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To describe the incidence of and risk factors for visual acuity (VA) loss and ocular complications in patients with juvenile idiopathic arthritis (JIA)-associated uveitis.
Multicenter retrospective cohort study.
327 patients (596 affected eyes) with JIA-associated uveitis managed at five tertiary uveitis clinics in the United States.
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study. Demographic and clinical characteristics were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers.
Loss of VA to 20/50 or to 20/200 or worse thresholds and the development of ocular complications.
At presentation, 240 (40.3%) eyes had a VA of 20/50 or worse; 144 (24.2%) had a VA of 20/200 or worse; 359 (60.2%) had at least one ocular complication. The incidences of VA loss to the 20/50 or worse and 20/200 or worse thresholds were 0.18 and 0.09 per eye-year (EY), respectively; the incidence of developing at least one new ocular complication over follow-up was 0.15/EY (95% confidence interval [CI]: 0.13/EY, 0.17/EY). However, among eyes with uveitis that had no complications at presentation, the rate of developing at least one ocular complication during follow up was lower (0.04/EY, 95% CI: 0.02, 0.06). Posterior synechiae, active uveitis, and prior intraocular surgery were statistically significantly associated with VA to the 20/50 or worse and 20/200 or worse thresholds, both at presentation and during follow-up. Increasing (time-updated) anterior chamber cell grade was associated with increased rates of visual loss in a dose-dependent fashion. Use of immunosuppressive drugs was associated with a reduced the risk of visual loss, particularly for the 20/50 or worse outcome (hazard ratio = 0.40, 95% CI: 0.21, 0.75, P<0.01).
Ocular complications and vision loss were common in our cohort. Increasing uveitis activity was associated with increased risk of vision loss and use of immunosuppressive drugs was associated with reduced risk of vision loss suggesting that control of inflammation and use of immunosuppression may be critical aspects in improving the outcomes of patients with JIA-related uveitis.
Juvenile idiopathic arthritis (JIA) refers to a group of heterogeneous arthritides that begin before 16 years of age and may be associated with uveitis, most commonly in patients who have antinuclear antibodies (ANA).1–3 JIA-related uveitis is an important cause of childhood uveitis in North America,4 with an estimated incidence of approximately 4.9 to 6.9 per 100,000 person-years and an estimated prevalence of 13 to 30 per 100,000 population.4–9
Because JIA-associated uveitis typically has an indolent and chronic course, children with this condition are at risk for ocular morbidity and visual loss, particularly if referred to a tertiary care setting late in the disease course.10,11 Structural ocular complications complicating JIA-related chronic uveitis include band keratopathy, posterior synechiae, cataract, glaucoma, hypotony, macular edema, epiretinal membrane, and optic disc edema, many of which lead to visual loss.2,3,6–17. The reported risks of reduced visual acuity to 20/50 range from 13 to 26% and of reduction to 20/200 range from 5% to 9% depending on series and practice type.6–10,16,17 Reported rates of visual acuity loss from small to medium-sized series range from 0.10 to 0.12 per eye-year (EY) for 20/50 or worse vision and 0.08/EY to 0.09/EY for vision loss to 20/200 or worse.10,12,16 Previous studies have suggested that even low-grade active inflammation is associated with an increased risk of developing visual loss over time and that use of immunomodulatory therapy (IMT) may reduce this risk, presumably by achieving better control of the intraocular inflammation and thereby reducing rates of complications that decrease vision. However, the sample sizes of these studies were relatively low, which has limited the precision of the results,10,12 and requiring that groups with possibly heterogeneous risk be lumped together and analyzed as a group, making it unclear whether very low levels of inflammation in fact are associated with increased risk of poor outcome.
The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study is a retrospective cohort study conducted at five referral-based uveitis practices in the United States, which provides a more extensive experience with the outcomes of JIA than has been reported previously. The purpose of our study was to analyze the incidence of and risk factors for vision loss among the 327 patients (596 eyes) with JIA associated uveitis in SITE, with a particular interest in evaluating the effect of low-grade active intraocular inflammation and treatment with IMT.
