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Clinical Features of Chinese Patients with Behçet’s Disease
Clinical Features of Chinese Patients with Behçet’s Disease Peizeng Yang, MD, PhD,1,2,3 Wang Fang, MD,1,2,3 Qianli Meng, PhD,1,2,3 Yalin Ren, PhD,1,2,3 Lin Xing, PhD,1,2,3 Aize Kijlstra, PhD2,4 Purpose: To characterize the clinical features of Behçet’s disease in Chinese patients. Design: Retrospective noncomparative case series. Participants: Seven hundred seventy-five eyes of 437 patients with Behçet’s disease initially examined from August, 1995, through June, 2006. Methods: The history, demographic parameters, and clinical findings of all consecutive Behçet’s patients referred to the uveitis study center of Sun Yat-sen University were reviewed. Laser flare-cell photometry (LFCM), fundus fluorescein angiography (FFA), optical coherence tomography (OCT), ultrasound biomicroscopy (UBM), and B-scan ultrasonography were performed in certain cases. Most patients were treated by immunosuppressive agents combined with oral corticosteroids. Main Outcome Measures: Patient demographics, clinical presentation, and auxiliary examination findings. Results: Four hundred thirty-seven patients were diagnosed with Behçet’s disease. There were 319 male and 118 female patients. Panuveitis was the most common type of uveitis in both genders, although anterior uveitis was seen more frequently in females. Retinal vasculitis, vitreitis, and retinitis were the most common ocular manifestations in these patients. Cataract and macular edema were the most common complications. Oral aphthae were the most frequent extraocular manifestation, followed by dermatologic lesions, and genital ulcers. The results of FFA, OCT, B-scan ultrasonography, LFCM, and UBM generally were in accordance with or comparable with clinical observations. At the final visit, uveitis was well controlled in 86.2% of patients. However, 20.4% of eyes became legally blind despite aggressive treatment. Kaplan-Meier analysis estimated the risk of losing useful vision (0.05) at 5 and 10 years for males and females as 29% versus 6% and 65% versus 33%, respectively. Conclusions: Behçet’s disease in Chinese patients mainly manifests as nongranulomatous uveitis frequently associated with oral aphthae and dermatologic lesions. Fundus fluorescein angiography, B-scan ultrasonography, LFCM, UBM, and OCT may provide much information about pathophysiologic hallmarks of Behçet’s disease. A combination of corticosteroids with other immunosuppressive agents is effective for most patients with Behçet’s disease. Males had a more severe course and were at higher risk for losing vision than females. Ophthalmology 2008;115:312–318 © 2008 by the American Academy of Ophthalmology.
Behçet’s disease is a chronic, relapsing, multisystemic inflammatory disease presumably caused by an autoimmune response. Its classical triad includes oral aphthae, genital ulcers, and recurrent iridocyclitis with hypopyon. Behçet’s disease typically has its onset in young and adult patients. The global distribution of Behçet’s disease is indicative of a distinct geographic pattern along the old Silk Route.1,2 Behçet’s disease is prevalent mainly in countries around the Mediterranean and Far East,3 such as Turkey, Iraq, Iran, Korea,4 and Japan.5 China is located in one of the highest
incidence areas. The authors’ previous study showed that Behçet’s uveitis is one of the most frequently encountered types of uveitis in China.6 The clinical features of Behçet’s disease have been well documented in some countries where the disease is endemic.4,5,7–11 Previous studies on Behçet’s disease in Chinese patients were published more than 25 years ago and included only a limited number of patients.12,13 This study was undertaken to evaluate the clinical characteristics and associated ocular complications in a large group of consec4
Originally received: December 15, 2006. Final revision: April 12, 2007. Accepted: April 13, 2007. Available online: August 10, 2007. Manuscript no. 2006-1445. 1 Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. 2 Uveitis Study Center and International Uveitis Study Laboratory of Sun Yat-sen University, Guangzhou, China. 3 State Key Laboratory of Ophthalmology of Sun Yat-sen University, Guangzhou, China.
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© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
Eye Research Institute Maastricht, Department of Ophthalmology, University Hospital Maastricht, Maastricht, Netherlands. Supported by the Fund for Innovative Research Groups of Guangdong Province, Guangzhou, China (grant no. 05200176); Key Project of Natural Science Foundation, Beijing, China (grant no. 30630064); National supporting project of China, Beijing, China; and “5010” Clinical Project of Sun Yat-sen University, Guangzhou, China. No author has a proprietary or financial interest in any product mentioned. Correspondence to Peizeng Yang, MD, PhD, Zhongshan Ophthalmic center, Xianlie Road 54, Guangzhou 510060, China. E-mail: [email protected]. ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2007.04.056
Yang et al 䡠 Behçet’s Disease in Chinese Patients utive Behçet’s patients in a referral uveitis center in China and to compare the results with those presented in the international literature. Furthermore, the use of new techniques such as laser flare-cell photometry (LFCM), optical coherence tomography (OCT), and ultrasound biomicroscopy (UBM) to observe the clinical presentation of the disease were evaluated.
Patients and Methods A retrospective study was performed based on the charts of 437 patients with Behçet’s disease referred to the uveitis study center of Sun Yat-sen University from August, 1995, through June, 2006. Most patients were referred by ophthalmologists, dermatologists, or internists from other hospitals all over China. The patients who fulfilled the diagnostic criteria of the International Study Group for Behçet’s Disease14 were included in the study. Because the diagnosis of Behçet’s disease is mainly a clinical one, extensive efforts were made to rule out other uveitis entities that could simulate this disease. If there was any doubt, the case was excluded from the study. Depending on clinical examination and laboratory test results, patients with tuberculosis, syphilis, sarcoidosis, and other types of retinal vasculitis were excluded from the study. The follow-up varied from 3 months to 10.5 years, with an average of 47 months. Among these patients, more than one third (35.2%) had been followed up for more than 5 years, and 175 (40.0%) had been followed up for between 1 and 5 years. A detailed history, including age; initial manifestations; laterality; symptoms; visual acuity; and, most importantly, related systemic manifestations (such as orogenital and dermatologic history, abnormalities in the central nervous system, and gastrointestinal disorders), medical therapy, surgical interventions, and diagnosis made in other hospitals, was obtained from each patient. All patients were examined by the same uveitis specialist (PY). Routine ocular examinations included best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, gonioscopy, and ophthalmoscopy through a dilated pupil. For patients in whom the fundus could not be visualized because of dense opacity of the ocular media, B-ultrasound photography was used to evaluate the vitreous body and retina. The severity of anterior chamber activity was estimated clinically by using the grading system made by Hogan et al15 and Kimura et al.16 Ultrasound biomicroscopy was performed unselectively in 191 eyes of 113 patients (78 with bilateral uveitis and 35 with unilateral uveitis). Fundus fluorescein angiography (FFA) was performed nonselectively in 88 patients to evaluate the changes in the retina, retinal blood vessels, and optic nerve. Laser flare-cell photometry also was performed in 52 cases (88 eyes) using the FC-2000 laser flare-cell meter version 1.0 (Kowa Company, Ltd., Tokyo, Japan). This examination also was performed concurrently in 33 (66 eyes) normal individuals as gender- and age-matched controls. Laboratory examinations, including counts of white blood cells, red blood cells, and platelets, antistreptolysin O titer, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, and rheumatoid factor, were performed in all patients to evaluate the relationship between these parameters and Behçet’s disease. Tuberculin skin testing and tests for syphilis (including rapid plasma reagin and microhemagglutination assay for Treponema pallidum) were performed, if needed, to rule out these 2 diseases. Liver and kidney functions and routine blood test results were evaluated regularly for patients treated with immunosuppressive agents. All the Behçet’s patients with posterior involvement or recurrent episodes generally were treated with corticosteroids combined
with 1 or 2 immunosuppressive agents, mostly cyclosporine and chlorambucil, and to a lesser degree with colchicine, azathioprine, and methotrexate. The treatment usually lasted for more than 1 year and for 2 or 3 years in certain patients. Corticosteroid eye drops and cycloplegic drugs also were used for the patients with anterior uveitis. For comparison of the present findings with those presented earlier by others, a literature search was performed using the PubMed database from 1980 to present (September 2006). References also were identified from the relevant articles and were obtained mainly from ophthalmologic journals. For analytic purposes, all obtained data were stored in an Excel computerized database (Microsoft, Redmond, WA). Analysis of ocular findings and complications was carried out according to the proportion of the eyes that had these features during the follow-up period. The Kaplan-Meier analysis was performed to evaluate the cumulative survival of eyes with a potential visual acuity of ⱖ0.05 in these patients. Results were analyzed using SPSS software version 11.0 (SPSS, Inc., Chicago, IL). For comparing the differences between genders, the Student t test, chi-square test, or Fisher exact test were used. P values less than 0.05 were accepted as statistically significant.
