Aphthous stomatitis

Published on 19/03/2015 by admin

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Aphthous stomatitis

Sandra A. Kopp and Justin J. Green

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Recurrent aphthous stomatitis (RAS) is the most common cause of oral ulceration. Aphthae, or ‘canker sores’, are characterized by the recurrence of one or more painful, shallow, sharply marginated ulcerations with a fibrinous base and surrounding erythematous halo on mobile, non-keratinized, oral mucosa. Three main types include minor, major, and herpetiform aphthae, which differ in size, duration, number, potential for scarring, and location of ulcerations. The etiology remains unclear; however, genetic predisposition, nutritional deficiencies, infections, hormonal changes, immunodeficiency, and environmental agents have been implicated. It is important to differentiate aphthae from other mucosal ulcerations, including herpes simples virus (HSV), other viral and bacterial infections (Epstein-Barr virus, cytomegalovirus, varicella zoster virus, coxsackie virus, syphilis, gonorrhea, tuberculosis), erythema multiforme, lichen planus, autoimmune bullous diseases (pemphigus vulgaris and cicatricial pemphigoid), contact dermatitis, chronic ulcerative stomatitis, and trauma before therapy is initiated. Malignancy and systemic vasculitis must also be considered in lesions that are not self-resolving.

Management strategy

The therapeutic approach to aphthae is dependent on the frequency of recurrence, duration, and severity of symptoms. In addition, underlying hematologic abnormalities, nutritional deficiencies, and medications should be considered as causative agents, as well as many systemic disorders such as inflammatory bowel disease, Crohn disease, Behçet disease, mouth and genital ulcers with inflamed cartilage syndrome (MAGIC syndrome), cyclic neutropenia, Sweet syndrome, reactive arthritis, HIV infection, and auto-inflammatory syndromes such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA syndrome). Stress is also thought to play a role in exacerbation of the disease. Unfortunately, because there is no curative treatment to date, the emphasis of treatment is on measures that may afford symptomatic relief and decrease occurrence, without significant adverse effects.

Topical corticosteroids are the mainstay of therapy. For milder disease, corticosteroids such as fluocinonide can be used. More potent corticosteroids such as clobetasol or halobetasol are appropriate for more severe episodes. Most practitioners suggest the use of topical therapy after meals. These can be applied in equal parts with an occlusive dressing such as Orabase for better adherence. Drug delivery can be enhanced by cotton-tip applications for 30 seconds and avoidance of eating and drinking for 30 minutes after application. Initial concentrations of 3–10 mg/mL of intralesional triamcinolone acetonide are helpful for major aphthae. Repeat injections over 2- to 4-week intervals are advised. Dexamethasone elixir 0.5 mg/5 mL three times daily used as a mouthwash or beclomethasone dipropionate aerosol spray can target ulcers on the soft palate or oropharynx. Elixirs can be combined with sucralfate or kaopectate to improve adhesion to ulceration. When used for less than 3 weeks, systemic absorption and hypothalamic-pituitary-adrenal axis suppression are unlikely.

RAS that elicits severe pain may require intermittent systemic corticosteroid therapy. Prednisone 1 mg/kg (40–60 mg) daily can be given with a 2-week taper or as ‘burst therapy’ for shorter periods. Concomitant therapy with topical corticosteroids may be helpful. Colchicine 0.6 mg two to three times daily and thalidomide 50–200 mg daily are the most effective steroid-sparing agents. Thalidomide is the only FDA-approved treatment for major aphthae in HIV-positive patients. Dapsone 100 mg daily, pentoxifylline 400 mg three times daily, and clofazimine 100 mg daily may also lead to suppression of aphthae. Anti-tumor necrosis factor (TNF-α) therapies may be effective in recalcitrant cases. Those patients who require suppressive therapy but cannot tolerate the side effects of systemic agents can try medications such as topical cyclosporine rinse 500 mg/5 mL three times daily, or interferonα2a 1200 IU daily as a 1-minute rinse and swallow.

Application of amlexanox 5% paste four times daily has been shown to reduce aphthous ulcer healing time, and the application of amlexanox OraDisc four times daily to prodromal areas of the buccal mucosa has shown promise in the prevention of recurrent minor aphthous ulceration.

Topical anesthetics such as lidocaine gel or spray, dyclonine, diphenhydramine (12.5/5 mL) or benzocaine are helpful for pain reduction. Patients must avoid desensitization of the entire oral vault, which may lead to self-induced trauma. A compounded anesthetic mouthwash (aluminum hydroxide–magnesium hydroxide, diphenhydramine, and lidocaine) has better mucosal adherence. Systemic non-steroidal anti-inflammatory drugs (NSAIDs), sucralfate suspension, 0.2% chlorhexidine gluconate mouthwash, triclosan, or tetracycline suspension (250 mg/5 mL) may provide pain relief and reduce healing time, although these are less effective than potent topical corticosteroids. Bioadhesives such as carboxymethylcellulose provide a protective film and may reduce healing time.

