A total of 165 patients with a diagnosis of ocular involvement in BS were analyzed. Their demographic characteristics, including age, age of disease onset, and concomitant medications are listed in Table 1. Mean age at the onset of BS was 31.81 ± 7.92 years and mean duration of BS was 10.64 ± 7.18 (1-35) years. Mean age at the onset of ocular involvement was 32.32 ± 7.96 (7-55) years. The mean initial dose of AZA was 150 mg once daily, which corresponded to 2 mg (or slightly higher) per kilogram body weight. During the treatment period, the highest dose of AZA was 250 mg/day, which corresponded to 3 mg/kg/d. The mean duration of treatment with AZA was 76.13 months.
In our study, all 165 patients received prednisolone at different doses ranging between 10 mg/d and 0.5 mg/kg according to the severity of their ocular disease. Cyclophosphamide (PCP) was used in 101 patients at a dose of 1 g per month, and colchicine was used in 56 patients at a daily dose of 0.5-2 mg. Also, methotrexate (MTX) was used in 50 patients at a dose of 15-25 mg per week, cyclosporine (CsA) was used in 30 patients at a daily dose of 3-5 mg/kg, infliximab was used in 12 patients at a daily dose of 3-5 mg/kg, and rituximab was used in 2 patients at a dose of 1 g on days 0 and 15.
Clinical manifestations in patients with Behçet’s syndrome:
Of the 165 patients with ocular involvement in BS, 103 (62.43%) were male and 62 (37.57%) were female. The male/female ratio was 1.66. All patients had mucocutaneous lesions. Recurrent oral aphthous ulceration was the initial manifestation of the disease in 163 patients (98.80%, 95% CI: ± 13.4), accompanied by genital ulceration (bipolar aphthous ulcers) in 104 patients (63%, 95% CI: ± 48.4), whereas 2 patients did not have any oral or genital aphthous ulcers. Skin aphthous lesions were present in 4 patients (2.42%, 95% CI: ± 18.70), a positive pathergy test was recorded in 72 patients (43.64%, 95% CI: ± 50), pseudofolliculitis occurred in 39 patients (23.64%, 95% CI: ± 42.2), and erythema nodosum was present in 26 patients (15.76%, 95% CI: ± 32).
Vascular involvement was present in 14 patients (8.49%, 95% CI: ± 9.1). Superficial thrombosis was observed in 5 patients (3.0%, 95% CI: ± 15.40), and 7 patients had deep vein thrombosis (4.24%, 95% CI: ± 20.2). One patient had superior vena cava syndrome (0.61%, 95% CI: ± 7.8), 1 patient had sagittal sinus thrombosis (0.61%, 95% CI: ± 7.8), 1 patient had aneurism of the carotid artery (0.61%, 95% CI: ± 7.8), and 1 patient had an aortic aneurysm (0.61%, 95% CI: ± 7.8).
Musculoskeletal involvement was seen in 22 patients (13.34%, 95% CI: ± 12.7): 18 had arthritis (10.91%, 95% CI: ± 31.3), 1 had avascular necrosis of the femoral head (0.61%, 95% CI: ± 7.8), 2 had ankylosing spondylitis (AS) (1.21%, 95% CI: ± 10.9), and 1 had arthralgia (0.61%, 95% CI: ± 7.8). Other less frequently detected manifestations were CNS involvement in 6 patients (3.64%, 95% CI: ± 18.7), epididymo-orchitis in 6 patients (3.64%, 95% CI: ± 18.7), renal involvement characterized by glomerulonephritis in 1 patient (0.61%, 95% CI: ± 7.8), Crohn disease in 1 patient (0.61%, 95% CI: ± 7.8), and multiple sclerosis (MS) in 1 patient (0.61%, 95% CI: ± 7.8). Table 2 summarizes the frequencies of clinical manifestations in our series.
