Genital ulcers are one of the cardinal signs of BS with a frequency of about 85%. They are oval or round with punched-out appearence. They usually begin as a papule, pustule or necrotic crust that ulcerate within a short period (Fig. 2). Genital ulcers of BS can be painful. Their borders are
<r* u Mr regular and oedematous and their base are covered with a yellow fibrin.
We have recently formally studied the fate of these genital ulcers in a sizeable group of patients (Mat et al., in print). If they are not secondarily infected they usually heal in 10-30 days. In males, genital ulcers occur mostly on scrotum (88.9%), penis, femoral and perianal regions. Large ulcers usually end up with scarring (89.4%). Scarring rate of small ulcers was 48.9%. In females, ulcers are commonly found on both major and minor labiae (Fig. 3). Vaginal and cervical lesions are less frequent. Similarly large ulcers heal with scar, while only 54% of small ulcers do so in females. The ulcers, located at the labia minor, do not result in scar while healing, rather similar to the situation in oral ulcers. It is also possible that mucosal scarring cannot be discerned by the naked eye.
The histopathology is similar to that seen in oral aphthous lesions. Neutrophil-predominating infiltrate is a feature of early lesions. In older lesions, the inflammatory cells are mostly lymphocytes, mixed with histiocytes and plasma cells. Presence of lymphocytic vasculitis has been reported in almost half of the cases, while leukocytoclastic vasculitis was rare (Chun et al., 1990). Other vascular changes such as thickening of the walls, end-othelial swelling, tendency to obliteration have also been reported particularly in small arteries and capillaries (Nazzaro, 1966).
Figure 2. Scrotal ulcers.
Figure 3. Multiple genital ulcers.
Pustular lesions may be found in various parts of the skin. Face, back, chest, shoulders, femoral regions, pubis and buttocks are the common sites. Acne and/or folliculitis (when the lesion is around a hair follicle). And acne-like lesions, located at the back, face or the upper torso—the common acne vulgaris sites—cannot be clinically differentiated from acne vulgaris even by experienced dermatologists. Sebum secretion in BS is as high as acne vulgaris (Yazici et al., 1987). Pustules, more commonly formed in the follicular lesions, are surrounded by an erythematous halo. They usually heal within 2-3 days. Contrary to the conventional wisdom these lesions are not sterile (Hatemi et al., 2004). Bacteriologic examination of the pustular lesions of BS showed that Staphylococcus aureus and Provotella spp. were significantly more common in pustules from BS, however coagulase-negative S. aureus was present in acne patients. The microbiology is somewhat different from acne vulgaris while it remains to be seen whether this infection is secondary or has a role in pathogen-esis. It is also worth noting here that these lesions are more frequent in BS patients with arthritis suggesting a reactive form of arthritis in BS (Diri et al., 2001; Tunc et al., 2002).
The histopathology of papulopustular lesions are similar to those of deep supurative folliculitis or acne vulgaris (Fig. 4). There is a neutrophil-pre-dominating infiltrate around the hair follicle, with or without destruction of the follicular epithelium and sebaceous gland. There may be intra-follicular abscess formation. By the release of the follicular content, perifollicular abscess, localized cellulitis and foreign body granulomatous reaction can be seen. Some of these lesions contain dilation of the infundibular portion of the follicle, with a lumen containing a plug of keratin and sebaceous material. By the development of such comedones, they resemble acne vulgaris both clinically and histopathologically (Ergun et al., 1998a). The small vessels display some thickening, fibrin deposition in the vessel wall and within the lumen, at times. These vascular changes are more likely to be secondary to acute inflammation or less likely can
be seen as a manifestation of neutro-philic vascular reaction in BS.
In brief it can be said that it is difficult to differentiate, both clinically and by histology, the acnelike lesions of BS from ordinary acne. Clinically, the most important differentiating feature is the presence, in BS, of these lesions at the arms and legs, unusual for ordinary acne.
5.4. Nodular lesions
Nodular lesions seen in BS may be due to pan-niculitis (erythema nodosum-like lesions) or superficial thrombophlebitis.
Erythema nodosum (EN)-like lesions are observed in 50% of the patients. They are most frequently detected in the shins, thighs and rarely in the upper extremities. They are characterized by painful erythematous-purple nodules (Fig. 5).
They can be few or many. Some may ulcerate. As they heal, hyperpigmentation is seen. They are more common in women (Tursen et al., 2003).
