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Risk of Hypotony in Juvenile Idiopathic Arthritis–Associated Uveitis
Risk of Hypotony in Juvenile Idiopathic Arthritis–Associated Uveitis AHMADREZA MORADI, INNA G. STROH, ASHVINI K. REDDY, DANA M. HORNBEAK, THERESA G. LEUNG, BRYN M. BURKHOLDER, AND JENNIFER E. THORNE OBJECTIVE:
To describe risk factors for hypotony in patients with juvenile idiopathic arthritis (JIA)-associated uveitis. DESIGN: Retrospective cohort study. METHODS: All patients with JIA-associated uveitis (N [ 108; affected eyes [ 196) evaluated and followed at the Wilmer Eye Institute from July 1984 through June 2014 were included in this study. Prevalence and incidence of hypotony (intraocular pressure [IOP] <5 mm Hg) and low IOP (5 mm Hg £ IOP < 8 mm Hg) and risk factors for developing hypotony were analyzed. RESULTS: At presentation, 9.3% of patients (7.1% of affected eyes) had hypotony. During a median follow-up of 5.3 years, the rate of developing hypotony and low IOP were 0.04 per eye-year (/EY; 95% confidence interval [CI]: 0.02/EY, 0.05/EY) and 0.06/EY (95% CI: 0.04/ EY, 0.08/EY), respectively. Risk factors for development of hypotony during follow-up appeared to be associated with more severe uveitic disease, such as the presence of panuveitis (adjusted hazard ratio [aHR], 43.1; P [ .004), anterior chamber cells or flare ‡ 3D (aHR, 25.6, P < .001), posterior synechiae (aHR, 5.9, P [ .02), and the use of oral corticosteroid (aHR 28.9; P [ .003) at the presenting examination. Receiving immunosuppressive drug therapy at the time of presentation was associated with a lower risk of development of hypotony (aHR, 0.02; P [ .002). CONCLUSIONS: Hypotony affects a small but significant proportion of patients with JIA-associated uveitis and is associated with signs of active and severe uveitis. Immunosuppression was associated with significantly lower risk of hypotony, suggesting that aggressive control of the inflammation may reduce risk of hypotony in JIAassociated uveitis. (Am J Ophthalmol 2016;169: 113–124. Ó 2016 Elsevier Inc. All rights reserved.)
J
UVENILE IDIOPATHIC ARTHRITIS (JIA) IS A COMMON
cause of anterior uveitis among children.1–3 It is typically characterized by a chronic bilateral anterior uveitis with insidious onset,3 affects approximately 10%– 20% of patients with JIA, and may result in substantial visual morbidity.4–8 Structural ocular complications, such as hypotony, band keratopathy, cataract, glaucoma, macular edema, and epiretinal membrane, occur commonly in JIA-associated uveitis.7,9–13 Hypotony has been estimated to occur in 10%–19% of patients with JIA-associated uveitis, rates higher than those observed in other pediatric uveitides,10,14 and with adult noninfectious uveitis.15 Given these complications, it is not surprising that patients with JIA-associated uveitis also exhibit high rates of visual impairment and blindness12,13 and an approximately 2-fold greater rate of visual impairment relative to other pediatric uveitides.14 Of the ocular complications associated with JIAassociated uveitis, chronic hypotony appears to have a particularly poor prognosis. Hypotony may result from the development of cyclitic membranes, which place traction on the ciliary body and can lead to its detachment.6,16 In the absence of such membranes, hypotony also may result from ciliary body atrophy owing to chronic inflammation with decreased aqueous production.6,16 Subsequent vision loss may occur owing to anterior chamber collapse, corneal edema, astigmatism, vitreous haze, macular edema (eg, hypotonous maculopathy), choroidal detachment, scleral collapse, macular compression, or disc edema.17 To better understand the impact of hypotony on patients with JIA uveitis, we describe the prevalence and incidence of hypotony, risk factors for developing hypotony, and its impact on visual outcomes among patients with JIAassociated uveitis managed at our center.
METHODS Supplemental Material available at AJO.com. Accepted for publication Jun 13, 2016. From the Departments of Ophthalmology (A.M., I.G.S., A.K.R., D.M.H., T.G.L., B.M.B., J.E.T.) and Epidemiology (J.E.T.), The Johns Hopkins University School of Medicine, Baltimore, Maryland. Inquiries to Jennifer E. Thorne, The Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 North Wolfe St, Woods Building, Room 476, Baltimore, MD 21287; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.06.026
©
2016
THIS STUDY RECEIVED APPROVAL FROM THE JOHNS HOPKINS
University School of Medicine Institutional Review Board for all aspects of this retrospective study. All work was compliant with the Health Insurance Portability and Accountability Act and in accordance with the principles of the Declaration of Helsinki.
ELSEVIER INC. ALL
RIGHTS RESERVED.
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STUDY POPULATION:
Medical records of 108 patients with JIA-associated uveitis (International Classification of Disease [ICD] codes: 714.30 þ 364.XX) seen between July 1984 and June 30, 2014 in the Division of Ocular Immunology at the Wilmer Eye Institute, Johns Hopkins Hospital, were identified. Diagnoses were based on review of case history and ophthalmologic examination by a uveitis specialist with ancillary testing guided by clinical findings. DATA COLLECTION:
Data were collected by chart review and entered into a standardized database.18 Data included demographic features (age, sex, and race), past history of arthritis, past history of uveitis, anatomic location of the uveitis as defined by the Standardization of Uveitis Nomenclature (SUN) Working Group,19 results of diagnostic testing, and medications (doses and routes) at each clinic visit. Ophthalmic findings at each visit included visual acuity, intraocular pressure (IOP), slit-lamp examination, grade of inflammation in the anterior chamber and in the vitreous by SUN criteria,19 and dilated fundus findings.
MAIN OUTCOME MEASURES:
The prevalence of hypotony (defined as IOP <5 mm Hg) and low IOP (defined as _5 mm Hg but lower than 8 mm Hg) at presentation IOP > and the incidence of these conditions during follow-up were assessed retrospectively. To calculate incidence rates of these outcomes, eyes with hypotony and low IOP were _8 mm Hg in follow-up compared with eyes with IOP > data. The following variables were assessed for potential association with hypotony and low IOP: age at presentation, age at the time of uveitis diagnosis, sex, race, visual acuity at presentation, any prior intraocular surgery, prior cataract surgery, prior glaucoma surgery, prior vitrectomy, inflammatory activity in the eye (anterior chamber cell, anterior chamber flare, vitreous cell, vitreous haze), anatomic location of the uveitis, duration of uveitis, presence of other structural ocular complications of uveitis (band keratopathy, posterior synechiae, cataract, epiretinal membrane, macular edema, optic nerve edema), and the treatment at presentation (topical corticosteroids, topical IOP lowering drops, immunosuppressive drug therapy, and/or oral corticosteroids). The development of new-onset complications among eyes affected with uveitis was noted on clinical examination. The development of new-onset cataract was defined as the presence of 1þ nuclear sclerosis, 1þ cortical change, or trace posterior subcapsular change seen on clinical examination in an eye in which no cataract had been reported on prior visits.
STATISTICAL
analysis was ANALYSIS: Statistical performed using Stata statistical software (version 10.0, 2007; Stata Corporation, College Station, Texas, USA). Frequencies and medians of demographic variables were tabulated for patients/eyes and compared using x2 test and t test for categorical and numerical data, respectively.
114
Incidence rates for ocular complications were calculated as the number of events divided by the number of eyeyears (EY) of the at-risk eyes. At-risk eyes included all eyes that were free of each respective outcome at presentation with at least 1 follow-up visit in our clinic. The 95% confidence intervals (CI) were calculated for the estimated incidence rates of ocular complications. For risk factor analyses regarding prevalence of hypotony or low IOP among eyes at cohort entry, crude and adjusted odds ratios (aOR) were calculated using univariate and multivariate logistic regression. Time-updated univariate and multivariate Cox proportional-hazards models were used to assess the potential risk factors for developing new-onset hypotony or low IOP among patients with JIA-associated uveitis and crude and adjusted hazard ratios reported. P values were 2-sided and nominal, with a value < .05 being considered as statistically significant.
