2.1. Prodromal Stage

Usually lasting 24 hours with itching and burning sensation.

2.2. Preulcerative Stage

Taking up to 3 days. In this stage development of a localized painful papular swelling because of keratinocyte vacuolization surrounded by a reactive erythemathous halo representing localized vasculitis with a dense mononuclear cell infiltrate are observed.

2.3. Ulcerative Stage

Usually lasting 1-16 days and only in rare cases when involving large ulcerations, up to 6 weeks; the already formed painful papule ulcerates and a fibrous membrane covers the ulcer which is infiltrated mainly by neutrophils, lymphocytes and plasma cells.

2.4. Healing Stage

With epithelial regeneration

The most common idiopathic intraoral ulcerative disease is Recurrent Aphthous Stomatitis (RAS). It affects 10-10% of the overall population. In children it represents 40% of the relapsing ulcers in children [3]. US study comprises 39,206 children aged 5-17 yr who were examined by 14 dentists and found out a prevalence of RAS of 1.23% in children [4].  RAS can have different time course. The simple chronic recurrent oral aphthous ulcers present with a limited number of small, quickly healing, minimally painful ulcers limited to the oral mucosa and recurring with 3–6 episodes annually. In complex aphthosis, there are a few or many slowly healing intensely painful ulcers on the oral and perhaps genital mucosa. The latter may also be perigenital, affecting the scrotum, vulva, anus, perineum and inguinal region. Complex aphthosis features include frequently appearing ulcers with either short lesion-free periods or even repeatedly recurrent ulcers, severe pain and even systemic effects such as interference with eating and the resultant problems of inadequate nutrition. A genome-wide association study, consisting of 461,106 participants reported heritability of RAS at 8.2% [5]. Moreover, a role of T cell regulation in the aetiology of mouth ulcers has been reported by the study.

The reason for complex aphthosis in 9.3 % of the patients is Behcet's syndrome, a disease first reported in 1937 by the Turkish dermatologist Hulusi Behcet [6] who described relapsing oral aphthae, genital ulcers and uveitis together as symptoms of a single clinical entity. It was subsequently found to be a multisystem disease, with vascular, joint, gastrointestinal, neurological, pulmonary and cardiac involvement. Nowadays it is well known that Behcet's syndrome is associated with HLA-B51 and polymorphic variants in IL-10 and IL-23R/IL-12RB2 genes [7,8] HLA-B51 frequency among inhabitants along the Silk Route population ranges 20–25% in the general population and 50–80% among BD patients. On the contrary, HLA-B51 frequency is approximately 2–8% in Northern Europe and the USA in the general population and 15% among BD patients. Interestingly, the risk of developing Behcet disease is lower among Turkish emigrants living in Germany than Turks living in Turkey. Therefore, there are other enviornmental factors besides genetics that are important for the development of the disease. In 1990 the German Registry for Adamantiades-Behçet Disease was founded. According to it Behcet's disease starts in 14.2% of the patients during childhood [9] Oral aphthae (98.5%), genital ulcers (64.7%), cutaneous manifestations (73.4%), ocular manifestations (51.6%), and arthropathies are the most frequent clinical manifestations in Germany.

Up to twenty percent of the patients with systemic lupus erythematosus (SLE) are being diagnosed in childhood. 20-40% of the children present with aphthous lesions [10]. Aphthous lesions are the second most common mucocutaneous manifestation, after the butterfly rash. They are usually found when the disease is active. Oral ulcers are commonly found in juvenile SLE patients, and the typical lesion is a painless palatal erythematous ulcer at masticatory or keratinized mucosa, especially the hard palate. However, most ulcers including oral discoid lesions and aphthous ulcers in juvenile SLE patients appear at the lining tissue of the oral cavity (e.g., nonkeratinized epithelium covering buccal mucosa, labial mucosa, alveolar mucosa, soft palate, ventral tongue and the floor of the mouth) and sometimes are unnoticed. Oral discoid lesion is a well-defined, atrophic plaque with white radiating keratotic striae and telangiectasia at lining mucosa, especially buccal mucosa and the soft palate [11] (Figure 4).

In 1987, Marshall et al. described a new periodic fever which is now known as PFAPA syndrome [12] The diagnosis of PFAPA (periodic fevers with aphthous stomatitis, pharyngitis, and adenitis) is established on the basis of clinical criteria that require the presence of a recurrent fever of early onset (<5 years) with a clockwork periodicity (usual interval <4 weeks) and ≥1 of the 3 associated symptoms (aphthosis, cervical adenitis, and pharyngitis), in the absence of upper respiratory tract infections and cyclic neutropenia.

Among the patients with RAS the frequency of celiac disease is between 4 and 40 percent. It should be acknowledged that oral lesions associated with celiac disease may precede gastrointestinal symptoms by several years, so screening for tissue transglutaminase and endomysial antibodies should be performed even in the absence of gastrointestinal lesions.

In cases of Crohn’s disease the oral symptoms constitute up to one half of the symptoms in children [13]. The observed changes might be specific (perioral erythema, facial edema, facial ulcers, swelling or fissures of the lips, cobblestoning, linear ulcers, gingivitis, papules, nodules, mucosal polyps, granulomatous cheilitis, pyostomatitis vegetans, (Figure 5) and nonspecific [14] Most commonly the lesions are observed in the lips, followed by the buccal mucosal and the gingiva.

Currently, the management of RAS is aimed at supportive care. No pharmacological treatment has been curative, although several modalities have been effective in decreasing pain and erythema and increasing the rate of reepithelialization associated with healing lesions. In general one should avoid hard, acidic and salty substances such as fruit juices, citrus fruits, tomatoes, and spices like pepper, paprika and curry, as well as alcoholic and carbonated beverages. Avoiding dental care products with sodium lauryl sulfate is also desirable.

Drugs that can be used to treat oral aphthous ulcers are corticosteroids, topical antiseptic/anti-inflammatory agents, and local anesthetics. Antiseptic agents and local anesthetics should be tried first; if these are ineffective, topical corticosteroids should be used. In severe cases, local measures can be combined with systemic drugs, e.g., colchicine, pentoxifylline, or prednisolone.

n cases of Behçet's disease colchicine should be the first choice [15] Shortterm corticosteroids in combination with other drugs such as colchicine can be used as an alternative in the treatment of acute attacks. Dapsone can also be used at this stage as an effective compound.  Patients with severe mucocutaneous disease or those who are unresponsive to the respected treatments can be treated with azathioprine. Cyclosporine and anti-TNF are other alternatives to control the disease in unresponsive cases. A current review of the Cochrane Collaboration analyzed 25 studies (22 of which were placebo- controlled) on systemic therapy (Prednisolone, Colchicine, Azathioprine, Cyclosporine) of oral aphthous ulcers and found no convincing evidence of efficacy [16].