Aphthous Ulcers 2

Introduction

Background

Commonly termed canker sores, aphthous ulcers, or aphthous stomatitis, have been the focus of study and research for many years, although the exact etiology of the lesions has yet to be identified. Categorized as an idiopathic disease, aphthous ulcers are frequently misdiagnosed, treated incorrectly, or simply ignored.

Recurrent aphthous ulcer (RAU), or recurrent aphthous stomatitis (RAS), represents a chronic inflammatory disease characterized by painful oral ulcers recurring with varying frequency. Examples of aphthous ulcers are shown in the images below.

Recurrent aphthae in floor of mouth, showing ovoid ulcer with inflammatory halo.

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Recurrent aphthae in floor of mouth, showing ovoid ulcer with inflammatory halo.

Typical aphthous ulcer in a common site, showing inflammatory halo surrounding a yellowish, round ulcer.

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Typical aphthous ulcer in a common site, showing inflammatory halo surrounding a yellowish, round ulcer.

Children with recurrent aphthous ulcers (canker sores) may reduce their oral food and fluid intake because of the associated pain and subsequently become dehydrated; therefore, aggressive therapy for the lesions can be important.

Recurrent aphthous ulcers (canker sores) may initially appear as erythematous, indurated papules that erode to form sharply circumscribed necrotic ulcers with a gray, fibrinous exudate and an erythematous halo. The 3 categories of recurrent aphthous ulcers (canker sores) are as follows:

• Minor aphthous ulcers (80-85% of recurrent aphthous ulcers [canker sores]) are 1-10 mm in diameter and heal spontaneously in 7-10 days.
• Major aphthous ulcers (also called Sutton disease) constitute 10-15% of recurrent aphthous ulcers (canker sores). These lesions are greater than 10 mm in diameter, take 10-30 days or more to heal, and may leave scars.
• Herpetiform ulcers (5-10% of recurrent aphthous ulcers [canker sores]) are multiple, clustered, 1-mm to 3-mm lesions that may coalesce into plaques. These usually heal in 7-10 days.

Pathophysiology

The pathophysiology of aphthous ulcers remains incompletely understood. The primary disorder appears to be the result of activation of the cell-mediated immune system. Early lesions show a cluster of macrophages and lymphocytes (predominantly cytotoxic and natural-killer T cells) at the preulcerative base, followed by formation of an ulcer with a neutrophilic base and an erythematous lymphocytic ring.

Patients with recurrent aphthous ulcers (canker sores) have increased numbers of cytotoxic CD8⁺ cells and decreased numbers of helper CD4⁺ cells in peripheral blood.¹ Lesions have elevated levels of interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-4, and IL-5;² they have a functional deficit of IL-10. Some lesions have also had mast-cell activation and degranulation. In vitro cytotoxicity to oral keratinocyte targets is greater in patients with active recurrent aphthous ulcers (canker sores) than in control subjects or in patients with traumatic ulcers. As expected with this abnormal immunologic activity, corticosteroids are effective therapy.

Aphthous ulcers may have abnormalities in cell communication and epithelial integrity. Lesions have increased expression of an adhesion molecule termed vascular cell adhesion molecule-1 (VCAM-1), E selectin, and keratinocyte intercellular adhesion molecule-1 (ICAM-1).³ Connexins (markers for the presence of gap junctions) are present in the oral mucosa of patients with recurrent aphthous ulcers (canker sores) in amounts similar to those present in normal mucosal tissue. Experimental treatment with irsogladine maleate, which reinforces gap junctional intercellular communication, is effective. Helicobacter pylori may or may not be involved in aphthous ulcer formation.^4,5

Factors predisposing patients to recurrent aphthous ulcers (canker sores) may include trauma, emotional stress,⁶ poor nutritional status, thiamine deficiency,⁷ vitamin B12 deficiency, malabsorption, celiac disease, regional enteropathy, menstruation, food hypersensitivity (eg, cow's milk),⁸ allergic reaction, and exposure to toxins (eg, nitrates in drinking water). Aphthous ulcers (canker sores) are more prevalent in nonsmokers and in smokers who quit but are diminished with nicotine replacement therapy.

Frequency

United States

Although recurrent aphthous ulcers (canker sores) are commonly believed to occur in approximately 20% of the general population, a study of medical and dental students revealed a prevalence of 31-66%.

International

The worldwide incidence is similar to that in the United States. Aphthous ulcers (canker sores) are found in all ethnic groups and geographic locations. The prevalence may be increased in affluent countries and socioeconomic classes.

Mortality/Morbidity

Aphthous ulcers (canker sores) are associated with local pain and discomfort. Symptoms usually last 2-10 days with minor and herpetiform ulcers and as long as 30 days with major ulcers. Most cases are self-limited and heal without sequelae in 7-14 days; however, major ulcers heal slowly (10-30 days or longer).

