Background
Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA); it is a serious manifestation carrying the risk of blindness if treatment is delayed or inadequate. The prevalence of JIA-associated uveitis (JIA-U) has been reported as ranging from 4.7 to 20.5% [
1‐
6] with local differences noted. Numerous reports have identified risk factors for JIA-U such as female sex, oligoarthritis, earlier arthritis onset, ANA-positivity, and RF-negativity in predominantly Caucasian cohorts [
2,
7,
8]. Do these characteristics also apply to JIA-U in East Asia? To date, there are very few reports from East Asia and the epidemiology, characteristics and risk factors for JIA-U in Japan are unclear.
Although we, the members of the Pediatric Rheumatology Association of Japan (PRAJ), issued recommendations for ophthalmologic screening intervals for JIA patients in Japan [
9,
10] (Table
1), these were based on other countries’ guidelines [
2,
11]. In any event, these recommendations were issued only one year before this study of patients in Japan, and therefore such recommendations did not apply to most of the patients included here. Given that the prevalence and characteristics of JIA-U in Japan were unclear, and pediatricians and ophthalmologists had little knowledge of the management of JIA-U, investigating these issues specifically in Japanese patients was warranted. Accordingly, in the present study, we aimed to establish the epidemiology, clinical characteristics, and risk factors for JIA-U in Japan and to compare these with data reported from other countries. Thus, we reviewed the charts of outpatients making regular hospital visits as of April 2016.
Table 1
Recommendations for ophthalmologic screening intervals for JIA patients in Japan [
9,
10]
・≤4 years from onset of arthritis |
Oligoarthrits, RF-negative polyarthritis, undifferentiated arthritis | ≥160 | Every 3 months | Every 6 months |
< 160 | Every 6 months | Every 6 months |
Psoriatic arthritis whose onset age is <4 years old | Regardless | Every 3 months | – |
Others | Regardless | Every 12 months | Every 12 months |
・4 < years, ≤7 years from onset of arthritis |
Oligoarthrits, RF-negative polyarthritis, undifferentiated arthritis | ≥160 | Every 6 months | Every 12 months |
< 160 | Every 12 months | Every 12 months |
Psoriatic arthritis whose onset age is <4 years old | Regardless | Every 6 months | – |
Others | Regardless | Every 12 months | Every 12 months |
・>7 years from onset of arthritis: Every 12 months. |
Discussion
This is the first report surveying the epidemiology and characteristics of JIA-U in Japan. Our results are compared with previous reports in Table
6. It is apparent that the prevalence of JIA-U in Japan is lower than reported earlier from North America and Europe. These previous reports revealed regional differences in the prevalence of JIA-U: 11.6–20.5% in North America and Europe [
1‐
5] and 4.7% in Taiwan [
6]. Another study reported that the prevalence of JIA-U in Asia is lower than in Scandinavia as well as the United States [
14]. Although these differences may be due to differences in study design, there may well also be an influence of race. Because almost all of the patients assessed in our survey were Asians, this population may have a lower incidence than predominantly Caucasian populations.
Table 6
Comparison of epidemiology and characteristics of JIA-U in our results vs. in previous reports
country | Japan | Switzerland | Germany | Norway | United States of America |
prevalence | 6.1% | 13.1% | 12% | 20.5% | 18% |
JIA subtype |
oligo | 81.8% | 48% | 41% | 46.1% | 78.9% |
RF + poly | 0% | 0% | 0% | 0% | 0% |
Systemic | 0% | 0.6% | 0% | 0% | 0% |
Rate of uveitis in oligo | 16.1% | 20.9% | 17.6% | 19.6% | 30.8% |
Rate of uveitis in all other type | 1.6% | 8.3% | 6.7% | 21.3% | 7.1% |
Risk ratio of uveitis in oligo | 10 | 2.5 | 2.6 | 0.9 | 4.3 |
femalea | 67.6% vs. 70.5%, p = 0.743 | 79.6% vs. 63.7%, p = 0.0009b | 74% vs. 62%, p = 0.012 | 65.6% vs. 66.3% | 76.9% vs. 70.2%, p = 0.332 |
ANA-positive (%)a | 52.3% vs. 22.2%, p < 0.0001 | 80.9% vs. 51%, p < 0.0001 | 86% vs. 42%, p < 0.01 | 42.5% vs. 23.2% | 54.9% vs. 35.9%, p = 0.017 |
RF-positive (%)a | 2.4% vs. 24.5%, p = 0.0004 | – | – | 1.1% vs. 2.7% | 0% vs. 11.1%, p = 0.013 |
the mean age of uveitis onset (yrs.) | 5.6 | 6.2 | 5.2 | 10.8(acute) and 3.2(chronic) | median 4.8 |