Results Of 437 patients, there were 319 men (73.0%) and 118 women (27.0%). All the patients except 7 (Wei ethnic group, n ⫽ 4; Hui ethnic group, n ⫽ 3) were Han Chinese. The mean age at the onset of uveitis was 29.8 years (range, 5–58 years). Forty-six patients (10.5%) had the first uveitis attack before the age of 20 years. Twelve patients (2.7%) were identified to have had the first onset of uveitis at the age of 50 years or older (Fig 1). A comparative study was performed to evaluate the difference in age at the onset of uveitis between males and females. The mean age at the onset of uveitis was 29.2 years (range, 5–58 years) in males and 31.6 years (range, 10 –58 years) in females (t ⫽ ⫺2.312; P ⫽ 0.021). With regard to familial clustering of the disease, only 2 patients showed this phenomenon. A 19-year-old female patient’s father had died of neuro-Behçet’s disease when he was in his 30s. Another case was a 36-year-old male. His two sisters were diagnosed with Behçet’s disease when they were in their 30s. However, these 2 sisters did not show any ocular involvement. Most patients showed extraocular manifestations (Table 1). All patients had recurrent oral aphthae. The second most common extraocular clinical manifestation was a dermatologic finding, followed by genital ulceration. Other abnormalities included arthritis, thrombophlebitis, gastrointestinal disorders, and epididymitis. As an unusual manifestation, a large skin ulcer was found in the right leg of a 22-year-old female patient (Fig 2 [available at http:// aaojournal.org]). Central nervous system involvement was noted in only 5 of 437 patients, including palsies of cranial nerves and mental changes. Recurrent oral aphthae was the most common presenting manifestation of the disease, followed by ocular involvement (Table 1). All patients showed intraocular inflammation, and 5 patients had keratoconjunctivitis, corneal neovascularization, or scleritis (Fig 3 [available at http://aaojournal.org]). Bilateral involvement was observed in 338 (77.3%) patients. The laterality of ocular involvement was not significantly different between genders ( ⫽ 1.3999; P ⫽ 0.237). The most frequent symptoms reported were decreased vision with recurrent attacks with or without red eyes (344 patients), followed by eye pain or floaters (52 patients) and tearing (41 patients). The intraocular inflammation seen in these patients included anterior uveitis, posterior uveitis, and panuveitis.
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Figure 1. Bar graph showing age at onset and the age at which the diagnosis of Behçet’s disease was made in the 437 patients.
The most frequent type of uveitis was panuveitis, 75.9% in males and 49.8% in females. Anterior uveitis was observed more frequently in females than in males (16.7% vs. 3.3%). The patients with bilateral involvement uniformly showed the same type of uveitis, although an asymmetrical intraocular inflammation was encountered at the early stage of the disease. Mild to moderate flare in the anterior chamber was observed in most cases, whereas numerous cells in the anterior chamber in most cases were observed at the first visit. During a uveitis attack in patients with panuveitis or anterior uveitis, flare and cell scores often increased markedly (data not shown). Hypopyon was noted in 32.4% of the involved eyes. Keratic precipitates were present in 491 (63.4%) of the affected eyes at the first visit. Keratic precipitates usually had small and dusty morphologic features and typically were distributed at the inferior triangle region of the corneal endothelium. Exudative fibrous membranes occasionally were seen in patients (Fig 4 [available at http://aaojournal.org]). Retinal vasculitis and vitreitis were the 2 most common clinical findings of uveitis (81.2% and 66.4%, respectively). The third most common ocular finding of uveitis was retinitis (53.2%). Usually, optic nerve atrophy, diffuse retinal atrophy, and ghost vessels (Fig 5 [available at http://aaojournal.org]) were the final features in patients with refractory retinal vasculitis and vitreitis. Hypopyon, vitreitis, retinal vasculitis, retinitis, retinal hemorrhage, and papillitis were more common in males than in females (Table 2 [available at http://aaojournal.org]). A variety of ocular complications, including complicated cataract, secondary ocular hypertension, and macular edema, were observed (Table 2). Overall, complicated cataract (including aphaTable 1. Frequency of Systemic Manifestations and Prevalence of Initial Manifestations in 437 Patients with Behçet’s Disease
Manifestations
Frequency (No. of Patients)
Oral aphthae Uveitis Skin lesions Genital ulceration Arthritis Thrombophlebitis Gastrointestinal disorders Epididymitis CNS involvement
437 435 341 253 171 70 49 20 5
CNS ⫽ central nervous system.
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%
Prevalence (No. of Patients)
%
100 99.5 78.0 57.9 39.1 16.0 11.2 6.3 1.1
309 57 31 23 12 5 0 0 0
70.7 13.0 7.1 5.3 2.8 1.1 0 0 0
kic and pseudophakic eyes) was the most common complication and was observed in 600 eyes (77.4%), most (77.2%) showing posterior subcapsular opacities. The eyes with cataract had varying degrees of visual impairment, and 68 (11.3%) of these eyes underwent surgery. Routine phacoemulsification with or without intraocular lens implantation in the capsular bag was performed in 46 (7.7%) eyes in the authors’ hospital after the inflammation was controlled completely for at least 6 months. A BCVA of ⱖ0.3 was achieved in 52.2% (24 eyes) of the operated eyes. The remaining 22 eyes with cataract (3.6%) underwent surgery at local hospitals. Among these 22 eyes, cataract surgery had been performed already in 7 eyes before the patient was referred to the authors. The other 15 eyes underwent cataract surgery at local hospitals after the inflammation was controlled completely in the authors’ uveitis study center. Visual acuity could be obtained in only 7 of these 15 eyes (range, hand movements to 0.4; median, 0.1). Secondary elevated intraocular pressure (IOP) was observed in 243 (31.4%) eyes, which ranged between 35 and 60 mmHg. A well-controlled IOP was achieved in 77.8% of the eyes after intraocular inflammation was controlled or antiocular hypertension agents were used. The other eyes underwent surgical interventions, including trabeculectomy, peripheral iridectomy (surgical or laser), drainage valve implantation, or cyclocryotherapy, in the authors’ hospital (38 eyes; 15.6%) or in other hospitals (16 eyes; 6.6%). All eyes but 12 achieved a normal IOP. Four patients (5 eyes) had BCVA of ⱕ0.05 because of optic atrophy caused by uncontrolled intraocular inflammation and IOP. Six patients (7 eyes) had BCVA of ⱕ0.05 because of uncontrolled IOP, although the intraocular inflammation was well controlled. Macular edema (Fig 6 [available at http://aaojournal.org]) constituted the second most common complication and was noted clinically or by examinations with FFA or OCT in 264 eyes (34.1%). Retinal detachment occurred in 74 eyes of 70 patients, of which 42 had exudative detachment, 22 had tractional detachment, and 10 had rhegmatogenous detachment. In 5 eyes with rhegmatogenous retinal detachment, only a scleral buckling was performed. Vitreoretinal surgery (vitrectomy combined with membrane removal, scleral buckling, endophotocoagulation, or endotamponades with expanding gas or silicone oil) was performed in 16 eyes. Indications for vitreoretinal surgery included epiretinal membrane in 12 eyes and macular hole in 4 eyes. Retinal photocoagulation was performed in 24 eyes for a capillary nonperfusion region. All the vitreoretinal surgery was performed after the inflammation was controlled completely for at least 6 months. Retinal reattachment was accomplished in 17 (85.8%) of 21 patients after a mean postoperative follow-up of 17.5 months. Visual improvement occurred in 12 (57.1%) patients, remained the same in 6 (28.6%) patients, and worsened in 3 (14.3%) patients, respectively.
Yang et al 䡠 Behçet’s Disease in Chinese Patients
Figure 8. Kaplan-Meier curves of cumulative survival of eyes with a potential visual acuity of ⱖ0.05 in male versus female patients with Behçet’s disease. A censored observation represents failure to follow-up or end point of this study.
The mean laser flare photometry value in the patients and controls was 24.0⫾20.6 photon counts/ms and 5.2⫾0.9 photon counts/ms, respectively (t ⫽ 4.524; P ⫽ 0.002). The mean number of anterior chamber cells in the 81 eyes of the patients and controls was 63.5⫾28.7 cells/0.5 mm3 and 0.9⫾0.8 cells/0.5 mm3, respectively (t ⫽ 17.143; P ⫽ 0.000). The cell counts detected by LFCM were not readable in the remaining 7 eyes because of severe anterior chamber inflammation. Dye leakage from the retinal capillaries (97.9%) and papillary (or peripapillary) capillaries (95.8%) were the 2 most frequent findings on FFA, followed by leakage from the retinal vessels, mostly retinal veins (76.4%). The other common features detected by FFA included cystoid macular edema (36.8%) and retinal vascular occlusion (22.2%). Ultrasound biomicroscopy revealed irregular sheetlike exudates in the ciliary body (94.8%), varying degrees of dotted echo (cells) in the anterior chamber (93.7%), and masslike exudates in the posterior chamber (86.4%; Fig 7 [available at http://aaojournal.org]). The result disclosed partial angle closure in 19 eyes (10.0%) and complete angle closure in 30 eyes (15.7%). In the 113 patients investigated by UBM, phacoemulsification and intraocular lens implantation was performed in 16 eyes. Ultrasound biomicroscopy showed intraocular lens dislocation in 2 eyes. In these 113 patients, routine glaucoma filtrating surgery had been performed in 13 eyes with secondary glaucoma unresponsive to antiglaucoma medications. Ultrasound biomicroscopy revealed closure of the internal incision of trabeculectomy in 4 eyes. Test results for syphilis were negative in all of the tested patients. Hepatitis B virus surface antigen results were positive in 45 (10.3%) patients. Forty-two (9.6%) patients had a history of tuberculosis and had been treated successfully before uveitis onset. Aspartate aminotransferase and alanine aminotransferase levels were abnormal in 25 (5.7%) and 27 (6.2%) patients, respectively. Blood-fasting sugar was more than 7.8 mmol/1 in 20 (4.6%) patients. Urea nitrogen and creatinine clearance rate were abnormal in 23 (5.3%) and 25 (5.7%) patients, respectively. Increased erythrocyte sedimentation rates and C-reactive protein levels were observed in 102 (23.3%) and 79 (18.1%) patients, respectively.