RESULTS CHARACTERISTICS OF THE STUDY POPULATION AT PRESENTATION: One hundred and eight patients (196
eyes) with JIA-associated uveitis were identified. The majority of patients were female (73%, n ¼ 79) and white (82%, n ¼ 85). The median age at onset of uveitis was 6 years (range, 0.5–35 years), with a median duration of uveitis prior to presentation of 4 years (range, 2.0 to 45.4 years). Of the 108 patients with JIA-associated uveitis, 12 (11.1%) (20 eyes, 10.2%) had documented history of hypotony prior to presentation. Ten patients (9.3%) (14 eyes, 7.1%) presented with hypotony, and 4 patients (3.7%) (5 eyes, 2.6%) presented with low IOP. Four patients (3.7%) presented with bilateral hypotony and 1 patient presented with bilateral low IOP. RISK FACTORS FOR HYPOTONY AT PRESENTATION:
Based on IOP at presentation, eyes were categorized as having hypotony (n ¼ 14 eyes, median IOP ¼ 1.5; range ¼ 0– 4 mm Hg), low IOP (n ¼ 5 eyes, median IOP ¼ 7; range ¼ _8 mm Hg (n ¼ 177 eyes; median 5–7 mm Hg), or IOP > IOP ¼ 15; range ¼ 8–38 mm Hg). Crude and adjusted logistic regression models identified several risk factors for hypotony and low IOP, which are summarized in Tables 1 and 2. All patients with hypotony were over age 14, and the majority (57.1%, n ¼ 8) were over age 18. Sex was not significantly associated with hypotony at presentation. Male sex was a risk factor for presenting with low IOP in univariate analysis (odds ratio [OR], 3.4; 95% CI, 1.3–8.8; P ¼ .01) but did not achieve conventional statistical significance in the multivariate analysis. _10 years duraIn the univariate analyses, patients with > tion of arthritis prior to presentation were significantly more likely to present with hypotony (OR, 16.2; 95% CI, 2.1–126.5; P ¼ .008). Patients who presented to our clinic
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_5 mm Hg) or Low TABLE 1. Characteristics of Eyes With Juvenile Idiopathic Arthritis–Associated Uveitis and Hypotony (<5 vs > _8 mm Hg) at Presentation: Results of Univariate Regression Analysis Intraocular Pressure (IOP <8 vs > _5 mm Hg) Hypotony (<5 vs >
IOP
Variable
<5 mm Hg
_ but <8 mm Hg 5<
> _8 mm Hg
(n ¼ 14)
(n ¼ 5)
(n ¼ 177)
OR (95% CI)
40 (2) 60 (3)
56.5 (100) 43.5 (77)
Reference 16.6 (2.1–129.4)
20 (1) 80 (4)
75.1 (133) 24.9 (44)
Reference 0.5 (0.2–1.4)
100 (5) 0
88.1 (156) 11.9 (21)
Reference 5.1 (1.5–17.7)
40 (2) 60 (3)
50.3 (89) 49.7 (88)
60 (3) 40 (2)
_14 y, % (n) Age at presentation > No 7.1 (1) Yes 92.9 (13) Sex Female 57.1 (8) Male 42.9 (6) _3 y, % (n) Age of diagnosis of uveitis < No 64.3 (9) Yes 35.7 (5) _4 y, % (n) Duration of uveitis at presentation > No 7.1 (1) Yes 92.9 (13) Intermediate and/or posterior localization, % (n) No 42.9 (6) Yes 57.1 (8) Any prior ocular surgery, % (n) No 7.1 (1) Yes 92.9 (13) Signs of inflammatory activity, % (n) _1þ Anterior chamber cells > No 78.6 (11) Yes 21.4 (3) _1þ Anterior chamber flare > No 21.4 (3) Yes 78.6 (11) Structural complications at presentation, % (n) Band keratopathy 92.9 (13) Posterior synechia 7.1 (1) Optic disc edema 21.4 (3) Treatment at presentation, % (n) Topical corticosteroid drops 78.6 (11) Topical mydriatic drops 21.4 (3) Topical glaucoma drops 0 Systemic immunosuppressive 35.7 (5) medications Oral corticosteroid use No 71.4 (10) Yes 28.6 (4) _ 20/200), % (n) Legal blindness at presentation (< No 14.3 (2) Yes 85.7 (12)
P Value
_8 mm Hg) Low IOP (<8 vs >
OR (95% CI)
P Value
Reference 6.9 (1.9–24.6)
.003*
Reference 3.4 (1.3–8.8)
.01*
.009*
Reference 3.2 (1.0–10.1)
.05*
Reference 13 (1.7–101.4)
.01*
Reference 5.4 (1.5–19.2)
.009*
88.7 (157) 11.3 (20)
Reference 9.7 (3.1–30.6)
<.001*
Reference 8.7 (3.2–24.0)
<.001*
80 (4) 20 (1)
72.9 (129) 27.1 (48)
Reference 35.3 (4.5–277)
<.001*
Reference 7.5 (2.6–22.0)
<.001*
80 (4) 20 (1)
62.5 (110) 37.5 (66)
Reference 0.5 (0.1–1.7)
.25
Reference 0.4 (0.1–1.4)
.16
40 (2) 60 (3)
51.1 (90) 48.9 (86)
Reference 3.8 (1.0–14.0)
.04*
Reference 2.9 (1.0–8.5)
.04*
40 (2) 100 (5) 0
27.1 (48) 27.7 (49) 3.9 (7)
34.3 (4.4–269) 0.2 (0.02–1.4) 6.8 (1.5–30.0)
.001* .10 .01*
10.1 (3.2–31.9) 1.2 (0.4–3.4) 4.6 (1.1–19.3)
<.001* .72 .04*
100 (5) 40 (2) 20 (1) 0
67.8 (120) 16.4 (29) 14.7 (26) 33.3 (59)
1.7 (0.4–6.2) 1.3 (0.3–5.0) N/A 1.2 (0.4–3.6)
2.5 (0.7–9.0) 1.8 (0.6–5.4) 0.3 (0.04–2.5) 0.7 (0.2–2.1)
.15 .28 .28 .54
60 (3) 40 (2)
91.5 (162) 8.5 (15)
Reference 3.9 (1.1–13.7)
.03*
Reference 5.0 (1.7–15.0)
.004*
60 (3) 40 (2)
88.1 (156) 11.9 (21)
Reference 41.5 (7.7–197.3)
<.001*
Reference 20.8 (6.8–63.6)
<.001*
.007*
0.19
.44 .42 N/A .8
IOP ¼ intraocular pressure; OR ¼ odds ratio. Asterisk indicates statistically significant P value.
4 or more years after the diagnosis of uveitis were 13-fold more likely to present with hypotony (95% CI, 1.7– 101.4; P ¼ .01). In over one-third (35.7%, n ¼ 5) of hypotonous eyes, uveitis was first diagnosed at 3 years of age or younger, as compared with 11.5% (n ¼ 21) of patients with nonhypotonous eyes (OR, 5.1; 95% CI, 1.5–17.7; VOL. 169
P ¼ .01). The median duration of uveitis was longer in _5 mm Hg (17.0 hypotonous eyes than in eyes with IOP > years vs 3.8 years; P ¼ .002). The vast majority of eyes with hypotony (92.9%, 13/14 eyes) had uveitis for longer than 5 years prior to presentation, whereas 44% of eyes _5 mm Hg (81/182) had uveitis longer than 5 with IOP >
HYPOTONY IN JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS
115
_5 mm Hg) or Low TABLE 2. Characteristics of Eyes With Juvenile Idiopathic Arthritis–Associated Uveitis and Hypotony (<5 vs > _8 mm Hg) at Presentation: Results of Multiple Regression Analysis Intraocular Pressure (IOP <8 vs > _5 mm Hg) Hypotony (<5 vs > Variable
a
Adjusted OR (95% CI)
_3 y, % (n) Age of diagnosis of uveitis < No Reference Yes 3.5 (0.3–40.2) Intermediate and/or posterior localization, % (n) No Reference Yes 16.9 (1.2–238) Any prior ocular surgery,a % (n) No Reference Yes 76.3 (1.7–3406) Signs of inflammatory activity,% (n) _1þ Anterior chamber cells > No Reference Yes 0.1 (0.00–2.6) _1þ Anterior chamber flare > No Reference Yes 0.9 (0.03–25.4) Band keratopathy 2.2 (0.1–32.2) Oral corticosteroid use No Reference Yes 46.6 (0.9–2297) Prior periocular corticosteroid injection(s) No Reference Yes 30.7 (1.4–669) _20/200), % (n) Legal blindness at presentation (< No Reference Yes 7.6 (0.9–65.3)
_8 mm Hg) Low IOP (<8 vs > P Value
a
Adjusted OR (95% CI)
P Value
.31
Reference 2.1 (0.3–14.5)
.46
.04*
Reference 13.0 (2.1–80.1)
.006*
.02*
Reference 3.1 (0.5–18.2)
.21
.16
Reference 0.3 (0.04–1.9)
.19
.97 .56
Reference 0.2 (0.02–2.1) 1.2 (0.17–8.4)
.18 .18
.05*
Reference 14.2 (1.4–145.6)
.02*
.03*
Reference 20.5 (2.8–147)
.003*
.06*
Reference 8.3 (1.2–56.2)
.03*
IOP ¼ intraocular pressure; OR ¼ odds ratio. Asterisk indicates statistically significant P value. a Adjusting for age of diagnosis of uveitis, type of uveitis, anterior chamber cells, anterior chamber flare, prior ocular surgery, band keratopathy, oral corticosteroid use, and legal blindness at presentation.