• Major aphthous ulcers (canker sores) have been known to leave substantial scars.
• The primary morbidity with any type of aphthous ulcer (canker sore) in the pediatric population is dehydration due to poor oral intake.
• Secondary bacterial infections are uncommon.

Race

Race does not appear to influence the frequency or severity of recurrent aphthous ulcers (canker sores).

Sex

Aphthous ulcers (canker sores) may be slightly more common in female individuals than in male individuals. Outbreaks occur most frequently during ovulation or before menstruation, and remissions are common during pregnancy.

Age

Recurrent aphthous ulcers (canker sores) begin in childhood or adolescence, with peak onset in persons aged 10-19 years. Frequency and severity diminish with age. Major aphthous ulcers (canker sores) may begin soon after puberty. Herpetiform recurrent aphthous ulcers (canker sores) tend to affect older persons.

Clinical

History

The diagnosis of aphthous ulcers (canker sores) is primarily clinical. Patients typically describe a prodromal stage of a burning or pricking sensation of the oral mucosa 1-2 days before the ulcer appears. Patients with recurrent aphthous ulcers (RAUs), or canker sores, often mention precipitating factors, such as local trauma or food hypersensitivity.

• During the review of systems, infants and small children should be assessed for decreased feeding, weight, and urine output. Associated symptoms, such as those below, suggest other diagnoses and are not associated with recurrent aphthous ulcers (canker sores).
  • Fever
  • Malaise
  • Myalgias
  • Arthralgias
  • Headache
  • Cough
  • Nausea
  • Vomiting
  • Abdominal pain
  • Diarrhea
  • Sore throat
  • Swollen or painful lymphadenopathy
  • Rash
  • Genital or conjunctival lesions
• Inquire about previous ulcers. The natural history of individual lesions is important because it is the benchmark against which treatment benefits are measured.
  • Age at onset should be noted because major recurrent aphthous ulcers (canker sores) begin after puberty, and herpetiform ulcers are uncommon in children.
  • The duration, location, and size of previous lesions should be noted, as well as the therapy received.
  • Having patients keep an ulcer diary for 1-3 months may be useful.
• Ask the patient about medication use, chemotherapy, radiation therapy, vitamin supplementation, and recent dietary changes.
• Assess for a family history of the following:
  • Aphthous ulcers (canker sores)
  • Inflammatory bowel disease
  • Gluten-sensitive enteropathy
  • Behçet disease
  • Systemic lupus erythematosus
• Review the patient's medical history. Consider Behçet disease; human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS); cancer; Crohn disease; immunocompromised state; cyclic neutropenia; mouth and genital ulcers with inflamed cartilage (MAGIC syndrome); and systemic lupus erythematosus.

Physical

Aphthous ulcers (canker sores) occur on areas of the mouth in which the mucosa is nonkeratinized and loosely attached, particularly the buccal mucosa, the labial mucosa, the floor of the mouth, the ventral surface of the tongue, and the soft palate. Ulcers may appear as single or multiple lesions, and they are easily distinguished from primary or secondary viral infections, bacterial infections (eg, necrotizing ulcerative gingivitis), dermatologic conditions (lichen planus, cicatricial pemphigoid, pemphigus), and traumatic injuries (contusions, lacerations, burns) by the healthy appearance of adjacent tissues and the lack of distinguishing systemic features.

• Minor ulcers are seldom larger than 5 mm but can be as large as 1 cm. They may be single or multiple. The ulcers are round-to-oval, they are covered by a gray or yellowish and fibrinous surface, and they are surrounded by an erythematous border.
• Major recurrent aphthous ulcers (canker sores) can be 1-3 cm in diameter. They are deeper than minor ulcers and often have a raised, irregular, erythematous border. Patients with a history of major recurrent aphthous ulcers (canker sores) often have residual scarring in the oral mucosa from previous lesions.
• Herpetiform aphthous ulcers appear as small (seldom >3 mm in diameter), tightly clustered lesions. They typically number 2-10 but may number as many as 100. They are not related to herpes simplex infections and do not present as or develop into vesicular lesions. The ulcers appear identical to minor aphthous ulcers with the exception of their small size, proximity to other lesions, and increased numbers. Confusion may arise if the lesions coalesce into a large lesion resembling major aphthous stomatitis.
• The rest of the mouth should appear normal. However, halitosis and necrotic, exudative, or bleeding gums may be present with the following: (1) necrotizing ulcerative gingivostomatitis; (2) erythematous tonsils with periodic fever, aphthous pharyngitis, and adenopathy (PFAPA) syndrome;^9,10 and (3) vesicular-ulcerative palatal lesions with coxsackieviral infection.
• Vital signs should be normal. Secondary bacterial infection, PFAPA syndrome, primary viral infection, or rheumatologic disorder may cause fever.
• Clinical evidence of dehydration may include decreased weight, tachycardia, hypotension, cool extremities, delayed capillary refill, depressed fontanelle, dry mucus membranes, decreased skin turgor, or decreased axillary moisture. Plotting the weight and height may reveal a trend toward the low percentiles for age; this finding suggests nutritional deficiency or malabsorption syndrome.
• Skin findings should be normal, but rash may be present with Behçet syndrome, erythema multiforme, hand-foot-and-mouth disease, herpes simplex infection, lichen planus, MAGIC syndrome, pemphigus, pemphigoid, Sweet syndrome, syphilis, systemic lupus erythematosus, varicella (chickenpox), or varicella zoster.
• The joints should be normal, but joints may be tender with effusion, erythema, or decreased range of motion in Reiter syndrome, systemic lupus erythematosus, or MAGIC syndrome.
• The eyes should be normal, but examination may reveal conjunctival lesions in patients with Behçet syndrome or cicatricial pemphigoid. Uveitis or iritis may be present with Reiter syndrome or Behçet syndrome.
• Cervical adenopathy should be minimal. Tender or markedly enlarged lymph nodes suggest PFAPA syndrome.

