Background

Uveitis is a leading cause of visual blindness in developed countries [1]. Many studies have reported the patterns of uveitis in different countries and ethnicities [2,3,4,5,6,7]. The distribution of the types and etiologies of uveitis is influenced by genetic, ethnic, geographic, environmental, and lifestyle factors [8]. As a result, the patterns of uveitis vary greatly according to the population and the time of research. For example, one report from Taiwan presented data demonstrating that the incidences of herpetic anterior uveitis, acute retinal necrosis, and cytomegalovirus (CMV) retinitis have increased, while those of toxoplasmosis and tuberculosis have decreased [9], compared with findings of a previous study [10]. Therefore, it is important to analyze the epidemiology of this disease in various regions over time.

In recent years, highly advanced diagnostic methods for uveitis, including optical coherent tomography and polymerase chain reaction (PCR) analysis for infectious agents using aqueous samples, have been developed. Consequently, the number of definite diagnoses has been gradually increasing [2]. However, a definite diagnosis can still not be reached in approximately 30–40% of patients newly diagnosed with uveitis [2, 4, 5, 11].

Region-specific information about the patterns of uveitis is helpful when the clinicians consider the diagnosis for newly arrived patients. There are many reports on this topic from both Japan and other countries [3,4,5,6,7, 12]. Previously, we have reported the patterns of newly arrived patients with uveitis at the University of Tokyo Hospital between 2004 and 2012 [2, 11]. In this institution, retrospective analysis of newly arrived patients with uveitis have been conducted over the past 50 years [2]. Therefore, we consider that the data from our hospital are representative of the changing patterns of uveitis in Japan.

In the current study, we investigated the records of patients who visited the University of Tokyo Hospital during 2013–2015 and compared the results to those of our previous studies (2004–2012) [2, 11].

Methods

We retrospectively investigated the clinical records of 750 newly arrived patients with uveitis (363 men, 387 women) who first visited the Uveitis Clinic of the University of Tokyo Hospital (a tertiary referral center located in central Tokyo) between January 2013 and December 2015. Patients with uveitis who had first visited before 2012 due to uveitis were excluded from the study. Conversely, patients who had first visited our clinic before 2012 for other reasons and then presented with uveitis during the study period were included in this study.

We collected clinicodemographic data, including age, sex, diagnosis, anatomic location of inflammation, laboratory test results of blood and urine, and chest X-ray and fluorescein fundus angiography findings from the patients’ clinical records. The ethics committee of the University of Tokyo Hospital allowed us to collect clinical data for this retrospective study.

We adopted the uveitis classification method used in a nationwide investigation of uveitis conducted in 2009 in Japan [13]. The anatomic diagnosis was evaluated according to the classification of the Standardization of Uveitis (SUN) Working Group, as anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis [14].

All patients with uveitis underwent blood tests (peripheral blood count, erythrocyte sedimentation rate, serum angiotensin-converting enzyme, glucose, rheumatoid factor, immunoglobulin [Ig] A, IgG, IgM, antinuclear antibody (double-stranded deoxyribonucleic acid [DNA] antibody and single-stranded DNA antibody), calcium, blood urea nitrogen, creatinine, creatine kinase, rapid plasma regain, Treponema pallidum latex agglutination, anti-human T-cell lymphotropic virus type I [HTLV-1] antibody, C-reactive protein, globulin fraction, IgM and IgG of toxoplasma, herpes simplex virus [HSV], varicella zoster virus [VZV], and CMV), urine tests, chest X-ray examination, and the Mantoux reaction test at the initial presentation. Additionally, PCR tests, β-d-glucan, HLA, interferon gamma release assays, diagnostic vitrectomy, and fluorescein angiography were performed when specific uveitis diseases were suspected; those examinations might be useful for judging the diagnosis. Quantitative PCR using aqueous humor and blood cultures was conducted when infectious uveitis was suspected; serum β-d-glucan testing (for suspected fungal endophthalmitis) and human leukocyte antigen (HLA) typing (for suspected acute anterior uveitis or Behçet’s disease) were also performed. Interferon-gamma release assays were conducted when the Mantoux reaction test was strongly positive. Moreover, vitreous fluid examinations were conducted when intraocular lymphoma was suspected. If inflammation was suspected in retina and/or optic disc, fluorescein angiography was performed if the patient consented to the procedure. Information obtained from fluorescein angiography was used to determine the anatomical location of uveitis and the presence or absence of retinal vasculitis and/or chorioretinitis for consideration in differential diagnosis of uveitis.