The histopathological features of nodular lesions of BS, are characterized by neutrophil-predominating infiltrate both in lobules and septum of the subcutis (Figs. 6 and 7). Rarely, the inflammatory cell infiltrate is dominated by lymphocytes. Neutrophilic vasculitis, involving mostly arterioles and venules, can be detected in almost half of the cases (Kim and Le Boit, 1998; Demirkesen et al., 2001) (Fig. 8). Involvement of veins and sometimes, even small arteries can be seen in a limited number of cases (Fig. 9). Chun et al. (1989) also reported the presence of lymphocytic vasculitis in 40% of their cases, however, they indicated that it may be a secondary phenomenon
rather than a primary vasculitis. Necrobiosis and leukocytoklasia are other common features of nodular lesions of BS. Granuloma formation is less frequent. By these features, nodular lesions of BS can be distinguished from EN associated with other diseases—where as a rule vasculitis is not found—but resemble nodular vasculitis (NV), another common type of panniculitis.
Superficial thrombophlebitis affects large and small veins of the lower extremities and is more common among men. Nodules are usually seen as unilateral, painful nodules or sting-like lesions following the vein tracts (Fig. 10). Great saphenous vein is the most affected site. The presence of
Figure 9. Neutrophilic vasculitis in a small- to medium-sized artery (HE x 10 0).
Figure 11. Superficial thrombophlebitis: Obliteration of the vein with partially organizing thrombus (HE x 40).
Figure 9. Neutrophilic vasculitis in a small- to medium-sized artery (HE x 10 0).
Figure 11. Superficial thrombophlebitis: Obliteration of the vein with partially organizing thrombus (HE x 40).
superficial thrombophlebitis clusters thrombosis in the big veins (Tunc et al., 2002).
In histology the involved veins are obliterated by organizing thrombi (Fig. 11). The walls show fibrous thickening, sometimes accompanied by mononuclear cell infiltrate. In early lesions, neu-trophils may be present at the vessel wall.
5.5. Sweet syndrome
The manifestations of Sweet syndrome are sometimes observed in BS. They are usually located on the face and extremities and consist of painful inflammatory nodules and plaques (Fig. 12) (Oguz
Figure 12. Sweet-like nodules on the face.
Figure 12. Sweet-like nodules on the face.
et al., 1992). Their frequency ranged from 2.1 to 4% in one series (Shi Hui-Li and Huang-Zheng-ji, 1993).
The histopathological examination reveals dense, diffuse or patchy neutrophilic infiltration within the dermis, sometimes extending to the subcutis. Leukocytoclasia and extravasated ery-trocytes are frequent. Prominent edema in the upper dermis, which may result in blister formation, is commonly found. Within the dermal infiltrate, vascular proliferation and swelling of the end-othelial cells are detected. There is no fibrin deposition. The epidermis may be slightly acanthotic or normal. In later stages, neutrophilic infiltration can be replaced by lymphohistiocytic infiltration.
Since some features of BS—like arthritis and oral ulcers—can also accompany the so-called idiopathic Sweet syndrome (Magro and Crowson, 1995), sometimes it becomes only an exercise in semantics whether a patient manifesting these lesions has primary or secondary Sweet's syndrome.
Pathergy reaction, one of the characteristic features of BS, is diagnostically useful. A 20-gauge needle insertion in the flexural site of the forearm skin causes a nonspecific inflammatory reaction after 48 h. Presence of 1-2 mm papule or pustule usually surrounded by an erythematous halo is interpreted as a positive reaction (Fig. 13). Only erythema without induration is considered as
negative. This reaction usually subsides in 4-5 days. Pathergy reaction is rarely observed in controls or in the other diseases (Tiiziin et al., 1980). Pathergy test is usually positive at the active phase of disease and male patients have stronger path-ergy reactions (Yazici et al., 1985).
A positive pathergy test is an important parameter in the diagnosis of BS in the Middle East and Mediterranean countries. The frequency of positive reaction is very low among the British (Yazici et al., 1984a) and the Korean patients (Bang et al., 2001). The specificity of the pathergy test is very high whereas the sensitivity of the reaction varies in different studies. The use of the disposable needles induces lesser amount of trauma and seems to account for the decrease (Ozarmagan et al., 1991). The application of the needles after blunting their surfaces and sterilization increase the rate of posi-tivity (Dilsen et al., 1993). The surgical cleaning of the forearm of the patients with povidone iodine reduced the positivity rate of the reaction from 48 to 27% compared to cleaning the arm with alcohol alone. This showed that trauma alone was not sufficient to explain the phenomenon (Fresko et al., 1993).
