Purpose
To analyze the role of baseline factors in long-term development of ocular complications in uveitis associated with juvenile idiopathic arthritis (JIA).
Design
Retrospective nonrandomized interventional case series.
Methods
Data of 117 affected eyes (65 patients) with JIA-associated uveitis with a minimum follow-up of 1 year were obtained. Development of complications was analyzed univariately and multivariately in relation to gender, age of onset of uveitis (<7 years or >7 years), and initial manifestation of JIA (as uveitis or as arthritis).
Results
Female-to-male ratio was 3:1 and follow-up for uveitis ranged from 1.1 to 27.5 years (median 7.6 years). Time interval between arthritis and uveitis was shorter in boys (median 0.3 year) than in girls (median 1.0 year) ( P < .01). At 5 years of follow-up boys suffered more frequently from cystoid macular edema (CME) (50% vs 4%; P < .01) and papillitis (31% vs 2%; P < .01), and needed more cataract surgery (59% vs 32%; P = .02). At 5 years of follow-up children with initial uveitis had more posterior synechiae, band keratopathy, and CME (all P ≤ .02), but less glaucoma ( P = .03). In multivariate analysis male gender appeared to be independently associated with cataract surgery (adjusted hazard ratio [HR] = 4.33; P < .01), CME (HR = 4.59; P = .01), and papillitis (HR = 4.10; P = .01). Development of posterior synechiae was independently associated with initial uveitis (HR = 3.21; P < .01).
Conclusions
Male gender and uveitis as initial manifestation of JIA were independently associated with a complicated course of JIA-associated uveitis. Age of onset of JIA-associated uveitis does not seem to have independent prognostic value for the course of this ocular disorder.
Silent, chronic anterior uveitis is a common complication of juvenile idiopathic arthritis (JIA). The uveitis may follow a severe course and complications are encountered frequently. Uveitis complicates the course of JIA in up to 38% of patients and it is the major systemic disease association of uveitis in childhood.
The current screening program is based on known risk factors for the development of uveitis in JIA (female gender, oligoarticular type of arthritis, seropositivity for antinuclear antibody [ANA], and onset of arthritis before the age of 6 years). However, despite intensive screening, uveitis in JIA can be worsened over time by many potentially sight-threatening complications such as cataract, secondary glaucoma, cystoid macular edema (CME), papillitis, band keratopathy, and posterior synechiae. Vision-disturbing complications at young age can also lead to amblyopia, a unique complication in young children.
Prognostic factors in JIA-associated uveitis are not clearly identified and the results of the studies are often controversial. Different studies pointed out that several factors could be associated with poor prognosis, including short intervals between the diagnosis of arthritis and uveitis, severity of uveitis at first examination, and male gender. However, gender as a prognosticator of severity or outcome of uveitis could not be confirmed by other authors. Young age at onset of ocular disease has been suggested as a negative prognostic factor for JIA-associated uveitis, but other authors could not confirm this correlation.
The purpose of this study was to evaluate the role of gender, age of onset of uveitis, and initial manifestation of JIA (as initial arthritis with later uveitis or initial uveitis with later arthritis) as prognostic factors of JIA-associated uveitis.
Patients and Methods
The medical records of 65 pediatric patients (117 affected eyes) with JIA-associated uveitis were reviewed. All of these children were examined between 1981 and 2008 at the Department of Ophthalmology, University Medical Centre, Utrecht, the Netherlands. All children with onset of JIA-associated uveitis before 16 years of age and a minimum follow-up of 1 year were included in the study. The diagnosis of JIA was based on the criteria of the International League against Rheumatism. All patients were seen by a pediatric rheumatologist who confirmed the diagnosis of JIA. Patients with JIA were being referred to our clinic for ophthalmologic screening according to the guideline of American Academy of Pediatrics.
As a tertiary uveitis center, we also get referrals of children with uveitis from primary and secondary ophthalmologic care. Some of these children were diagnosed primarily with uveitis and only secondly with JIA, sometimes years after the diagnosis of uveitis.
Evaluation of uveitis was made according to the criteria of the International Uveitis Study Group. Uveitis was diagnosed if 1+ or more cells in the anterior chamber were seen over at least 2 eye examinations. We considered uveitis as chronic if the duration of the active ocular inflammation was longer than 3 months.
