JIA-associated uveitis frequently has been reported to result in visual impairment as a result of structural ocular complications such as cataract.1,6,7,9,19
We reviewed our experience with JIA-associated uveitis over 21 years in order to estimate in the effect of treatment with topical corticosteroids on the development of cataract over time. Because of the retrospective design of this study, the results must be interpreted with caution. A referral bias may exist because our institution is a tertiary care medical center, and it is likely that more severe cases of JIA-associated uveitis were referred to our center as suggested by high frequencies of ocular complications and poor visual acuity, and by the long duration of uveitis prior to presentation to our clinic.8
However, the frequency of cataract and other ocular complications at presentation in our cohort8
was similar to that reported from other tertiary care centers,5,6
but was ~33% higher than that found in a population-based study in which the frequency of ocular complications at presentation was 45%.20
In some analyses such as those evaluating each grade of anterior chamber inflammation, the number of events was small, which limited the precision of relative risks for these characteristics and may have increased the likelihood of a type II error (i.e., the inability to detect a statistically significant difference when one in fact exists). Due to its retrospective nature, our study lacked a protocol for grading the progression of cataract or for treating active uveitis. However, our clinic employees a divisionally standardized approach to the treatment of uveitis including a standardized tapering schedule for topical corticosteroids and follow up schedule. It is also possible that patients with more severe disease or those exposed to higher doses of topical corticosteroids, oral corticosteroids, or immunosuppressive drug therapy may have been seen more frequently than patients with milder disease and thus, the likelihood of ascertaining the outcome of interest (e.g., new-onset cataract) could have been greater for these patients. However the rate of follow up visits for patients receiving only topical corticosteroids was similar to the rate of visits for those patients receiving oral corticosteroids or immunosuppressive drugs, suggesting that any bias in ascertainment of cataract development was limited. The above potential limitations aside, our study suggests that the risk of cataract development is lower among eyes treated with a dose of topical corticosteroids ≤ 3 drops daily as compared to higher daily doses of topical corticosteroids after controlling for active uveitis, use of other forms of corticosteroids, and use of immunosuppressive drug therapy.
The incidence rate of new-onset cataract in our cohort was 0.04/EY, which is approximately one-half the rate of cataract development in adults with posterior and panuveitides observed in our clinic (0.08/EY to 0.10/Y depending on series).13-15
After controlling for potential confounding, active anterior chamber inflammation at increasing levels and the presence of posterior synechiae at presentation were statistically significantly associated with the development of cataract (). The presence of posterior synechiae at presentation has been reported previously to be associated with the development of ocular complications and visual loss,9,21
and specifically with cataract formation, presumably because the presence of posterior synechiae is a surrogate marker for more severe uveitic disease.21-23
Furthermore, one study has reported that patients with JIA-related uveitis who present to the ophthalmologist with posterior synechiae are less likely to undergo remission of the uveitis and therefore typically require long-term therapy with topical corticosteroids even if the uveitis is mild.21
In our cohort the presence of posterior synechiae and active inflammation were stronger risk factors for developing cataract over time than was the use of corticosteroids; thus supporting the premise that suppression of the uveitis is critical to avoiding the development of ocular complications, such as cataract, among these patients.8,9
Increasing duration of uveitis at the presenting examination was associated with a decreased risk of cataract development during follow up after controlling for confounding variables. Although this result initially appears to be counter-intuitive, it likely represents a form of survivor bias whereby eyes with milder disease do not develop cataract as rapidly and therefore were without cataract at presentation. The patients with more severe disease likely already had cataract or cataract surgery at the time of presentation and thus, were censored for the analyses of cataract development during follow up. Furthermore, any effect of eyes with longer duration of uveitis or more severe disease who had not developed cataract by the time they presented to our clinic were controlled for at least in part by including the grade of anterior chamber inflammation and the presence of posterior synechiae at presentation in the multivariate analysis.
