement has been described with the use of a dental paste containing chlortetracycline 3%.9
Topical sucralfate is effective in treating RAS ulcerations when administered at 5mL, 4 times/day. Sucralfate exerts a soothing effect on lesions by adhering to mucous membrane tissues and forming a protective barrier on the affected site. This drug is commonly used to treat peptic ulcers.
|Tetracycline Mouth Wash 5%|
Expiration: after 6 months
|Instructions for Use:|
Shake before each use. Apply 5mL of the suspension solution for 5 minutes in the mouth cavity up to 5 times daily. For intensive therapy, the same dose should be held for 10-15 minutes in the mouth.
|Box 1: Preparation and use of chemically stable tetracycline suspension. Adapted from the New German Pharmacopoeia for compounded medication: Rezepturhinweise: Tetracyclinhydrochlorid in zahnärztlichen Anwendungen und Mundspülungen.8|
Topical steroids, such as triamcinolone acetonide and prednisolone (2 times/day), are formulated as oral pastes, and are commonly used in the management of RAS. Additionally, therapeutic benefit can be derived from a mouthwash containing betamethasone. Of concern is the fact that the long-term use of steroids may predispose patients to developing local candidiasis. Combination therapy with a topical anesthetic during the day and a steroid paste at night is widely accepted as the optimal treatment regimen. An intralesional injection of triamcinolone (0.1-0.5mL per lesion) can be considered for painful single aphthae. For the treatment of genital aphthous ulcers, a combination of fluorinated steroids and antiseptics that are formulated in a cream base can be effective (e.g., dexamethasone 0.1% + chlorhexidine 1% or flumetasone 0.02% + clioquinol 3%).
Application of 5-aminosalicylic acid 5% cream (applying a small amount to cover the aphthae 3 times/day), or a toothpaste containing amyloglucosidase and glucose oxidase can reduce pain and lessen the duration of oral aphthae.10 A topical prostaglandin E2 gel prevented the appearance of new aphthae in a short-term study involving a small number of patients.11 According to the experience of several patients, raw egg white may partially soften oral pain in RAS. Interestingly, the number of aphthae and frequency of recurrence are reduced during phases of smoking compared with phases of abstinence; experimental data confirmed the anti-inflammatory effect of nicotine and biochanin A on keratinocytes.12,13 Also, a small study showed the remission of aphthosis during therapy with chewable nicotine tablets.14
Colchicine has been shown to reduce the number and duration of lesions in up to 63% of patients with RAS.15 Treatment over 6 weeks, followed by long-term (years) therapy (1-2mg/day) is recommended. However, relapse following treatment discontinuation is common. Physicians must ensure that appropriate contraceptive methods are practiced by patients before initiating treatment. From our experience, combination therapy with colchicine and pentoxifylline, benzathine penicillin, immunosuppressants, or interferon-alpha (IFN-á) is possible.
In uncontrolled studies, pentoxifylline (300mg, 1-3 times/day) was shown to be effective against orogenital aphthae. The response rates in children ranged between 36% and 63%.16
Systemic corticosteroids are used as rescue treatment in
patients with acute exacerbation and in those who
inadequately responded to therapy with colchicine and pentoxifylline. Oral prednisolone, or its equivalent, at 10-30mg/day for up to 1 month can be administered during an outbreak. From our experience, intravenous (IV) pulse therapy at 100mg/day for 3 days results in quick improvement for severe cases of RAS without the side-effects that are associated with long-term prednisolone use. Patient surveillance during therapy is advisable.
Dapsone (100mg/day) can be used for oral and genital
aphthae, however, rapid relapses can occur after discontinuation of treatment. Intermittent administration of ascorbic acid and the reduction of smoking are useful in averting hematologic side-effects.17
Under standard (100-300mg/day) or low (50mg/day) dosing levels of thalidomide, a dose-dependent effect against orogenital ulcerations emerges within 7-10 weeks following treatment. Due to teratogenicity and other potentially severe side-effects, therapy should be reserved for exceptional cases, such as in patients with persistent peripheral neuropathy.
