4.3.2 Aphtha / Mucosal disease

Recurrent oral aphthae are considered as the most common mucosal lesions. They affect up to 2-10% of people with a 3-month recurrence rate of 50% and a lifetime prevalence of >35%. They are more common in females. Recurrent oral aphthae are more commonly seen with increasing age. Recurrent genital aphthous ulcers are much less common. Family history has been reported in 24-46%.

Aphthae present as acute, recurrent and chronic multiple, small, round or ovoid ulcers, having a yellow floor and surrounded by an erythematous halo, usually occurring first in childhood or adolescence.

The aetiology of recurrent aphthae is unclear. Many factors have been implicated in disease pathogenesis, including vitamin B and/or folic acid deficiency or resorption defect, anemia (including serum iron/ ferritin deficiency), neutropenia, stress, diverse bacterial and viral pathogens, hormonal changes, trauma, drugs, food hypersensitivity (chocolate, coffee, peanuts, cereals, almonds, strawberries, cheese, tomatoes and wheat flour containing gluten). Smoking seems to increase severity and the frequency of recurrence of oral aphthae. A weak association with HLAB12 and HLA-DR2 has been described in certain populations.

Minor oral aphthae are usually concentrated in the anterior part of the mouth, are superficial, <1 cm in diameter (usually 4-5 mm) and tend to heal within 10-14 days.

Major oral aphthae are >10 mm in diameter, deeper, can last for weeks. Herpetiform aphthae are small (1-2 mm), multiple lesions (5-100) may be present at the same time. Individual aphthae are grey and without a delineating erythematous border, making them difficult to visualize. Aphthae induce pain in eating and speaking. A single crop of ulcers may last for approximately 7-14 days, the period of remission between attacks is variable.

Herpetiform aphthae may coalesce to larger lesions and are predominantly detected in female patients and have a later age onset than the other types.

Minor aphthae involve the non-keratinized mucosa of the oral cavity (labial and buccal mucosa, the floor of the mouth and the ventral or lateral surface of the tongue) or genital mucosa. Lesions are more rounded on the labial or buccal mucosa and elongated in the buccal sulcus. Major aphthae have a predilection for lips, tongue, soft palate, and the palatal fauces and cause significant pain and dysphagia (frequent in patients with “malignant” aphthae: HIV infection, Adamantiades-Behçet’s disease). Herpetiform aphthae may involve any non-keratinized mucosa but characteristically affect the lateral margins and ventral surface of the tongue and the floor of the mouth.

Non-specific. Hemoglobin, full blood count, erythroycte sedimentation rate, c-reactive protein, serum vitamin B complex, serum/red cell folate, iron, ANA, ENA, HHV-PCR, anti-gliadin and anti-endomysial autoantibodies, Coxsackie- and Echo-Virus serum titres. Bacterial and viral swabs for specific microbe examination.

Early aphthae: Disruption of the epithelial ductal orifice of minor salivary glands and moderate mononuclear (lymphocytic) infiltrate surrounding the duct and the lobules of minor salivary glands.

Developing aphthae: Small focal ulceration immediately above the excretory duct of minor salivary glands with consequent development of a fibropurulent membrane. Mononuclear cells and neutrophilic acute inflammatory infiltrate are seen at the base of the ulcer and, within it, a fibrinous exudate but only occasionally in adjacent and subjacent tissues where mononuclear (lymphocytic) cells predominate.

Usually recurrent with varying frequency (2-12x/year up to intervals of few days). Decrescendo and crescendo courses of years have been observed. Female patients may relate the onset of aphthae to their menstrual cycle, pregnancy, and dysmenorrhea. Aphthae usually improve during pregnancy and may be affected by sex steroids.

Aphthous ulcers may occur at sites of trauma, particularly due to toothbrushing, or the site of a local anesthetic injection and dental treatment. The use of certain drugs (sodium hypochlorite, piroxicam, phenobarbital, phenindione, niflumic acid, nicorandil, gold salts, captopril, non-steroidal anti- inflammatory drugs) may induce oral aphthae.

The spectrum of differential diagnoses is broad and one should always examine the mucosa of oral and ano-genital areas, as well as the rest of the skin.

One of the important differential diagnosis is Adamantiades-Behçet disease which is a chronic recurrent systemic vasculitis in which oral and genital ulcers are major diagnostic criteria. 99% of patients have recurrent oral aphthae. Recurrent genital aphthous ulcers are seen in 65%. In 85% of patients, the first manifestation is oral aphthae, while 4% start with genital aphthous ulcers (2nd most frequent symptom). About 10% of the patients with recurrent severe aphthosis in Caucasian populations develop Adamantiades-Behçet disease; the likelihood is higher in the eastern Mediterranean region, Middle East and Asia. Clinical diagnostic criteria are applied.

Other systemic or localized diseases are;

• gastrointestinal inflammatory diseases (ulcerative colitis, Crohn’s disease, celiac disease),

• infections (herpes simplex, zoster, infectious mononucleosis, hand foot and mouth disease, herpangina, HIV infection, syphilis, acute necrotizing ulcerative gingivitis, candidiasis),

• autoimmune diseases (lupus erythematosus, Sweet syndrome, reactive arthritis, MAGIC syndrome, sarcoidosis),

• bullous and lichenoid dermatoses (lichen planus, erythema multiforme and its variants, incl. • Stevens-Johnson syndrome and toxic epidermal necrolysis,

• bullous autoimmune disorders (pemphigus vulgaris, cicatricial pemphigoid, epidermolysis bullosa acquisita, linear IgA dermatosis),

• other oral disorders (allergic contact stomatitis, drug-induced ulcerative stomatitis, geographic stomatitis,

• PFAPA syndrome (periodic fever, aphthous ulcers, pharyngitis, cervical adenitis).

Hard, acidic and salty food, alcohol and carbonated beverages should be avoided.

The aim of minor and major aphthae treatment is to decrease symptoms; reduce ulcer number, size and pain and increase disease-free periods. Approved therapies include topical corticosteroids, topical antiseptics (reduction of new aphthae) and topical anesthetics (pain relief). However, topical calcineurin inhibitors such as topical pimecrolimus or tacrolimus can also be applied.

In severe cases, topical treatment can be combined with systemic therapy, e.g. with colchicine, pentoxifylline or prednisolone.