years (OR, 7.2; 95% CI, 0.9–57.0; P ¼ .06). Furthermore, eyes with evidence of increased disease severity including other structural ocular complications, such as posterior synechiae, were more likely to present with hypotony. The majority of eyes with hypotony at presentation (57.1%, n ¼ 8) had inflammation in the vitreous or posterior pole. These eyes were 17 times more likely to have hypotony (aOR, 16.9; 95% CI, 1.2–238; P ¼ .04) when compared with eyes with isolated anterior uveitis. Eyes with panuveitis (35.7%, n ¼ 5) were 13 times more likely to present with hypotony (OR, 13.3; 95% CI, 3.5–51.3, P < .001), and eyes with intermediate uveitis (21.4%, n ¼ 3) were 6.7 times more likely to present with hypotony (OR, 6.7; 95% CI, 1.5–30.0; P ¼ .01) compared with eyes with anterior uveitis. Eyes with active disease as _1þ were more defined by anterior chamber (AC) flare > likely to present with hypotony (OR, 3.8; 95% CI, 1.0– 14.0; P ¼ .04) or low IOP (OR, 2.9; 95% CI, 1.0–8.5; 116
P ¼ .04); however, this risk factor was not statistically significant in the multivariate model. Hypotony was associated with poor vision at presentation. The majority of hypotonous eyes (85.7%, n ¼ 12) were legally blind (aOR, 7.6; 95% CI, 0.9–65.3; P ¼ .06), and the rest (14.3%, n ¼ 2) had visual acuity impairment _20/50 but >20/200). No eyes with hypotony at presenta(< tion had visual acuity of 20/40 or better, whereas 77.5% (n ¼ 141) of nonhypotonous eyes had visual acuity of 20/ 40 or better at presentation. Four out of 14 hypotonous eyes at presentation had no follow-up visit. Over a median follow-up period of 11.5 years, 5 out of 10 hypotonous eyes at presentation showed no change in their visual acuity at the end of the follow-up period. Four eyes showed worsening of visual acuity (including 3 eyes with no light perception [NLP]), and only 1 eye showed slight improvement in vision from light perception (LP) to count finger (CF).
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FIGURE 1. Kaplan-Meier estimate of development of hypotony (intraocular pressure <5) during follow-up in eyes with juvenile idiopathic arthritis–associated uveitis that were event-free at presentation.
Eyes with a prior history of at least 1 intraocular surgery were statistically significantly more likely to present with hypotony (aOR, 76.3; 95% CI, 1.7–3406, P ¼ .02). Thirteen of 14 hypotonous eyes (92.8%) had undergone cataract surgery prior to presentation, whereas 33 out of 182 eyes (18.3%) without hypotony had undergone cataract surgery at presentation. Subanalysis revealed that 82% of aphakic eyes at presentation had hypotony, vs only 9% of pseudophakic eyes at presentation (x2, P < .0001). Three hypotonous eyes had history of prior glaucoma surgery (2 eyes had trabeculectomy and 1 eye had peripheral laser iridotomy), and there was no significant association with hypotony (OR, 1.9; 95% CI, 0.5–7.3; P ¼ .36). Use of oral corticosteroid at presentation was a strong risk factor for hypotony (aOR, 46.6; 95% CI, 0.9–2297; P ¼ .05) and low IOP (aOR, 14.2; 95% CI, 1.4–145.6; P ¼ .02). Eyes with history of periocular corticosteroid injections were more likely to present with hypotony (aOR 30.7; 95% CI 1.4–669; P ¼ .03) or low IOP (aOR, 20.5; 95% CI, 2.8–147; P ¼ .003). Use of topical glaucoma drops, topical corticosteroids, mydriatic drops, glaucoma drops, or immunosuppressive drugs were not associated with hypotony or low IOP at presentation. INCIDENCE OF OCULAR COMPLICATIONS AMONG EYES WITH JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS AND HYPOTONY/LOW INTRAOCULAR PRESSURE:
Seventy-eight percent of patients were seen in follow-up, and the median follow-up period of these patients was 5.3 VOL. 169
years (range, 2 weeks to 29.7 years). During follow-up, 26 of 137 developed hypotony, with a rate of 0.04 per eyeyear (95% CI, 0.02/EY–0.05/EY, Figure 1), and 38 of 132 eyes developed low IOP (IOP <8 mm Hg) at the rate of 0.06 (95% CI, 0.04/EY–0.08/EY) (Table 3). Although 4 out of 5 eyes with low IOP at presentation developed hypotony for at least 1 visit during follow-up at a rate of 0.48/EY (95% CI, 0.13/EY–1.23/EY), only 1 eye had sustained hypotony. During the follow-up period, some eyes improved in terms of IOP measurements, but the increases in IOP were typically 1–2 mm Hg. Although a small number of eyes had increases in IOP enough to move from the ‘‘hypotony’’ group to the ‘‘low IOP’’ group, no eyes _8 mm Hg improved enough to achieve sustained IOP > (eg, the ‘‘normal IOP’’ group). Of the 26 eyes with newly diagnosed hypotony during follow-up, 12 had a history of recent glaucoma surgery. The median time between glaucoma surgery and development of new hypotony was 0.17 years (range: 1 week to 6.9 years). Among eyes with recent glaucoma surgery during follow-up, 9 eyes had recent tube shunt surgery, 2 eyes had recent trabeculectomy, and 1 eye had history of surgical peripheral iridotomy. The majority of hypotonous eyes had visual impairment or legal blindness at the time of presentation. Among eyes with low IOP at presentation, the incidence rate of visual impairment (worse than 20/50 but better than 20/200) was 0.21/EY (95% CI, 0.01/EY–1.19/EY), vs 0.06/EY _8 mm Hg (95% CI, 0.04/EY–0.08/EY) in eyes with IOP >
HYPOTONY IN JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS
117
118 TABLE 3. Incidence Rate of Ocular Complications Among Eyes With Juvenile Idiopathic Arthritis–Associated Uveitis and Hypotony (<5 mm Hg) or Low Intraocular Pressure (<8 mm Hg) at Presentation
Total (n ¼ 153)
Outcome
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Visual acuity loss Low vision (20/50 to 20/200) Legal blindness (20/200 or worse) Structural complications Ocular hypertension (IOP > 21 mmHg) Glaucomatous damage _0.2 increase in CDR) (> Hypotony (IOP <5 mm Hg) Low IOP (IOP <8 mm Hg) Cataract Intraocular surgeries Any glaucoma procedurec Trabeculectomy Tube shunt Laser peripheral iridotomy Vitrectomy
Events/ At Risk
Ratea (95% CI)/EY
Low IOP _ But<8 mm (5 mm Hg < Hg, n ¼ 5)
Hypotony (<5 mm Hg, n ¼ 10) Events/ At Risk
Rate (95% CI)/EY
Events/ At Risk
Rate (95% CI)/EY
IOP <8 mm Hg (n ¼ 15) Events/ At Risk
Rate (95% CI)/EY
_8 mm Hg (n ¼ 138)b IOP > Events/ At Risk
Rate (95% CI)/EY
Incidence Rate Ratio _8 <8 vs > (95% CI)
P Value
29/113 24/126
0.06 (0.04–0.09) 0/0 0.04 (0.02–0.06) 0/1
N/A 0
1/2 1/3
0.21 (0.01–1.19) 0.15 (0.00–0.84)
1/2 1/4
0.21 (0.01–1.19) 0.12 (0.00–0.67)
28/111 23/122
0.06 (0.04–0.08) 0.04 (0.02–0.57)
3.7 (0.1–22.3) 3.1 (0.1–19.3)
.13 .16
41/93
0.11 (0.08–0.15) 0/6
0
2/3
0.36 (0.04–1.29)
2/9
0.03 (0.00–0.09)
39/84
0.13 (0.09–0.18)
0.2 (0.02–0.8)
.004*
24/97
0.05 (0.03–0.07) 0/1
0
2/3
0.08 (0.01–0.29)
2/4
0.06 (0.01–0.21)
22/93
0.05 (0.03–0.07)
1.3 (0.1–5.1)
.34
26/137 38/132 35/78
0.04 (0.02–0.05) N/A 0.06 (0.04–0.08) N/A 0.27 (0.21–0.33) 0/0
N/A N/A N/A
4/5 N/A 2/2
0.48 (0.13–1.23) 4/5 N/A N/A 3.64 (0.44–13.13) 2/2
0.48 (0.13–1.23) 22/132 0.03 (0.02–0.05) 15.6 (3.9–45.8) <.001* N/A 38/132 0.06 (0.04–0.08) N/A N/A 3.64 (0.44–13.13) 25/76 0.112 (0.08–0.16) 32.3 (3.7–126) .001*
0 0 0 0 0.02 (0.00–0.09)
2/5 0/4 2/4 0/5 2/4
0.12 (0.01–0.43) 0 0.12 (0.01–0.43) 0 0.21 (0.03–0.74)
0.02 (0.00–0.06) 0 0.02 (0.00–0.06) 0 0.04 (0.01–0.13)
27/143 0.03 (0.02–0.5) 7/149 0.01 (0.00–0.02) 23/149 0.03 (0.02–0.04) 5/145 0.005 (0.00–0.01) 17/145 0.02 (0.01–0.03)
0/10 0/10 0/10 0/9 1/7
CDR ¼ cup-to-disc ratio; IOP ¼ intraocular pressure. Asterisk indicates statistically significant P value. a Rate is events occurring in affected eyes per eye-year (EY) at risk. b Considered as the reference group. c Defined as trabeculectomy, tube shunt, and/or laser peripheral iridotomy.