Abnormal results in antistreptolysin O titer and rheumatoid factor assay were observed in only 20 (4.6%) and 28 (6.4%) patients, respectively. Consultation with internists was recommended to these patients who had abnormal results. No underlying systemic disorders definitely attributed to the uveitis were found in these patients. The mean age at which the diagnosis of Behçet’s disease was made was 33.4 years (Fig 1). A delay in diagnosis was observed in 232 patients, ranging from 1 month to 15 years, with a mean of 3.1 years. The initial diagnosis made in other hospitals often included panuveitis, posterior uveitis, vitreous opacity or hemorrhage, uveitis, anterior uveitis, or iritis. Because of the recurrent and chronic nature of Behçet’s disease, a more aggressive therapy strategy was used for these patients. Systemic corticosteroids (usually 20 –25 mg/day at the beginning) combined with immunosuppressive agent(s), mostly cyclosporine, chlorambucil, or both, were used in patients with recurrent uveitis attacks or with posterior involvement. Additionally, patients with anterior chamber inflammation also were treated with topical corticosteroids and cycloplegic agents. The dosages of corticosteroids and other immunosuppressive agents were adjusted according to the severity of uveitis or their side effects. Immunosuppressive agents were decreased in dosages or were discontinued if severe side effects occurred during treatment. Most patients had markedly impaired vision at the first examination. The initial BCVA was 0.05 or less in 281 (36.3%) of 775 eyes. The final BCVA was 0.05 or less in 20.4% of eyes after a median follow-up of 47 months. Kaplan-Meier survival analysis estimated the risks of loss of useful vision (0.05) to be 6.4%, 10.7%, 24.5%, and 62.2% at 1, 3, 5, and 10 years, respectively. The risks of losing vision at 5 and 10 years for males and females were 29% versus 6% and 65% versus 33%, respectively (log-rank ⫽ 20.143; P ⫽ 0.000; Fig 8). In 95.2% of the patients, the oral aphthae were well controlled after a mean follow-up of 47 months (range, 3 months–10.5 years). Skin lesions, uveitis, and genital ulcers were controlled in 87.1%,
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Discussion This study characterizes the clinical features of Behçet’s disease in Chinese patients based on the data of 437 cases referred to the uveitis study center of the Sun Yat-sen University. These clinical features are, by and large, similar to those reported by others.7–10,12,13,17,18 Oral aphthae, skin lesions, and genital ulcers were the typical extraocular findings in Behçet’s disease. Most patients showed bilateral nongranulomatous anterior, posterior, or panuveitis with a chronic and relapsing course. Severe uveitis was observed more frequently in males. Retinal vasculitis, vitreitis, and retinitis were the most common clinical features in these patients. Cataract and macular edema were the most common complications. Importantly, this study revealed a much lower familial clustering in Chinese patients as compared with other ethnic groups.19,20 Using UBM, this study disclosed a variety of changes in or around the ciliary body in these patients. The study also quantitatively evaluated the cells in the anterior chamber of patients with anterior reaction and breakdown of the blood–aqueous barrier. The Chinese patients with Behçet’s disease in the present study showed a male predominance, quite in contrast to the previous studies on Chinese12,13 and Japanese7 patients, in which slightly more females were described. The discrepancy between these results and that of others may be the result of a bias toward patients with severe and refractory uveitis seen in the uveitis referral center in this study. Males, unlike females, usually showed a severe sightthreatening uveitis and therefore were referred preferentially. Females have been reported to be equally or more frequently affected in the United States and England21 compared with those in Turkey. This also may reflect a
geographic (genetic, environmental, or both) influence on the pathogenesis of Behçet’s disease. Behçet’s disease is a disorder involving a variety of systems or organs.1 Oral aphthae were the most common manifestation in most studies (86%–100%),10,12,13,17,18 supporting this sign as the essential feature for the diagnosis of Behçet’s disease (Table 3). Dermatologic lesions were present in approximately three fourths of patients in this series, which is roughly in agreement with that reported in other studies. Genital ulcers were recorded in 57.9% of the patients in this series, and this rate was lower than that reported in previous reports on Chinese patients.12,13 This discrepancy may be explained by the different diagnostic criteria: the international criterion14 was used in this study, whereas the Japanese criterion was applied in the earlier studies. The presence of oral aphthae is absolutely necessary for diagnosis of Behçet’s disease according to the international criteria, whereas emphasis is put on the composition of major signs in the Japanese criteria. Furthermore, earlier reports may have been biased because of the specialty of the investigators. For instance, one study12 was reported by ophthalmologists, and the other13 was reported by ophthalmologists and internists. Very few patients with neurological lesions were identified, which could be a result of the referral bias in this series. Uveitis has been considered to be an important feature in Behçet’s disease. Almost all the Behçet’s patients in this uveitis referral center had this manifestation. Only 2 patients without uveitis were for routine ocular examination because they had been diagnosed previously as having Behçet’s disease in the Rheumatology Department of the other institution. Uveitis occurred mostly in patients belonging to the 20s through 50s age group in this study, which is similar to that presented by others.9,10,17,18 The frequency of bilateral involvement in this study was 77.3%, generally consistent with results reported earlier (78%–95%).1,8,10,17,18 Posterior involvement taking on the form of posterior or panuveitis is the most common type of ocular finding in all se-
Table 3. Characteristics of Behçet’s Disease in China, Japan, Turkey, the United Kingdom, and Brazil
Clinical Features
Present Study, China, 2006
Geng et al,12 China (Tianjin), 1985
Chung et al,13 China (Taiwan), 1986
Barra et al,17 Brazil, 1991
Atmaca et al,9 Turkey, 1996
Muhaya et al,7 Japan/UK, 2000
Ambresin et al,18 Switzerland, 2002
Tugal-Tutkun et al,10 Turkey, 2004
No. of cases Mean age (range), yrs Male-to-female ratio Ocular lesions Oral aphthae Genital ulcers Skin lesions Articular lesions Gastrointestinal lesions Vascular lesions Neurologic lesions Urinary lesions Epididymitis Pulmonary lesions
437 29.8 (5–58) 2.70:1 99.5% 100% 57.9% 78% 39.1% 11.2% 16.0% 1.1% 0 6.3% 0
42 ? (10–50) 1:2 50.0% 95.2% 95.2% 90.5% — — — — — — —
53 39.5 (16–78) 1.7:1 66.0% 100% 71.7% 73.6% 64.2% 18.9% 3.8% 11.3% 1.9% 12.1% 5.7%
49 29.6 (9–61) 2.5:1 100% 98% 55.1% 51.0% 44.9% 2.0% 4.1% 6.1% — — —
540 30.7 (13–73) 5.2:1 98% — — — — — — — — — —
35/19 43.2/35.4 0.89:1/0.74:1 — — — — — — — — — — —
35 29.4 4:1 71% 86% 35% 60% 60% — 20% 20% — — —
880 30 (9–71) 2.1:1 100% 100% 59.8% 55.4% 34.0% — 4.7% 4.2% — — —
—, not mentioned.
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Yang et al 䡠 Behçet’s Disease in Chinese Patients ries.1,8,10,17,18,22,23 This study also showed a high frequency of posterior segment involvement. Retinal vasculitis is a common finding of Behçet’s disease. In the current patients, retinal vasculitis was found ophthalmoscopically in 81.2% of eyes with posterior involvement, similar to data presented earlier in Turkish patients (89%).10 Furthermore, FFA showed that 97.9% of the eyes had dye leakage from retinal capillaries in this study. Hypopyon is regarded as a hallmark finding in ocular Behçet’s disease.1 Nevertheless, it can be a relatively transient sign, usually disappearing in a few days. Hypopyon was observed in 32.4% of the affected eyes in the present patients, similar to that reported by others.17,18 A few patients had keratoconjunctivitis, corneal neovascularization, or scleritis. A number of ocular complications has been described in patients with Behçet’s disease in the literature.1,2,8,10,17,18,20,24 This study generally revealed a similar result, although cataract was encountered far more frequently in this study than in others. Long-standing intraocular inflammation with frequent recurrences and long-term corticosteroid therapy probably are responsible for this result. Iris synechiae and angle closure induced by recurrent nongranulomatous anterior uveitis and, possibly, the administration of corticosteroids may be responsible for an elevated IOP. Macular edema has been considered to be an important reason for decreased vision in uveitis. In this series, ophthalmoscopic examination showed that macular edema was present in approximately one third of the patients. This was confirmed by OCT examination (Fig 4 [available at http://aaojournal.org]). A moderate or marked anterior chamber reaction has been considered to be a feature of Behçet’s disease with anterior involvement.1 At the initial visit in the authors’ hospital, most patients showed moderate to intensive flare with cells in the anterior chamber when examined by slitlamp biomicroscopy. The results of LFCM performed on certain patients with anterior uveitis were in accordance with those observed with the slit lamp. Fundus fluorescein angiography has been considered to be a useful tool to evaluate changes of the retina and the retinal vasculature. This study showed a variety of changes in patients with Behçet’s disease. Leakage from the capillaries of the retina and optic disc and from retinal vessels were the most common features. It should be pointed out that in 9 of 67 eyes with retinal leakage as found by FFA, ophthalmoscopy failed to show any abnormalities. This result indicates that the absence of macroscopic changes in the retina does not preclude retinal abnormalities in Behçet’s uveitis. Fundus fluorescein angiography seems to evaluate precisely the early and subclinical retinal involvement. These results also showed that B ultrasound is helpful in evaluating the posterior segment when ocular media are obstructed and that OCT is useful in assessing the anatomic condition of the macula. High-frequency UBM provides a useful tool to illustrate the changes in the ciliary body and its surrounding tissues in vivo.25 Using this technique, a variety of changes in all the unselected patients was found, including in 9 eyes in which neither fundus examination nor fluorescein angiography showed active inflammation. The predominant findings
were miscellaneous exudates around the ciliary body or in the anterior chamber and posterior chamber. Of particular note is that snowbank exudates at the pars plana were observed in 29 of 191 eyes, indicating that this sign reflects the presence of intermediate uveitis.26 Ultrasound biomicroscopy is a precise tool to evaluate the extent and severity of ciliary body involvement in Behçet’s disease and therefore may provide an additional guide for the treatment of Behçet’s uveitis. It has been well known that uveitis is usually recurrent or chronic and that the visual prognosis is poor in Behçet’s disease. A number of patients eventually became blind 4 to 5 years after uveitis onset.1,21,27 Although most patients achieved complete control of ocular inflammation after treatment, approximately one fifth of the patients became legally blind after a mean follow-up of 47 months in this study. Unexpectedly, the Kaplan-Meier analysis showed that the risk of losing useful vision in Behçet’s patients was approximately 65% and 33% in males and females, respectively. This estimated survival of useful vision is lower than that reported by others.10 One of reasons for this KaplanMeier result could be that most patients were referred several years after the onset of uveitis. Inappropriate treatment in local hospitals may have resulted in irreversible damage to the retina and optic nerve. Another possibility is that a number of patients were not treated regularly in the authors’ hospital mostly because of long traveling distances or economic reasons. Most of these patients already had lost their useful vision when they came back for another examination. In fact, relatively good vision often was obtained in patients who were treated at an early stage and were in good compliance with the treatment regimen. In conclusion, this study addresses the clinical features of Chinese patients with Behçet’s disease. It is characterized by posterior or generalized uveitis with a chronic nature and with recurrent episodes. Complications occurred mostly in patients with longstanding intraocular inflammation. Complicated cataract, macular edema, and secondary ocular hypertension were the main complications observed in this series. Oral aphthae were the most frequent extraocular manifestation, followed by dermatologic lesions and genital ulcers. Conventional auxiliary examinations (FFA and B-scan ultrasonography) are helpful in assessing ocular changes in Behçet’s disease, whereas novel techniques including LFCM, UBM, and OCT may provide additional information. Corticosteroids combined with immunosuppressive agents are effective in the treatment of intraocular inflammation as well as extraocular lesions. Early and appropriate intervention is very important for improvement of the visual prognosis in patients with Behçet’s disease.