Causes

Precipitating factors include trauma, salivary gland dysfunction, stress, genetic predisposition, local infections, nutritional deficiencies, GI disorders, systemic disorders, food allergy or hypersensitivity, hormonal fluctuations, and chemical exposure.

• Trauma: Local injury, such as that caused by an accidental bite, dental injection, toothbrush bristle, or ingestion of sharp food, may precipitate aphthous ulcers in individuals who are susceptible. Traumatic piercing uncommonly occurs in keratinized mucosal epithelium, and recurrent aphthous ulcers (canker sores) are rare in keratinized mucosa.
• Stress: Psychological and physiologic stress may increase the risk of aphthous ulcers.⁶ Individuals with aphthous ulcers have had higher-than-average anxiety scores and cortisol levels. Antidepressant therapy may be effective in some patients.
• Genetic predisposition: A family history of recurrent aphthous ulcer (canker sore) is common, though familial penetrance has not been identified as a specific category. recurrent aphthous ulcers (canker sores) may be associated with human leukocyte antigen (HLA) haplotypes B51 (also common in Behçet syndrome), Cn7, A2, B12, and Dr5.
• Local infection: Several infectious agents have been identified in association with aphthous ulcer lesions, including human herpesvirus (HHV)-6,¹¹ HHV-8, varicella zoster virus, human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV)-1, HSV-2, Helicobacter species, and L-forms of streptococci.¹² However, authorities generally agree that aphthous ulcers and RAU do not represent acute infections and are not contagious.
• Nutritional deficiencies: Deficiencies of iron; folic acid; zinc; and vitamins B-1, B-2, B-6, B-12, and C have all been implicated in recurrent aphthous ulcers (canker sores). Oxidative stress and diminished antioxidant activity (vitamin E and selenium) may also predispose individuals to recurrent aphthous ulcers (canker sores).¹³
• GI disorders, such as regional enteropathy (Crohn disease), ulcerative colitis, and celiac disease (gluten-sensitive enteropathy), may result in aphthous ulcers. The ulcers may be the only presenting symptom or the only symptom that is evident for a number of years in patients with GI disorders; therefore, a high degree of suspicion should be maintained when patients present with recurrent aphthous ulcers (canker sores).
• Systemic disorders: Disorders such as cyclic neutropenia, Reiter syndrome, Behçet disease, or HIV infection may result in aphthous ulcers (canker sores).
• Food allergy and hypersensitivity: Flavoring agents, essential oils, benzoic acid, cinnamon, gluten, cow's milk,⁸ coffee, chocolate, potatoes, cheese, figs, nuts, citrus fruits, and certain spices have been implicated in some individuals with recurrent aphthous ulcers (canker sores).
• Hormonal fluctuations: In some women, recurrent aphthous ulcers (canker sores) are associated with the menstrual cycle, with outbreaks most commonly occurring during ovulation or before menstruation. A diminished incidence of recurrent aphthous ulcers (canker sores) during pregnancy has been reported.
• Chemical exposures: High levels of nitrates in drinking water have been associated with aphthous ulcers.¹⁴ The nitrates may induce cytochrome b ₅ reductase activity. Sodium lauryl sulfate (SLS), a detergent commonly used in toothpaste, may be a trigger of aphthous ulceration in some individuals.^15,16 Use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with aphthous ulcers.¹⁷ Smoking and nicotine exposure do not increase, and may actually decrease, the risk of aphthous ulcers.
• Significant correlations have been shown between the severity of aphthous stomatitis and hygiene of the oral cavity.¹⁸ Good hygiene reduces not only the number of outbreaks but also the severity.