2/15 0/14 2/14 0/14 3/11
25/128 0.03 (0.02–0.05) 0.5 (0.1–1.9) 7/128 0.01 (0.00–0.02) 0 21/135 0.03 (0.02–0.04) 0 5/131 0.006 (0.00–0.01) 0 14/134 0.02 (0.01–0.03) 2.4 (0.4–8.7)
.16 N/A N/A N/A .09*
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FIGURE 2. Kaplan-Meier (KM) estimate of development of legal blindness (visual acuity 20/200 or worse) during follow-up in eyes that were hypotony-free at presentation. The dashed line represents the KM estimate for eyes that stayed hypotony-free during followup, and the constant line refers to eyes with new hypotony during follow-up.
at presentation (incidence rate ratio, 3.7; 95% CI, 0.1– 22.3, P ¼ .13). The incidence of legal blindness (20/200 or worse) was 0.12/EY in the eyes with low IOP (95% CI, 0.00/EY–0.67/EY) and 0.04/EY (95% CI, 0.02/EY–0.06/ _8 mm Hg (incidence rate ratio, EY) in the eyes with IOP > 3.1; 95% CI, 0.1–19.3, P ¼ .16) (Figure 2). RISK FACTORS FOR DEVELOPMENT OF HYPOTONY DURING FOLLOW-UP: Univariate Cox regression analysis
demonstrated that eyes with panuveitis (HR, 9.7; 95% CI, 3.2–29.1, P < .001), prior intraocular surgery (HR, 2.4; 95% CI, 1.1–5.5, P ¼ .03), any structural ocular complications (defined as posterior synechiae, band keratopathy, cataract, glaucoma, optic disc edema, epiretinal membrane, or choroidal neovascularization; HR, 77.9; _3þ (HR, 2.5; 95% CI, 1.9–33.6, P ¼ .005), AC cell > _1þ (HR, 3.8; 95% 95% CI, 1.0–6.7, P ¼ .04), AC flare > CI, 1.6–9.0, P ¼ .003), visual impairment (HR, 7.4; 95% CI, 2.9–18.9, P ¼ .04), legal blindness (HR, 2.9; 95% CI, _3 corticosteroid 1.0–7.9, P ¼ .04), and treatment with < drops per day (HR, 3.0; 95% CI, 1.2–7.9, P ¼ .02) at presentation were more likely to develop hypotony during follow-up. Patients who were receiving immunosuppressive therapy at presentation were statistically significantly less likely to develop hypotony during follow-up (HR, 0.1; 95% CI, 0.02–1.0, P ¼ .05) (Table 4, Figure 3). After adjustment for statistically significant risk factors from the crude analysis, panuveitis remained associated with hypotony (aHR, 43.14; 95% CI, 3.27–569; P ¼ .004), as VOL. 169
did oral corticosteroid treatment (aHR, 28.95; 95% CI, _3þ AC cell or 3.14–267.37, P ¼ .003), presenting with > flare (aHR, 25.6; 95% CI, 4.53–144.93, P < .001), treating with lower dose of corticosteroid drops (aHR, 7.32; 95% CI, 1.34–39.9, P ¼ .02), presence of posterior synechiae (aHR, 5.89; 95% CI, 1.28–26.91, P ¼ .02), and visual impairment (aHR, 4.23; 95% CI, 1.01–17.69, P ¼ .05) at presentation (Table 5). In contrast, treatment with immunosuppressive drug therapy was associated with lower rates of hypotony (aHR, 0.02; 95% CI, 0.00–0.10, P ¼ .002). Use of time-updated analyses for AC cell or flare and treatment with topical or oral corticosteroids or immunosuppressive drug therapy did not alter the results observed in the multivariable analysis (data not shown).
DISCUSSION HEREIN WE PRESENT OUR FINDINGS OF HYPOTONY AND LOW
IOP in a series of 108 consecutive patients with JIAassociated chronic uveitis observed at a single tertiarycare center over 30 years. Although retrospective data necessitates cautious interpretation owing to its inherent potential biases, we observed a small but significant proportion of patients with hypotony in our cohort. In our study, hypotony was present in 9.3% of patients at presentation. This is comparable to the 1.7%–19% range reported in other cohorts.10,14,15,20 Over a median follow-up period
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TABLE 4. Factors Influencing the Risk of Hypotony (<5 mm Hg) and Low Intraocular Pressure (IOP <8 mm Hg) in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Results of Univariate Cox Proportional-Hazards Regressions Hypotony (<5 mm Hg) (n ¼ 137, Events ¼ 26) Variable
Age at presentation (y) <6 6–12 13–18 >18 Age at the time of uveitis diagnosis <4 y 4–9 y >9y Sex Female Male Race White Black Other Duration of uveitis prior to presentation (per year) Duration of uveitis at presentation <6 months 6 months to 2 years >2 years Type of uveitis Anterior Intermediate or AntþInt Panuveitis Ocular surgery history Any intraocular surgery Prior vitrectomy Prior cataract surgery Prior glaucoma surgerya Signs of inflammatory activity Anterior chamber cells Quiet 0.5þ 1þ 2þ 3þ or worse Anterior chamber flare Quiet 1þ 2þ 3þ or worse Structural complications at presentation Any structural complications Posterior synechiae Epiretinal membrane Treatment at presentation Topical corticosteroid drops None 1–3 drops/d >3 drops/d
HR (95% CI)
P Value
Low IOP (<8 mm Hg) (n ¼ 132, Events ¼ 38) HR (95% CI)
P Value
Reference 2.9 (0.8–11.1) 1.3 (0.2–7.7) 3.5 (01.0–12.4)
.11 .79 .05*
Reference 2.7 (0.9–7.7) 1.9 (0.5–6.4) 2.9 (1.0–8.1)
.07 .32 .04*
Reference 1.8 (0.5–6.1) 1.2 (0.3–4.6)
.36 .79
Reference 1.8 (0.6–5.3) 2.5 (0.8–7.5)
.30 .11
Reference 2.5 (1.1–5.6)
.03*
Reference 2.2 (1.1–4.5)
.03
Reference 3.1 (1.2–7.9) 0.7 (0.1–5.0) 1.04 (1.0–1.1)
.02* .69 .006*
Reference 2.1 (0.8–5.5) 3.3 (1.1–9.7) 1.02 (0.99–1.05)
.13 .03 .05
Reference 1.0 (0.3–3.3) 1.4 (0.6–3.5)
.96 .43
Reference 1.0 (0.4–2.8) 1.3 (0.6–2.9)
.99 .44
Reference 0.8 (0.2–3.5) 9.7 (3.2–29.1)
.77 <.001*
Reference 1.4 (0.5–4.0) 7.5 (2.6–21.7)
.50 <.001
