manifestations suggestive of systemic vasculitis [351, 360]. In a study performed by us on the diagnostic value of ANCA testing in patients with scleritis associated with GPA, ANCA titers were highly speciÞc and sensitive for GPA in patients with scleritis [361]: of 23 patients with scleritis in which ANCA titers were obtained, all seven patients with positive titers had limited or generalized GPA and none of the 16 patients with negative ANCA titers had GPA.

Positive ANCA testing conÞrms the diagnosis of the highly limited forms of GPA in a patient with scleritis and pathological detection of necrotizing granulomas with or without inßammatory microangiopathy [338].

Either type of ANCA (C- or P-ANCA) can be found in patients with generalized, limited, or highly limited forms of GPA with ophthalmic involvement [338, 360, 361].

The discovery of ANCA as a speciÞc and sensitive index of generalized disease in GPA is likely to improve the prognosis for patients with this disease by facilitating earlier diagnosis and detection of relapse. However, a single positive ANCA test should be interpreted with caution.

6.1.10.5 Diagnosis

The diagnosis of GPA is generally made on the basis of the clinicopathological Þndings of necrotizing granulomatous lesions of the upper and lower respiratory tract, glomerulonephritis, and frequent vasculitis involving other organ systems. The American College of Rheumatology established criteria for the diagnosis of GPA [362]. The presence of two or more of the following four criteria was associated with a sensitivity of 88.2% and a speciÞcity of 92% for GPA: (1) abnormal urinary sediment (red cell casts or Þve blood cells per high power Þeld); (2) abnormal Þndings on chest radiograph (nodules, cavities, or Þxed inÞltrates); (3) oral ulcers or nasal discharge; and (4) granulomatous inßammation (in the vessel wall, perivascular, or extravascular).

Cultures and special stains must be done to rule out infectious causes of granulomatous inßammation, such as acid-fast bacilli and fungi.

In its typical presentation, the clinicopathologic complex of GPA usually provides ready differentiation from other disorders. However, if

all the typical features are not present at once, it needs to be differentiated from the other vasculitides, GoodpastureÕs syndrome, relapsing polychondritis, tumors of the upper airway or lung, and infectious diseases, such as histoplasmosis, mucocutaneous leishmaniasis, and rhinoscleroma,aswellasnoninfectiousgranulomatous diseases. ANCA testing is an important adjunct in the diagnosis of GPA because it has been found to be 99% speciÞc and 96% sensitive for the active generalized condition [340]. Because of its high speciÞcity, a positive test is suggestive of GPA, even in patients without compatible clinical and histopathological Þndings. However, because ANCA is positive only in 67% of patients with active limited disease and in 32% of patients in full remission after limited disease [340], a negative ANCA test does not exclude the diagnosis, especially in patients with limited clinical features and characteristic histological Þndings.

Pathologic detection of necrotizing granulomas with or without vasculitis in involved extraocular tissues (nasal mucosal, sinus tissue, skin, and lung) conÞrms the diagnosis of GPA in a patient with compatible systemic clinical Þndings with or without positive ANCA testing. Pathological detection of necrotizing granulomas with or without inßammatory microangiopathy in conjunctiva and/or scleral specimens in association with complete and, especially, limited clinical features conÞrms the diagnosis of GPA even if the ANCA testing is negative.

In the absence of characteristic ocular histological Þndings, a positive ANCA test is suggestive of highly limited GPA, although not diagnostic. In the absence of positive ANCA test, the presence of characteristic ocular histological Þndings without systemic clinical features does not support the diagnosis of GPA.