the mean age of arthritis onset (yrs.)a | 3.8 vs. 6.8 | 4.3 vs. 7.3 | 3.8 vs. 7.0 | – | median 2.8 vs. 7.7 |
time from arthritis onset to uveitis diagnosis | median 2 yrs. | mean 1.8 yrs. | median 5.5 months | – | – |
uveitis diagnosis before the arthritis diagnosis | 4.9% | 12.7% | 10% | – | 24% |
anterior uveitis | 79.3% | 100% | 83% | – | 80% |
bilateral uveitis | 53.7% | 60.6% | 70% | – | 72% |
asymptomatic uveitis | 58.5% | 69.7% | – | – | – |
Our study confirmed that oligoarthritis, earlier arthritis onset, ANA-positivity, RF-negativity and anti-CCP antibody-negativity could be risk factors for JIA-U in Japanese as well as in predominantly Caucasian populations. Several reports showed that oligoarthritis was the most common subtype of JIA with uveitis [
2,
15,
16]. Likewise, in our study most patients (81.8%) with uveitis had oligoarthritis. While oligoarthritis accounts for approximately 50% of all JIA patients in North America and Europe [
2,
4,
5,
17], the proportion is smaller in Japan and many patients have systemic and RF-positive polyarthritis. The reason for the low prevalence of JIA-U in Japan may be related to the lower proportion of oligoarthritis in Japan than in North America and Europe. We compared the rate of uveitis in oligoarthritis patients and other arthritis patients between Japan and other countries (Table
6). The risk of uveitis in oligoarthritis patients in Japan is 10-fold, which is much higher than in oligoarthiritis patients in other countries. None of the patients with systemic arthritis and RF-positive polyarthritis developed uveitis - consistent with previous reports [
2,
4,
5,
7,
18]. Because patients with these types of arthritis have little risk of developing uveitis, in such cases, autoinflammatory diseases such as Blau syndrome, or infections should be considered rather than JIA. In the present study, it was difficult to determine the frequency of the HLA-B27 allele because too few patients were tested, but Japanese JIA is characterized by a low incidence of enthesitis-related arthritis, as shown in Table
2. In addition, psoriatic arthritis is also very rare. Previous reports [
19,
20] indicated that mean ANA titers tend to be high, with a significantly higher prevalence of ANA ≥1:320 in JIA patients with uveitis; our study also indicated a significant difference at ≥1:640.
The mean age of onset of JIA-U has been variably reported to be between 3.2–10.9 years [
1,
2,
5,
18]; almost all cases are diagnosed before arthritis onset or within 4 years of onset [
2,
4,
5,
15], and particularly within one year of the first ophthalmologic examination [
2,
5] (not shown in Table
6). Furthermore, 10–24% patients develop uveitis before arthritis onset [
1,
2,
18]. More than 80% of the locations affected by uveitis are anterior and 60.6 to 72% are bilateral [
1,
2,
18]. Ocular complications including glaucoma, cataract, band-keratopathy, and posterior synechia at uveitis diagnosis were seen in between 37.3 and 56% of uveitis patients [
1,
2]. Because the presence of complications will influence the visual prognosis, early diagnosis and treatment of uveitis is crucial. However, failure to have regular ocular examinations may lead to delayed diagnosis because JIA-U is asymptomatic and insidious in many cases [
2]. In the present study, 36.6% of patients had ocular symptom at uveitis diagnosis; one of the reasons for the large number of patients with ocular symptoms may be the lack of regular routine ophthalmologic examinations in Japan. Similar to previous reports, the most commonly affected location of the uveitis was anterior, whereas fewer cases were bilateral. In our study, the median age at diagnosis of uveitis was 5 years, 80.5% of the patients developed uveitis before they reached 8 years of age, and 95.1% developed it under 7 years of arthritis onset. Thus, the risk of onset of uveitis is high for patients under 8 years of age and under 7 years from arthritis onset. These results suggest that recommendations for standard ophthalmological follow-up of Japanese JIA patients should consider patient age, and time from arthritis onset.
Except for two patients, all were treated with MTX, a medication previously shown to be effective for uveitis [
21‐
23]. However, we could not determine whether treatment with MTX was effective in the present study.