2.7 (1.4–5.5) 1.9 (0.5–8.3) 2.1 (0.9–4.6) 4.5 (1.8–11.3)
.005 .35 .07 .001
2.4 (1.1–5.5) 4.9 (1.4–16.6) 2.9 (1.2–6.6) 2.6 (0.9–7.5)
.03* .01* .01* .09
Reference 2.1 (0.7–6.2) 0.9 (0.2–3.2) 1.7 (0.5–6.2) 3.0 (1.0–8.9)
.17 .86 .42 .04*
Reference 2.3 (0.8–6.8) 4.7 (1.8–12.2) 86.5 (13–576)
.14 .001* <.001*
7.9 (1.9–33.6) 2.8 (1.3–6.0) 6.2 (1.8–21.1)
.005* .01* .003*
Reference 3.0 (1.2–7.9) 1.0 (0.4–2.4)
.02* .96
Reference 1.6 (0.6–4.3) 0.6 (0.2–2.0) 3.0 (1.2–7.9) 3.0 (1.2–7.6)
.37 .37 .02 .02
Reference 2.1 (0.9–4.7) 3.3 (1.5–7.3) 215.7 (18.7–2485) 2.8 (1.3–6.2) 2.1 (1.1–4.2) 4.7 (1.4–15.5)
Reference 4.0 (1.7–9.3) 1.0 (0.5–2.1)
.08 .004 <.001 .01 .03 .01
.001 .98 Continued on next page
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TABLE 4. Factors Influencing the Risk of Hypotony (Continued ) Hypotony (<5 mm Hg) (n ¼ 137, Events ¼ 26) Variable
HR (95% CI)
Topical mydriatic drops Topical IOP-lowering drops Oral corticosteroid Immunosuppressive agents Prior priocular corticosteroid injection(s) Visual acuity at presentation 20/40 or better 20/50 to 20/160 20/200 or worse
1.8 (0.7–4.2) 2.3 (0.9–6.3) 2.4 (0.8–6.8) 0.1 (0.02–1.0) 3.3 (1.3–8.3) Reference 7.4 (2.9–18.9) 2.9 (1.0–7.9)
Low IOP (<8 mm Hg) (n ¼ 132, Events ¼ 38)
P Value
HR (95% CI)
P Value
.20 .09 .12 .05* .01*
1.5 (0.7–3.4) 1.8 (0.8–4.3) 3.0 (1.1–7.8) 0.7 (0.3–1.6) 2.3 (1.0–5.0)
.28 .17 .02 .42 .04
<.001* .04*
Reference 3.5 (1.4–8.7) 3.1 (1.3–7.4)
.006 .01
CI ¼ confidence interval; HR ¼ hazard ratio; IOP ¼ intraocular pressure. Asterisk indicates statistically significant P value. a Includes tube, trabeculectomy, peripheral iridotomy, endoscopic cyclophotocoagulation, goniotomy trab, goniotomy.
FIGURE 3. Kaplan-Meier (KM) estimate of development of hypotony during follow-up in eyes that were hypotony-free at presentation. The constant line represents eyes treated with immunosuppressive therapy (IMT) at presentation, and the dashed line represents eyes that had not received IMT at presentation.
of 5.3 years, 26 of 137 at-risk eyes in this series developed hypotony at the rate of 0.04/EY, which is similar to the rate reported for pediatric uveitis patients (0.03/EY)21 and the rate reported for JIA-associated uveitis patients within the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study (0.028/EY).15 However, this rate was 6.7-fold higher than that reported among all noninfectious uveitis patients (adults and children) enrolled in the VOL. 169
SITE study (0.006/EY).15 Because all these reports are based on retrospective data from tertiary uveitis clinics, the risk of hypotony may be lower in general ophthalmology clinics following patients with JIA uveitis. Interestingly, the rate of hypotony in this study is lower than that reported in our previous report (0.09/EY).11 This finding may reflect that the risk of and the type of ocular complications change through the course of the disease,2,22 or may
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TABLE 5. Factors Influencing the Risk of Hypotony (<5 mm Hg) and Low Intraocular Pressure (<8 mm Hg) in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Results of Multivariate Cox Proportional-Hazards Regressionsa Hypotony (<5 mm Hg) (n ¼ 137, Events ¼ 26) Variable
Sex Female Male Race White Others Duration of uveitis at presentation <6 months 6 months to 2 years >2 years Type of uveitis Anterior Intermediate or anterior/intermediate Panuveitis Anterior chamber cells/flare Quiet or <1 1þ 2þ 3þ or worse History of intraocular surgeryb Posterior synechiae Treatment at presentation Topical corticosteroid drops None 1–3 drops/day >3 drops/day Oral corticosteroid Immunosuppressive agents Visual acuity at presentation 20/40 or better 20/50 to 20/200 20/200 or worse
HR (95% CI)
P Value
Low IOP (<8 mm Hg) (n ¼ 132, Events ¼ 38) HR (95% CI)
P Value
Reference 2.78 (0.51–15.19)
.24
Reference 4.31 (1.46–12.74)
.008*
Reference 2.94 (0.71–12.13)
.14
Reference 2.89 (1.00–8.37)
.05*
Reference 1.11 (0.21–5.76) 2.31 (0.44–12.06)
.90 .32
Reference 0.97 (0.28–3.31) 0.67 (0.20–2.22)
.96 .51
Reference 0.06 (0.00–1.02) 43.14 (3.27–569.30)
.05* .004*
Reference 1.61 (0.29–9.00) 4.05 (0.54–30.34)
.59 .17
Reference 2.68 (0.76–9.42) 0.42 (0.04–4.35) 25.62 (4.53–144.93) 1.22 (0.20–7.33) 5.89 (1.28–26.91)
.12 .46 <.001* .83 .02*
Reference 0.94 (0.36–2.46) 5.42 (0.87–33.72) 13.94 (4.22–46.08) 7.14 (1.79–28.53) 1.67 (0.55–5.08)
.90 .07 <.001* .005* .37
Reference 7.32 (1.34–39.90) 0.75 (0.18–3.11) 28.95 (3.14–267.37) 0.02 (0.00–0.10)
.02* .69 .003* .002*
Reference 2.61 (0.87–7.83) 0.88 (0.38–2.07) 5.16 (1.13–23.48) 0.60 (0.18–1.91)
.08 .77 .03* .39
Reference 4.23 (1.01–17.69) 2.81 (0.46–17.36)
.05* .26
Reference 2.54 (0.73–8.76) 1.01 (0.22–4.64)
.14 .98
CI ¼ confidence interval; HR ¼ hazard ratio; IOP ¼ intraocular pressure. Asterisk indicates statistically significant P value. a Adjusted for sex, race, duration of uveitis at presentation, type of uveitis, anterior chamber cells/flare, history of intraocular surgery, posterior synechia, treatment regimen (topical corticosteroid, oral corticosteroid, immunosuppressive agents), and visual acuity at presentation. b Includes cataract surgery, vitrectomy, tube trabeculectomy, peripheral iridotomy, endoscopic cyclophotocoagulation, goniotomy.