References 1. Evereklioglu C. Current concepts in the etiology and treatment of Behcet disease. Surv Ophthalmol 2005;50:297–350. 2. Michelson JB, Friedlaender MH. Behcet’s disease. Int Ophthalmol Clin 1990;30:271–7. 3. Idil A, Gürler A, Boyvat A, et al. The prevalence of Behcet’s disease above the age of 10 years: the results of a pilot study
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4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
conducted at the Park Primary Health Care Center in Ankara, Turkey. Ophthalmic Epidemiol 2002;9:325–31. Chang HK, Kim JW. The clinical features of Behcet’s disease in Yongdong districts: analysis of a cohort followed from 1997 to 2001. J Korean Med Sci 2002;17:784 –9. Yoshida A, Kawashima H, Motoyama Y, et al. Comparison of patients with Behcet’s disease in the 1980s and 1990s. Ophthalmology 2004;111:810 –5. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res 2005;30:943– 8. Muhaya M, Lightman S, Ikeda E, et al. Behcet’s disease in Japan and in Great Britain: a comparative study. Ocul Immunol Inflamm 2000;8:141– 8. Atmaca LS. Fundus changes associated with Behcet’s disease. Graefes Arch Clin Exp Ophthalmol 1989;227:340 – 4. Atmaca LS, I˙dil A, Batiog˘lu F. A descriptive study on Behcet’s disease. Acta Ophthalmol Scand 1996;74:403– 6. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis in Behcet disease: an analysis of 880 patients. Am J Ophthalmol 2004;138:373– 80. Saylan T, Mat C, Fresko I, Melikoglu M. Behcet’s disease in the Middle East. Clin Dermatol 1999;17:209 –23. Geng L, Ohno S, Wang YH, Higuchi M. Clinical observations on Behcet’s disease in Tianjin, China. Jpn J Ophthalmol 1985;29:310 – 4. Chung YM, Liu JH, Tsi ST. Behcet’s disease in Taiwan-a review of 53 cases. Jpn J Ophthalmol 1986;30:318 –23. International Study Group for Behcet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet 1990;335:1078 – 80. Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior uveitis. Am J Ophthalmol 1959;155–70.
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16. Kimura SJ, Thygeson P, Hogan MJ. Signs and symptoms of uveitis. II. Classification of the posterior manifestations of uveitis. Am J Ophthalmol 1959;171– 6. 17. Barra C, Belfort R Jr, Abreu MT, et al. Behcet’s disease in Brazil—a review of 49 cases with emphasis on ophthalmic manifestations. Jpn J Ophthalmol 1991;35:339 – 46. 18. Ambresin A, Tran T, Spertini F, Herbort C. Behcet’s disease in western Switzerland: epidemiology and analysis of ocular involvement. Ocul Immunol Inflamm 2002;10:53– 63. 19. Nishiura K, Kotake S, Ichiishi A, Matsuda H. Familial occurrence of Behcet’s disease. Jpn J Ophthalmol 1996;40: 255–9. 20. Nishiyama M, Nakae K, Umehara T. A study of familial occurrence of Behcet’s disease with and without ocular lesions. Jpn J Ophthalmol 2001;45:313– 6. 21. Demirog˘lu H, Baris¸ta I˙, Dündar S. Risk factor assessment and prognosis of eye involvement in Behcet’s disease in Turkey. Ophthalmology 1997;104:701–5. 22. Colvard DM, Robertson DM, O’Duffy JD. The ocular manifestations of Behcet’s disease. Arch Ophthalmol 1977;95: 1813–7. 23. Benezra D, Cohen E. Treatment and visual prognosis in Behcet’s disease. Br J Ophthalmol 1986;70:589 –92. 24. Elgin U, Berker N, Batman A. Incidence of secondary glaucoma in Behcet disease. J Glaucoma 2004;13:441– 4. 25. Fledelius HC. Ultrasound in ophthalmology. Ultrasound Med Biol 1997;23:365–75. 26. Foster CS, Vitale AT. Diagnosis and Treatment of Uveitis. Philadelphia: W.B. Saunders; 2002:19 –20. 27. Pivetti Pezzi P, Gasparri V, De Liso P, Catarinelli G. Prognosis in Behcet’s disease. Ann Ophthalmol 1985;17:20 –5.
Yang et al 䡠 Behçet’s Disease in Chinese Patients
Figure 2. Photograph showing a large skin ulcer present in a 22-year-old woman with Behçet’s disease.
Figure 3. Photograph showing coexistence of scleritis with uveitis found in a 22-year-old woman with Behçet’s disease.
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Figure 4. Fibrous membrane observed on (A) slit-lamp microscopy and (B) ultrasound biomicroscopy in a 28-year-old woman with Behçet’s disease.
Figure 5. Optic nerve atrophy, diffuse retinal atrophy, retinal pigment clumping, and ghost vessels seen in a 13-year-old male patient with Behçet’s disease.
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Figure 6. Optical coherence tomography (OCT) showing cystoid macular edema in a 42-year-old woman with Behçet’s disease.
Yang et al 䡠 Behçet’s Disease in Chinese Patients
Figure 7. Ultrasound biomicroscopy showing a variety of findings in patients with Behçet’s disease: (A) dotted echo in the anterior chamber; (B) anterior synechiae at the root of the iris and angle closure; (C) detachment of the ciliary body; and (D) massive exudates at the basal vitreous body.
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Ophthalmology Volume 115, Number 2, February 2008 Table 2. Ocular Findings in Male and Female Patients with Behçet’s Disease at Presentation or during Follow-up Involved Eyes* Ocular Findings
Total Eyes (n ⫽ 691), No. (%)
Male (n ⫽ 499), No. (%)
Female (n ⫽ 192), No. (%)
Chi-Square Results
P Value
Retinal vasculitis Cataract† Vitreitis Papillitis Retinitis Macular edema Hypopyon Elevated IOP BRVO Persistent posterior synechiae Retinal hemorrhage Optic atrophy Iris depigmentation Retinal atrophy Retinal detachment Pars plana exudates Epiretinal membrane formation RPE proliferation Disc and/or retinal NV Phthisis bulbi Macular degeneration or atrophy Iris bombe Iris nodules Posterior vitreous detachment Iris neovascularization Macular hole Neovascular glaucoma
251 (32.4) 600 (77.4) 515 (74.5) 465 (67.3) 412 (59.6) 264 (38.2) 251 (32.4) 243 (31.4) 216 (31.3) 185 (23.9) 148 (21.4) 112 (16.2) 84 (12.1) 81 (11.7) 74 (10.7) 69 (10.0) 66 (9.6) 65 (9.4) 50 (7.2) 29 (3.8) 27 (3.9) 27 (3.5) 22 (2.8) 21 (3.0) 17 (2.2) 13 (1.9) 13 (1.7)
210 (36.7) 499 (87.2) 427 (85.6) 368 (73.7) 339 (67.9) 217 (43.5) 210 (36.7) 181 (31.6) 179 (35.9) 139 (24.3) 127 (25.5) 93 (18.6) 65 (11.3) 67 (13.4) 62 (12.4) 53 (10.6) 49 (9.8) 53 (10.6) 38 (7.6) 25 (4.4) 23 (4.6) 21 (3.7) 17 (3.0) 18 (3.6) 13 (2.3) 10 (2.0) 10 (1.7)
41 (20.2) 101 (49.8) 88 (45.8) 97 (50.5) 73 (38.0) 47 (24.5) 41 (20.2) 62 (30.5) 37 (19.3) 46 (22.9) 21 (10.9) 19 (9.9) 19 (9.4) 14 (7.3) 12 (6.3) 17 (8.9) 17 (8.9) 12 (6.3) 12 (6.3) 4 (2.0) 4 (2.1) 6 (3.0) 5 (2.5) 3 (1.6) 4 (2.0) 3 (1.6) 3 (1.5)
18.664 120.420 115.337 33.985 51.542 21.218 18.664 0.084 17.783 0.222 17.352 7.801 0.623 5.043 5.529 0.476 0.150 3.109 0.385 2.396 2.356 0.228 0.141 1.967 0.065‡ 0.152‡ 0.068‡
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.771 0.000 0.638 0.000 0.005 0.430 0.025 0.019 0.490 0.699 0.078 0.535 0.122 0.125 0.633 0.703 0.161 0.798 0.697 0.794
BRVO ⫽ branch retinal vein occlusion; IOP ⫽ intraocular pressure; NV ⫽ neovascularization; RPE ⫽ retinal pigmental epithelium. *The fundus was not visible in 73 eyes of male patients and 11 eyes of female patients because of dense opacities in the lens or in the vitreous body. The frequencies of fundus changes indicate the number of eyes with fundus change(s) of total number of the affected eyes. † Including aphakic or pseudophakic eyes after cataract surgery. ‡ Fisher exact test, odds ratio.