The following information from the medical data of the patients was recorded: date of birth, gender, date of onset of uveitis, date of diagnosis of JIA, location and course of uveitis (acute or chronic), laterality, ocular complications, surgical procedures, treatment, and follow-up. The time interval between arthritis and uveitis was calculated from the date of diagnosis of arthritis to the date of diagnosis of uveitis. Laboratory results of antinuclear antibodies and HLA-B27 were also registered. The following ocular complications were registered: cataract requiring surgery, secondary glaucoma, posterior synechiae, band keratopathy, CME, papillitis, strabismus, and amblyopia. Because of difficulties in objective measurement of cataract formation we used cataract surgery as a measure for cataract. Secondary glaucoma was defined as the presence of pathologic cupping of the optic disc seen by ophthalmoscopy and/or a glaucomatous visual field defect, in combination with intraocular pressure (IOP) higher than 21 mm Hg, or both. Ocular hypertension without the presence of pathologic disc cupping and/or glaucomatous visual field defect was not scored. CME was defined as the presence of macular thickening with cyst formation observed by indirect ophthalmoscopy or by optical coherence tomography (OCT).
Slit-lamp and fundus examination were performed by an ophthalmologist specialized in pedriatic uveitis. Additionally, all children in our clinics were being seen by an orthoptist at the initial visit and regularly during the follow-up to detect development of strabismus and amblyopia. Patients were subdivided according age at onset of uveitis into a younger-onset (uveitis onset <7 years of age) or older-onset group (uveitis onset >7 years of age). Two different types of initial manifestation of JIA were distinguished: initial manifestation as arthritis with later diagnosis of uveitis (classic); and initial manifestation as uveitis followed later by development of arthritis, making the diagnosis of JIA possible. Children in whom the signs of uveitis were present at initial eye screening after the diagnosis of JIA were considered as patients with classic manifestation of JIA.
The use of topical (anti-inflammatory, long-term mydriatics), periocular (perioperative, therapeutic), and systemic therapy (corticosteroids and immunomodulatory therapy) were noted.
Statistical analysis of the data was performed with SPSS 15.0.1 (SPSS Inc, Chicago, Illinois, USA). We performed the analysis “by eye,” including all affected eyes in the analysis. However, analysis “by patient” was used in comparison of baseline constant host characteristics between subgroups: laterality, ANA status, administration of systemic therapy, and duration of follow-up. Statistical analysis of ocular complications was performed “by eye” with correction for paired eyes in the analysis.
The Pearson χ 2 test or Fisher exact test was used for univariate analysis of categorical variables. Mann-Whitney U test was used to compare means of not normally distributed variables. Cox proportional hazard regression with correction of standard error with clustering using robust method was applied in multivariate analysis to identify independent predictive factors of unfavorable prognosis. Baseline variables with P ≤ .05 in univariate analysis and clinically significant potential confounders were entered into the multivariate analysis. For the multivariate analysis of ocular complications we entered age of onset of uveitis (as a numeric variable), gender, initial manifestation of JIA, ANA serologic status, presence of posterior synechiae at first visit to an ophthalmologist (except for analysis of risk factors for development of posterior synechiae themselves), and time between the diagnosis of arthritis and uveitis into the Cox proportional hazard regression model. All multivariate models were adjusted for therapy administration (periocular injections, systemic corticosteroids, and immunomodulatory therapy). P values of less than .05 were considered statistically significant. All significances were 2-tailed. In the presentation of the results we used the mean if the data were normally distributed (by Kolmogorov-Smirnov test; P > 0.05) and median if not normally distributed.
Results
General Characteristics of the Study Population
Of 65 patients, 117 eyes were affected by uveitis. Bilateral disease was observed in 52 of 65 patients (80%). We observed the typical manifestation as silent anterior uveitis in 116 eyes (99%) and panuveitis in 1 eye (1%). One HLA-B27-positive patient with unilateral disorder had acute uveitis, while all other patients suffered from chronic anterior uveitis. Time between the diagnosis of arthritis and uveitis varied, with a median of 0.7 years (range 0 to 12.3 years; Table 1 ). Fifty-five patients (85%) were ANA positive and in 3 patients ANA status was unknown. Follow-up of the whole group ranged from 1.1 to 27.5 years with median of 8.2 years.