reflect changes in referral patterns (eg, earlier referral) or more aggressive treatment patterns (eg, earlier institution of immunosuppression or biological therapy earlier). Indeed, the proportion of patients referred to our center already receiving immunosuppressive drug therapy prior to presentation increased 4-fold over of the course of this study (P < .001). After adjustment for potentially confounding factors, risk factors for hypotony at presentation included prior intraocular surgery, inflammation in the posterior segment, prior oral corticosteroid use, and legal blindness at presentation. We also observed an increased risk of low IOP and 122
hypotony in boys, but this was only significant for low IOP in multivariate analysis. Similarly, prior studies have been equivocal regarding whether sex is a risk factor for ocular complications in JIA-associated uveitis, with most data indicating either no sex predilection or a higher risk of complications in boys.23–25 During follow-up, statistically significant risk factors for developing hypotony included clinical characteristics that imply more severe uveitis. Panuveitis, use of oral corticosteroid therapy (eg, only children with the most sightthreatening uveitis receive oral corticosteroids in order to avoid the risk of growth retardation in the majority of
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_3þ AC cell or flare, presence of pospatients), presence of > terior synechiae, and visual impairment at presentation all were associated with the risk of subsequent hypotony. Although all levels of anterior chamber inflammation at presentation were associated with subsequent hypotony, multivariate analysis showed this association to be statisti_3þ AC cell or flare, suggesting that cally significant for > the most severe levels of inflammation are associated with hypotony. However, even moderate inflammation still may be harmful, as suggested by the univariate analyses. A history of intraocular surgery, especially cataract surgery or vitrectomy, was associated with hypotony both at presentation and during follow-up. However, this association was not statistically significant for incident hypotony after adjustment for other factors. The increase in the risk of hypotony after cataract surgery was less than that reported by the SITE research group for patients with noninfectious uveitis (aHR ¼ 7.5); however, this cohort contained both children and adults.15 Therefore the difference could be attributable to disparate responses of the eyes to cataract surgery within different age groups, or could be a result of longer uveitis duration among adult patients in the SITE cohort. Hypotony is a known side effect of cataract surgery in nonuveitic eyes through different mechanisms: wound leak, not apparent on slit-lamp examination but diagnosed through ultrasound biomicroscopy26,27; inadvertent cyclodialysis clefts28,29; rotation of IOL haptic into a cyclodialysis cleft30; and the haptic of the IOL causing ciliochoroidal irritation.31 Hypotony occurs in uveitic eyes after cataract surgery for similar reasons. As the researchers in the SITE research group suggested,
cataract development usually occurs in patients with more severe uveitis, which can drive both the incidence of cataract requiring surgery and the incidence of hypotony.15 The majority of hypotonous eyes (12 of 14) were legally blind at the time of presentation to our clinic. Developing new hypotony during follow-up also was associated with poor visual outcome. During follow-up, eyes with IOP <8 had worse visual acuity outcomes than those eyes without hypotony, thus underscoring the importance of avoiding the development of hypotony. Fortunately, use of immunosuppressive drug therapy was associated with a substantial decrease in the rate of developing hypotony even after adjustment for potential confounding. This finding further underscores the importance of early and aggressive treatment with immunosuppressive drug therapy in JIA-associated uveitis and agrees with other published studies demonstrating the utility of immunosuppression in improving the clinical and visual outcomes of patients with JIA-related uveitis.12,13,32,33 In conclusion, hypotony is a severe complication of longstanding inflammation in eyes with JIA-associated uveitis. The presence of panuveitis, oral corticosteroid treatment, baseline visual impairment, severe intraocular inflammation, and posterior synechiae were associated with greater risk of developing hypotony during follow-up. Developing new hypotony was associated with poor visual outcome. In contrast, the use of immunosuppressive therapy was associated with significantly lower risk of hypotony, suggesting that early diagnosis and referral, as well as appropriate inflammatory control with immunosuppressive drug therapy, may reduce risk of hypotony in JIA-associated uveitis.
FUNDING/SUPPORT: SUPPORTED IN PART BY THE KIDS UVEITIS RESEARCH AND EDUCATION (KURE) FUND AT THE WILMER EYE Institute, Baltimore, Maryland. Financial disclosures: Jennifer E. Thorne: Funding from NEI, Allergan; Advisory Board Member for AbbVie and Xoma; Consultant for Gilead. The following authors have no financial disclosures: Ahmadreza Moradi, Inna G. Stroh, Ashvini K. Reddy, Dana M. Hornbeak, Theresa G. Leung, and Bryn M. Burkholder. All authors attest that they meet the current ICMJE criteria for authorship.
REFERENCES 1. Foster CS. Diagnosis and treatment of juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol 2003; 14(6):395–398. 2. Vitale AT, Graham E, de Boer JH. Juvenile idiopathic arthritis-associated uveitis: clinical features and complications, risk factors for severe course, and visual outcome. Ocul Immunol Inflamm 2013;21(6):478–485. 3. Heiligenhaus A, Heinz C, Edelsten C, et al. Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors. Ocul Immunol Inflamm 2013;21(3):180–191. 4. Kanski JJ, Shun-Shin GA. Systemic uveitis syndromes in childhood: an analysis of 340 cases. Ophthalmology 1984; 91(10):1247–1252.
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5. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol 1990;34(4):253–267. 6. Holland GN, Stiehm ER. Special considerations in the evaluation and management of uveitis in children. Am J Ophthalmol 2003;135(6):867–878. 7. Edelsten C, Reddy MA, Stanford MR, Graham EM. Visual loss associated with pediatric uveitis in English primary and referral centers. Am J Ophthalmol 2003;135(5):676–680. 8. Angeles-Han ST, Yeh S, Vogler LB. Updates on the risk markers and outcomes of severe juvenile idiopathic arthritisassociated uveitis. Int J Clin Rheumtol 2013;8(1):109–121. 9. Foster CS, Barrett F. Cataract development and cataract surgery in patients with juvenile rheumatoid arthritis-associated iridocyclitis. Ophthalmology 1993;100(6):809–817. 10. Kump LI, Castaneda RA, Androudi SN, Reed GF, Foster CS. Visual outcomes in children with juvenile idiopathic
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11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
arthritis-associated uveitis. Ophthalmology 2006;113(10): 1874–1877. Woreta F, Thorne JE, Jabs DA, Kedhar SR, Dunn JP. Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol 2007;143(4):647–655. Thorne JE, Woreta F, Kedhar SR, Dunn JP, Jabs DA. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol 2007; 143(5):840–846. Gregory AC, Kempen JH, Daniel E, et al. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis. Ophthalmology 2013;120(1): 186–192. Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology 1996; 103(3):375–383. Daniel E, Pistilli M, Pujari SS, et al. Risk of hypotony in noninfectious uveitis. Ophthalmology 2012;119(11): 2377–2385. Yu EN, Paredes I, Foster CS. Surgery for hypotony in patients with juvenile idiopathic arthritis-associated uveitis. Ocul Immunol Inflamm 2007;15(1):11–17. Schubert HD. Postsurgical hypotony: relationship to fistulization, inflammation, chorioretinal lesions, and the vitreous. Surv Ophthalmol 1996;41(2):97–125. Thorne JE, Jabs DA, Peters GB, Hair D, Dunn JP, Kempen JH. Birdshot retinochoroidopathy: ocular complications and visual impairment. Am J Ophthalmol 2005;140(1): 45–51. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140(3):509–516. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology 2009; 116(8):1544–1551. Rosenberg KD, Feuer WJ, Davis JL. Ocular complications of pediatric uveitis. Ophthalmology 2004;111(12):2299–2306.
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22. Zak M, Fledelius M, Pedersen KF. Ocular complications and visual outcome in juvenile chronic arthritis: a 25year follow-up study. Acta Ophthalmol Scand 2003;81(3): 211–215. 23. Sabri K, Saurenmann RK, Silverman ED, Levin AV. Course, complications, and outcome of juvenile arthritis-related uveitis. J AAPOS 2008;12(6):539–545. 24. Ayuso KV, Cate HA, van der Does P, Rothova A, de Boer JH. Male gender as a risk factor for complications in uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol 2010;149(6):994–999. 25. Moradi A, Amin RM, Thorne JE. The role of gender in juvenile idiopathic arthritis-associated uveitis [Review]. J Ophthalmol 2014;2014:461078. 26. Sicco thoe Schwartzenberg GW, Pavlin CJ. Occult wound leak diagnosed by ultrasound biomicroscopy in patients with postoperative hypotony. J Cataract Refract Surg 2001; 27(4):549–554. 27. Machemer HF, Roters S. Ultrasound biomicroscopy of chronic hypotony after cataract extraction. J Cataract Refract Surg 2001;27(2):327–329. 28. Mushtaq B, Chiang MY, Kumar V, et al. Phacoemulsification, persistent hypotony, and cyclodialysis clefts. J Cataract Refract Surg 2005;31(7):1428–1432. 29. Maffett MJ, O’Day DM. Cyclodialysis cleft following a scleral tunnel incision. Ophthalmic Surg 1994;25(6):387–388. 30. Lee YC, Chung FL, Chen CC. Intraocular pressure and foveal thickness after phacoemulsification. Am J Ophthalmol 2007; 144(2):203–208. 31. Jahn CE. Reduced intraocular pressure after phacoemulsification and posterior chamber intraocular lens implantation. J Cataract Refract Surg 1997;23(8):1260–1264. 32. Paroli MP, Abbouda A, Restivo L, Sapia A, Abicca I, Pivetti Pezzi P. Juvenile idiopathic arthritis-associated uveitis at an Italian tertiary referral center: clinical features and complications. Ocul Immunol Inflamm 2015;23(1): 74–81. 33. Lerman MA, Burnham JM, Chang PY, et al. Response of pediatric uveitis to tumor necrosis factor-a inhibitors. J Rheumatol 2013;40(8):1394–1403.