Ocular manifestations in patients with Behçet’s syndrome:
Ophthalmic manifestations in patients with BS are noted in Table 2. Of the 165 patients with ocular BS, 163 had posterior uveitis (98.80%, 95% CI: ± 13.4), 102 had anterior uveitis (61.82%, 95% CI: ± 48.80), and 157 had retinal vasculitis (95.15%, 95% CI: ± 25.0).
Of 8 patients who had posterior uveitis without retinal vasculitis, 6 had only posterior uveitis, and 2 patients had both posterior and anterior uveitis. In 3 patients, AZA was prescribed after MTX was discontinued because of resistance. In 1 patient, AST and ALT elevation (three times as much as the normal value) was caused by MTX toxicity so that AZA was administered. In 3 patients with incomplete response to MTX, AZA was added to MTX. Two of these 3 patients also received colchicine together with AZA and MTX.
All adverse events induced by azathioprine:
In 11 out of 165 patients (6.67%), AZA therapy was discontinued or tapered prematurely due to adverse events. The adverse events leading to AZA discontinuation are shown in Table 3. One patient developed basal cell carcinoma (BCC) after 5 years of AZA use. Two patients were hospitalized because of high fever and chills, nausea, arthralgia, and increased serum level of liver enzymes, which resolved after drug discontinuation. In 1 patient, adverse events after the start of AZA treatment led to hospitalization due to concomitant pancreatitis and hepatitis. Another 2 patients treated with a dose of 150 mg/d (2 mg/kg/d) had severe leukopenia, which resolved after temporary drug discontinuation.
The dosage of AZA was reduced in 4 patients due to elevated values of liver function tests (LFT). In 4 patients treated with a dose of 150-250 mg/d (2-3 mg/kg), LFT values increased more than or less than three times as much as the upper limit of normal (ULN), so their dosage was reduced to 50-150 mg/d (0.5-1.5 mg/kg), after which liver enzymes values returned to normal (Table 3).
In 1 patient LFT increased more than 3-fold the ULN after treatment for 6 months with 200 mg/d AZA. The dosage was changed to 150 mg/d, after which the patient recovered. One patient who used 150 mg/d AZA had increased LFT less than 3-fold the ULN after 3 months. The dosage was reduced to 100 mg/d and the patient recovered. In another patient treated with 250 mg/d AZA for 28 months, LFT increased less than 3-fold ULN. The dosage was change to 150 mg/d, and again, the patient recovered. In 1 patient treated with 200 mg/d for 3 months, LFT increased more than 3-fold the ULN and the patient reported nausea. Therefore the dose was reduced to 100 mg/d, and the patient recovered (Table 3).
Hepatitis and pancreatitis (LFT > 3-fold the ULN, alkaline phosphatase (ALP) > 3-fold the ULN, and increased amylase up to 302) were side effects seen in 1 patient after treatment with 150 mg/d for 3 months. The patient recovered after AZA was discontinued.
In 1 patient treated with 100 mg/d AZA, nausea and vomiting appeared after 3 years; these side effects resolved after the drug was discontinued (Table 3).
Transient severe leukopenia was recorded in 2 patients who received 150 mg/d (2 mg/kg) AZA, one in the first month of treatment (WBC count 2300) and one after 3 months (WBC count 1900). They both recovered after 1 month without any change in treatment (Table 3).
In 2 patients AZA was discontinued because of allergy. In 1 patients who was prescribed 150 mg/d (2 mg/kg/d), fever, arthralgia and skin involvement (redness) appeared after 1 week, along with increased LFT (more than 2-fold the ULN). This patient recovered after the drug was discontinued. In the other patient, the initial dose of 50 mg/d (0.5 mg/kg/d) was associated with allergic reactions (skin redness) and the drug was discontinued.
In 1 patient who received 150 mg/d (2 mg/kg/d) AZA for 5 years, the patient stopped the drug due to recovery from ocular disease for 1 year. However, this patient later developed BCC (Table 3).