Graefes Arch Clin Exp Ophthalmol (2005) 243: 11471152 DOI 10.

1007/s00417-005-0005-8

CLINICAL I NVESTIGATION

Masaru Takeuchi Hideyuki Hokama Rintaroh Tsukahara Takeshi Kezuka Hiroshi Goto Jun-ichi Sakai Masahiko Usui

Risk and prognostic factors of poor visual outcome in Behcets disease with ocular involvement

Received: 3 December 2004 Revised: 1 April 2005 Accepted: 10 April 2005 Published online: 28 June 2005 # Springer-Verlag 2005

M. Takeuchi (*) . H. Hokama . R. Tsukahara . T. Kezuka . H. Goto . J.-i. Sakai . M. Usui Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku Shinjuku-Ku, Tokyo, 160-0023, Japan e-mail: takeuchi@tokyo-med.ac.jp Tel.: +81-3-33426111 Fax: +81-3-33469170

Abstract Purpose: The purpose of the study was to determine factors correlated with the progression of irreversible visual disturbance in Behcets disease (BD) with ocular involvement. Methods: Forty-seven BD patients with ocular inflammation, who presented with the first ocular episode, and who had been followed continuously for 5 10 years in our hospital, were studied. Charts were reviewed for gender, onset age of uveitis, complete or incomplete type BD, HLA-B51 status, final visual acuity at the last remission period, mean number of ocular attacks per year, and clinical findings of iridocyclitis with profuse hypopyon, strong vitreous opacity blocking the observation of retinal vessels, diffuse retinal vasculitis, and exudates with hemorrhage within the retinal vascular arcade. Results: Patients with a visual acuity of 20/200 and those with >20/200 differed significantly in the mean

number of ocular attacks per year and clinical findings of strong vitreous opacity and exudates within the retinal vascular arcade, but not with regard to the other factors. In addition, the frequency of ocular attacks showed a significant negative correlation with the outcome of visual acuity. Logistic regression analysis indicated a significant association of an average of more than three ocular attacks per year, strong vitreous opacity, and exudates within the retinal vascular arcade with poor visual outcome. Conclusions: This study indicates that more than three ocular attacks per year, strong vitreous opacity, and exudates within the retinal vascular arcade are the risk and prognostic factors for a poor outcome of visual acuity in BD patients. Keywords Behcets disease . Uveitis . Risk factor . Prognostic factor . Statistical analysis

Introduction
Behcets disease (BD) is a chronic, recurrent, multisystemic disorder in which ocular, oral, cutaneous, genital, vascular, and neurologic involvements are prominent features [3, 10, 32]. Among them, eye involvement, which can lead to blindness, is a serious complication of BD [26]. The etiology of BD remains elusive, although viral and streptococcal infections and autoimmunity have been suggested [5, 8, 11, 14, 15, 20]. Most of the patients with ocular-type BD manifest disturbances of their vision, but the prognosis

related to vision varies. Some reports have demonstrated a complete loss of vision in many of the BD patients, whereas others have reported little loss of vision. A recent report has indicated that the visual outcome of BD had improved when comparing cases in the 1980s and 1990s [33]. The risk and prognostic factors for the outcome of visual acuity might be much influenced by the severity of the disease. Ascertainment of the visual prognosis of the involved eyes is difficult at the time of diagnosis. Most patients with chronic endogenous uveitis including BD have no disturbance of their visual acuity at the beginning of the disease.

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After onset, the progression to permanent visual impairment with no improvement, even in the remission periods, takes several years. In this study, we aimed to identify the risk and prognostic factors for the visual outcome of recent cases of ocular-type BD by variate analysis and logistic regression analysis by using the clinical records of BD patients who presented with the first ocular episode at our clinic and who had been followed continuously at the same medical care facility for 510 years.