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To describe risk factors for hypotony in patients with juvenile idiopathic arthritis (JIA)-associated uveitis. DESIGN: Retrospective cohort study. METHODS: All patients with JIA-associated uveitis (N [ 108; affected eyes [ 196) evaluated and followed at the Wilmer Eye Institute from July 1984 through June 2014 were included in this study. Prevalence and incidence of hypotony (intraocular pressure [IOP] <5 mm Hg) and low IOP (5 mm Hg £ IOP < 8 mm Hg) and risk factors for developing hypotony were analyzed. RESULTS: At presentation, 9.3% of patients (7.1% of affected eyes) had hypotony. During a median follow-up of 5.3 years, the rate of developing hypotony and low IOP were 0.04 per eye-year (/EY; 95% confidence interval [CI]: 0.02/EY, 0.05/EY) and 0.06/EY (95% CI: 0.04/ EY, 0.08/EY), respectively. Risk factors for development of hypotony during follow-up appeared to be associated with more severe uveitic disease, such as the presence of panuveitis (adjusted hazard ratio [aHR], 43.1; P [ .004), anterior chamber cells or flare ‡ 3D (aHR, 25.6, P < .001), posterior synechiae (aHR, 5.9, P [ .02), and the use of oral corticosteroid (aHR 28.9; P [ .003) at the presenting examination. Receiving immunosuppressive drug therapy at the time of presentation was associated with a lower risk of development of hypotony (aHR, 0.02; P [ .002). CONCLUSIONS: Hypotony affects a small but significant proportion of patients with JIA-associated uveitis and is associated with signs of active and severe uveitis. Immunosuppression was associated with significantly lower risk of hypotony, suggesting that aggressive control of the inflammation may reduce risk of hypotony in JIAassociated uveitis. (Am J Ophthalmol 2016;169: 113–124. Ó 2016 Elsevier Inc. All rights reserved.)
J
UVENILE IDIOPATHIC ARTHRITIS (JIA) IS A COMMON
cause of anterior uveitis among children.1–3 It is typically characterized by a chronic bilateral anterior uveitis with insidious onset,3 affects approximately 10%– 20% of patients with JIA, and may result in substantial visual morbidity.4–8 Structural ocular complications, such as hypotony, band keratopathy, cataract, glaucoma, macular edema, and epiretinal membrane, occur commonly in JIA-associated uveitis.7,9–13 Hypotony has been estimated to occur in 10%–19% of patients with JIA-associated uveitis, rates higher than those observed in other pediatric uveitides,10,14 and with adult noninfectious uveitis.15 Given these complications, it is not surprising that patients with JIA-associated uveitis also exhibit high rates of visual impairment and blindness12,13 and an approximately 2-fold greater rate of visual impairment relative to other pediatric uveitides.14 Of the ocular complications associated with JIAassociated uveitis, chronic hypotony appears to have a particularly poor prognosis. Hypotony may result from the development of cyclitic membranes, which place traction on the ciliary body and can lead to its detachment.6,16 In the absence of such membranes, hypotony also may result from ciliary body atrophy owing to chronic inflammation with decreased aqueous production.6,16 Subsequent vision loss may occur owing to anterior chamber collapse, corneal edema, astigmatism, vitreous haze, macular edema (eg, hypotonous maculopathy), choroidal detachment, scleral collapse, macular compression, or disc edema.17 To better understand the impact of hypotony on patients with JIA uveitis, we describe the prevalence and incidence of hypotony, risk factors for developing hypotony, and its impact on visual outcomes among patients with JIAassociated uveitis managed at our center.
METHODS Supplemental Material available at AJO.com. Accepted for publication Jun 13, 2016. From the Departments of Ophthalmology (A.M., I.G.S., A.K.R., D.M.H., T.G.L., B.M.B., J.E.T.) and Epidemiology (J.E.T.), The Johns Hopkins University School of Medicine, Baltimore, Maryland. Inquiries to Jennifer E. Thorne, The Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 North Wolfe St, Woods Building, Room 476, Baltimore, MD 21287; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.06.026
©
2016
THIS STUDY RECEIVED APPROVAL FROM THE JOHNS HOPKINS
University School of Medicine Institutional Review Board for all aspects of this retrospective study. All work was compliant with the Health Insurance Portability and Accountability Act and in accordance with the principles of the Declaration of Helsinki.
ELSEVIER INC. ALL
RIGHTS RESERVED.
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STUDY POPULATION:
Medical records of 108 patients with JIA-associated uveitis (International Classification of Disease [ICD] codes: 714.30 þ 364.XX) seen between July 1984 and June 30, 2014 in the Division of Ocular Immunology at the Wilmer Eye Institute, Johns Hopkins Hospital, were identified. Diagnoses were based on review of case history and ophthalmologic examination by a uveitis specialist with ancillary testing guided by clinical findings. DATA COLLECTION:
Data were collected by chart review and entered into a standardized database.18 Data included demographic features (age, sex, and race), past history of arthritis, past history of uveitis, anatomic location of the uveitis as defined by the Standardization of Uveitis Nomenclature (SUN) Working Group,19 results of diagnostic testing, and medications (doses and routes) at each clinic visit. Ophthalmic findings at each visit included visual acuity, intraocular pressure (IOP), slit-lamp examination, grade of inflammation in the anterior chamber and in the vitreous by SUN criteria,19 and dilated fundus findings.
MAIN OUTCOME MEASURES:
The prevalence of hypotony (defined as IOP <5 mm Hg) and low IOP (defined as _5 mm Hg but lower than 8 mm Hg) at presentation IOP > and the incidence of these conditions during follow-up were assessed retrospectively. To calculate incidence rates of these outcomes, eyes with hypotony and low IOP were _8 mm Hg in follow-up compared with eyes with IOP > data. The following variables were assessed for potential association with hypotony and low IOP: age at presentation, age at the time of uveitis diagnosis, sex, race, visual acuity at presentation, any prior intraocular surgery, prior cataract surgery, prior glaucoma surgery, prior vitrectomy, inflammatory activity in the eye (anterior chamber cell, anterior chamber flare, vitreous cell, vitreous haze), anatomic location of the uveitis, duration of uveitis, presence of other structural ocular complications of uveitis (band keratopathy, posterior synechiae, cataract, epiretinal membrane, macular edema, optic nerve edema), and the treatment at presentation (topical corticosteroids, topical IOP lowering drops, immunosuppressive drug therapy, and/or oral corticosteroids). The development of new-onset complications among eyes affected with uveitis was noted on clinical examination. The development of new-onset cataract was defined as the presence of 1þ nuclear sclerosis, 1þ cortical change, or trace posterior subcapsular change seen on clinical examination in an eye in which no cataract had been reported on prior visits.
STATISTICAL
analysis was ANALYSIS: Statistical performed using Stata statistical software (version 10.0, 2007; Stata Corporation, College Station, Texas, USA). Frequencies and medians of demographic variables were tabulated for patients/eyes and compared using x2 test and t test for categorical and numerical data, respectively.
114
Incidence rates for ocular complications were calculated as the number of events divided by the number of eyeyears (EY) of the at-risk eyes. At-risk eyes included all eyes that were free of each respective outcome at presentation with at least 1 follow-up visit in our clinic. The 95% confidence intervals (CI) were calculated for the estimated incidence rates of ocular complications. For risk factor analyses regarding prevalence of hypotony or low IOP among eyes at cohort entry, crude and adjusted odds ratios (aOR) were calculated using univariate and multivariate logistic regression. Time-updated univariate and multivariate Cox proportional-hazards models were used to assess the potential risk factors for developing new-onset hypotony or low IOP among patients with JIA-associated uveitis and crude and adjusted hazard ratios reported. P values were 2-sided and nominal, with a value < .05 being considered as statistically significant.