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Behçet’s disease is a chronic, relapsing, multisystemic inflammatory disease presumably caused by an autoimmune response. Its classical triad includes oral aphthae, genital ulcers, and recurrent iridocyclitis with hypopyon. Behçet’s disease typically has its onset in young and adult patients. The global distribution of Behçet’s disease is indicative of a distinct geographic pattern along the old Silk Route.1,2 Behçet’s disease is prevalent mainly in countries around the Mediterranean and Far East,3 such as Turkey, Iraq, Iran, Korea,4 and Japan.5 China is located in one of the highest
incidence areas. The authors’ previous study showed that Behçet’s uveitis is one of the most frequently encountered types of uveitis in China.6 The clinical features of Behçet’s disease have been well documented in some countries where the disease is endemic.4,5,7–11 Previous studies on Behçet’s disease in Chinese patients were published more than 25 years ago and included only a limited number of patients.12,13 This study was undertaken to evaluate the clinical characteristics and associated ocular complications in a large group of consec4
Originally received: December 15, 2006. Final revision: April 12, 2007. Accepted: April 13, 2007. Available online: August 10, 2007. Manuscript no. 2006-1445. 1 Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. 2 Uveitis Study Center and International Uveitis Study Laboratory of Sun Yat-sen University, Guangzhou, China. 3 State Key Laboratory of Ophthalmology of Sun Yat-sen University, Guangzhou, China.
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© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
Eye Research Institute Maastricht, Department of Ophthalmology, University Hospital Maastricht, Maastricht, Netherlands. Supported by the Fund for Innovative Research Groups of Guangdong Province, Guangzhou, China (grant no. 05200176); Key Project of Natural Science Foundation, Beijing, China (grant no. 30630064); National supporting project of China, Beijing, China; and “5010” Clinical Project of Sun Yat-sen University, Guangzhou, China. No author has a proprietary or financial interest in any product mentioned. Correspondence to Peizeng Yang, MD, PhD, Zhongshan Ophthalmic center, Xianlie Road 54, Guangzhou 510060, China. E-mail: [email protected]. ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2007.04.056
Yang et al 䡠 Behçet’s Disease in Chinese Patients utive Behçet’s patients in a referral uveitis center in China and to compare the results with those presented in the international literature. Furthermore, the use of new techniques such as laser flare-cell photometry (LFCM), optical coherence tomography (OCT), and ultrasound biomicroscopy (UBM) to observe the clinical presentation of the disease were evaluated.
Patients and Methods A retrospective study was performed based on the charts of 437 patients with Behçet’s disease referred to the uveitis study center of Sun Yat-sen University from August, 1995, through June, 2006. Most patients were referred by ophthalmologists, dermatologists, or internists from other hospitals all over China. The patients who fulfilled the diagnostic criteria of the International Study Group for Behçet’s Disease14 were included in the study. Because the diagnosis of Behçet’s disease is mainly a clinical one, extensive efforts were made to rule out other uveitis entities that could simulate this disease. If there was any doubt, the case was excluded from the study. Depending on clinical examination and laboratory test results, patients with tuberculosis, syphilis, sarcoidosis, and other types of retinal vasculitis were excluded from the study. The follow-up varied from 3 months to 10.5 years, with an average of 47 months. Among these patients, more than one third (35.2%) had been followed up for more than 5 years, and 175 (40.0%) had been followed up for between 1 and 5 years. A detailed history, including age; initial manifestations; laterality; symptoms; visual acuity; and, most importantly, related systemic manifestations (such as orogenital and dermatologic history, abnormalities in the central nervous system, and gastrointestinal disorders), medical therapy, surgical interventions, and diagnosis made in other hospitals, was obtained from each patient. All patients were examined by the same uveitis specialist (PY). Routine ocular examinations included best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, gonioscopy, and ophthalmoscopy through a dilated pupil. For patients in whom the fundus could not be visualized because of dense opacity of the ocular media, B-ultrasound photography was used to evaluate the vitreous body and retina. The severity of anterior chamber activity was estimated clinically by using the grading system made by Hogan et al15 and Kimura et al.16 Ultrasound biomicroscopy was performed unselectively in 191 eyes of 113 patients (78 with bilateral uveitis and 35 with unilateral uveitis). Fundus fluorescein angiography (FFA) was performed nonselectively in 88 patients to evaluate the changes in the retina, retinal blood vessels, and optic nerve. Laser flare-cell photometry also was performed in 52 cases (88 eyes) using the FC-2000 laser flare-cell meter version 1.0 (Kowa Company, Ltd., Tokyo, Japan). This examination also was performed concurrently in 33 (66 eyes) normal individuals as gender- and age-matched controls. Laboratory examinations, including counts of white blood cells, red blood cells, and platelets, antistreptolysin O titer, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, and rheumatoid factor, were performed in all patients to evaluate the relationship between these parameters and Behçet’s disease. Tuberculin skin testing and tests for syphilis (including rapid plasma reagin and microhemagglutination assay for Treponema pallidum) were performed, if needed, to rule out these 2 diseases. Liver and kidney functions and routine blood test results were evaluated regularly for patients treated with immunosuppressive agents. All the Behçet’s patients with posterior involvement or recurrent episodes generally were treated with corticosteroids combined
with 1 or 2 immunosuppressive agents, mostly cyclosporine and chlorambucil, and to a lesser degree with colchicine, azathioprine, and methotrexate. The treatment usually lasted for more than 1 year and for 2 or 3 years in certain patients. Corticosteroid eye drops and cycloplegic drugs also were used for the patients with anterior uveitis. For comparison of the present findings with those presented earlier by others, a literature search was performed using the PubMed database from 1980 to present (September 2006). References also were identified from the relevant articles and were obtained mainly from ophthalmologic journals. For analytic purposes, all obtained data were stored in an Excel computerized database (Microsoft, Redmond, WA). Analysis of ocular findings and complications was carried out according to the proportion of the eyes that had these features during the follow-up period. The Kaplan-Meier analysis was performed to evaluate the cumulative survival of eyes with a potential visual acuity of ⱖ0.05 in these patients. Results were analyzed using SPSS software version 11.0 (SPSS, Inc., Chicago, IL). For comparing the differences between genders, the Student t test, chi-square test, or Fisher exact test were used. P values less than 0.05 were accepted as statistically significant.
Results Of 437 patients, there were 319 men (73.0%) and 118 women (27.0%). All the patients except 7 (Wei ethnic group, n ⫽ 4; Hui ethnic group, n ⫽ 3) were Han Chinese. The mean age at the onset of uveitis was 29.8 years (range, 5–58 years). Forty-six patients (10.5%) had the first uveitis attack before the age of 20 years. Twelve patients (2.7%) were identified to have had the first onset of uveitis at the age of 50 years or older (Fig 1). A comparative study was performed to evaluate the difference in age at the onset of uveitis between males and females. The mean age at the onset of uveitis was 29.2 years (range, 5–58 years) in males and 31.6 years (range, 10 –58 years) in females (t ⫽ ⫺2.312; P ⫽ 0.021). With regard to familial clustering of the disease, only 2 patients showed this phenomenon. A 19-year-old female patient’s father had died of neuro-Behçet’s disease when he was in his 30s. Another case was a 36-year-old male. His two sisters were diagnosed with Behçet’s disease when they were in their 30s. However, these 2 sisters did not show any ocular involvement. Most patients showed extraocular manifestations (Table 1). All patients had recurrent oral aphthae. The second most common extraocular clinical manifestation was a dermatologic finding, followed by genital ulceration. Other abnormalities included arthritis, thrombophlebitis, gastrointestinal disorders, and epididymitis. As an unusual manifestation, a large skin ulcer was found in the right leg of a 22-year-old female patient (Fig 2 [available at http:// aaojournal.org]). Central nervous system involvement was noted in only 5 of 437 patients, including palsies of cranial nerves and mental changes. Recurrent oral aphthae was the most common presenting manifestation of the disease, followed by ocular involvement (Table 1). All patients showed intraocular inflammation, and 5 patients had keratoconjunctivitis, corneal neovascularization, or scleritis (Fig 3 [available at http://aaojournal.org]). Bilateral involvement was observed in 338 (77.3%) patients. The laterality of ocular involvement was not significantly different between genders ( ⫽ 1.3999; P ⫽ 0.237). The most frequent symptoms reported were decreased vision with recurrent attacks with or without red eyes (344 patients), followed by eye pain or floaters (52 patients) and tearing (41 patients). The intraocular inflammation seen in these patients included anterior uveitis, posterior uveitis, and panuveitis.