Behçet’s disease was diagnosed based on criteria established by the Behçet’s Disease Research Committee of Japan [15]. For sarcoidosis, we used the criteria established by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders [16, 17]. For Vogt–Koyanagi–Harada disease (VKH), we adopted previously reported criteria [18]. For herpetic iritis [19], patients with active skin lesions associated with ophthalmic herpes zoster (i.e., the vesicular rash involving the periocular skin, such as the eyelids, medial canthal area, or the tip of the nose, known as Hutchinson’s sign) were clinically diagnosed and classified as VZV iritis. Patients without a skin lesion were subjected to PCR assays for HSV, VZV, and CMV DNA using anterior chamber fluid. The presence of > 100 copies/mL of viral DNA were judged as a positive finding. Patients with negative PCR results for HSV, VZV, and CMV DNA, and good response to anti-herpetic treatment were classified as herpetic iridocyclitis (clinical diagnosis), while those who did not undergo PCR assays were classified as suspected herpetic iritis. The diagnoses of bacterial and fungal endophthalmitis were based on matching of ocular symptoms suggesting bacterial or fungal etiology, the results of laboratory tests (blood culture, serum β-d-glucan), detection of bacterial or fungal DNA in aqueous humor samples by broad-range PCR [20, 21], and a response to antibiotics or antifungal drugs. As for intraocular lymphoma, we diagnosed this disease if at least two of the following four criteria were met: cytology >class 3, interleukin (IL)-10/IL-6 ratio > 1 or IL-10 > 50 pg/mL in the intraocular fluid [22], κ/λ ratio on fluorescence-activated cell sorting analysis, and positive PCR results for immunoglobulin heavy chain (IgH) gene rearrangement [23]. Regarding acute anterior uveitis (AAU), patients with unique symptoms of ankylosing spondylitis, ulcerative colitis, or psoriasis were diagnosed as having systemic disease-associated uveitis. Those with HLA-B27 were diagnosed as AAU, while those without HLA-B27 or with unknown HLA typing were diagnosed as unclassified uveitis. We diagnosed ocular tuberculosis based on a combination of ocular symptoms indicating tuberculous etiology, laboratory tests, and response to anti-tuberculosis therapy. Consequently, we used the diagnostic criteria for presumed ocular tuberculosis [24]. The diagnostic criteria for diabetic iritis in this study were (1) acute severe iridocyclitis in patients with poor glycemic control (HbA1c ≥ 8.0%) and (2) other investigations for systemic disease associated with uveitis were negative [25]. For HTLV-1 [26], acute zonal occult outer retinopathy (AZOOR) [27], and rubella virus-associated uveitis [28], we adopted the criteria described in previous reports [26,27,28]. Juvenile chronic iridocyclitis was diagnosed by the typical ocular findings and clinical courses, as described in a previous report [29].

Statistical analyses were performed using the χ-squared test in SPSS for Windows, version 14.0 (SPSS Inc., Chicago, IL, USA). We compared the frequency of each disease between 2013 and 2015 with those between 2004 and 2012. A p value < 0.05 was considered statistically significant.

Results

Figure 1 shows the age distribution of the patients with uveitis that visited our institution between 2013 and 2015. The mean age was 56.4 ± 18.5 years (men: 56.9 ± 18.9 years, women: 56.1 ± 18.9 years). The most common age category was 60–69 years for both men and women. Among a total of 750 newly arrived patients with uveitis, 445 patients (59.3%) received a definite diagnosis. Table 1 presents the distribution of patients who were given a definite diagnosis. The three most common diagnoses were herpetic iridocyclitis (HSV, VZV, and CMV) in 56 patients (7.5%), sarcoidosis in 46 (6.1%), and Behçet’s disease in 31 (4.4%).

Fig. 1
figure 1

Distribution of 750 patients with uveitis from 2013 to 2015 by age and sex Uveitis was more frequent in the age group of 60–69 years among both men and women

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Table 1 Distribution of uveitis among new patients (2013–2015)
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Patients with herpetic iridocyclitis were divided into five groups by diagnostic method. Of these, CMV DNA positivity was the most common diagnostic method (n = 34, 60.7%), followed by skin lesions of herpes zoster ophthalmicus (n = 12, 21.4%), VZV DNA positivity (n = 5, 8.9%), HSV DNA positivity (n = 3, 5.4%), and clinical diagnosis only (n = 2, 3.6%) (Table 2).

Table 2 Diagnostic methods for herpetic iritis
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Table 3 shows the distributions of patients with uveitis according to three age groups (< 20 years, 20–59 years, and ≥ 60 years). In these patients, juvenile chronic iridocyclitis, Behçet’s disease, and herpetic iridocyclitis were the most common diagnoses, respectively. Definite diagnoses were not made for the remaining 305 patients (39.1%). Among these patients, suspected sarcoidosis was the most frequent diagnosis (n = 167, 22.3%), which accounted for 54.8% of all suspected diagnoses.

