Epidemiology

Prevalence and Incidence

Although found worldwide, BD has a distinct geographic distribution and is most prevalent along the ancient Silk Route, extending from Eastern Asia to the Mediterranean. Turkey has been reported to have the highest prevalence: 80–420 cases per 100,000 population, followed by Japan: 7–8.5/100,000 [4–6]. Nevertheless, it should be noted that the study of Azizerli et al. from Turkey with the highest prevalence consisted of the population aged 12 and older [4]. Its prevalence has been reported to be 2–30/100,000 in the Asian continent and 0.1–7.5/100,000 in Europe and the USA [6]. While its prevalence in Germany was reported to be 20.75 per 100,000 Turkish descendants, it was only 0.42 per 100,000 German origin [7]. The incidence per 100,000 inhabitants is reported to be 0.75–0.89 in Japan [8], 0.24 in Northern Italy [9], and 0.12–0.33 in the United States [10].

Of all uveitis cases, BD constitutes 15.3% in Israel and around 20% in Japan [11–13].

Age of Onset

Most patients with BD first report their symptoms during the second or third decade of their life [14, 15]. However, juvenile onset is more common in countries with a higher prevalence of the disease [16, 17].

The Gender Factor

Earlier studies from the Middle East and Turkey have shown a male preponderance contrary to the ones from Asia and the United States [7, 18]. Recent studies, however, suggest a more even male-to-female ratio [19]. The gender factor also seems to affect the clinical manifestations and prognosis. The disease has generally a more severe course in men with a younger age of onset.

Etiopathogenesis

Although the etiology is still unclear, some currently unknown triggering factor(s) in the presence of a genetic susceptibility seem to play a major role in the pathogenesis of BD. Recently, some authors suggest that BD is an autoinflammatory disorder [20–23]. Whatever the triggering factor is, endothelium is the most likely target tissue with resulting vasculitis and/ or thrombosis as the consequences of inflammation. The quite frequent coexistence of thrombosis and arterial aneurisms implicates a primary vascular pathology rather than a major coagulation defect in BD. Furthermore, many immunological abnormalities related with both innate and acquired immunity have been reported in BD, most of which still await for explanation, interrelation, and confirmation. The most closely associated risk factor for BD, and in some countries for disease severity, is human leukocyte antigen HLA-B51 and especially its allele HLAB51 01 positivity [24–26]. The role of HLA class I antigens such as B51 is the presentation of endogenous antigens synthesized within the cell to CD8+ cytotoxic-suppressor T cells. It is not yet clear whether B51 is a marker of susceptibility or severity in BD. However, it must be emphasized that the presence of HLA-B51 is not enough to cause BD. Many people may have genetic predisposition, but relatively few develop the disease.

Clinical Features and Diagnosis

Although Behçet’s disease may affect almost any system of the body with exacerbations and remissions of inflammation, the key clinical manifestations are recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions.

The diagnosis of Behçet’s disease may be challenging since there are no specific laboratory tests and pathognomonic findings. In addition, the presentation and the course of the disease may vary due to ethnic, geographical, and individual characteristics. It may be more difficult to

diagnose incomplete or atypical forms. On the other hand, some of the symptoms may present later in the course of the disease which may challenge the diagnosis. Various sets of diagnostic criteria have been proposed, the two most commonly used ones being the criteria by the Behçet’s Disease Research Committee of Japan [27] and the International Study Group Criteria for the Diagnosis of Behçet’s Disease [28]. The Behçet’s Disease Research Committee classifies the disease into complete and incomplete types according to major and minor diagnostic criteria (Table 12.1). On the other hand, the diagnostic criteria of the International Study Group for Behçet’s Disease is briefly summarized in Table 12.2 and requires the presence of oral aphthous ulcers for the diagnosis. Although these criteria are primarily intended to define and classify Behçet’s patients for participation in research studies, their sensitivity and specificity are high, being 91% and 96% for The International Study Group for Behçet’s Disease and 92% and 89% for The Behçet’s Disease Research Committee criteria, respectively.

Recurrent oral ulcers are reported in almost all patients and are the most common presenting feature of the disease [29]. Only the oral ulcers that recur at least three times over a 12-month period are considered as a manifestation of Behçet’s disease. A study showed that 52.2% of patients developed overt manifestations of Behçet’s disease at an average of 7.7 years after the onset of oral ulcers [30]. The frequency of recurrence was 9.8 times per year in progressive cases.

Genital ulcers are larger, deeper, and more painful than oral ulcers. Unlike oral ulcers, they heal slowly and leave a scar due to associated necrotizing vasculitis.

The skin lesions seen in BD are erythema nodosum-like lesions, pseudofolliculitis, papulopustular lesions, acneiform nodules in postadolescent patients not receiving corticosteroids observed by a physician, cutaneous hypersensitivity, and thrombophlebitis which is usually found on the extremities. Other described skin

Table 12.1 The Behçet’s Disease Research Committee diagnostic criteria

Major

1. Recurrent oral aphthous ulcers

2. Skin lesions

Erythema nodosum-like lesions Folliculitis, acneiform lesions Thrombophlebitis

Cutaneous hypersensitivity 3. Genital ulcers

4. Ocular disease Iridocyclitis Posterior uveitis

Minor

1.Arthritis

2.Epididymitis

3. Intestinal symptoms attributed to ileocecal ulcerations

4. Vascular symptoms

5. Neurologic symptoms attributed to nervous system involvement

Complete type: The presence of all four major criteria

Incomplete type:

1. The presence of three major criteria

2. Two major and two minor criteria

3. Ocular disease plus one major criteria

4. Ocular disease plus two minor criteria

Table 12.2 The International Study Group for Behçet’s Disease diagnostic criteria

Recurrent oral ulceration

Plus 2 of:

Recurrent genital ulceration

Eye involvement (anterior, intermediate, posterior uveitis)

Skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules consistent with Behçet’s disease)

Positive pathergy test

lesions include pyoderma gangrenosum, Sweet’s syndrome, extragenital ulcers, purpura, erythema multiforme, and vesicles. The incidence of skin involvement varies greatly in the literature but is approximately seen in 80% of patients [21].

Pathergy (cutaneous hypersensitivity) is the upregulated inflammatory response to a minor trauma, is not unique to the skin, and can be observed in large vessels, joints, and eyes in