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Figure 1. Bar graph showing age at onset and the age at which the diagnosis of Behçet’s disease was made in the 437 patients.
The most frequent type of uveitis was panuveitis, 75.9% in males and 49.8% in females. Anterior uveitis was observed more frequently in females than in males (16.7% vs. 3.3%). The patients with bilateral involvement uniformly showed the same type of uveitis, although an asymmetrical intraocular inflammation was encountered at the early stage of the disease. Mild to moderate flare in the anterior chamber was observed in most cases, whereas numerous cells in the anterior chamber in most cases were observed at the first visit. During a uveitis attack in patients with panuveitis or anterior uveitis, flare and cell scores often increased markedly (data not shown). Hypopyon was noted in 32.4% of the involved eyes. Keratic precipitates were present in 491 (63.4%) of the affected eyes at the first visit. Keratic precipitates usually had small and dusty morphologic features and typically were distributed at the inferior triangle region of the corneal endothelium. Exudative fibrous membranes occasionally were seen in patients (Fig 4 [available at http://aaojournal.org]). Retinal vasculitis and vitreitis were the 2 most common clinical findings of uveitis (81.2% and 66.4%, respectively). The third most common ocular finding of uveitis was retinitis (53.2%). Usually, optic nerve atrophy, diffuse retinal atrophy, and ghost vessels (Fig 5 [available at http://aaojournal.org]) were the final features in patients with refractory retinal vasculitis and vitreitis. Hypopyon, vitreitis, retinal vasculitis, retinitis, retinal hemorrhage, and papillitis were more common in males than in females (Table 2 [available at http://aaojournal.org]). A variety of ocular complications, including complicated cataract, secondary ocular hypertension, and macular edema, were observed (Table 2). Overall, complicated cataract (including aphaTable 1. Frequency of Systemic Manifestations and Prevalence of Initial Manifestations in 437 Patients with Behçet’s Disease
Manifestations
Frequency (No. of Patients)
Oral aphthae Uveitis Skin lesions Genital ulceration Arthritis Thrombophlebitis Gastrointestinal disorders Epididymitis CNS involvement
437 435 341 253 171 70 49 20 5
CNS ⫽ central nervous system.
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%
Prevalence (No. of Patients)
%
100 99.5 78.0 57.9 39.1 16.0 11.2 6.3 1.1
309 57 31 23 12 5 0 0 0
70.7 13.0 7.1 5.3 2.8 1.1 0 0 0
kic and pseudophakic eyes) was the most common complication and was observed in 600 eyes (77.4%), most (77.2%) showing posterior subcapsular opacities. The eyes with cataract had varying degrees of visual impairment, and 68 (11.3%) of these eyes underwent surgery. Routine phacoemulsification with or without intraocular lens implantation in the capsular bag was performed in 46 (7.7%) eyes in the authors’ hospital after the inflammation was controlled completely for at least 6 months. A BCVA of ⱖ0.3 was achieved in 52.2% (24 eyes) of the operated eyes. The remaining 22 eyes with cataract (3.6%) underwent surgery at local hospitals. Among these 22 eyes, cataract surgery had been performed already in 7 eyes before the patient was referred to the authors. The other 15 eyes underwent cataract surgery at local hospitals after the inflammation was controlled completely in the authors’ uveitis study center. Visual acuity could be obtained in only 7 of these 15 eyes (range, hand movements to 0.4; median, 0.1). Secondary elevated intraocular pressure (IOP) was observed in 243 (31.4%) eyes, which ranged between 35 and 60 mmHg. A well-controlled IOP was achieved in 77.8% of the eyes after intraocular inflammation was controlled or antiocular hypertension agents were used. The other eyes underwent surgical interventions, including trabeculectomy, peripheral iridectomy (surgical or laser), drainage valve implantation, or cyclocryotherapy, in the authors’ hospital (38 eyes; 15.6%) or in other hospitals (16 eyes; 6.6%). All eyes but 12 achieved a normal IOP. Four patients (5 eyes) had BCVA of ⱕ0.05 because of optic atrophy caused by uncontrolled intraocular inflammation and IOP. Six patients (7 eyes) had BCVA of ⱕ0.05 because of uncontrolled IOP, although the intraocular inflammation was well controlled. Macular edema (Fig 6 [available at http://aaojournal.org]) constituted the second most common complication and was noted clinically or by examinations with FFA or OCT in 264 eyes (34.1%). Retinal detachment occurred in 74 eyes of 70 patients, of which 42 had exudative detachment, 22 had tractional detachment, and 10 had rhegmatogenous detachment. In 5 eyes with rhegmatogenous retinal detachment, only a scleral buckling was performed. Vitreoretinal surgery (vitrectomy combined with membrane removal, scleral buckling, endophotocoagulation, or endotamponades with expanding gas or silicone oil) was performed in 16 eyes. Indications for vitreoretinal surgery included epiretinal membrane in 12 eyes and macular hole in 4 eyes. Retinal photocoagulation was performed in 24 eyes for a capillary nonperfusion region. All the vitreoretinal surgery was performed after the inflammation was controlled completely for at least 6 months. Retinal reattachment was accomplished in 17 (85.8%) of 21 patients after a mean postoperative follow-up of 17.5 months. Visual improvement occurred in 12 (57.1%) patients, remained the same in 6 (28.6%) patients, and worsened in 3 (14.3%) patients, respectively.
Yang et al 䡠 Behçet’s Disease in Chinese Patients
Figure 8. Kaplan-Meier curves of cumulative survival of eyes with a potential visual acuity of ⱖ0.05 in male versus female patients with Behçet’s disease. A censored observation represents failure to follow-up or end point of this study.
The mean laser flare photometry value in the patients and controls was 24.0⫾20.6 photon counts/ms and 5.2⫾0.9 photon counts/ms, respectively (t ⫽ 4.524; P ⫽ 0.002). The mean number of anterior chamber cells in the 81 eyes of the patients and controls was 63.5⫾28.7 cells/0.5 mm3 and 0.9⫾0.8 cells/0.5 mm3, respectively (t ⫽ 17.143; P ⫽ 0.000). The cell counts detected by LFCM were not readable in the remaining 7 eyes because of severe anterior chamber inflammation. Dye leakage from the retinal capillaries (97.9%) and papillary (or peripapillary) capillaries (95.8%) were the 2 most frequent findings on FFA, followed by leakage from the retinal vessels, mostly retinal veins (76.4%). The other common features detected by FFA included cystoid macular edema (36.8%) and retinal vascular occlusion (22.2%). Ultrasound biomicroscopy revealed irregular sheetlike exudates in the ciliary body (94.8%), varying degrees of dotted echo (cells) in the anterior chamber (93.7%), and masslike exudates in the posterior chamber (86.4%; Fig 7 [available at http://aaojournal.org]). The result disclosed partial angle closure in 19 eyes (10.0%) and complete angle closure in 30 eyes (15.7%). In the 113 patients investigated by UBM, phacoemulsification and intraocular lens implantation was performed in 16 eyes. Ultrasound biomicroscopy showed intraocular lens dislocation in 2 eyes. In these 113 patients, routine glaucoma filtrating surgery had been performed in 13 eyes with secondary glaucoma unresponsive to antiglaucoma medications. Ultrasound biomicroscopy revealed closure of the internal incision of trabeculectomy in 4 eyes. Test results for syphilis were negative in all of the tested patients. Hepatitis B virus surface antigen results were positive in 45 (10.3%) patients. Forty-two (9.6%) patients had a history of tuberculosis and had been treated successfully before uveitis onset. Aspartate aminotransferase and alanine aminotransferase levels were abnormal in 25 (5.7%) and 27 (6.2%) patients, respectively. Blood-fasting sugar was more than 7.8 mmol/1 in 20 (4.6%) patients. Urea nitrogen and creatinine clearance rate were abnormal in 23 (5.3%) and 25 (5.7%) patients, respectively. Increased erythrocyte sedimentation rates and C-reactive protein levels were observed in 102 (23.3%) and 79 (18.1%) patients, respectively.