Antimetabolites (Azathioprine and Methotrexate)
Azathioprine (Imuran®, GlaxoSmithKline) at 50-150mg/day
can reduce the frequency and extent of severe orogenital aphthosis in ABD, as demonstrated in placebo-controlled studies.18 It is contraindicated for women who are pregnant or breastfeeding, and it is not recommended for use in pediatric patients. During treatment, blood cell count and liver function should be monitored. Methotrexate (7.5-20mg/week) has been proven to be effective in severe orogenital aphthosis. While on therapy, folic acid should be administered intermittently.
Cyclosporine A, at a dosage of 3-6mg/kg, was shown to be effective in about 50% of ABD patients with respect to aphthosis.19 However, abrupt withdrawal of therapy may lead to a rebound phenomenon. Due to the potential for severe side-effects from therapy, clinical and serologic vigilance must be observed.
Recombinant IFN-á preparations, IFN-á 2a and 2b, have not been tried for RAS; however, they have successfully treated ABD. A study evaluating the efficacy and safety of systemic IFN-á in patients with ABD reported complete or partial remission of mucocutaneous lesions.20 Intermediate or high doses of IFN-á 2a (6-9 x 106 units, 3 times/week) seemed to be more effective than the low dose (3 x 106 units 3 times/week). The low dose may be recommended for maintenance therapy if the treatment is shown to be effective within 1-4 months. Disease recurrences after stopping IFN therapy were common, but reinstatement of therapy also elicited a rapid response.
Infliximab (Remicade®, Centocor) at 5mg/kg IV can be administered at different time intervals. As early as several days following the first dose, rapid healing can occur, even in patients with refractory recurrent disease who exhibit both oral and genital ulcers. It is possible that relapses may not occur within the first 6 weeks of starting therapy. Etanercept (Enbrel®, Amgen-Wyeth) at 25mg, twice weekly, given subcutaneously) appears to be effective on oral, but not on genital aphthae.21
Monotherapy with chlorambucil on orogenital ulcerations in ABD demonstrated a good response when administered at an initial dose of 0.1mg/kg, followed by a low maintenance dose of 2mg/day.22 Orogenital aphthae in ABD patients also improved when using pulse therapy combined with cyclophosphamide. Treatment with alkylating agents should be limited exclusively to patients with severe forms of systemic aphthosis.22
Other Systemic Therapies
In a study involving 13 patients, minocycline (100mg/day) was found to be effective in genital aphthosis, but it was ineffective against oral aphthosis.23 For the immunomodulator, levamisole, treatment at 150mg/day on
3 consecutive days/week during attacks has been occasionally reported to be effective against orogenital aphthae.24,25 Subcutaneous testosterone, administered once yearly, was shown to be effective in individual female patients who developed aphthae premenses.26 Also, oral contraceptives containing high levels of estrogen can be used successfully; improvement may be expected after 3-6 months.
Localized topical regimens are considered to be the standard treatment in mild cases of RAS. In more severe cases, topical therapies are likewise very useful in reducing the healing time, but they are often ineffective at prolonging disease-free intervals. For most patients with RAS, monotherapy with colchicine, or in combination with either pentoxifylline or the short-term use of prednisolone, is satisfactory. Furthermore, highly efficacious drugs from a wide spectrum of immunomodulatory agents are available. However, they should not be utilized without first cautiously weighing the risks and the benefits for each patient.
- Rogers RS 3rd. Complex aphthosis. Adv Exp Med Biol 528:311-6 (2003).
- Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet 335(8697):1078-80 (1990 May).
- Zouboulis CC. Adamantiades-Behçet disease. In: Wolff K, Goldsmith LA, Katz SI, et al. (Eds.). Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York:McGraw-Hill. pp. 1620-6 (2008).
- Zouboulis CC. Adamantiades-Behçet’s disease. In: Katsambas AD, Lotti TM (Eds.). European Handbook of Dermatological Treatments, 2nd edition. Berlin:Springer. pp. 16-26 (2003).
- Piccione N. Use of chlorhexidine in the therapy of some stomatological diseases. Minerva Stomatol 28(3):209-14 (1979 Jul-Sep).
- Saxen MA, Ambrosius WT, Rehemtula KF, et al. Sustained relief of oral aphthous ulcer pain from topical diclofenac in hyaluronan: a randomized, double-blind clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84(4):356-61 (1997 Oct).
