Apremilast Application as Treatment of Oral Ulcers in Behçet Syndrome

0.6 5.2 people per 100,000 inhabitants. It is noted that the prevalence in these countries increases depending on whether people are of 1). ABSTRACT Several symptoms are present in the Behçet Syndrome, including oral ulcers, genital ulcers, skin lesions, eye injuries, severe problems such as meningitis, blood clots Inflammation of the digestive system and blindness can also occur. The Behçet Syndrome mainly affects countries of the Mediterranean basin, but it can also affect the Middle East, and the Far East, for instance. The prevalence in Western Europe and the United States is between 0.6 to 5.2 people per 100,000 inhabitants. The cause of Behçet Syndrome is still unknown, although some factors such as genetics, and that the environment may play a role. Currently, there is no cure for the Behçet Syndrome and the treatments are focused on alleviating the pain and preventing severe problems. Apremilast was approved by the FDA for the treatment of psoriatic arthritis and moderate to severe plaque psoriasis. Since 2019 it has also been used for the treatment of oral ulcers associated with Behçet’s disease and there have been successful results in pain relief within a few weeks. However, further studies should be conducted. Abbreviations:

: Prevalence of Behçet syndrome. Prevalence showed as with Behçet syndrome per 100 000 of population.
Although genetic and environmental factors are directly involved in the pathogenesis of BD, the main cause is still unknown, despite it being believed that the disease is due to an autoimmune process triggered by an infectious or environmental agent in a person who is genetically predisposed [15]. T cells have been found to be the major lymphocytes implicated in the pathogenesis of BD, and the IL-8 produced by T cells has been correlated with disease activity (including vascular) [16,17]. BD has also been considered an autoinflammatory disease [18] and this is corroborated due to the similarities with Crohn's Disease, which is considered an autoinflammatory disease [19,20]. A genome study conducted in BD patients reported an association for BD of Interleukin 4 (IL-4), Intelerukin 10 (IL-10), Interleukin 12 (IL-12), Interleukin 13 (IL-13), Interferon-γ (INF-γ) and IL23R -IL12RB2 loci. Similarly, two associations were identified in the 1p31.3 (IL23R-IL12RB2) and 1q32.1 (IL10) chromosomes, which predispose people with BD [21,22]. BD is associated with a range between IL23R and IL12RB2. An increase in Th1, Th17, CD4 + and CD8 + T cells was also found, and activity was observed in γδ + T cells in both serum and tissues of diagnosed patients with BD, suggesting that innate and adaptive immunity are involved in the pathogenesis of this disease [23,24]. The diagnosis of BD is not easy to detect in patients with oligosymptomatology. However, many authors apply their criteria or a combination thereof with the diagnostic criteria issued by the International Study Group (ISG). These criteria consist of the identification of clinical characteristics such as oral ulcers, genital ulcers, eye injuries, skin lesions and the pathergy test (Table 1). 97-99% of the cases detected with BD, mucocutaneous lesions represent the distinctive clinical manifestation, and genital ulcerations represent 85% [25][26][27].  [25].

Criteria Descriptions
Recurrent oral ulcerations Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which recurred at least 3 times in one 12-month period.

Plus 2 of the Following Criteria in the Absence of Other Clinical Explanations:
Recurrent genital ulceration Aphthous ulceration or scarring, observed by physician or patient. the results showed an improvement in oral and genital ulcers, pseudofolliculitis and erythema nodosum in patients who were treated with colchicine, that is, this drug significantly improved overall symptoms of the disease [30]. Systemic Corticosteroids (CSs) in many cases have been used for the treatment of BD, it is the case of Prednisolone that is used in doses of 0.5 -1 mg/kg [31]. In a study carried out with 54 prescribed patients with intestinal BD, they were treated with CS and showed encouraging results due to complete remission of the disease in 46.3% of cases, unfortunately, after one year, 35.2% of patients showed corticosteroid dependence [32]. Corticosteroids are used to treat several of the manifestations of BD. However, many patients become resistant or dependent.

Apremilast as Treatment of Oral Ulcers Manifested in Behçet Syndrome
Apremilast (APR) is a small molecule approved by the United States Food and Drug Administration (USFDA) for the treatment of adults with psoriatic arthritis and moderate to severe plaque psoriasis and since 2019 it has been approved for the treatment of oral ulcers associated with Behçet's disease [39]. Clinical studies developed with apremilast have demonstrated its efficacy and safety against oral ulcers in BD patients [40]. BD who presented oral and genital ulcers refractory to multiple treatments, including TNF inhibitors [49].

Conclusion
Due to the nature of Behçet's disease, the studies carried out with apremilast suggest its employability in the treatment.
However, it is necessary to carry out long-term studies and also evaluate other possible pharmaceutical forms and administration routes of the drug to improve its bioavailability.