The methods of the SITE Cohort Study have been described elsewhere.18 For the purposes of this analysis, all patients diagnosed with JIA19 (or oligoarticular and rheumatoid factor negative polyarticular juvenile rheumatoid arthritis [JRA] prior the publication of the newer criteria) and having an associated chronic uveitis from the SITE cohort were included. Enthesis-related acute or recurrent alternating anterior uveitis was not including. The patients reported here had been examined between January 1978 and December 2007 inclusive. All participating centers had approval from their Institutional Review Boards for the study18
Data had been entered into a database using a computer-based standardized data entry form set specifically prepared for the SITE Study18. The system included quality control checks, requiring correction of potential errors in real time. Data evaluated this report include: demographic characteristics, ophthalmologic examination findings, and all medications that patients (or eyes) were receiving at each clinic visit, including dose and route of administration. Ophthalmologic examinations included measurement of visual acuity, intraocular pressure (IOP) assessment, and details regarding the activity and complications of the uveitis.
Incidence rates of and risk factors for the loss of visual acuity were the primary outcomes. Loss of visual acuity was evaluated among those at risk as the first measurement of a visual acuity of 20/50 or worse (visual impairment) or 20/200 or worse (legal blindness), thresholds according to recommendations of the Standardization of Uveitis Nomenclature (SUN) Working Group.20 Ocular complications evaluated included posterior synechiae, band keratopathy, ocular hypertension (IOP > 21 mm Hg and IOP ≥ 30 mm Hg were assessed), hypotony (IOP < 5 mm Hg), epiretinal membrane, and macular edema. In addition the history of ophthalmic surgeries was assessed, including cataract and glaucoma surgery. All outcomes were assessed at every clinical visit. Measurements of prevalent reduction of visual acuity or ocular complications of inflammation were based on the presence of these characteristics at the first study visit.
The frequencies of patient- and eye-specific characteristics were tabulated. Visual acuities, recorded in the SITE dataset as Snellen equivalents, were transformed to logarithm of the minimum angle of resolution (logMAR) scores to facilitate analyses. Incidence rates were calculated as the number of events divided by the number of person-years or eye-years at risk; 95% confidence intervals were calculated for each rate. Crude and adjusted hazard ratios using Cox regression models were calculated to assess both baseline and longitudinal risk factors for the incidence of reduced visual acuity to 20/50 or worse and to 20/200 or worse.21 P-values were nominal and 2-sided. Time-updated multiple regression models containing all exposure variables with statistically significant associations for each visual acuity outcome, and models generated by stepwise procedures with the cutoff for inclusion in the final model of P <0.05 were constructed. All multiple regression models controlled for demographic characteristics including age, gender, race, bilateral disease, and uveitis duration. All analyses accounted for correlation between eyes in patients with bilateral disease using robust techniques.22 Analyses were performed with the Stata 9.0 statistical package (Stata Corporation, College Station, TX).
The demographic and clinical characteristics of the study population are summarized as Table 1. Three hundred twenty-seven patients with JIA-related uveitis were included in the study. The median age of diagnosis of JIA was 4.1 years with a range from 4 months to 16.9 years. The follow up duration ranged from 0 to 24 years, with a median follow up of 2.62 years among patients seen more than once. The majority of the participants were white (85.3%) and female (80.1%). At presentation, 269 (82%) of patients had bilateral uveitis. Of the 596 affected eyes, 240 (40.3%) eyes initially had a visual acuity of 20/50 or worse and 144 (24.2%) were 20/200 or worse. At presentation, 35% of the eyes in this study had at least 1+ anterior chamber cell, and 29% of eyes had posterior synechiae. Sixty percent of affected eyes (59% of patients) had at least one ocular complication, 20.6% had two ocular complications, and 7.2% of eyes had more than two ocular complications at the time of presentation.