- Graykowski EA, Kingman A. Double-blind trial of tetracycline in recurrent aphthous ulceration. J Oral Pathol 7(6):376-82 (1978).
- New German Pharmacopoeia for compounded medication: Rezepturhinweise: Tetracyclinhydrochlorid in zahnärztlichen Anwendungen und Mundspülungen. Govi-Verlag Pharmazeutischer Verlag Eschborn (2005).
- Henricsson V, Axell T. Treatment of recurrent aphthous ulcers with Aureomycin mouth rinse of Zendium dendrifice. Acta Odontol Scand 43(1):47-52 (1985 Mar).
- Collier PM, Neill SM, Copeman PW. Topical 5-aminosalicylic acid: a treatment for aphthous ulcers. Br J Dermatol 126(2):185-8 (1992 Feb).
- Taylor LJ, Walker DM, Bagg J. A clinical trial of prostaglandin E2 in recurrent aphthous ulceration. Br Dent J 175(4):125-9 (1993 Aug).
- Ussher M, West R, Steptoe A, et al. Increase in common cold symptoms and mouth ulcers following smoking cessation. Tob Control 12(1):86-8 (2003 Mar)
- Kalayciyan A, Orawa H, Fimmel S, et al. Nicotine and biochanin A, but not cigarette smoke, induce anti-inflammatory effects on keratinocytes and endothelial cells in patients with Behçet’s disease. J Invest Dermatol 127(1):81-9 (2007 Jan)
- Bittoun R. Recurrent aphthous ulcers and nicotine. Med J Aust 154(7):471-2 (1991 Aug).
- Fontes V, Machet L, Huttenberger B, et al. Recurrent aphhous stomatitis: treatment with colchicine. An open trial of 54 cases. Ann Dermatol Venereol 129(12):1365-9 (2002 Dec).
- Garcia Callejo FJ, Orts Alborch MH, Molrant Ventura A, et al. Recurrent aphthous stomatitis and clinical response to pentoxifylline. Acta Otorrinolaringol Esp 50(8):671-3 (1999 Nov-Dec).
- Altenburg A, Abdel-Naser MB, Seeber H, et al. Practical aspects of management of recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol 21(8):1019-26 (2007 Sep).
- Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behçet’s syndrome. N Engl J Med 322(5):281-5 (1990 Feb).
- Zouboulis CC. Morbus Adamantiades-Behçet. In: Mrowietz U (Ed.). Ciclosporin in der Dermatologie. Stuttgart: Thieme pp. 38-51 (2003).
- Zouboulis CC, Orfanos CE. Treatment of Adamantiades- Behçet’s disease with systemic interferon alfa. Arch Dermatol 134(8):1010-6 (1998 Aug).
- Sfikakis PP, Markomichelakis N, Alpsoy E, et al. Anti-TNF 21. therapy in the management of Behçet’s disease: Review and basis for recommendations. Rheumatology (Oxford) 46(5):736-41 (2007 May).
- Altenburg A, Papoutsis N, Orawa H, et al. Epidemiology and clinical manifestations of Adamantiades-Behçet disease in Germany – current pathogenetic concepts and therapeutic possibilities. J Dtsch Dermatol Ges 4(1):49-64 (2006 Jan).
- Oyama N, Inoue M, Matsui T, et al. Minocycline effects on the clinical symptoms in correlation with cytokines produced by peripheral blood mononuclear cells stimulated with streptococcal antigens in Behcet’s disease. In: Hamza M (Ed). Behçet’s Disease. Tunis:Publications Adhoua. pp. 481-6 (1997).
- Olson JA, Silverman S Jr. Double-blind study of levamisole therapy in recurrent aphthous stomatitis. J Oral Pathol 7(6):393-9 (1978).
- Orfanos CE, Garbe C (Eds.). Therapie der Hautkrankheiten, 2nd ed. Berlin:Springer. pp. 577-83 (2002).
- Misra R, Anderson DC. Treatment of recurrent premenstrual orogenital aphthae with implants of low doses of testosterone. BMJ 299(6703):834 (1989 Sep).