Recurrent Aphthous Stomatitis

[tirath]

Recurrent aphthous stomatitis (RAS) is a disorder characterized by recurring ulcers in the oral mucosa in patients with no other signs of disease. RAS appears to represent several pathological states with similar clinical manifestations, including immunologic disorders, hematologic deficiencies, and allergic or psychological abnormalities. RAS affects 20% of the general population and is classified according to clinical characteristics as minor ulcers, major ulcers and herpetiform ulcers.
Minor ulcers, which comprise more than 80% of RAS cases, are less than 1 cm in diameter and heal without scars. Major ulcers are over 1 cm in diameter, take longer to heal and often scar on healing. Herpetiform ulcers are considered a distinct clinical entity that manifests as recurrent crops of dozens of small ulcers throughout the oral mucosa.

The primary known etiology for RAS is heredity. Studies indicate that there is an increased susceptibility to RAS among children of RAS-positive parents.1 Other associated factors include local trauma and nutritional disorders, such as deficiencies in vitamin B12, folic acid and serum iron.2 Patients with RAS may have an abnormal immunologic response to their own oral mucosal tissue. It was once assumed that RAS was a form of recurrent herpes simplex virus (HSV) infection; however, studies have shown that HSV cannot be cultured from RAS lesions, and HSV antigens are usually not detectable in these lesions.3 It is also well documented that cessation of smoking increases the frequency and severity of RAS.4

The first episode of RAS most frequently begins during the second decade of life, and in individual patients may be precipitated by minor trauma or menstruation. The lesions are confined to the oral mucosa and begin with prodromal burning sensation any time from 2 to 48 hours before an ulcer appears. For minor RAS, ulcerations are well-circumscribed, round, sometimes covered by a yellow-gray pseudomembrane and surrounded by an erythematous halo. Their duration is about one to two weeks. Ulcerations heal without scarring, and are usually confined to non-keratinized oral mucosa.

Major RAS ulcers are greater than 1 cm in diameter, well-circumscribed and round, with indurated margins. The lesions heal slowly, and leave scars that may result in decreased mobility of the uvula and tongue and destruction of portions of the oral mucosa.

The herpetiform is the least common type of RAS and is usually found in clusters of dozens of lesions that heal without scarring.

RAS is the most common cause of recurring oral ulcers. It is essentially diagnosed by exclusion of other diseases. The history should emphasize symptoms of blood dyscrasias, connective tissue disease such as lupus, gastrointestinal complaints, and associated skin, eye, genital or rectal lesions. Laboratory investigation is indicated in patients with major RAS, when RAS is worsening, when RAS begins after age 25, or when there are associated signs and symptoms. Laboratory tests may include a complete blood count, iron/folate/Vitamin B12 levels, and an anti-nuclear antibody titer to screen for systemic illnesses.

2009 Study shows efficacy of Vit B 12:
A team of physicians at Ben-Gurion University of the Negev has discovered that a nightly dose of vitamin B12 is a simple, effective, and low-risk therapy to prevent recurrent aphthous stomatitis (RAS), better known as “canker sores. The researchers tested the effect of vitamin B12 on 58 randomly selected RAS patients who received either a dose of 1,000 mcg of B12 by mouth at bedtime or a placebo and then were tested monthly for 6 months. Approximately three quarters (74%) of the patients of the treated group and only a third (32%) of the control group achieved remission at the end of the study. The treated patients expressed greater comfort, reported less pain, fewer ulcers, and shorter outbreaks during the 6 months, while among the control group the average pain level decreased during the first half of the period but increased during the second half.

Topical Therapy

Medication prescribed to treat RAS should relate to the severity of the disease. In mild cases, with two or three small lesions, use of topical coating agents such as Orabase or Zilactin is appropriate. Pain relief can be obtained with the use of a topical anesthetic agent, such as benzocaine in Orabase.

In more severe cases, the use of a high potency topical steroid preparation, such as fluocinonide, betamethasone or clobetasol, placed directly on the lesion shortens healing time and the size of the ulcer.

Other topical preparations that have been shown to decrease the healing time of minor RAS lesions include amlexanox paste and topical tetracycline.

Systemic Therapy

For patients with major aphthae or severe cases of multiple minor aphthae who do not respond to topical therapy the use of systemic therapy should be considered. Pentoxifylline (PTX) can be used systemically to control ulcers that do not respond to topical medication. PTX is a methylxanthine compound related to caffeine and theophylline. It is used chiefly to treat peripheral vascular disease because it increases the flexibility of red blood cells and enhances blood flow to ischemic limbs. It also increases neutrophil chemotaxis and motility, and decreases the clumping of neutrophils. And it has anti-inflammatory properties by decreasing the production of cytokines and by decreasing the effect of the cytokines on leukocytes. Several reports suggest that PTX is effective in preventing aphthous ulcers.

Wahba-Yahav reported that patients with RAS who did not respond to topical steroid showed significant success with PTX therapy.5 Another study demonstrated the efficacy of PTX in treating patients with recurrent ulcers with no significant side effects and supported the use of PTX in refractory cases of major RAS.6

Another systemic medication that has been used with success in treating ulcers that are unresponsive to topical medication is colchicine. Colchicine is an anti-inflammatory agent that limits leukocyte activity by binding to tubulin, a cellular microtubular protein, and, therefore, inhibiting protein polymerization.7 It also inhibits lysosomal degranulation and increases the level of cyclic AMP, which decreases both the chemotactic and the phagocytic activity of neutrophils.8

Colchicine is also shown to inhibit cell-mediated immune responses.9 Clinically, colchicine has been used for acute gouty arthritis, psoriasis, dermatitis herpetiformis, leukocytoclastic vasculitis and urticarial vasculitis. There have been published reports that show the benefit of using colchicine in treating major RAS and preventing further recurrences of ulcers.10,11

Reported adverse effects of colchicine include myopathy, peripheral neuritis and gastrointestinal toxicity, including nausea, vomiting, diarrhea and abdominal pain. It has also been known to induce blood dyscrasias, and is considered a potent teratogen that should be avoided during pregnancy.

