**2. History and diagnosis**

The disease, currently known all over the world as "Behçet disease", "Behçet syndrome", "Behçet's triad", "Morbus Behçet" or "Tri-symptom Behçet" was first recognized by Dr. Hulusi Behçet (1889-1948) with a patient in 1924 (Tuzun, 2006; Ustun, 2002; Kartal Durmazlar & Kandi, 2011). This patient, who had been examined because of eye disturbances, recurrent oral and genital ulcers both in Istanbul and Vienna for 40 years, was given several diagnoses. Some doctors thought of tuberculosis or syphilis while some other doctors said a microorganism which was not present in Europe might have caused the disease. Hulusi Behçet, who continued to examine the patient after his loss of vision, thought that the causative agent was a virus. In the next several years he met two more patients with similar to that was seen in the previous patient. Hulusi Behçet thought the symptoms of these three patients were the symptoms of a new disease and reported his ideas on this topic firstly in 1936, in the Journal of Skin and Venereal Diseases (Tuzun, 2006; Ustun, 2002; Kartal Durmazlar & Kandi, 2011; Saylan, 1997). Later, in 1937 he wrote clear examples of symptomatic triad, which are still used as criterias worlwide for diagnosis of Behçet's disease, in Dermatologische Wochenschrift. In the same year at the meeting of the Society of Paris Dermatology he declared that several factors may cause the etiology of the disease, which still can be an acceptable statement. Later he diagnosed further patients and published in German as "Tri-Symptomenkomplex" in 1939, and in English as "Triple symptom complex" in 1940 (Tuzun, 2006; Ustun, 2002; Kartal Durmazlar & Kandi, 2011; Saylan, 1997; Evereklioglu, 2006). In subsequent years, this unique disorder drew the attention, and the term "Behçet syndrome" was first used by Jensen in 1941 (Jensen, 1941). The term "Behçet disease" was first used by Fiegenbaum and Kornblueth in 1946 (Kartal Durmazlar & Kandi, 2011; Figenbaum, 1946; Dilsen, 1996; Alpsoy, 2009). On 13 September

Venous Thrombosis in Behcet's Disease 45

As a systemic disease, Behcet's disease involves visceral organs also such as the gastrointestinal tract, pulmonary, musculoskeletal, and neurological systems (Table 2)

> Non-migratory monoarthritis or oligoarthritis, rarely polyarthritis, characterized by non-specific inflammatory-type synovitis. Favors large joints such as the knee (most commonly), ankle, wrist, and elbow as well as proximal interphalangeal and metacarpophalangeal joints. Spinal and sacroiliac involvements are uncommon. *Symptoms and signs:* arthralgia, tenderness, swelling, limitation of joint movement,

warmth, morning stiffness, and redness at the articular site

Aorta and pulmonary artery aneurysms, infarct and hemorrhage, pleural effusion, pulmonary thromboembolism, tracheobronchial ulcerations, pneumonitis, mediastinitis, paranchymal fibrosis, arteriobronchial fistula, cor pulmonale, hilar and mediastinal lymphadenopathy, and lobular perfusion defects. *Symptoms:* hemoptysis, cough, dyspnea, and pleuritic chest pain

Ulcerative lesions especially terminal ileum, cecum, occasionally in

*Symptoms:* anorexia, dysphagia, dyspepsia, vomiting, flatulence, vague abdominal discomfort, distention and pain, bloating, and diarrhea.

Superficial and deep obliterative thrombophlebitis in lower extremity, varices, embolization, infarction, bleeding ulcers. Veins are affected more frequently than arteries. Large vessel thromboses in superior and inferior vena cava with a caput medusa, deep femoral and subclavian veins can occur. Occasionally, aorta, carotid, and popliteal aneurysms, radial artery occlusion, and thromboses of the hepatic (Budd-Chiari syndrome), mesenteric, pulmonary, iliac and renal veins

Inner ear involvement cochlear and peripheral vestibular disturbances, tinnitus, deafness, dizziness, unilateral or bilateral

sensorineural hearing, orthostatic disequilibrium

Perforation can occur and malabsorbtion is common

with intracranial hypertension, mesenteric artery aneurysm

Coronary artery disease, myocardial infarction, endocarditis, myocarditis, pericarditis, aortitis, valvular disease (aortic/mitral regurgitation), intracardiac thrombus, endomyocardial fibrosis,

Microscopic hematuria and proteinuria (microalbuminuria) with normal renal functions, or rapidly progressive anti-neutrophylic

antibody-associated vasculitis, cresentic or proliferative glomerulonephritis (focal segmental or sclerosing, diffuse or mesangial), IgA nephritis, renal vein thrombosis, amyloidosis,

nephrotic syndrome, renal failure

esophagus and stomach.

arrhythmia

(Evereklioglu, 2005).

