Aphthous Ulcers
- Author: Crispian Scully, MD, PhD, CBE, MDS, MRCS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FRCPath, FMedSci, FHEA, FUCL, DSc, DChD, DMed(HC), Dr (HC) ; Chief Editor: Arlen D Meyers, MD, MBA more...
Background
Recurrent aphthous stomatitis (RAS) is a common condition, restricted to the mouth, that typically starts in childhood or adolescence as recurrent small, round, or ovoid ulcers with circumscribed margins, erythematous haloes, and yellow or gray floors. A positive family history of similar ulcers is common, and the natural history is typically of resolution in the third decade of life.
Ulcers with similar clinical features but rarely resolving spontaneously with age may be termed "aphthous-like ulcers," and may then be associated with systemic conditions such as Behçet syndrome, auto-inflammatory syndromes, gastrointestinal disease, or immune defects such as HIV/AIDS.
Traumatic ulcer on ventrum/lateral margin of tongue; these must be differentiated from aphthae. Pathophysiology
The etiology of recurrent aphthous stomatitis (RAS) is not entirely clear, and aphthae are therefore termed idiopathic. RAS may be the manifestation of a group of disorders of quite different etiology, rather than a single entity.
Despite many studies trying to identify a causal microorganism, RAS does not appear to be infectious, contagious, or sexually transmitted. Immune mechanisms appear at play in persons with a genetic predisposition to oral ulceration.
A genetic basis exists for some RAS. This is shown by a positive family history in about one third of patients with RAS, an increased frequency of HLA types A2, A11, B12, and DR2, and susceptibility to RAS which segregates in families in association with HLA haplotypes. RAS probably involves cell-mediated mechanisms, but the precise immunopathogenesis remains unclear. Phagocytic and cytotoxic T cells probably aid in destruction of oral epithelium that is directed and sustained by local cytokine release.
Patients with active RAS have an increased proportion of gamma-delta T cells compared with control subjects and patients with inactive RAS. Gamma-delta T cells may be involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Compared with control subjects, individuals with RAS have raised serum levels of cytokines such as interleukin (IL)–6 and IL-2R, soluble intercellular adhesion modules (ICAM), vascular cell adhesion modules (VCAM), and E-selectin; however, some of these do not correlate with disease activity.
Cross-reactivity between a streptococcal 60- to 65-kd heat shock protein (hsp) and the oral mucosa has been demonstrated, and significantly elevated levels of serum antibodies to hsp are found in patients with RAS. Lymphocytes of patients with RAS have reactivity to a peptide of Mycobacterium tuberculosis. Some cross-reactivity exists between the 65-kd hsp and the 60-kd human mitochondrial hsp. Monoclonal antibodies to part of the 65-kd hsp of M tuberculosis react with Streptococcus sanguis. RAS thus may be a T cell–mediated response to antigens of S sanguis, which cross-react with the mitochondrial hsp and induce oral mucosal damage. RAS patients have an anomalous activity of the toll-like receptor TLR2 pathway that probably influences the stimulation of an abnormal Th1 immune response.
Predisposing factors found may include any of the following:
- Hematinic deficiency: Up to 20% of patients are deficient of iron, folic acid (folate), or vitamin B.
- Malabsorption in gastrointestinal disorders: About 3% of patients experience these disorders, particularly celiac disease (gluten-sensitive enteropathy) but, occasionally, Crohn disease, pernicious anemia, and dermatitis herpetiformis. HLA DRW10 and DQW1 may predispose patients with celiac disease to RAS.
- Cessation of smoking: This may precipitate or exacerbate RAS in some cases.
- Stress: This underlies RAS in some cases; ulcers appear to exacerbate during school or university examination times.
- Trauma: Biting of the mucosa and wearing of dental appliances may lead to some ulcers; RAS is uncommon on keratinized mucosae.
- Endocrine factors in some women: RAS is clearly related to the progestogen level fall in the luteal phase of the menstrual cycle, and ulcers may then temporarily regress in pregnancy.
- Allergies to food: Food allergies occasionally underlie RAS; the prevalence of atopy is high. Patients with aphthae may occasionally have a reaction to cow's milk, and may have been weaned at an early age.
- Sodium lauryl sulphate (SLS): This is a detergent in some oral healthcare products that may aggravate or produce oral ulceration.
- Immune deficiencies: Ulcers similar to RAS may be seen in patients with HIV, neutropenias and some other immune defects.
- Drugs, especially NSAIDs, alendronate, and nicorandil:[1] These may produce lesions clinically similar to RAS.
Epidemiology
Frequency
United States
RAS affects 5-66% of the population. Approximately 1% of children from higher socioeconomic groups in developed countries have RAS; however, 40% of selected groups of children can have a history of RAS, with ulceration beginning before age 5 years and with the frequency of affected patients increasing with age.
Mortality/Morbidity
Most patients with RAS are otherwise well.
Race
RAS have been reported in all races
Sex
A slight female predominance exists.