Table 3 Frequency of new patients with uveitis (2013–2015) by age
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Table 4 shows the distribution of uveitis categorized by anatomical location (anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis). In this study, 289 out of 750 patients (38.5%) had anterior uveitis, 12 (1.6%) had intermediate uveitis, 94 (12.5%) had posterior uveitis, and 355 (47.3%) had panuveitis. The distribution of uveitis according to anatomical site did not differ from that in our previous studies [2].

Table 4 Shifts in the distribution of anatomic localization of uveitis (2004–2015) [2, 11]
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Table 5 shows the shifting numbers and distributions of the uveitis cases diagnosed at the University of Tokyo Hospital over 12 years. Compared with our previous studies since 2004 [2, 11], the present analysis showed that the incidences of herpetic iridocyclitis, intraocular lymphoma, bacterial endophthalmitis, fungal endophthalmitis, and juvenile chronic iridocyclitis have been increasing. Additionally, sarcoidosis, Behçet’s disease, and VKH disease have been decreasing in recent years. However, the increases or decreases of these disease frequencies were not statistically significant (p > 0.05 for all).

Table 5 Shifts in the number and distribution (%) of diagnosed uveitis cases (2004–2015) [2, 11]
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Table 6 reports the distribution of the age of patients at the first visit in this study (2013–2015) and previous studies (2004–2006, 2007–2009, and 2010–2012). The average ages of new patients were 52.0, 51.6, 53.6, and 56.4 years, respectively, indicating that the average age has been gradually increasing.

Table 6 Shifts in the numbers of new patients with uveitis according to age (2004–2015) [2, 11]
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Discussion

In this study, the most frequent uveitis categories in patients aged < 20, 20–59, and ≥ 60 years were juvenile chronic iridocyclitis, Behçet’s disease, and herpetic iridocyclitis, respectively. A previous study conducted in our hospital (2010–2012) showed that the most frequent types of uveitis in the same age groups were juvenile chronic iridocyclitis, Behçet’s disease, and sarcoidosis, respectively [11]. In comparison with the findings of the previous study, an increase in the incidence of herpetic iridocyclitis in patients aged ≥60 years was observed. A possible reason for this new finding might be the progression of aging in Japan [30]. In fact, the incidence of infections, such as herpes zoster, in the elderly has been shown to be increasing in other countries as well [31].

Compared with the previous studies from our hospital [2, 11], the ratios of herpetic iridocyclitis (7.5%), intraocular lymphoma (4.1%), bacterial endophthalmitis (3.1%), fungal endophthalmitis (2.1%), and juvenile chronic iridocyclitis (2.3%) were increased in this study.

We speculated that the increase of herpetic iridocyclitis patients may be attributed to the recurring use of PCR assays for HSV, VZV, and CMV DNA using anterior chamber fluid. The increase in intraocular lymphoma may be due to two reasons. First, that we passively conducted diagnostic vitrectomy for patients suspected of having intraocular lymphoma. Second, that there has been an increase in the number of patients with primary central nervous system lymphoma [32]. The increases of patients with bacterial and fungal endophthalmitis were considered to be due to advances in the relevant diagnostic methods. Broad-range real-time PCR for bacterial DNA [19] and fungus DNA [20] were employed using both anterior chamber fluid and vitreous fluid. Moreover, the increase of juvenile chronic iridocyclitis might be related to the increasing number of patients aged < 20 years old in our hospital. In Japan, juvenile chronic iridocyclitis was not commonly associated with juvenile idiopathic arthritis [33]. The number of patients with juvenile chronic iridocyclitis without juvenile idiopathic arthritis in this study was also larger than the number of patients with both juvenile chronic iridocyclitis and juvenile idiopathic arthritis.

Notably, the ratios of scleritis, sarcoidosis, Behçet’s disease, and VKH have been gradually decreasing over the past years in our institution. We cannot find adequate reasons for the decreasing frequencies of these diseases.

Another interesting finding of this study is the trend for increasing age of newly arrived patients with uveitis. Compared to the data from 2004 to 2006, the average age of the patients with uveitis in the current study (2013–2015) was 4.6 years higher. A possible reason for the older age of patients with uveitis might be the rapid aging of the Japanese population [30]. Thus, it can be expected that the frequencies of herpetic iridocyclitis and intraocular lymphoma will be further increasing in the future in Japan. Indeed, the average age of patients with herpetic iridocyclitis or intraocular lymphoma in the current study was 62.5 ± 14.8 years and 72.0 ± 12.0 years, respectively. Further studies should be continued to clarify the trends of the patterns of uveitis.

The limitations of this study include its retrospective design, that it was conducted in a tertiary referral center, and that the study period was only 3 years. However, 750 patients were included in this study, and we believe that the current study’s findings could reflect the current trends of uveitis in Japan.

Conclusions

The recent patterns of uveitis in the central Tokyo area revealed increasing trends of herpetic iridocyclitis and intraocular lymphoma. Because the patterns of uveitis are continuously changing, ongoing investigations of the predominant types of uveitis are needed.