Thalidomide has been shown to reduce the incidence and severity of RAS. The drug was first marketed in Europe in the 1950s as a non-addictive sedative agent, but it was withdrawn from the market nearly 40 years ago after the discovery of its teratogenicity.

Thalidomide has returned to the medical arena, with the Food and Drug Administration approving it as a treatment for erythema nodosum leprosum in July 1998. It suppresses monocytic synthesis of TNF-alpha and accelerates TNF-alpha messenger ribonucleic acid transcript degradation.12 Thalidomide also displays anti-inflammatory characteristics as well as antiangiogenic properties. Several reports have been published reporting positive results when treating severe recurrent ulcers with thalidomide.13,14

Thalidomide has many serious adverse effects, including teratogenicity, peripheral neuropathy, and other minor adverse effects, such as dizziness and somnolence. To minimize the risk of teratogenicity, the System for Thalidomide Education Prescribing Safety (S.T.E.P.S.) program has been instituted to control and monitor the use of thalidomide. Under the program, clinicians are required to provide comprehensive counseling to patients and to complete surveys. Patients who receive thalidomide must also comply with several regulations, including completing consent forms when receiving thalidomide, agreeing to two simultaneous forms of contraception and presenting a negative pregnancy test during each monthly follow-up appointment.

Careful consideration must be given when thalidomide therapy is warranted for patients with major RAS that does not respond to other treatment. The clinician must carefully weigh both the benefits and risks of using thalidomide, reserving it for the most resistant and severe cases of major RAS. Only clinicians knowledgeable in its potential side effects should prescribe thalidomide.2

        

[divyanshee]

Cryosurgery and Laser therapies can also be used to treat aphthous ulcers

        

[sushantpatel_doc]

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.

Key Words: 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

Topical TherapyDietary 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

Local Anesthetics
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.

Local Cauterization
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.

Tetracycline
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

Sucralfate
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%
Composition:
Tetracycline hydrochloride 5.0gm
Methyl-4-hydroxybenzoate 0.1gm
Sodium citrate 6.5gm
Propylene glycol 0.6gm
Sorbitol solution 70% (noncrystalizable) 65.5gm
Traganth 0.5gm
Purified water to 118.2gm

Preparation:
Dissolve 4-methyl hydroxybenzoate in propylene glycol.
Dissolve sodium citrate in purified water.
Mix dry traganth and tetracycline hydrochloride. Mix with an equal part of sorbitol solution and form a gel with the rest of the sorbitol solution.
Add the sodium citrate solution in portions and stir.
Add the propylene glycol together with the dissolved methyl-4-hydroxybenzoate and stir.
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
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%).

New Findings
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

Systemic TherapyColchicine
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.

Pentoxifylline
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

Corticosteroids
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
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

Thalidomide
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
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.

Interferon-alpha (IFN-á)
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.

Biologics
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

Alkylating Agents
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 TherapiesIn 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.

ConclusionLocalized 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.

        

[Anonymous]

I think healing depends upon the patients diet, immunity & effect of any drug.
What about stomatitis that occurs due to cheek biting does that have any treatment coz that can cause pain in the buccal mucosa as well as the tooth?
Correcting tooth occlusion in a older age & increasing the sensitivity is not possible.
Any suggestions plz?

        

[Anonymous]

there is also a psychological factor in any apthous ulcers and stomatitis

        

[divyanshee]

Removal of the etiology is the only and best treatment option

        

[Anonymous]

divyanshee wrote:

Removal of the etiology is the only and best treatment option

yes but if the etilogy is psychological than removing it is a big problem. a dentist cannot offer psychotherapy.

veeren

        

[Anonymous]

I think removing the etiology that is stress or psycology is vry dificult. if that is not the etiology then what other remedy?

        

[tirath]

psychological consultant required

        

[Anonymous]

In mild cases—topical application of protective emolient base like dentogel, orasep, gummex
Topical tetracycline mouthwashes
Topical corticosteroids like triamcinolone
Vit B12
Chlorhexidine mouthwashes

In severe cases—Fluocinolone gel,clobatasol cream or beclamethasone spray
Injection corticosteroid in lesion
Chlortetracycline mouthwash
Dapsone or thalidomide
Surgery

        

[Anonymous]

Another thing to remeber is that if these treatments fail one must not forget that an important differential diagnosis is HERPES SIMPLEX that also elicits ulcers that are recurrent

        

[sushantpatel_doc]

DIFFERENTIAL DIAGNOSIS OF RAS is HSV infection

TREATMENT for this includes:

Topical anaesthetics such as lignocaine, dyclonine hydrochloride or benzocain hydrochloride
Topical anti-infectives to prevent secondary infections
Diphenylhydramine hydrochloride i.e benadryl solution with equal amounts of milk of magnesia’
Fluids in diet foer hydration
Oral hygiene maintenance

SPECIFICALLY::

Acyclovir1000-1600mg/day for 7days
Other antiviral agents like Idoxiurdine,cytotosine arabinoside and adenine arabinoside

IMPORTANT;;;;traumatic infections of dentists fingers called HERPETIC WHITLOW is a dental hazard
hence uniform precautions to be taken during treatment

        

[Author]

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