Trigger avoidance can be useful. Predisposing factors include food (nuts, chocolate, tomatoes, citrus fruits, and spices), alcohol and carbonated beverages, trauma, menstruation, and stress. A food diary may be of value in identifying an offending agent. Certain medications, such as β-blockers, NSAIDs, and antioxidants, as well as sensitivity to sodium lauryl sulfate found in toothpaste, may contribute to the recurrence of aphthae. Hormonal therapy may alleviate RAS associated with menstruation. Reassurance of the benignity of this condition is paramount, and relaxation techniques or biofeedback can be discussed if stress is found to be a significant trigger.

Specific investigations

First-line therapies

imageVitamin and mineral deficiency replacement A
imageTopical corticosteroids A
imageAmlexanox 5% paste A
imageIntralesional corticosteroids B
imageTetracycline suspension A
imageAntimicrobial mouth rinses A
imageSucralfate A
imageHydroxypropyl cellulose/carboxymethylcellulose C

An evaluation of the efficacy and safety of amlexanox oral adhesive tablets in the treatment of recurrent minor aphthous ulceration in a Chinese cohort: a randomized, double- blind, vehicle-controlled, unparallel multicenter clinical trial.

Liu J, Zeng X, Chen Q, Cai Y, Chen F, Wang Y, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 475–81.

Patients (n = 212) with oral aphthae were enrolled in a randomized, double-blind, vehicle-controlled, clinical trial. Amlexanox 5% adhesive tablets or placebo was applied four times daily to the ulcer. Patients were evaluated at day 4 and day 6. The reduction in ulcer pain and lesion size was statistically significant at day 4, and reduction of all parameters, including erythema and exudation, was statistically significant at day 6. No systemic side effects were reported.

Sucralfate suspension as a treatment of recurrent aphthous stomatitis.

Rattan J, Schneider M, Arber N, Gorsky M, Dayan D. J Intern Med 1994; 236: 341–3.

Sucralfate applied four times daily to ulcers was found to be superior to antacid (aluminum hydroxide and magnesium hydroxide) and placebo with regard to duration of pain, reduction in healing time, response to first treatment, and duration of remission. The 2-year prospective, randomized, double-blind, placebo-controlled, crossover trial included 21 patients unresponsive to conventional therapy.

A randomized, placebo-controlled, double-blind study of sucralfate applied four times daily to oral and genital ulcerations of Behçet disease resulted in reduced frequency, healing time and pain in oral ulcerations, and reduced healing time and pain in genital ulcerations.

Second-line therapies

imageOral corticosteroids A
imageColchicine A
imageThalidomide A
imageDapsone A
imageZinc sulfate A

Third-line therapies

imagePentoxifylline A
imageClofazimine B
imageAscorbate C
imageVitamin B12 A
imageTopical cyclosporine D
imageOral interferon-α2a C
imageEtretinate E
imageCO2 laser D
imagePenicillin G potassium troches A
imageEtanercept E
imageAdalimumab E
imageSilver nitrate B
imageFumaric esters E
imageMontelukast A

A randomized, double-blind, placebo-controlled trial of pentoxifylline for the treatment of recurrent aphthous stomatitis.

Thornhill MH, Baccaglini L, Theaker E, Pemberton MN. Arch Dermatol 2007; 143: 463–70.

Twenty-six patients were randomized to pentoxifylline 400 mg three times daily or placebo. Patients taking pentoxifylline had less pain, smaller ulcers, fewer ulcers, and more ulcer-free days, but this was not statistically significant. However, smaller median ulcer size in the treatment group was statistically significant. Adverse events were common and included dizziness, headaches, gastrointestinal symptoms, and fatigue.

According to the study, patients taking the active drug stated that if it was shown to be effective in the treatment of aphthous ulcers, they would not want to use it because of the side effects.

Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy.

Femiano F, Buonaiuto C, Gombos F, Lanza A, Cirillo N. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 402–7.

In this double-blind, randomized placebo-controlled trial of 60 patients with minor RAS patients were split equally into treatment groups of prednisone 25 mg daily tapered over 2 months, 10 mg montelukast daily for 1 month, then every other day for the second month, and cellulose (placebo). Both interventions significantly reduced number of lesions and pain relief compared to placebo; however, prednisone was more effective than montelukast. This suggests montelukast may be a safer alternative to prednisone.

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