Table 2 summarizes the incidence rates for structural ocular complications and for visual acuity loss observed during the follow-up period (median duration of follow-up = 2.6 years, range: 1 month to 24 years or 767 person-years [1448 eye-years of follow-up]). The incidence of visual loss to the 20/50 or worse threshold was 0.20/person-year ([PY, for either eye] or 0.18/eye-year [EY, for affected eyes]). The incidence of visual loss to 20/200 or worse was 0.14/PY or 0.09/EY. We also found that among patients with new visual acuity loss to 20/50 and 20/200, 54% and 62% respectively maintained vision loss to this level for at least two visits (data not shown). During the observed follow-up time, 40% of patients (37% of eyes) developed at least one new ocular complication (rate = 0.17/PY and 0.15/EY). Ocular hypertension (rates = 0.17/PY and 0.10/EY), band keratopathy (0.14/PY and 0.14/EY), and posterior synechiae (0.12/PY and 0.10/EY) were the most common complications observed.
Because it is possible that eyes of patients with one or more ocular complications at presentation had more severe disease, we evaluated the incidence of developing the first ocular complication among uveitic eyes that had no ocular complications when the patient entered the study. Among these eyes, the rate of developing a first ocular complication during follow-up was 0.04/EY (95% CI: 0.02, 0.06). This result was statistically significantly lower than the overall rate of developing an ocular complication among all uveitic eyes (rate = 0.15/EY, 95% CI: 0.13, 0.17, P= 0.01).
Tables 3 summarizes the risk factors for the development of loss of visual acuity across the 20/50 or worse and the 20/200 or worse thresholds. After controlling for demographic characteristics, bilateral uveitis and duration of uveitis, the presence of posterior synechiae, abnormal IOP, active uveitis (as indicated by ≥1+ cells in the anterior chamber or presence of ≥0.5+ vitreous haze), and history of prior intraocular surgery were all statistically significantly associated with an increased risk of developing 20/50 or worse vision during follow-up. In addition, the time-updated evaluation of presence of anterior chamber cell showed a dose–response type relationship as demonstrated by an increased risk of developing 20/50 or worse visual acuity both in the crude and adjusted regression models. The presence of any band keratopathy at presentation was associated with an increased risk of incident 20/50 or worse vision in the univariate analyses, but was not statistically significant after adjusting for the other variables in the multiple regression model (hazard ratio [HR] = 1.20; 95% confidence interval [CI]: 0.97, 1.49, P = 0.10). Use of any corticosteroids over follow-up also was associated with visual loss to 20/50 or worse (adjusted HR= 1.38, 95% CI: 1.11, 1.71, P< 0.01), which arose from patients who were using oral corticosteroids (adjusted HR for oral corticosteroids = 1.43, 95% CI: 1.15, 1.79, P<0.01) rather than topical corticosteroids (adjusted HR = 0.67, 95% CI: 0.17, 2.70, P =0.57). Use of IMT evaluated longitudinally over follow-up time was associated with a statistically significant decrease in the risk of visual acuity loss to the 20/50 or worse after controlling for confounding variables (HR = 0.40; 95% CI: 0.21, 0.75; P<0.01).
For the 20/200 or worse visual acuity outcome, risk factor analysis revealed that the presence of posterior synechiae, active uveitis (as defined above), band keratopathy, oral corticosteroid use, and prior intraocular surgery were associated with increased incidence (see Table 3). The presence of anterior chamber cells evaluated in a time-dependent manner demonstrated a dose-dependent increase in the risk of developing 20/200 or worse visual acuity as well, whereas time-updated abnormal IOP did not. When ocular hypertension and hypotony were re-evaluated as separate risk factors, neither were statistically significantly associated with an increased risk of 20/200 or worse visual acuity. In the adjusted model (controlling for demographic characteristics, duration of uveitis, visual acuity at presentation, active uveitis, posterior synechiae, history of prior surgery and use of oral corticosteroids), use of IMT evaluated longitudinally over follow-up time was associated with a tendency toward decreased incidence of 20/200 or worse visual acuity (adjusted HR = 0.80, 95% CI: 0.62, 1.02, P=0.08).