Articular manifestations

Audiovestibular features

Thoracic involvement

GIS

involvement

Vascular involvement

Cardiac involvement

Renal involvement

Manifestations Characteristics

1947, international dermatologic societies came together in Zurich and named the disease as "Morbus Behçet", which honored the first describer of "triple symptom complex" after Zurich Medical Faculty Professor Mischner's proposal. In fact, several authors before Hulusi Behçet described one or several individual findings of this disorder. Among these physicians, for example, Hippocrates in the fifth century BC reported some individual symptoms attributed to an originally endemic and epidemic disease. But, due to sporadic appereance of the disease in the course of time, the disease became less significant and was forgotten. There were also other physicians who described one or several individual findings of this disorder, for example, Janin (1772), Reis (1906), Blüthe (1908), Gilbert (1920, 1921, 1923), Planner and Remenowsky (1922), Weve (1923), Shigeta (1924), Adamantiades (1930), Dascalopoulos (1932), Whitwell (1934), Nishimura (1936), Blobner (1937) reported several individual findings of this disorder. However, all these papers ascribed the findings either to another disease, such as tuberculosis, syphilis, sepsis or allergy, or to a coincidence and none of them indicated a new or a single syndrome with "classical triad" (Kartal Durmazlar & Kandi, 2011; Alpsoy 2009; Evereklioglu, 2006, 2007a, 2007b, 2007c; Freigenbaum, 1956). The disease is sometimes named as Adamantiades-Behcet's disease, however, Behcet's disease should be preferred as suggested by International Associations and Societies of "Behcet" (Mendes et al., 2009).

Several diagnostic criteria have been developed during the years, all have in common the 3 major features of oral ulceration, genital ulceration and eye lesion (16). Today, International Study Group criteria for the diagnosis of Behcet's disease is used worldwide (Table 1) (International Study Group diagnostic criteria, 1990.).


\*Findings applicable only in the absence of other clinical explanations

Table 1. International Study Group diagnostic criteria, 1990.

1947, international dermatologic societies came together in Zurich and named the disease as "Morbus Behçet", which honored the first describer of "triple symptom complex" after Zurich Medical Faculty Professor Mischner's proposal. In fact, several authors before Hulusi Behçet described one or several individual findings of this disorder. Among these physicians, for example, Hippocrates in the fifth century BC reported some individual symptoms attributed to an originally endemic and epidemic disease. But, due to sporadic appereance of the disease in the course of time, the disease became less significant and was forgotten. There were also other physicians who described one or several individual findings of this disorder, for example, Janin (1772), Reis (1906), Blüthe (1908), Gilbert (1920, 1921, 1923), Planner and Remenowsky (1922), Weve (1923), Shigeta (1924), Adamantiades (1930), Dascalopoulos (1932), Whitwell (1934), Nishimura (1936), Blobner (1937) reported several individual findings of this disorder. However, all these papers ascribed the findings either to another disease, such as tuberculosis, syphilis, sepsis or allergy, or to a coincidence and none of them indicated a new or a single syndrome with "classical triad" (Kartal Durmazlar & Kandi, 2011; Alpsoy 2009; Evereklioglu, 2006, 2007a, 2007b, 2007c; Freigenbaum, 1956). The disease is sometimes named as Adamantiades-Behcet's disease, however, Behcet's disease should be preferred as suggested by International Associations

Several diagnostic criteria have been developed during the years, all have in common the 3 major features of oral ulceration, genital ulceration and eye lesion (16). Today, International Study Group criteria for the diagnosis of Behcet's disease is used worldwide (Table 1)

Plus any two of the following:

Eye lesions Anterior uveitis, posterior uveitis, cells in the vitreous on slit-

Skin lesions Erythema nodosum observed by the physician or patient,

on corticosteroids treatment Pathergy Read by physician at 24-48 hours (The test is performed by

more than 2 mm in diameter.

in one 12-month period

Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient recurring at least three times

Aphthous ulceration or scarring, observed by physician or

lamp examination; or retinal vasculitis observed by

pseudofolliculitis, papulopustular lesions; or acneiform nodules observed by physician in post adolescent patients not

introducing a 20-gauge or smaller sterile needle 5 mm obliquely into the patient's flexor aspect of the avascular forearm skin without injection of saline under sterile conditions. The test is considered positive if there is an indurated erythematous small papule or pustule formation of

and Societies of "Behcet" (Mendes et al., 2009).