Abnormal results in antistreptolysin O titer and rheumatoid factor assay were observed in only 20 (4.6%) and 28 (6.4%) patients, respectively. Consultation with internists was recommended to these patients who had abnormal results. No underlying systemic disorders definitely attributed to the uveitis were found in these patients. The mean age at which the diagnosis of Behçet’s disease was made was 33.4 years (Fig 1). A delay in diagnosis was observed in 232 patients, ranging from 1 month to 15 years, with a mean of 3.1 years. The initial diagnosis made in other hospitals often included panuveitis, posterior uveitis, vitreous opacity or hemorrhage, uveitis, anterior uveitis, or iritis. Because of the recurrent and chronic nature of Behçet’s disease, a more aggressive therapy strategy was used for these patients. Systemic corticosteroids (usually 20 –25 mg/day at the beginning) combined with immunosuppressive agent(s), mostly cyclosporine, chlorambucil, or both, were used in patients with recurrent uveitis attacks or with posterior involvement. Additionally, patients with anterior chamber inflammation also were treated with topical corticosteroids and cycloplegic agents. The dosages of corticosteroids and other immunosuppressive agents were adjusted according to the severity of uveitis or their side effects. Immunosuppressive agents were decreased in dosages or were discontinued if severe side effects occurred during treatment. Most patients had markedly impaired vision at the first examination. The initial BCVA was 0.05 or less in 281 (36.3%) of 775 eyes. The final BCVA was 0.05 or less in 20.4% of eyes after a median follow-up of 47 months. Kaplan-Meier survival analysis estimated the risks of loss of useful vision (0.05) to be 6.4%, 10.7%, 24.5%, and 62.2% at 1, 3, 5, and 10 years, respectively. The risks of losing vision at 5 and 10 years for males and females were 29% versus 6% and 65% versus 33%, respectively (log-rank ⫽ 20.143; P ⫽ 0.000; Fig 8). In 95.2% of the patients, the oral aphthae were well controlled after a mean follow-up of 47 months (range, 3 months–10.5 years). Skin lesions, uveitis, and genital ulcers were controlled in 87.1%,
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Discussion This study characterizes the clinical features of Behçet’s disease in Chinese patients based on the data of 437 cases referred to the uveitis study center of the Sun Yat-sen University. These clinical features are, by and large, similar to those reported by others.7–10,12,13,17,18 Oral aphthae, skin lesions, and genital ulcers were the typical extraocular findings in Behçet’s disease. Most patients showed bilateral nongranulomatous anterior, posterior, or panuveitis with a chronic and relapsing course. Severe uveitis was observed more frequently in males. Retinal vasculitis, vitreitis, and retinitis were the most common clinical features in these patients. Cataract and macular edema were the most common complications. Importantly, this study revealed a much lower familial clustering in Chinese patients as compared with other ethnic groups.19,20 Using UBM, this study disclosed a variety of changes in or around the ciliary body in these patients. The study also quantitatively evaluated the cells in the anterior chamber of patients with anterior reaction and breakdown of the blood–aqueous barrier. The Chinese patients with Behçet’s disease in the present study showed a male predominance, quite in contrast to the previous studies on Chinese12,13 and Japanese7 patients, in which slightly more females were described. The discrepancy between these results and that of others may be the result of a bias toward patients with severe and refractory uveitis seen in the uveitis referral center in this study. Males, unlike females, usually showed a severe sightthreatening uveitis and therefore were referred preferentially. Females have been reported to be equally or more frequently affected in the United States and England21 compared with those in Turkey. This also may reflect a
geographic (genetic, environmental, or both) influence on the pathogenesis of Behçet’s disease. Behçet’s disease is a disorder involving a variety of systems or organs.1 Oral aphthae were the most common manifestation in most studies (86%–100%),10,12,13,17,18 supporting this sign as the essential feature for the diagnosis of Behçet’s disease (Table 3). Dermatologic lesions were present in approximately three fourths of patients in this series, which is roughly in agreement with that reported in other studies. Genital ulcers were recorded in 57.9% of the patients in this series, and this rate was lower than that reported in previous reports on Chinese patients.12,13 This discrepancy may be explained by the different diagnostic criteria: the international criterion14 was used in this study, whereas the Japanese criterion was applied in the earlier studies. The presence of oral aphthae is absolutely necessary for diagnosis of Behçet’s disease according to the international criteria, whereas emphasis is put on the composition of major signs in the Japanese criteria. Furthermore, earlier reports may have been biased because of the specialty of the investigators. For instance, one study12 was reported by ophthalmologists, and the other13 was reported by ophthalmologists and internists. Very few patients with neurological lesions were identified, which could be a result of the referral bias in this series. Uveitis has been considered to be an important feature in Behçet’s disease. Almost all the Behçet’s patients in this uveitis referral center had this manifestation. Only 2 patients without uveitis were for routine ocular examination because they had been diagnosed previously as having Behçet’s disease in the Rheumatology Department of the other institution. Uveitis occurred mostly in patients belonging to the 20s through 50s age group in this study, which is similar to that presented by others.9,10,17,18 The frequency of bilateral involvement in this study was 77.3%, generally consistent with results reported earlier (78%–95%).1,8,10,17,18 Posterior involvement taking on the form of posterior or panuveitis is the most common type of ocular finding in all se-
Table 3. Characteristics of Behçet’s Disease in China, Japan, Turkey, the United Kingdom, and Brazil
Clinical Features
Present Study, China, 2006
Geng et al,12 China (Tianjin), 1985
Chung et al,13 China (Taiwan), 1986
Barra et al,17 Brazil, 1991
Atmaca et al,9 Turkey, 1996
Muhaya et al,7 Japan/UK, 2000
Ambresin et al,18 Switzerland, 2002
Tugal-Tutkun et al,10 Turkey, 2004
No. of cases Mean age (range), yrs Male-to-female ratio Ocular lesions Oral aphthae Genital ulcers Skin lesions Articular lesions Gastrointestinal lesions Vascular lesions Neurologic lesions Urinary lesions Epididymitis Pulmonary lesions
437 29.8 (5–58) 2.70:1 99.5% 100% 57.9% 78% 39.1% 11.2% 16.0% 1.1% 0 6.3% 0
42 ? (10–50) 1:2 50.0% 95.2% 95.2% 90.5% — — — — — — —
53 39.5 (16–78) 1.7:1 66.0% 100% 71.7% 73.6% 64.2% 18.9% 3.8% 11.3% 1.9% 12.1% 5.7%
49 29.6 (9–61) 2.5:1 100% 98% 55.1% 51.0% 44.9% 2.0% 4.1% 6.1% — — —
540 30.7 (13–73) 5.2:1 98% — — — — — — — — — —
35/19 43.2/35.4 0.89:1/0.74:1 — — — — — — — — — — —
35 29.4 4:1 71% 86% 35% 60% 60% — 20% 20% — — —
880 30 (9–71) 2.1:1 100% 100% 59.8% 55.4% 34.0% — 4.7% 4.2% — — —
—, not mentioned.
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Yang et al 䡠 Behçet’s Disease in Chinese Patients ries.1,8,10,17,18,22,23 This study also showed a high frequency of posterior segment involvement. Retinal vasculitis is a common finding of Behçet’s disease. In the current patients, retinal vasculitis was found ophthalmoscopically in 81.2% of eyes with posterior involvement, similar to data presented earlier in Turkish patients (89%).10 Furthermore, FFA showed that 97.9% of the eyes had dye leakage from retinal capillaries in this study. Hypopyon is regarded as a hallmark finding in ocular Behçet’s disease.1 Nevertheless, it can be a relatively transient sign, usually disappearing in a few days. Hypopyon was observed in 32.4% of the affected eyes in the present patients, similar to that reported by others.17,18 A few patients had keratoconjunctivitis, corneal neovascularization, or scleritis. A number of ocular complications has been described in patients with Behçet’s disease in the literature.1,2,8,10,17,18,20,24 This study generally revealed a similar result, although cataract was encountered far more frequently in this study than in others. Long-standing intraocular inflammation with frequent recurrences and long-term corticosteroid therapy probably are responsible for this result. Iris synechiae and angle closure induced by recurrent nongranulomatous anterior uveitis and, possibly, the administration of corticosteroids may be responsible for an elevated IOP. Macular edema has been considered to be an important reason for decreased vision in uveitis. In this series, ophthalmoscopic examination showed that macular edema was present in approximately one third of the patients. This was confirmed by OCT examination (Fig 4 [available at http://aaojournal.org]). A moderate or marked anterior chamber reaction has been considered to be a feature of Behçet’s disease with anterior involvement.1 At the initial visit in the authors’ hospital, most patients showed moderate to intensive flare with cells in the anterior chamber when examined by slitlamp biomicroscopy. The results of LFCM performed on certain patients with anterior uveitis were in accordance with those observed with the slit lamp. Fundus fluorescein angiography has been considered to be a useful tool to evaluate changes of the retina and the retinal vasculature. This study showed a variety of changes in patients with Behçet’s disease. Leakage from the capillaries of the retina and optic disc and from retinal vessels were the most common features. It should be pointed out that in 9 of 67 eyes with retinal leakage as found by FFA, ophthalmoscopy failed to show any abnormalities. This result indicates that the absence of macroscopic changes in the retina does not preclude retinal abnormalities in Behçet’s uveitis. Fundus fluorescein angiography seems to evaluate precisely the early and subclinical retinal involvement. These results also showed that B ultrasound is helpful in evaluating the posterior segment when ocular media are obstructed and that OCT is useful in assessing the anatomic condition of the macula. High-frequency UBM provides a useful tool to illustrate the changes in the ciliary body and its surrounding tissues in vivo.25 Using this technique, a variety of changes in all the unselected patients was found, including in 9 eyes in which neither fundus examination nor fluorescein angiography showed active inflammation. The predominant findings
were miscellaneous exudates around the ciliary body or in the anterior chamber and posterior chamber. Of particular note is that snowbank exudates at the pars plana were observed in 29 of 191 eyes, indicating that this sign reflects the presence of intermediate uveitis.26 Ultrasound biomicroscopy is a precise tool to evaluate the extent and severity of ciliary body involvement in Behçet’s disease and therefore may provide an additional guide for the treatment of Behçet’s uveitis. It has been well known that uveitis is usually recurrent or chronic and that the visual prognosis is poor in Behçet’s disease. A number of patients eventually became blind 4 to 5 years after uveitis onset.1,21,27 Although most patients achieved complete control of ocular inflammation after treatment, approximately one fifth of the patients became legally blind after a mean follow-up of 47 months in this study. Unexpectedly, the Kaplan-Meier analysis showed that the risk of losing useful vision in Behçet’s patients was approximately 65% and 33% in males and females, respectively. This estimated survival of useful vision is lower than that reported by others.10 One of reasons for this KaplanMeier result could be that most patients were referred several years after the onset of uveitis. Inappropriate treatment in local hospitals may have resulted in irreversible damage to the retina and optic nerve. Another possibility is that a number of patients were not treated regularly in the authors’ hospital mostly because of long traveling distances or economic reasons. Most of these patients already had lost their useful vision when they came back for another examination. In fact, relatively good vision often was obtained in patients who were treated at an early stage and were in good compliance with the treatment regimen. In conclusion, this study addresses the clinical features of Chinese patients with Behçet’s disease. It is characterized by posterior or generalized uveitis with a chronic nature and with recurrent episodes. Complications occurred mostly in patients with longstanding intraocular inflammation. Complicated cataract, macular edema, and secondary ocular hypertension were the main complications observed in this series. Oral aphthae were the most frequent extraocular manifestation, followed by dermatologic lesions and genital ulcers. Conventional auxiliary examinations (FFA and B-scan ultrasonography) are helpful in assessing ocular changes in Behçet’s disease, whereas novel techniques including LFCM, UBM, and OCT may provide additional information. Corticosteroids combined with immunosuppressive agents are effective in the treatment of intraocular inflammation as well as extraocular lesions. Early and appropriate intervention is very important for improvement of the visual prognosis in patients with Behçet’s disease.