Age
RAS typically starts in childhood or adolescence.
Shotts RH, Scully C, Avery CM, Porter SR. Nicorandil-induced severe oral ulceration: a newly recognized drug reaction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Jun 1999;87(6):706-7. [Medline].
Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. Jan 2005;49(1):31-47, vii-viii. [Medline].
Albanidou-Farmaki E, Deligiannidis A, Markopoulos AK, Katsares V, Farmakis K, Parapanissiou E. HLA haplotypes in recurrent aphthous stomatitis: a mode of inheritance?. Int J Immunogenet. Dec 2008;35(6):427-32. [Medline].
Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health Syst Pharm. Jan 1 2001;58(1):41-50; quiz 51-3. [Medline].
Borra RC, de Mesquita Barros F, de Andrade Lotufo M, Villanova FE, Andrade PM. Toll-like receptor activity in recurrent aphthous ulceration. J Oral Pathol Med. Mar 2009;38(3):289-98. [Medline].
Calderon PE, Valenzuela FA, Carreno LE, Madrid AM. A possible link between cow milk and recurrent aphtous stomatitis. J Eur Acad Dermatol Venereol. Jul 2008;22(7):898-9. [Medline].
de Abreu MA, Hirata CH, Pimentel DR, Weckx LL. Treatment of recurrent aphthous stomatitis with clofazimine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Nov 2009;108(5):714-21. [Medline].
Edres MA, Scully C, Gelbier M. Use of proprietary agents to relieve recurrent aphthous stomatitis. Br Dent J. Feb 22 1997;182(4):144-6. [Medline].
Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphthous stomatitis. Cutis. Sep 2001;68(3):201-6. [Medline].
Femiano F, Gombos F, Scully C. Recurrent aphthous stomatitis unresponsive to topical corticosteroids: a study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide. Int J Dermatol. May 2003;42(5):394-7. [Medline].
Gallo Cde B, Mimura MA, Sugaya NN. Psychological stress and recurrent aphthous stomatitis. Clinics (Sao Paulo). 2009;64(7):645-8. [Medline].
Lo Muzio L, della Valle A, Mignogna MD, et al. The treatment of oral aphthous ulceration or erosive lichen planus with topical clobetasol propionate in three preparations: a clinical and pilot study on 54 patients. J Oral Pathol Med. Nov 2001;30(10):611-7. [Medline].
Marakoglu K, Sezer RE, Toker HC, Marakoglu I. The recurrent aphthous stomatitis frequency in the smoking cessation people. Clin Oral Investig. Jun 2007;11(2):149-53. [Medline].
McCullough MJ, Abdel-Hafeth S, Scully C. Recurrent aphthous stomatitis revisited; clinical features, associations, and new association with infant feeding practices?. J Oral Pathol Med. Nov 2007;36(10):615-20. [Medline].
Meng W, Dong Y, Liu J, et al. A clinical evaluation of amlexanox oral adhesive pellicles in the treatment of recurrent aphthous stomatitis and comparison with amlexanox oral tablets: a randomized, placebo controlled, blinded, multicenter clinical trial. Trials. May 6 2009;10:30. [Medline].
Piskin S, Sayan C, Durukan N, Senol M. Serum iron, ferritin, folic acid, and vitamin B12 levels in recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol. Jan 2002;16(1):66-7. [Medline].
Porter S, Scully C. Aphthous ulcers (recurrent). Clin Evid. 2004;12:360-361.
Porter SR, Hegarty A, Kaliakatsou F, Hodgson TA, Scully C. Recurrent aphthous stomatitis. Clin Dermatol. Sep-Oct 2000;18(5):569-78. [Medline].
Porter SR, Scully C, Pedersen A. Recurrent aphthous stomatitis. Crit Rev Oral Biol Med. 1998;9(3):306-21. [Medline].
Scully C. Clinical practice. Aphthous ulceration. N Engl J Med. Jul 13 2006;355(2):165-72. [Medline].
Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. Feb 2003;134(2):200-7. [Medline].
Scully C, Hodgson T. Recurrent oral ulceration: aphthous-like ulcers in periodic syndromes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Dec 2008;106(6):845-52. [Medline].
Scully C, Hodgson T, Lachmann H. Auto-inflammatory syndromes and oral health. Oral Dis. Nov 2008;14(8):690-9. [Medline].
Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M. Recurrent aphthous stomatitis. Quintessence Int. Feb 2000;31(2):95-112. [Medline].
Volkov I, Rudoy I, Freud T, Sardal G, Naimer S, Peleg R, et al. Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis: arandomized, double-blind, placebo-controlled trial. J Am Board Fam Med. 2009;22:9-16.
Gulcan E, Toker S, Hatipoğlu H, Gulcan A, Toker A. Cyanocobalamin may bebeneficial in the treatment of recurrent aphthous ulcers even when vitamin B12levels are normal. Am J Med Sci. 2008;336:379-82.