Separate analyses evaluating risk factors only at the presenting visit were performed for both visual acuity outcomes and yielded similar results. Furthermore, step-wise regression models also were performed to evaluate the effectiveness of IMT and these models did not alter the results presented herein (data not shown).
In this large retrospective cohort of patients with JIA-associated uveitis, we assessed the incidence of loss of visual acuity and of ocular complications and found that the time-updated presence of posterior synechiae, active anterior chamber inflammation, and intraocular surgery were associated with increased risk of incident vision loss across both visual acuity thresholds (20/50 or worse and 20/200 or worse) in a statistically significant fashion. These findings are consistent with the published literature.2,4, 6–13,15,16 Further, our results demonstrated a “dose-response” relationship between the severity of anterior chamber cell grade and the risk for visual acuity loss during follow-up, particularly for anterior chamber cell of 1+ or greater. This finding remained statistically significant for both visual acuity loss thresholds, for crude and adjusted models, and for analyses utilizing risk factors at presentation and time-varying risk factors. The result suggests, not surprisingly, that the presence and degree of intraocular inflammation is a significant risk factor for visual loss among patients with JIA-associated uveitis, and that 1+ or higher grade AC cells is associated with increased risk of visual loss. Grade 0.5+ anterior chamber cell was not associated with a large or significantly higher degree of visual loss after adjusting for other factors.
We observed that the use of immunosuppressive drugs was associated with a statically significantly reduced risk of at least moderate visual loss, a finding previously reported.12 However because the patients reported by Thorne and colleagues12 likely overlap with some of the patients in this current cohort, we performed a sub-analysis evaluating this association in the SITE cohort with the Hopkins patients removed, which demonstrated the same overall pattern as that reported here including all patients. Indeed, the results were similar in each center. Our results also suggested that use of immunosuppressive drugs was associated with a reduced risk of developing blindness, although our results did not quite achieve statistical significance. Nevertheless, avoidance of moderate vision loss provides an adequate indication to advocate use of immunosuppressive therapy in patients with chronic uveitis related to JIA. Given evidence supporting the relative safety and effectiveness of immunosuppressive drug therapy in the treatment of a variety of ocular inflammatory diseases,23–33 the threshold for starting immunosuppression in cases that are not easily and stably controlled by simpler means should be low. Our ability to conduct sub-analyses investigating various types of IMT was limited by indication for treatment bias, as drugs typically employed for more severe cases would tend to have worse outcomes. Indeed, because IMT generally is used for more severe cases, our data likely underestimate the benefits of IMT. It is possible that results would have been even more favorable had use of TNF-inhibitors—believed to be effective for this condition34—been widely used at the time that our patients were treated. Further, we lacked adequate sample size to analyze treatment outcomes according to the specific immunosuppressive agent used. Indeed the SITE Research Group is collecting additional data on TNF-inhibitors so perhaps we will have adequate power to perform these analyses in the future.
We found that eyes of patients that presented to our clinics without developing any ocular complications prior to presentation were less likely to develop ocular complications during the observed follow-up (rate = 0.04/EY versus 0.15/EY, P=0.01). This observation may reflect a lesser degree of severity in those cases without complications at the time of presentation, or a benefit of early successful treatment, or both. If we assume that uveitis specialists are more effective in preventing these complications, then these data could support previous publications suggesting that early referral to a uveitis specialist is associated with better clinical outcomes.11,35 The high risk of complications observed even under tertiary care also suggests that these patients may benefit from early tertiary management.