References 1. Evereklioglu C. Current concepts in the etiology and treatment of Behcet disease. Surv Ophthalmol 2005;50:297–350. 2. Michelson JB, Friedlaender MH. Behcet’s disease. Int Ophthalmol Clin 1990;30:271–7. 3. Idil A, Gürler A, Boyvat A, et al. The prevalence of Behcet’s disease above the age of 10 years: the results of a pilot study
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4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
conducted at the Park Primary Health Care Center in Ankara, Turkey. Ophthalmic Epidemiol 2002;9:325–31. Chang HK, Kim JW. The clinical features of Behcet’s disease in Yongdong districts: analysis of a cohort followed from 1997 to 2001. J Korean Med Sci 2002;17:784 –9. Yoshida A, Kawashima H, Motoyama Y, et al. Comparison of patients with Behcet’s disease in the 1980s and 1990s. Ophthalmology 2004;111:810 –5. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res 2005;30:943– 8. Muhaya M, Lightman S, Ikeda E, et al. Behcet’s disease in Japan and in Great Britain: a comparative study. Ocul Immunol Inflamm 2000;8:141– 8. Atmaca LS. Fundus changes associated with Behcet’s disease. Graefes Arch Clin Exp Ophthalmol 1989;227:340 – 4. Atmaca LS, I˙dil A, Batiog˘lu F. A descriptive study on Behcet’s disease. Acta Ophthalmol Scand 1996;74:403– 6. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis in Behcet disease: an analysis of 880 patients. Am J Ophthalmol 2004;138:373– 80. Saylan T, Mat C, Fresko I, Melikoglu M. Behcet’s disease in the Middle East. Clin Dermatol 1999;17:209 –23. Geng L, Ohno S, Wang YH, Higuchi M. Clinical observations on Behcet’s disease in Tianjin, China. Jpn J Ophthalmol 1985;29:310 – 4. Chung YM, Liu JH, Tsi ST. Behcet’s disease in Taiwan-a review of 53 cases. Jpn J Ophthalmol 1986;30:318 –23. International Study Group for Behcet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet 1990;335:1078 – 80. Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. I. Anterior uveitis. Am J Ophthalmol 1959;155–70.
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16. Kimura SJ, Thygeson P, Hogan MJ. Signs and symptoms of uveitis. II. Classification of the posterior manifestations of uveitis. Am J Ophthalmol 1959;171– 6. 17. Barra C, Belfort R Jr, Abreu MT, et al. Behcet’s disease in Brazil—a review of 49 cases with emphasis on ophthalmic manifestations. Jpn J Ophthalmol 1991;35:339 – 46. 18. Ambresin A, Tran T, Spertini F, Herbort C. Behcet’s disease in western Switzerland: epidemiology and analysis of ocular involvement. Ocul Immunol Inflamm 2002;10:53– 63. 19. Nishiura K, Kotake S, Ichiishi A, Matsuda H. Familial occurrence of Behcet’s disease. Jpn J Ophthalmol 1996;40: 255–9. 20. Nishiyama M, Nakae K, Umehara T. A study of familial occurrence of Behcet’s disease with and without ocular lesions. Jpn J Ophthalmol 2001;45:313– 6. 21. Demirog˘lu H, Baris¸ta I˙, Dündar S. Risk factor assessment and prognosis of eye involvement in Behcet’s disease in Turkey. Ophthalmology 1997;104:701–5. 22. Colvard DM, Robertson DM, O’Duffy JD. The ocular manifestations of Behcet’s disease. Arch Ophthalmol 1977;95: 1813–7. 23. Benezra D, Cohen E. Treatment and visual prognosis in Behcet’s disease. Br J Ophthalmol 1986;70:589 –92. 24. Elgin U, Berker N, Batman A. Incidence of secondary glaucoma in Behcet disease. J Glaucoma 2004;13:441– 4. 25. Fledelius HC. Ultrasound in ophthalmology. Ultrasound Med Biol 1997;23:365–75. 26. Foster CS, Vitale AT. Diagnosis and Treatment of Uveitis. Philadelphia: W.B. Saunders; 2002:19 –20. 27. Pivetti Pezzi P, Gasparri V, De Liso P, Catarinelli G. Prognosis in Behcet’s disease. Ann Ophthalmol 1985;17:20 –5.
Yang et al 䡠 Behçet’s Disease in Chinese Patients
Figure 2. Photograph showing a large skin ulcer present in a 22-year-old woman with Behçet’s disease.
Figure 3. Photograph showing coexistence of scleritis with uveitis found in a 22-year-old woman with Behçet’s disease.
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Figure 4. Fibrous membrane observed on (A) slit-lamp microscopy and (B) ultrasound biomicroscopy in a 28-year-old woman with Behçet’s disease.
Figure 5. Optic nerve atrophy, diffuse retinal atrophy, retinal pigment clumping, and ghost vessels seen in a 13-year-old male patient with Behçet’s disease.
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Figure 6. Optical coherence tomography (OCT) showing cystoid macular edema in a 42-year-old woman with Behçet’s disease.
Yang et al 䡠 Behçet’s Disease in Chinese Patients
Figure 7. Ultrasound biomicroscopy showing a variety of findings in patients with Behçet’s disease: (A) dotted echo in the anterior chamber; (B) anterior synechiae at the root of the iris and angle closure; (C) detachment of the ciliary body; and (D) massive exudates at the basal vitreous body.
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Ophthalmology Volume 115, Number 2, February 2008 Table 2. Ocular Findings in Male and Female Patients with Behçet’s Disease at Presentation or during Follow-up Involved Eyes* Ocular Findings
Total Eyes (n ⫽ 691), No. (%)
Male (n ⫽ 499), No. (%)
Female (n ⫽ 192), No. (%)
Chi-Square Results
P Value
Retinal vasculitis Cataract† Vitreitis Papillitis Retinitis Macular edema Hypopyon Elevated IOP BRVO Persistent posterior synechiae Retinal hemorrhage Optic atrophy Iris depigmentation Retinal atrophy Retinal detachment Pars plana exudates Epiretinal membrane formation RPE proliferation Disc and/or retinal NV Phthisis bulbi Macular degeneration or atrophy Iris bombe Iris nodules Posterior vitreous detachment Iris neovascularization Macular hole Neovascular glaucoma
251 (32.4) 600 (77.4) 515 (74.5) 465 (67.3) 412 (59.6) 264 (38.2) 251 (32.4) 243 (31.4) 216 (31.3) 185 (23.9) 148 (21.4) 112 (16.2) 84 (12.1) 81 (11.7) 74 (10.7) 69 (10.0) 66 (9.6) 65 (9.4) 50 (7.2) 29 (3.8) 27 (3.9) 27 (3.5) 22 (2.8) 21 (3.0) 17 (2.2) 13 (1.9) 13 (1.7)
210 (36.7) 499 (87.2) 427 (85.6) 368 (73.7) 339 (67.9) 217 (43.5) 210 (36.7) 181 (31.6) 179 (35.9) 139 (24.3) 127 (25.5) 93 (18.6) 65 (11.3) 67 (13.4) 62 (12.4) 53 (10.6) 49 (9.8) 53 (10.6) 38 (7.6) 25 (4.4) 23 (4.6) 21 (3.7) 17 (3.0) 18 (3.6) 13 (2.3) 10 (2.0) 10 (1.7)
41 (20.2) 101 (49.8) 88 (45.8) 97 (50.5) 73 (38.0) 47 (24.5) 41 (20.2) 62 (30.5) 37 (19.3) 46 (22.9) 21 (10.9) 19 (9.9) 19 (9.4) 14 (7.3) 12 (6.3) 17 (8.9) 17 (8.9) 12 (6.3) 12 (6.3) 4 (2.0) 4 (2.1) 6 (3.0) 5 (2.5) 3 (1.6) 4 (2.0) 3 (1.6) 3 (1.5)
18.664 120.420 115.337 33.985 51.542 21.218 18.664 0.084 17.783 0.222 17.352 7.801 0.623 5.043 5.529 0.476 0.150 3.109 0.385 2.396 2.356 0.228 0.141 1.967 0.065‡ 0.152‡ 0.068‡
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.771 0.000 0.638 0.000 0.005 0.430 0.025 0.019 0.490 0.699 0.078 0.535 0.122 0.125 0.633 0.703 0.161 0.798 0.697 0.794
BRVO ⫽ branch retinal vein occlusion; IOP ⫽ intraocular pressure; NV ⫽ neovascularization; RPE ⫽ retinal pigmental epithelium. *The fundus was not visible in 73 eyes of male patients and 11 eyes of female patients because of dense opacities in the lens or in the vitreous body. The frequencies of fundus changes indicate the number of eyes with fundus change(s) of total number of the affected eyes. † Including aphakic or pseudophakic eyes after cataract surgery. ‡ Fisher exact test, odds ratio.
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