Materials and methods

We retrospectively reviewed the clinical charts of Japanese BD patients who had ocular inflammation, who presented with the first ocular episode at the Ophthalmology Clinic of Tokyo Medical University Hospital between January 1993 and December 1998, and who had been followed continuously for more than 5 years in our hospital. BD was diagnosed in our clinic according to the criteria established by the Behcets Disease Research Committee of Japan [19]: (1) complete type; presence of four major lesions (oral aphthae, genital ulceration, uveitis, and skin lesion), and (2) incomplete type; three major lesions, or uveitis and one major plus two minor lesions (arthritis, vascular lesions, central nervous system involvement, epididymitis, and digestive organ lesions). Patients with amblyopia were excluded. Clinical charts were reviewed for gender, onset age of uveitis, complete or incomplete type BD, HLA-B51 status, visual acuity at the last remission, mean number of ocular attacks per year, and clinical findings of iridocyclitis, vitreous opacity, diffuse retinal vasculitis confirmed by fluorescein angiography, and exudates with hemorrhage within retinal vascular arcade. Since BD induces recurrent ocular inflammation, and since every episode of inflammation is generally variable, data obtained at the first visit to the clinic are unlikely to reflect the true severity of the disease. To overcome this issue, we evaluated the mean number of ocular attacks in both eyes per year and the clinical findings observed in all the follow-up periods. The first ocular episode is occasionally severe and may cause permanent visual disturbance. When we refer to the first restored visual acuities as the initial visual acuity of the BD patients, we ignore damage caused by the first ocular episode. The patients had no amblyopia, and their visual acuity before the first ocular episode was presumed to be 20/20. Accordingly, we considered that adoption of first restored visual acuity might not be suitable for this type of study and used only the visual acuity at the last remission in the study period. In this study, visual acuity was measured by a Japanese standard Landolt visual acuity chart, and patients were divided into two groups according to visual acuity of the eye with the worse vision at the last remission during the study

period. The cutoff visual acuity was set at 20/200 [2], which is commonly used in studies of visual prognosis in BD to indicate a loss of useful vision. Group A had visual acuity 20/200, and group B had visual acuity >20/200. Data were analyzed with JMP version 5 (Business Unit of SAS, Cary, N.C.). Group proportions for the above parameters were compared by using the unpaired t-test, the MannWhitney U-test, and the 2 test with Bonferronis correction. A correlation of continuation variables was analyzed by Spearmans correlation coefficient by rank. Logistic regression analysis was used to identify prognostic factors that contributed to disturbance of visual acuity of BD.

Results
Table 1 compares group A and group B with respect to the male/female ratio, mean age of the uveitis onset, number of patients with complete type BD defined by involvement of all four major symptoms (uveitis, oral aphthae, cutaneous lesions, and genital ulcers), and number of patients possessing HLA-B51. No statistically significant differences were observed between these two groups for all these factors. Figure 1 shows the correlation between the mean number of ocular attacks per year and the visual acuity in all 47 BD patients enrolled in this study. Visual acuity measured by a Japanese standard Landolt visual acuity chart and converted to logarithm visual acuity (log VA) was used in this analysis. As the frequency of ocular attacks increased, log VA deteriorated, exhibiting a high negative correlation (=0.76, P<0.0001). In addition, as shown in Fig. 2, the mean number of ocular attacks per year was significantly higher in group A than in group B (3.690.37 vs 1.51 0.71, P<0.0001). Table 2 indicates the frequencies of clinical ocular features of severe iridocyclitis with profuse hypopyon observed by slit-lamp without gonioscope, strong vitreous opacity that blocks the observation of retinal vessels, exudates with hemorrhage within the retinal vascular arcade, and diffuse retinal vasculitis established by fluorescein angiography in group A and group B. According to Bonferronis
Table 1 Characteristics of patients and the disease in each group Character Group A (n=16) 13/3 36.62.94 2 5 Group B (n=31) 26/5 37.22.11 9 15 P value 0.8218 0.8552 0.1873 0.2557

Gender ratio (M/F) Age of uveitis onset Complete typea (no. of patients) HLA-B51 (no. of patients)
a

Complete type of BD is defined as involving all four major symptoms of uveitis, oral aphthae, cutaneous lesions, and genital ulcers

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Table 3 Logistic regression analysis of the risk of poor visual acuity outcome among characteristics of patients and diseases Character Odds ratio 0.891 3.980 1.177 0.226 13.93 95% Confidence interval 1.1531.085 0.0390.092 0.7510.978 1.9620.192 0.5102.301 P value 0.9174 0.4339 0.8494 0.1613 0.0031

Male Age of uveitis onset HLA-B51 Complete type Recurrent typea

a

Recurrent type Ocular inflammatory attacks with a frequency of more than three times per year