As with all retrospective studies, our results must be interpreted with caution. Selection bias may be present in the patients receiving immunosuppressive drugs, as patients who are more reliable and compliant with treatment and follow-up could be more likely to receive these drugs. It is also possible that sicker patients seen in these tertiary care centers are followed more closely than the general population of those with JIA associated uveitis. Referral bias likely exists in this study as all participant centers are tertiary, referral-based clinical centers, so the absolute risk of adverse events may be higher than would be reported in less specialized settings.36,37 The risk factor associations reported here might have been less strong had a general population sample been available, but it is unlikely that the pattern of association would be qualitatively different. Furthermore, the results of this study are consistent with other referral-based studies, and therefore likely are generalizable to the tertiary setting. Regional differences in follow-up and treatment may exist between the different clinics, although published guidelines38 typically were utilized for the systemic treatment for JIA-associated chronic uveitis in this cohort, as the founders of the participating centers were leaders in developing these Guidelines. Indeed, practitioners in the participating centers treated chronic uveitis including JIA uveitis with immunosuppressive medications in a similar manner as the guidelines which were published in 2000, so while it is plausible that regional differences in follow-up and treatment could exist, we do not believe they would be significant. Further, analyses stratifying by clinic did not reveal significant differences among the clinics.
For outcomes that may be reversible in some instances, such as reduction in visual acuity, the risk reported provides an upper bound on risk, under the assumption of survival analysis that eyes never recover visual acuity, which is not always the case. We elected to analyze the data in a manner similar to previous reports, following SUN analysis guidelines,20 in order to facilitate comparison, and because results are more readily interpretable. Given that any visual loss is undesirable, and that any imprecision in measuring visual acuity likely would be balanced across different levels of covariates, it is unlikely that results would have been qualitatively different had a more complicated approach been undertaken; while confidence intervals might have been wider with such an approach, the high degree of significance suggests it is unlikely that our conclusions would have been changed by such an approach. Indeed, the impact of immunosuppression may be greater than we have estimated, as typically immunosuppression would have been used for the most severe cases, such that our observation of its benefit may be underestimated. While the study’s power is considerably more than in previous reports, small to moderate effect sizes may not have been detectable with the available study power. Although the study includes patients whose outcomes previously have been reported,12 the outcomes of the remainder of the cohort were similar, justifying inclusion of the previously reported cases in order to optimize the study’s statistical precision. Strengths of the study include its large sample size (327 patients, 596 affected eyes), the large amount of follow-up time, and the standardized methods of chart review across the multiple sites at each clinical visit. We found at presentation that the frequencies of visual impairment and of blindness were similar to those reported by other studies from tertiary care centers10–13,16,17,39 but are about 20–30% higher than what has been reported in population-based registries,8,9,36,37 and those studies reported data from secondary and tertiary referral centers combined,6,7 as would be expected.
In conclusion, ocular complications and vision loss occurred frequently among patients with JIA-related chronic uveitis in the SITE cohort who were receiving tertiary care. Active uveitis had a statistically significant dose-dependent association with loss of visual acuity for levels of anterior chamber cell of 1+ or higher. Use of immunosuppressive drugs was associated with a reduced risk of vision loss by about 60%. These observations provide support of the concept that aggressive treatment of intraocular inflammation is critical to the prevention of visual loss among patients with JIA-related uveitis.
THIS STUDY WAS SUPPORTED PRIMARILY BY GRANT EY014943 FROM THE NATIONAL EYE INSTITUTE, NATIONAL INSTITUTES OF HEALTH, Bethesda, Maryland (Dr. Kempen). Additional support was provided by the Paul and Evanina Mackall Foundation, Philadelphia, Pennsylvania, and Research to Prevent Blindness Inc (RPB), New York, New York. Dr. Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Dr. Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Drs. Jabs and Rosenbaum are a Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Levy-Clarke was previously and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute.
The authors indicate no financial conflict of interest.
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