Heiligenhaus et al. stated that ocular complications at the first visit to an ophthalmologist could be predictive of ocular complications at final observation [
2]. In addition, Woreta et al. concluded that a short interval between arthritis and uveitis onset, ANA-positivity and the degree of ocular inflammation at the initial diagnosis, were all risk factors for complications [
24]. Previous reports showed that cataract is associated with systemic steroid therapy, the amount of steroid eye drops and degree of ocular inflammation [
25‐
28]. We found that the proportion of patients with complications increased from 31.7% at the first visit to an ophthalmologist to 56.1% at the final observation, and it was especially striking that the number of patients with cataract increased 3-fold over this period. Patients with complications at the initial diagnosis indeed had significantly more complications at the final observation, but there was no association between the presence of complications and age at diagnosis of uveitis, or the time from arthritis onset to uveitis diagnosis, and ANA-positivity. There were also no significant differences between complications and persisting active uveitis at the final observation. In addition, we found that systemic steroid therapy had no influence on cataract formation, and the presence of cataract at the first visit had no influence on the surgical history. JIA-U carries a risk of decreased visual acuity and blindness [
29,
30]. While none of the patients lost their eyesight over the observation period in our study, more than half did not fully recover visual acuity or had decreased visual acuity at the final observation. Steroid eye drops, oral MTX, and biological agents (IFX and ADA) were mainly used for treatment, and especially biological agents had been employed in a high proportion of patients. This may be one of the reasons why there was no loss of eyesight and few patients with severely decreased vision in our study.
While female sex is reported as a risk factor for JIA-U, severity of the uveitis may be greater in males [
31‐
33]. In comparison, in our study, female sex was not a risk factor for JIA-U, but males with uveitis did have a significantly higher incidence of active uveitis at the last observation.
This study has some limitations. It included 726 Japanese JIA patients, representing approximately 1/4 of all JIA patients in Japan and an estimated half of all patients treated in medical centers specialized in pediatric rheumatic diseases. Although Japan is divided into 47 prefectures, there are only about 80 pediatric rheumatologists and they are unevenly distribution locally, so general pediatricians treat JIA in areas where there are no pediatric rheumatologists. On the other hand, because severe cases are often referred to a pediatric rheumatologist, many JIA-U will be treated by pediatric rheumatologists. Accordingly, the prevalence of uveitis in Japan as established here may actually be even less than 6% of all JIA patients.
Just as there are few pediatric rheumatologists, so there are also few ophthalmologists who specialize in uveitis in Japan. In addition, although the standardization of uveitis nomenclature (SUN) working group reported criteria to evaluate uveitis [
34], few ophthalmologists in Japan use these criteria. Therefore, in the present study, because pediatricians extracted the records written by each ophthalmologist there were some uninterpretable data, especially the location of uveitis. Because of the retrospective nature of this study, there were also some missing data such as data on visual acuity. Although we issued recommendations for ophthalmologic screening intervals for JIA in 2015 [
9], because we issued it one year before this study, most patients were not receiving screening according to this recommendation. Hence, only 34% of patients had regular ophthalmologic screening before uveitis diagnosis, and 34% had ocular symptoms at the time of uveitis diagnosis in this study. JIA-U is typically asymptomatic and insidious [
2], so if patients have regular ophthalmologic examinations, ocular symptoms may be identified less frequently at the time of JIA diagnosis, but more often beforehand.
We did not collect data on the degree of ocular inflammation and the dose of steroids, and so we were unable to analyze potential associations between uveitis and these factors. Also, we did not collect detailed data on dose and timing of drug use for any drugs other than steroids, so we could not analyze the effects of these treatments on uveitis. Thus, because detailed analysis of treatment was difficult in this study, we plan an additional study in cooperation with ophthalmologists in future.
Acknowledgments
We thank the children and parents participating in the study. We thank Dr. Ryuhei Yasuoka, Dr. Toaki Kohagura, Dr. Naoki Abe, Dr. Haruna Nakaseko, Dr. Shinji Kawabe (Department of Immunology and Infectious Diseases, Aichi Children’s Health and Medical Center, Obu, Japan), Dr. Takuji Murata, Dr. Yuko Sugita (Department of Pediatrics, Osaka Medical College, Takatsuki, Japan), Dr. Hiroshi Nihira (Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan), Dr. Kanako Mitsunaga, Dr. Akiko Yamaide (Department of Allergy and Rheumatology, Chiba Children’s Hospital, Chiba, Japan), Dr. Naoki Shimojo, Dr. Yuzaburo Inoue, Dr. Hironori Sato (Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan), Dr. Shunichiro Takezaki (Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan), Dr. Fumiko Okazaki (Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan), Dr. Tomo Nozawa, Dr. Asami Oohara, Dr. Ayako Murase and Dr. Tetsuya Tsuchida (Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan) for collecting the medical records. We thank Dr. Syuji Takei (Department of Pediatrics, Kagoshima University Graduate School of Medicine, Kagoshima, Japan) for analyzing data. We thank Dr. Norihiro Nishimoto (Department of Molecular Regulation for Intractable Disease, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan) and Dr. Toshihiro Matsui (Department of Rheumatology, Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Japan) for research planning.