Fig. 1 Spearmans correlation coefficient by rank between average number of ocular attacks per year and log visual acuity (VA). Visual acuity was measured by a Japanese standard Landolt visual acuity chart and converted to log VA. Each point represents one BD patient and indicates the average number of ocular attacks per year (= 0.76, P<0.0001)

Fig. 2 Number of ocular attacks per year in BD patients of each group. Each point represents one BD patient and indicates the average number of ocular attacks per year. The average of each group is denoted by a horizontal bar (group A=3.690.37, group B=1.510.71)

correction, a P value of less than 0.005 is considered statistically significant. Thus, strong vitreous opacity and exudates with hemorrhage within the retinal vascular arcade were found significantly more frequently in group A than in group B. Table 3 shows the results of a logistic regression analysis conducted to identify the prognostic factors associated with poor visual outcome defined as visual acuity equal to or less than 20/200, by using the variables of male ratio, age of uveitis onset, HLA-B51, complete type BD, and more than three ocular attacks per year on average. As predicted, the mean number of ocular attacks was a dominant prognostic factor of poor visual outcome and was the only parameter significant at the level of the 95% confidence interval. Subsequently, prognostic factors associated with poor visual outcome were analyzed for the four parameters of clinical ocular findings. As shown in Table 4, clinical findings of strong vitreous opacity and exudates within the retinal vascular arcade were highly associated with poor outcome of visual acuity at the significant level of the 95% confidence interval. These results indicated that BD patients with ocular attacks recurring at a frequency of more than three times per year, those who manifested strong vitreous opacity preventing observation of retinal vessels, and those with exudates within the retinal vascular arcade had a 13-, 15-, and nine-fold, respectively, increased risk of visual acuity deteTable 4 Logistics regression analysis of the risk of poor visual acuity outcome among clinical findings

Table 2 Clinical findings in BD patients of each group Character No. of patients (%) Group A Severe iridocyclitis Strong vitreous opacity Exudates in retinal vascular arcade Diffuse vasculitis 9 (56.3) 14 (87.5) 14 (87.5) 15 (93.6) Group B 8 (25.8) 9 (29.0) 11 (35.5) 24 (77.4) 0.041 0.0001 0.0004 0.1306 P value

Character

Odds ratio

95% Confidence interval 0.2501.588 0.4992.449 0.2072.251 1.2901.818

P value 0.1720 0.0048 0.0262 0.8517

Severe iridocyclitis Intensive vitreous opacity Exudates in retinal vascular arcade Diffuse vasculitis

3.457 14.98 9.365 1.315

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rioration to 20/200 or less, compared with patients who had no such clinical findings.

Discussion
This study provides evidence that strong vitreous opacity, exudates within the retinal vascular arcade, and ocular attacks more than three times per year are risk factors associated with poor visual outcome in ocular type of BD patients and are also prognostic factors for permanent visual disturbance. The occurrence of ocular manifestation in BD is apparently more common in men than in women in all parts of the world [1, 4, 17]. The male gender and early onset age have been reported as risk factors for disturbance of vision and as prognostic factors in BD [6, 17]. In the present study, however, neither the male ratio nor the mean age of onset of ocular inflammation were statistically different in BD with unfavorable visual acuity compared with BD with favorable visual acuity, and neither were also prognostic factors for poor visual outcome. In addition, although involvement of the central nervous system (CNS), vascular thrombosis, and skin lesions have been demonstrated to be prognostic factors of poor visual outcome [6, 25], vascular thrombosis was not found in the BD patients enrolled in this study, and CNS disorders were noted only in three of the patients, thereby precluding a statistical analysis of these two factors. The rate of skin involvement in the patients with unfavorable visual acuity was also comparable with that in the patients with favorable visual acuity (data not shown). Cystoid macular edema (CME) is a clinical sign frequently observed in posterior uveitis, including ocular type of BD. A medical history of CME was noted in almost all the BD patients enrolled in this study. On the other hand, optic nerve atrophy is a consequence of ocular inflammatory reactions and invariably results in the disturbance of vision. Since these problems are unlikely to contribute to the difference in visual outcome, we excluded CME and optic nerve atrophy from the present statistical analysis. The risk and prognostic factors for the outcome of visual acuity might be greatly influenced by the severity of the disease. Benezra and Cohen [2] reported that the loss of useful visual acuity occurred in 74% of 49 ocular-type BD patients at 610 years after the onset of ocular symptoms. However, Sakamoto et al. [25] recorded an unfavorable visual outcome in 35 of 101 eyes (about 35%) in BD patients, whereas Pivetti Pezzi et al. [23] found this outcome in 45%. In our study, poor visual acuity outcome was observed in 16 of 47 BD patients (approximately 34%). These discrepancies might be related to the fact that clinical outcomes of BD, in terms of the number of ocular attacks per year and visual acuity, have improved in the 1990s compared with the 1980s, although treatment has remained mostly unaltered [33]. However, regional differences in the