| Characteristics | Age of Uveitis Onset | P Value | Gender | P Value | Initial Manifestation of JIA | P Value | |||
|---|---|---|---|---|---|---|---|---|---|
| 0–7 Years N = 48 (%) | 7–16 Years N = 17 (%) | M N = 18 (%) | F N = 47 (%) | Uveitis N = 15 (%) | Arthritis N = 50 (%) | ||||
| Females, n (%) | 35 (73) | 12 (71) | >.99 | NA | 47 (100) | NC | 7 (47) | 40 (80) | .02 b |
| Age of onset, median (range) | NC | NC | NC | 4.3 (1.7–13.8) | 4.2 (1.7–16.0) | .48 | 4.0 (1.7–12.1) | 4.5 (1.5–16.0) | .68 |
| Bilateral, n (%) | 42 (88) | 10 (59) | .03 b | 16 (89) | 36 (77) | .33 | 14 (93) | 38 (76) | .27 |
| Time between diagnosis of arthritis and uveitis, a median (range) | 0.7 (0–6.7) | 2.0 (0–12.3) | .02 b | 0.3 (0–5.0) | 1.0 (0–12.3) | .02 b | 0.3 (0.1–7.3) | 0.8 (0–12.3) | .86 |
| Uveitis as initial manifestation of JIA | 12 (25) | 3 (18) | .74 | 8 (44) | 7 (15) | .02 b | 15 (100) | NA | NC |
| Follow-up, a median (range) | 8.3 (1.1–27.5) | 7.2 (1.2–23.1) | .51 | 11.0 (1.1–27.5) | 7.2 (1.1–22.9) | .05 b | 12.6 (1.1–27.5) | 6.1 (1.1–23.1) | .07 |
| ANA-seropositive | 42 (91) | 13 (81) | .36 | 16 (94) | 39 (87) | .66 | 11 (73) | 44 (94) | .05 b |
| Systemic corticosteroids | 18 (38) | 8 (47) | .53 | 8 (44) | 18 (39) | .78 | 10 (67) | 16 (33) | .02 b |
| Immunomodulatory therapy | 39 (81) | 12 (71) | .49 | 15 (83) | 36 (77) | .74 | 12 (80) | 39 (78) | >.99 |
Age of Onset of Uveitis
Age of onset of uveitis varied from 1.5 to 16 years (median 4.2; Table 1 ). Bilateral disease was more frequent in the group with the uveitis onset <7 years of age: 42 of 48 patients (88%), versus 10 of 17 patients (59%) in the older-onset group ( P = .03). The time interval between the diagnosis of arthritis and uveitis was shorter in the younger-onset group ( P = .02) ( Table 1 ). There were no significant differences between 2 age groups in gender distribution, duration of follow-up, ANA serologic status, and treatment strategies ( Table 1 ).
Gender
The female-to-male ratio in the whole group was 3:1. General characteristics of the study population according to gender subgroups are provided in Table 1 . Time between the diagnosis of arthritis and uveitis was shorter in boys (0.3 years) than in girls (1.0 years; P = .02; Table 1 ). Additionally, boys presented with uveitis as initial manifestation of JIA more frequently than girls (44% of boys vs 15% of girls; P = .02; Table 1 ). No difference in HLA-B27 status was observed between boys and girls with initial uveitis.
Initial Manifestation of Juvenile Idiopathic Arthritis
Children initially presenting with uveitis were less frequently ANA positive ( P = .05) ( Table 1 ). They also needed more intensive treatment with more frequent use of systemic corticosteroids ( P = .02; Table 1 ).
Complications
Cumulative incidences of ocular complications according to baseline characteristics are presented in Table 2 . Posterior synechiae were the most frequent complication at onset of uveitis and they were present in 12/117 (10%) of eyes ( Supplemental Table 1 at AJO.com ). Nobody from our series presented with secondary glaucoma, CME or papillitis. Furthermore, no differences in frequencies of complications at onset of uveitis were observed between groups ( Supplemental Table 1 at AJO.com ).
| Complications | Total Percentage of Affected Eyes (± 95% CI) | Gender | P Value | Initial Manifestation of JIA | P Value | ||
|---|---|---|---|---|---|---|---|
| M | F | Uveitis | Arthritis | ||||
| |||||||
| Secondary glaucoma (%) b | 2 (± 2) | NA | 2 | >.99 | NA | 2 | >.99 |
| Cataract surgery (%) | 6 (± 4) | 6 | 6 | >.99 | 3 | 7 | .68 |
| Posterior synechiae (%) | 27 (± 8) | 47 | 20 | <.01 c | 62 | 16 | <.01 c |
| Band keratopathy (%) | 5 (± 4) | 12 | 2 | .06 | 14 | 2 | .03 c |
| CME (%) | 8 (± 5) | 21 | 3 | <.01 c | 11 | 7 | .67 |
| Papillitis (%) | 4 (± 4) | 12 | 1 | .03 | 7 | 4 | .60 |
| Strabismus (%) | 3 (± 3) | 7 | 3 | .32 | 9 | 3 | .23 |
| Amblyopia (%) | 10 (± 5) | 16 | 9 | .31 | 19 | 8 | .16 |
| |||||||
| Secondary glaucoma (%) | 14 (± 7) | 17 | 14 | .76 | 4 | 18 | .11 |
| Glaucoma surgery (%) | 8 (± 5) | 10 | 8 | .70 | 8 | 9 | >.99 |
| Cataract surgery (%) | 24 (± 8) | 56 | 9 | <.01 c | 56 | 13 | <.01 c |