6.1.11 Adamantiades–Behçet’s Disease

AdamantiadesÐBeh•etÕs disease (ABD) is a chronic relapsing systemic vasculitis of unknown etiology characterized by oral ulceration, genital ulceration, and ocular inßammation. Although Hippocrates had already noted the association

between ocular inßammation and oral and genital ulcers [363], it was Benedictos Adamantiades, a Greek ophthalmologist, who Þrst recognized the disease as a distinct entity in 1931 [364]. Hulusi Beh•et [365], a Turkish professor of dermatology, publishing in the German dermatologic literature, which was very widely read at the time (1937), also published on a series of patients with this syndrome, naming it for himself, giving the name its most common eponymic name.

6.1.11.1 Epidemiology

The prevalence of ABD has a peculiar distribution as most cases have been reported from Japan and the eastern Mediterranean countries, especially along ancient silk trade routes. The highest reported prevalence is in Japan, with 7Ð8.5 cases per 100,000 population [366]. However, the disease may occur worldwide. Our series of cases with ocular ABD have been reported from the USA with a higher than expected proportion of Hispanic patients [367].

Although the number of male patients exceeds females in Turkish [368], Israeli [369], and Japanese clinic populations [370], reports from the US clinic populations have equal numbers of male and female patients [367, 371]. Male sex and early age of the onset of ABD are associated with greater severity [369].

There is no association between HLA antigens and ABD in Northern European and American populations [372, 373]. By contrast, in Japanese and Mediterranean populations, ABD is associated with the histocompatibility B5 antigen, and particularly the B51 subgroup [374, 375].

6.1.11.2 Systemic Manifestations

Systemic manifestations of ABD include oral and genital mucosal ulcers. In addition to that, there may be involvement of the skin, joints, major vessels, gastrointestinal tract, and central nervous system.

Mucosal oral ulcers, ranging from 2 to 10 mm in diameter, are typically round or oval, with a central yellow base, and surrounded by a red halo. They are exceedingly painful and can appear on the buccal mucosa, lips, tongue, and pharynx. These ulcers heal in 3Ð30 days usually without scarring, and typically are recurrent.

Mucosal ulcers of the vulva and vagina in females and of the scrotum and penis in males are similar to the oral ulcers, but tend to be deeper and often scar. Genital ulcerations recur less frequently than oral ulcerations. Nonmucosal genital ulcers are nodular with central ulceration.

The skin lesions typical of ABD include erythema nodosum, pustules, and papules, all considered to be manifestations of cutaneous vasculitis. However, because cutaneous vasculitis is common in other systemic diseases, skin lesions are nonspeciÞc. Erythema nodosum is an eruption of tender, raised, red nodules, usually conÞned to the lower extremities, that usually resolves without ulceration in a matter of weeks. Pustular vasculitis or papulopustular eruption also may occur in ABD. A nonspeciÞc skin sensitivity to simple trauma or pathergy test has been reported in patients with ABD; the presence of marked redness, swelling, and/or a pustular lesion 24Ð48 h after a sterile skin prick, or after intradermal injection of air or saline, is interpreted as a positive result. However, because this test has a lower positivity rate in British and North American patients with ABD, it is not helpful for diagnosis in these clinical populations [376].

Nonmigrating, recurrent, seronegative, nondeforming arthritis, affecting knees, ankles, and wrist, may occur in up to 60% of patients with ABD [377]. Cardiovascular involvement includes venous and arterial occlusion and aneurysms, with venous involvement being twice as common as arterial involvement. Venous involvement includes deep vein occlusion (superior vena cava, inferior vena cava, femoral and subclavian veins, or common iliac and hepatic vein) and superÞcial thrombophlebitis. Arterial involvement includes stenosis or occlusion of subclavian, renal, carotid, or femoral arteries. Cardiovascular involvement in ABD carries a poor prognosis [377]. Gastrointestinal ulcerations may occur, particularly in the lower ileum and right side of colon; they may perforate and require hemicolectomy and distal ileal resection. Central nervous system manifestations of ABD can cause sensory, motor, or neuropsychiatric symptoms. Meningoencephalitis can cause headache, fever, stiff neck, cerebrospinal pleocytosis, and focal neurologic deÞcits.