clinical manifestation of this disease might also be an important factor. Mishima et al. [17] have indicated that the visual outcome of the anterior segment type uveitis in BD is more favorable than the outcome of the posterior segment and panophthalmic types with recurrent retinal edema, exudates, and hemorrhage particularly in the macular region. Considering the above findings together with our present results, a lesion is more likely to cause irreversible visual disturbance if it is located within the retinal vascular arcade, because photoreceptor cells and ganglion cells present in the macular area are gradually damaged by the inflammatory cells. However, our study indicates that strong vitreous opacity is also a risk and prognostic factor for poor visual outcome. Visual disturbance caused by vitreous opacity results in hazy media, which usually seems to be temporary and reversible. However, since strong vitreous opacity is mainly caused by a severe inflammatory lesion that lies somewhere in the retina but that cannot be observed because of the opacity, the neural retina might be damaged by inflammatory products, such as cytokines and nitric oxide [7, 9, 21, 27]. In this study, the frequency of ocular attacks showed a high negative correlation with visual outcome of BD, and the mean number of ocular attacks per year was 3.690.37 in patients of group A (unfavorable visual acuity group), which was statistically higher than that of group B (favorable visual acuity group; 1.510.71). Moreover, ocular attacks of more than three times per year represented the prognostic factor associated with poor visual outcome, demonstrating that repeated ocular inflammation causes a disturbance of vision, independent of the severity or location of the lesion. Several papers have assessed the risk factors for the prognosis of visual acuity of uveitis including BD. However, some of these reviewed all the charts of patients during long-term follow-up periods. Patients with a short history of uveitis obviously possess better visual acuity than those with a long history. Risk factors for patients with a long history of uveitis may not be risk factors in patients with a short history. Findings of patients with a short history of the disease should not be applied directly to patients with a long history. Moreover, to ensure validity of comparisons, only the data of patients followed at the same medical care facilities for a certain period should be utilized in the analysis. Therefore, we have reviewed the clinical charts of only those BD patients who presented with the first ocular symptoms at the Ophthalmology Clinic of Tokyo Medical University Hospital between January 1993 and December 1998 and who had been followed-up continuously for 510 years in our hospital, in this study. No uniformly effective drug therapy for uveitis of BD has yet been described. Although conventional drugs such as colchicines, corticosteroids, chlorambucil, cyclophosphamide, and cyclosporine have been employed for preventing and ameliorating ocular inflammation, their efficacy

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is uncertain, especially in severe cases [12, 16, 18, 22, 29]. We have also administered systemic corticosteroids and cyclosporine in addition to topical corticosteroid dosage for BD patients with severe ocular inflammation. Since systemic treatment was given almost exclusively to BD patients with an unfavorable visual outcome and who belong to group A in this study, a statistical analysis considering the systemic regimen could not be performed. Recent reports have indicated that blockade of tumor necrosis factor alpha (TNF) by using infliximab, a chimeric monoclonal antibody against TNF, is an effective treatment in ocular inflammation of BD, although sideeffects after multiple infusions of infliximab, including

serious infections and development of autoantibodies against double-stranded DNA, have been observed in some patients [24, 28, 30]. In addition, the efficacy of interferon alfa-2a for severe ocular BD has been demonstrated [13, 31]. In the future, the risk and prognostic factors for the visual outcome of BD should be modified if these new beneficial therapies become common treatments for severe BD.
Acknowledgements This work was supported by Grant-in-Aid 16591769 for Scientific Research from the Japan Society for the Promotion of Science.

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