It has been claimed that surgical procedures, similar to what is observed in pathergy, might also lead to nonspecific inflammatory reaction as in pathergy reaction. There is only anecdotal evidence that surgical intervention in BS patients causes a nonspecific, heightened inflammation as in pathergy reaction while in a formal study we demonstrated wound healing was normal (Mat et al., 1998).
The intensity of pathergy reaction is not the same in every case, besides, there is considerable intra and interobserver variation (Altac et al., 1982).
In response to a needle-prick, a dermal inflammation composed of lymphocytes, neutrophils, eosinophils, mainly localized around the vessels are detected starting after 12 h, becoming denser at 24 h (Ergun et al., 1998b). Edema and leukocytocl-asia are seen in most cases. Intraepidermal pustules develop, correlated with the clinical pathergy response. Epithelial necrosis can be observed in some cases (Nazarro, 1966). Vascular changes such as endothelial swelling, thickening and homogenization of the wall of the small blood vessels, vascular obliteration, even leukocyto-clastic vasculitis were reported by some authors (Nazzaro, 1966; Bang et al., 2001; Jorizzo et al., 1985). However, some authors maintain that the histopathology of pathergy lesions demonstrate mixed inflammatory infiltrate without vasculitis (Ergun et al., 1998b; Haim et al., 1976).
Haim et al. (1976) and Gilhar et al. (1989) reported an increase in the number of mast cells, however, this finding was not confirmed by the others (Ergun et al., 1998b).
Later at 48 h, mononuclear inflammatory cells predominate, mostly T lymphocytes (Gul et al., 1996). Small clusters of neutrophils and plasma cells may also be detected. The majority of the T cells express CD4. The endothelial cells express ICAM-1 strongly, and E-selectin moderately, while VCAM-1 is not expressed (Gul et al., 1995). According to the expression patterns of these adhesion molecules, Gul et al. (1995) suggested that the direct epidermal injury was the cause of cutaneous inflammation in pathergy in BS. We have recently suggested that injury to the skin of BS patients elicits a T helper 1 (TH1)-cell response owing to IL-12-mediated production of IFN-g by CD4+ T cells. Consistently, the concentrations of chemokines that are active on mon-ocytes/macrophages and TH1-cells, such as MCP-1 and IFN-g-inducible chemokines, IP-10, Mig, and iTac, are increased during the pathergy reaction and the increases are correlated with the extent of mononuclear-cell infiltration at the site of inflammation (Melikoglu et al., 2002). An increased release of cyokines from the keratinocytes, such as IL-6 and IL-1X, as a result of skin injury and overproduction of various cytokines by T cells and monocytes have also been reported by others (Fujii et al., 1983; Hamzaoui et al., 1990; Sakane, 1991; Mege et al., 1993; Ben Ahmed et al., 2004). It seems that the initial reaction to needle-prick is nonspecific, but later on an increase in cytokine release may play the major role in pathergy.
The propensity to sustained inflammation in BS can be shown simply by the intradermal injection of monosodium urate (MSU) crystals. This causes an erythema and induration at the injection site in BS patients (Cakir et al., 1991) that does not go away at 48 h when compared to controls. It was interesting to note that this reaction could not be suppressed by etanercept (Melikoglu et al., 2005).
Rare cutaneous manifestations of BS include pyoderma gangrenosum-like lesions, erythema multiforme, pernio-like lesions, neutrophilic ec-crine hidradenitis, bullous lesions due to ne-crotizing vasculitis, and Kaposi sarcoma (Lee et al., 1997; Cantini et al., 1998; Bilic and Mutasim, 2001; Nijsten et al., 2002; Mercader-Garcia et al., 2003; Lee et al., 1989; Louthrenoo et al., 2003; Kotter et al., 2001).
In histology the central areas of pyoderma gangrenosum display a necrotizing, neutrophil-rich infiltration usually with ulceration. In the adjacent areas, lymphocyte predominating infiltrate is detected mainly around and within the vessel walls. Luminal fibrin deposition, mural necrosis of the vessels or leukocytoclastic vasculitis are rare findings due to maximal tissue reaction, but do not reflect a primary vasculitis.
In a well-developed lesion of erythema multiforme, the most prominent feature is the hydropic degeneration of the basal keratinocytes in epidermis. Many apoptotic cells, called Civatte bodies are present, together with the lymphocytes at the dermoepidermal junction. Papillary dermis is usually edematous. Perivascular lymphohistiocytic infiltration is seen in the upper dermis. Rarely, eosinophils may also be present. In severe cases, epidermal necrosis may result in blister formation.