Longitudinal data analysis was utilized to assess the effect of variable daily doses of topical corticosteroids on the development of cataract during follow up in an effort to better determine a daily dose associated with a reasonably low risk of cataract development if topical corticosteroids are required chronically. We were able to control with each flare of uveitis (including the severity of the anterior chamber inflammation) and for the concomitant use of other forms of corticosteroids, both known to cause cataract,24
and for use of immunosuppressive drug therapy which has been reported to slow cataract development and progression.23
After controlling for these confounding variables, use of topical corticosteroids ≤ 3 drops daily was associated with an 87% reduction in the risk of new-onset cataract when compared to 4 drops daily or more. Although the risk of cataract development among eyes of patients receiving topical corticosteroids ≤ 3 drops daily was not zero (rate = 0.01/EY), our data imply that it may be a reasonable threshold, as the risk of cataract development was substantially higher with higher doses of topical corticosteroids.
Our follow up was moderately long (median of 4 years, range 6 months to 15 years), but we cannot assess the effect of decades of topical corticosteroid therapy. It is possible that the cumulative dose of topical corticosteroid could affect the risk of cataract. However, in our cohort the cumulative dose of topical corticosteroids was higher in eyes that did not develop cataract as compared to eyes that did develop cataract (6810 drops versus 3050 drops; P < 0.001); therefore a higher cumulative dose among patients taking topical corticosteroids > 3 drops daily or among those developing cataract could not explain this study's findings. Analyses involving cumulative doses of topical corticosteroids are subject to biases such as variable dose velocity (e.g., higher daily doses over short periods of time at times of uveitis activity), variable duration of follow up (which was longer among patient with eyes that did not develop cataract in our cohort), and variable ascertainment of daily dosing in between follow up visits (e.g., tapering of topical corticosteroid drops performed by other ophthalmologists participating in the care of the patient), making these analyses less helpful in estimating a threshold dose for clinical use on a chronic basis. Nevertheless it is possible that with very long follow up (e.g., > 10 years) the rate of cataract development could change and even doses of topical corticosteroids ≤3 drops daily might appear less safe.
Furthermore because of a lack of standardization of cataract grading, we were unable to assess progression of cataract among eyes of patients who presented to our clinic with cataract. We performed a subgroup analysis to assess the risk of cataract surgery among eyes treated with topical corticosteroids, which allowed those eyes with cataract at presentation to be included in the analysis. The results were similar to those reported for risk of new-onset cataract with a 68% reduction in cataract surgery risk for eyes receiving ≤ 3 drops daily of topical corticosteroids (RR = 0.32; P = 0.05); however, the results were not statistically significant after controlling for potential confounding. It is likely that because the number of eyes that underwent cataract surgery during follow up was small (N = 14) that the sample size for this analysis was not adequate to achieve conventional statistical significance despite the rather substantial effect size observed. Future prospective studies observing larger populations of patients with JIA-associated uveitis and utilizing standardized cataract grading protocols would be helpful to further investigate the effect of topical corticosteroid therapy on the progression of cataract among these patients.
In summary, presence of posterior synechiae, active uveitis, and use of topical corticosteroids at presentation were statistically significant risk factors for the development of cataract after controlling for other potentially confounding variables. The risk of cataract increased as the number of drops of topical corticosteroids received daily increased in a somewhat dose-dependent fashion; this risk increased dramatically between dosages of 3 times daily (rate of cataract = 0.01/EY and 4 times daily (rate of cataract = 0.07/EY) and was independent of uveitis activity, severity, duration, and number of relapses of uveitis. Eyes receiving ≤ 3 drops of topical corticosteroid daily had an 87% reduced risk of developing a new cataract during follow up compared to eyes treated with higher daily doses. These data imply that in the setting of suppressed uveitis, patients with JIA-associated chronic anterior uveitis may be treated with low doses of topical corticosteroids (≤ 3 drops daily) over moderate periods of follow up with a low risk of developing cataract.