Recurrent oral ulceration

Recurrent genital ulceration

(International Study Group diagnostic criteria, 1990.).

patient

\*Findings applicable only in the absence of other clinical explanations Table 1. International Study Group diagnostic criteria, 1990.

ophthalmologist

As a systemic disease, Behcet's disease involves visceral organs also such as the gastrointestinal tract, pulmonary, musculoskeletal, and neurological systems (Table 2) (Evereklioglu, 2005).


Venous Thrombosis in Behcet's Disease 47

Histopathological studies revealed cellular infiltrations consisting of lymphocytes, plasmocytes, monocytes and PMN in varying degrees, depending on the stage of lesion in BD. Since cytokines are involved in the regulation of functions of lymphocytes and phagocytes, they are playing important role in the pathogenesis of the disease (Durmazlar et al, 2009). Chemotactic and phagocytic activity of neutrophils in patients with BD has been reported to be high (19). Increased spontaneous secretion of Tumor necrotizing factor (TNFα), Interleukin-6 (IL-6) and Interleukin-8 (IL-8) in monocyte cultures obtained from BD patients have been reported (Mege et al., 1993). IL-8 secretion after incubation of human dermal microvascular endothelial cells with serum of BD patients indicates that chemotaxis is an initial process of inflammation. IL-8 upregulates neutrophil chemotaxis as mRNA expression have been reported to be more prominent in patients with active BD than in patients with inactive disease (Evereklioglu, 2005). IL-8, a major chemokine known as neutrofil activating factor, attract and activate leukocytes has been assumed to represent such a notable link between immune system activation and endothelial alterations in BD (Durmazlar et al., 2009; Evereklioglu, 2005; Tursen, 2009). It has been suggested that Th1 type cytokines and chemokines including IL-17, largely produced by activated CD4+ and CD8+ T cells, are involved in the recruitment of neutrophils to the site of inflammation. Activated neutrophils in

BD patients produce significant quantities of IL-12 and IL-18 (Pay et al., 2007).

immunopathogenesis of Behcet's disease (Pay et al., 2007).

The pathogenesis of thrombotic events in BD is not fully understood. The primary abnormalities of the coagulation, anticoagulation, or fibrinolytic systems have not been confirmed yet in BD. The main factor responsible for the increased frequency of thrombosis in BD is thought to be endothelial dysfunction caused by vascular inflammation (Evereklioglu, 2005). There is accumulating evidence for inflammation markers as a result of thrombosis. Deep vein thrombosis significantly associates with the male gender and a positive pathergy test (Houman et al., 2001). A number of studies have explored the pathogenesis of thrombophilia in Behçet's disease. Neither deficiency in protein C, in protein S, in factor V Leiden and in antithrombin III nor resistance to activated protein C and anticardiolipin antibody levels seem to be correlated with vascular thrombosis in Behçet's disease (Houman et al., 2001; Espinosa et al., 2002; Hirohata & Kikuchi, 2003). In BD, there is an occlusive inflammatory thrombus formation, strictly adherent to inflamed vessel wall, which is typically not complicated with thromboembolism (Lakhanpal et al., 1985; Kobayashi et al., 2000; Matsumoto et al., 1991). There are increased thrombin generation, fibrinolysis, and thrombomodulin in Behçet's disease, but these abnormalities are not related to thrombosis (Espinosa et al., 2002). These results therefore suggest that thrombophilia in Behçet's disease may be related more to inflammation than to clotting disorder (Hirohata & Kikuchi, 2003). Studies have disclosed the occurrence of antiendothelial cell antibodies, increased E-selectin and myeloperoxydase expression in Behçet's disease (Houman et al., 2001; Espinosa et al., 2002; Hirohata & Kikuchi, 2003). As neutrophils from active Behçet's disease release increased amounts of myeloperoxydase, it is probable that neutrophil activation as well as the expression of antiendothelial cell antibodies may play an important role in the development of endothelial inflammatory damages, leading to thrombophilia (Houman et al., 2001; Espinosa et al., 2002; Hirohata & Kikuchi, 2003). Figure 1 summarizes the

Homocysteine (Hcy) is an intermediary sulphydryl-containing aminoacid formed during the conversion of methionine to cysteine. Its sulphydryl group can cause direct endothelial cytotoxicity, inhibition of glutathione peroxidase and nitric oxide, interference with clotting


CNS \_ central nervous system; GIS \_ gastrointestinal system.

Table 2. Additional Systemic Features of Behcet Disease (From Evereklioglu, 2005).
