Recurrent Aphthous Stomatitis

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 References

1. Miller MF, Garfunkel AA, Ram CA, Ship II. The inheritance of recurrent aphthous stomatitis. Observations on susceptibility. Oral Surg 1980;49:409-412.

2. Kim Y, Greenberg MS. Management of patients with severe oral mucosal disease. Alpha Omegan, 2001;94:18-23.

3. Scully C. Are viruses associated with aphthae and oral vesiculoerosive disorders? Br J Oral Max Surg 1993;31:173-179.

4. Axell T, Henricsson V. Association between recurrent aphthous ulcers and tobacco habits. Scan J Dent Res 1985;93:239-242.

5. Wahba-Yahav AV. Pentoxifylline in intractable recurrent aphthous stomatitis: an open trial. J Am Acad Dermatol 1995:22:680-682.

6. Chandrasekhar J, Liem AA, Cox NH, Paterson AW. Oxypentifylline in the management of recurrent apthous ulcers: an open clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:564-567.

7. Sullivan TP, King LE, Boyd AS. Colchicine in dermatology. J Am Acad Dermatol 1998; 39:993-999.

8. Greenberg MS. Drugs used for connective-tissue disorders and oral mucosal diseases. In: Ciancio SG. Editor. ADA Guide to Dental Therapeutics. Chicago: ADA Publishing; 2000. p 438-453

9. Mekori YA, Baram D, Goldberg A, Klajman A. Inhibition of delayed hypersensitivity reactions in mice by colchicines: mechanism of inhibition of contact sensitivity in vivo. Cell Immunol 1989;120:330-340.

10. Ruah CB, Stram JR, Chasin WD. Treatment of severe recurrent aphthous stomatitis with colchicine. Arch Otolaryngol Head Neck Surg 1988;114:671-675.

11. Katz J, Langevitz P, Shemer J, et al. Prevention of recurrent aphthous stomatitis with colchicine: an open trial. J Am Acad Dermatol 1994;31:459-461.

12. Moreira AL, Sampaio E, Zmuizinas A, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor-alpha by enhancing mRNA degradation. J Exp Med 1993; 177:1675-1680.

13. Mascaro JM, Lecha M, Torras H. Thalidomide in the treatment of recurrent, necrotic, and giant mucocutaneous aphthae and aphthosis. Arch Dermatol 1979; 115:636-637.

14. Revuz J, Guillaume JC, Janier M, et al. Crossover study of thalidomide versus placebo in severe recurrent aphthous stomatitis. Arch Dermatol 1990;118;923-927.

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