| Posterior synechiae (%) | 31 (± 9) | 50 | 25 | .02 c | 64 | 22 | <.01 c |
| Band keratopathy (%) | 14 (± 7) | 27 | 9 | .03 c | 40 | 6 | <.01 c |
| CME (%) | 14 (± 7) | 41 | 3 | <.01 c | 29 | 10 | .04 c |
| Papillitis (%) | 8 (± 5) | 21 | 3 | .01 c | 17 | 6 | .20 |
| Strabismus (%) | 4 (± 4) | 12 | 2 | .10 | 14 | 2 | .05 c |
| Amblyopia (%) | 12 (± 6) | 24 | 8 | .05 c | 24 | 9 | .08 |
| |||||||
| Secondary glaucoma (%) | 25 (± 10) | 26 | 24 | .85 | 9 | 32 | .03 c |
| Glaucoma surgery (%) | 30 (± 10) | 35 | 28 | .55 | 18 | 35 | .14 |
| Cataract surgery (%) | 42 (± 11) | 59 | 32 | .02 c | 57 | 35 | .08 |
| Posterior synechiae (%) | 40 (± 11) | 56 | 33 | .06 | 61 | 33 | .02 c |
| Band keratopathy (%) | 16 (± 8) | 22 | 12 | .33 | 35 | 7 | .01 c |
| CME (%) | 19 (± 9) | 50 | 4 | <.01 c | 41 | 12 | .01 c |
| Papillitis (%) | 12 (± 7) | 31 | 2 | <.01 c | 23 | 8 | .12 |
| Strabismus (%) | 4 (± 4) | 9 | 3 | .55 | 11 | 3 | .21 |
a Additional exact frequencies of the complications are available at AJO.com in Supplemental Table 1 .
b Within the first 1 year of follow-up no cases with glaucoma surgery were observed.
Age of Onset of Uveitis
Frequencies of complications from onset up to 10 years of follow-up did not differ between the patients with onset <7 and >7 years of age.
Gender
Boys exhibited more complications at different points of follow-up, including posterior synechiae, cataract surgery, band keratopathy, CME, papillitis, and amblyopia ( Table 2 ). Posterior synechiae were more common in boys at up to 3 years of follow-up (50% vs 25%; all P ≤ .02; Table 2 ). CME occurred significantly more frequently in boys at all standard points of follow-up (all P ≤ .05) ( Table 2 , Supplemental Table 1 at AJO.com ). Papillitis was significantly more frequently seen in boys at up to 5 years of follow-up (31% vs 2%; P < .01) ( Table 2 ). Boys underwent cataract surgery more frequently. After 3 years of follow-up 56% of boys’ eyes were operated on for cataract in contrast with 9% of girls’ eyes ( P < .01). At 5 years of follow-up this difference was still significant (59% in boys vs 32% in girls; P = .02; Table 2 ).
Additional analysis of complication frequencies in boys and girls was performed within a group with classic manifestation of JIA only (manifestation with initial arthritis). This analysis still revealed significant differences in frequencies of CME, papillitis, and cataract surgery between boys and girls in disadvantage of boys ( Supplemental Table 2 at AJO.com ).
Initial Manifestation of Juvenile Idiopathic Arthritis
The initial uveitis group was more frequently characterized by the presence of posterior synechiae, band keratopathy, cataract surgery, and CME ( Table 2 ). Children with initial uveitis had significantly more posterior synechiae at all standard follow-up points (all P ≤ .02) ( Table 2 ). Band keratopathy was also more frequent in the initial uveitis group during the first 5 years of follow-up ( P ≤ 0.03; Table 2 ). CME was more often diagnosed in the group with initial uveitis; this difference was noted from 3 up to 10 years of follow-up (67% of the eyes from the initial uveitis group vs 29% of the eyes from the initial arthritis group; all P ≤ .04). In contrast, secondary glaucoma was less common in the group with initial uveitis compared to the group with initial arthritis at 5 years of follow-up (9% vs 32%; P = .03; Table 2 ).
Multivariate Analysis of Prognostic Factors for Complications
No independent baseline risk factors for secondary glaucoma, strabismus, and amblyopia were found. Male gender appeared to be an independent risk factor for cataract surgery (adjusted hazard ratio [HR] = 4.33; 95% CI: 1.86–9.47; P < .01; Supplemental Figure 1 at AJO.com ), development of CME (HR = 4.59; 95% CI: 1.64–11.61; P = .01; Supplemental Figure 2 at AJO.com ), and papillitis (HR = 4.10; 95% CI: 1.21–13.44; P = .01; Supplemental Figure 3 at AJO.com ). Uveitis as initial JIA manifestation was only independently associated with development of posterior synechiae (HR = 3.21; 95% CI: 1.47–6.36; P < .01; Supplemental Figure 4 at AJO.com ).
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