Cantini et al. (1998) described a BS patient with recurrent, multiple, papulonodular cutaneous lesions on the palm and fingers of both hands. The lesions were roundish, erythematous, painful, bluish-red nodules, 0.5-1 cm in diameter, with a ''pernio-like'' aspect. Histologic examination revealed a perivascular neutrophilic infiltrate.
Neutrophilic eccrine hidradenitis, another neu-trophil-mediated disorder, has recently been reported in some BS patients (Bilic and Mutasim, 2001; Nijsten et al., 2002; Mercader-Garcia et al., 2003). Neutrophilic eccrine hidradenitis is a rare entity that usually presents as asymptomatic ery-thematous papules that disappear spontaneously in 1-3 weeks. However, it may be polymorphic, pruritic, recurrent or even chronic. The histopa-thology of neutrophilic eccrine hidradenitis reveals a dense neutrophilic infiltration around and within the eccrine secretory coil, sometimes together with necrosis of the eccrine secretory gland epithelium. Degenerative changes may include the whole secretory epithelium or can be seen as individual cells with increased cytoplasmic eosinophilia. It typically occurs in patients receiving chemotherapeutic drugs for malignancies, but other associations have also been reported (Nijsten et al., 2002).
Recurrent aphthous lesions, located extragenitally, mostly in the intertriginous areas such as infra-mammary, axillary regions, interdigital areas of the foot, have also been reported in BS (Azizlerli et al., 1992).Their clinical appearance resemble those seen in genital areas and they heal with scar tissue formation. In the skin biopsies, vasculitis was reported as the most prominent feature (Azizlerli et al., 1992).
The prevalence of Th-2 cell-mediated diseases, such as atopy and atopic diseases, in Behcet's disease, a Th-1 cell-mediated disease, has been looked at by several authors. As expected in a Th-1 disease the prevalence of atopy and atopic diseases were significantly lower in BS patients than in controls (Chang et al., 2003). On the other hand, dermographism was found to be common (Din? et al., 2000).
Eye involvement is the most serious manifestation of BS. The overall frequency is about 50%, with a higher frequency in young males and a much lower frequency in older females. It runs a course of exacerbations and remissions, which may lead to blindness in some patients. Ocular involvement is usually bilateral but unilateral involvement may be seen. Panuveitis is the most common form of uveitis (Tugal-Tutkun et al., 2004; Kural-Seyahi et al.,
2003). Late-onset eye disease has a better prognosis. Loss of useful vision mostly occurs in the first 7 years of the disease. It is quite rare for patients to develop eye disease after the initial 4-5 years of the disease course (Kural-Seyahi et al., 2003).
Patients usually complain of ocular pain, ocular discomfort and visual blurring. The primary lesion in eye involvement is retinal vasculitis, mainly involving the veins (Kim, 1997). Fundoscopic examination reveals choroidal and retinal exudates, hemorrhages, cytoid bodies or white patches, venous thrombosis, papilledema and macular disease. Hypopyon, a hallmark of BS, is seen much less commonly than retinal lesions. Retinal lesions, which are sight threatening, are distinctly more common among the male (Tugal-Tutkun et al.,
2004). Hypopyon occurs in about 10% of the BS patients with eye involvement and always indicates accompanying severe retinal disease. Recurrent inflammatory activity may lead to anterior and posterior synechia, secondary glaucoma, optic atrophy and macular degeneration. Conjunctivitis and episcleritis are rare in BS. Conjunctival ulcerations revealed intraepithelial and perivascular infiltration with neutrophils and lymphocytes (Matsuo et al., 2002).
Arthritis and arthralgia are seen in about 50% of BS patients. Mono or oligoarticular involvement is common. The most frequently involved joints are knees, ankles, hands and elbow joints. Axial or hip involvement is rare (Yurdakul et al., 1983). An association of arthritis and acneiform lesions was noted (Diri et al., 2001; Tunc et al., 2002).
Local myositis is occasionally seen in BS, but serum levels of muscle enzyme are not increased (Arkin et al., 1980; Yazici et al., 1981). The prevalence of fibromyalgia in BS is around 10%, mostly in female patients with mild-to-moderate activity (Yavuz et al., 1998).
BS is a systemic vasculitis, affecting both arteries and veins of any diameter (Lie, 1992; Koc et al., 1992). Venous involvement is more frequent and may result in superficial thrombophlebitis, deep-vein thrombosis of the extremities, caput medusa, superior vena cava or Budd-Chiari syndrome (Plotkin et al., 1985). Thrombophlebitis occurs in one-third of all patients and it is more common in man. It is more frequently observed in leg veins, in decreasing order in vena cava inferior and superior, dural sinuses, axillary vein, brachial vein and the portal vein. Thrombi strictly adhere to the vein wall and for this reason the risk of embolization is low. Recurrent deep-vein thrombophlebitis of legs may lead to stasis dermatitis and leg ulcers around the ankle. Occlusion of the vena cava superior or inferior may lead to the vena cava syndrome, whereas obliteration of the hepatic vein may cause Budd-Chiari syndrome. Budd-Chiari syndrome is a rare complication of BS, however, it has a mortality rate of 60% (Saatci et al., 1993).
Pulmonary artery aneurysms are seen in 1-2% of mainly the male patients. (Hamuryudan et al., 2004). It frequently (>80%) coexists with thrombophlebitis of the big veins. Haemoptysis is the most common symptom.
Involvement of great vessels sometimes is referred to as vasculo-Behcet's disease. It mainly affects the aorta, showing irregular fibrous thickening in all layers and focal aneurysmal dilatation (Fukuda et al., 1980). There is loss or interruption of medial elastic fibers, perivascular lymphocytic infiltration, and proliferation of vasa vasorum. In active aortitis, the cellular infiltrate was predominantly neutrophils, lymphocytes and plasma cells, admixed with histiocytes and eosinophils (Matsumoto et al., 1991).
Sometimes, granulomatous inflammation with giant cells in the media can be detected. Accumulation of mucopolysaccharidase within the media, as a degenerative change was reported (Balic,
1995). The pathogenesis of arterial aneurysms are thought to be obliterative endarteritis of vaso vasorum, resulting in dilatation and aneurysm or pseudoaneurysm formation (Rosenthal et al., 1982; Gruber and Weisman, 1983). Luminal obstruction by organized thrombi in venous occlusions is the main pathological feature.
5.13. Neurologic manifestations of Behcet's syndrome
Two main types of CNS lesions are seen (Siva et al., 2001; Akman-Demir et al., 1999). The more common is the parenchymal lesion (80%). Dural sinus thrombi, on the other hand, account for 20% of the cases. A prevalence of neurological involvement was found as 5.3% in a prospective study among the Turkish patients (Serdaroglu, 1998). The CNS disease is more severe among the males as is true for most of the other lesions of BS. The dural sinus thrombi have a much more favorable course and it is rare to see both parenchymal and dural sinus thrombi at the same time.
The common presenting features are headache and pyramidal signs—with or without cerebellar findings. Isolated cerebellar involvement is uncommon and so is peripheral neuropathy, a feature helpful in differentiating BS from other vasculi-tides (Siva and Yazici, 2004).
Cerebrospinal fluid findings are nonspecific. These findings are mild pleocytosis and slight elevation in protein concentration, normal or low glucose level.
In imaging, the lesions are more commonly located in the basal areas. Small vessel vasculitis, a mild inflammatory cell infiltration, demyeliniza-tion and degenerative changes can all be seen on microscopy (Yuh et al., 1994; Hirohita, 2004).
Gastrointestinal involvement shows geographical variation in different populations. It is common among patients from Japan and Korea (Lee, 1986), but rare in Turkish patients (Yurdakul et al., 1996). The main complaints are abdominal pain, diarrhea and melena/hematochezia. The pathologic hallmark of intestinal BS is known to be the presence of a few punched-out ulcers of variable size. There may be deep ulcers resulting in perforation. These ulcers usually appear in the iliocecal region but they may be present at any site, throughout the digestive system (Lee et al., 2001). Ano-rectal involvement is very rare in BS but common in inflammatory bowel disease. Multiple, small shallow ulcers have also been reported in esophagus, stomach and duedonum in some cases of BS (Mori et al., 1983; Good et al., 1982).
5.15. Behcet's syndrome in children
BS in childhood is rare (Kone-Paut et al., 1998) It affects both sexes equally. When compared to the frequency of clinical manifestations with adults, no difference was observed in the frequency of oral and genital ulcerations, but erythema nodosum and folliculitis are more common in Juvenile BS (Azizlerli, 2002). Family history is more common in JBS cases (Kone-Paut et al., 1999).
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