RESULTS CHARACTERISTICS OF THE STUDY POPULATION AT PRESENTATION: One hundred and eight patients (196
eyes) with JIA-associated uveitis were identified. The majority of patients were female (73%, n ¼ 79) and white (82%, n ¼ 85). The median age at onset of uveitis was 6 years (range, 0.5–35 years), with a median duration of uveitis prior to presentation of 4 years (range, 2.0 to 45.4 years). Of the 108 patients with JIA-associated uveitis, 12 (11.1%) (20 eyes, 10.2%) had documented history of hypotony prior to presentation. Ten patients (9.3%) (14 eyes, 7.1%) presented with hypotony, and 4 patients (3.7%) (5 eyes, 2.6%) presented with low IOP. Four patients (3.7%) presented with bilateral hypotony and 1 patient presented with bilateral low IOP. RISK FACTORS FOR HYPOTONY AT PRESENTATION:
Based on IOP at presentation, eyes were categorized as having hypotony (n ¼ 14 eyes, median IOP ¼ 1.5; range ¼ 0– 4 mm Hg), low IOP (n ¼ 5 eyes, median IOP ¼ 7; range ¼ _8 mm Hg (n ¼ 177 eyes; median 5–7 mm Hg), or IOP > IOP ¼ 15; range ¼ 8–38 mm Hg). Crude and adjusted logistic regression models identified several risk factors for hypotony and low IOP, which are summarized in Tables 1 and 2. All patients with hypotony were over age 14, and the majority (57.1%, n ¼ 8) were over age 18. Sex was not significantly associated with hypotony at presentation. Male sex was a risk factor for presenting with low IOP in univariate analysis (odds ratio [OR], 3.4; 95% CI, 1.3–8.8; P ¼ .01) but did not achieve conventional statistical significance in the multivariate analysis. _10 years duraIn the univariate analyses, patients with > tion of arthritis prior to presentation were significantly more likely to present with hypotony (OR, 16.2; 95% CI, 2.1–126.5; P ¼ .008). Patients who presented to our clinic
AMERICAN JOURNAL OF OPHTHALMOLOGY
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_5 mm Hg) or Low TABLE 1. Characteristics of Eyes With Juvenile Idiopathic Arthritis–Associated Uveitis and Hypotony (<5 vs > _8 mm Hg) at Presentation: Results of Univariate Regression Analysis Intraocular Pressure (IOP <8 vs > _5 mm Hg) Hypotony (<5 vs >
IOP
Variable
<5 mm Hg
_ but <8 mm Hg 5<
> _8 mm Hg
(n ¼ 14)
(n ¼ 5)
(n ¼ 177)
OR (95% CI)
40 (2) 60 (3)
56.5 (100) 43.5 (77)
Reference 16.6 (2.1–129.4)
20 (1) 80 (4)
75.1 (133) 24.9 (44)
Reference 0.5 (0.2–1.4)
100 (5) 0
88.1 (156) 11.9 (21)
Reference 5.1 (1.5–17.7)
40 (2) 60 (3)
50.3 (89) 49.7 (88)
60 (3) 40 (2)
_14 y, % (n) Age at presentation > No 7.1 (1) Yes 92.9 (13) Sex Female 57.1 (8) Male 42.9 (6) _3 y, % (n) Age of diagnosis of uveitis < No 64.3 (9) Yes 35.7 (5) _4 y, % (n) Duration of uveitis at presentation > No 7.1 (1) Yes 92.9 (13) Intermediate and/or posterior localization, % (n) No 42.9 (6) Yes 57.1 (8) Any prior ocular surgery, % (n) No 7.1 (1) Yes 92.9 (13) Signs of inflammatory activity, % (n) _1þ Anterior chamber cells > No 78.6 (11) Yes 21.4 (3) _1þ Anterior chamber flare > No 21.4 (3) Yes 78.6 (11) Structural complications at presentation, % (n) Band keratopathy 92.9 (13) Posterior synechia 7.1 (1) Optic disc edema 21.4 (3) Treatment at presentation, % (n) Topical corticosteroid drops 78.6 (11) Topical mydriatic drops 21.4 (3) Topical glaucoma drops 0 Systemic immunosuppressive 35.7 (5) medications Oral corticosteroid use No 71.4 (10) Yes 28.6 (4) _ 20/200), % (n) Legal blindness at presentation (< No 14.3 (2) Yes 85.7 (12)
P Value
_8 mm Hg) Low IOP (<8 vs >
OR (95% CI)
P Value
Reference 6.9 (1.9–24.6)
.003*
Reference 3.4 (1.3–8.8)
.01*
.009*
Reference 3.2 (1.0–10.1)
.05*
Reference 13 (1.7–101.4)
.01*
Reference 5.4 (1.5–19.2)
.009*
88.7 (157) 11.3 (20)
Reference 9.7 (3.1–30.6)
<.001*
Reference 8.7 (3.2–24.0)
<.001*
80 (4) 20 (1)
72.9 (129) 27.1 (48)
Reference 35.3 (4.5–277)
<.001*
Reference 7.5 (2.6–22.0)
<.001*
80 (4) 20 (1)
62.5 (110) 37.5 (66)
Reference 0.5 (0.1–1.7)
.25
Reference 0.4 (0.1–1.4)
.16
40 (2) 60 (3)
51.1 (90) 48.9 (86)
Reference 3.8 (1.0–14.0)
.04*
Reference 2.9 (1.0–8.5)
.04*
40 (2) 100 (5) 0
27.1 (48) 27.7 (49) 3.9 (7)
34.3 (4.4–269) 0.2 (0.02–1.4) 6.8 (1.5–30.0)
.001* .10 .01*
10.1 (3.2–31.9) 1.2 (0.4–3.4) 4.6 (1.1–19.3)
<.001* .72 .04*
100 (5) 40 (2) 20 (1) 0
67.8 (120) 16.4 (29) 14.7 (26) 33.3 (59)
1.7 (0.4–6.2) 1.3 (0.3–5.0) N/A 1.2 (0.4–3.6)
2.5 (0.7–9.0) 1.8 (0.6–5.4) 0.3 (0.04–2.5) 0.7 (0.2–2.1)
.15 .28 .28 .54
60 (3) 40 (2)
91.5 (162) 8.5 (15)
Reference 3.9 (1.1–13.7)
.03*
Reference 5.0 (1.7–15.0)
.004*
60 (3) 40 (2)
88.1 (156) 11.9 (21)
Reference 41.5 (7.7–197.3)
<.001*
Reference 20.8 (6.8–63.6)
<.001*
.007*
0.19
.44 .42 N/A .8
IOP ¼ intraocular pressure; OR ¼ odds ratio. Asterisk indicates statistically significant P value.
4 or more years after the diagnosis of uveitis were 13-fold more likely to present with hypotony (95% CI, 1.7– 101.4; P ¼ .01). In over one-third (35.7%, n ¼ 5) of hypotonous eyes, uveitis was first diagnosed at 3 years of age or younger, as compared with 11.5% (n ¼ 21) of patients with nonhypotonous eyes (OR, 5.1; 95% CI, 1.5–17.7; VOL. 169
P ¼ .01). The median duration of uveitis was longer in _5 mm Hg (17.0 hypotonous eyes than in eyes with IOP > years vs 3.8 years; P ¼ .002). The vast majority of eyes with hypotony (92.9%, 13/14 eyes) had uveitis for longer than 5 years prior to presentation, whereas 44% of eyes _5 mm Hg (81/182) had uveitis longer than 5 with IOP >
HYPOTONY IN JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS
115
_5 mm Hg) or Low TABLE 2. Characteristics of Eyes With Juvenile Idiopathic Arthritis–Associated Uveitis and Hypotony (<5 vs > _8 mm Hg) at Presentation: Results of Multiple Regression Analysis Intraocular Pressure (IOP <8 vs > _5 mm Hg) Hypotony (<5 vs > Variable
a
Adjusted OR (95% CI)
_3 y, % (n) Age of diagnosis of uveitis < No Reference Yes 3.5 (0.3–40.2) Intermediate and/or posterior localization, % (n) No Reference Yes 16.9 (1.2–238) Any prior ocular surgery,a % (n) No Reference Yes 76.3 (1.7–3406) Signs of inflammatory activity,% (n) _1þ Anterior chamber cells > No Reference Yes 0.1 (0.00–2.6) _1þ Anterior chamber flare > No Reference Yes 0.9 (0.03–25.4) Band keratopathy 2.2 (0.1–32.2) Oral corticosteroid use No Reference Yes 46.6 (0.9–2297) Prior periocular corticosteroid injection(s) No Reference Yes 30.7 (1.4–669) _20/200), % (n) Legal blindness at presentation (< No Reference Yes 7.6 (0.9–65.3)
_8 mm Hg) Low IOP (<8 vs > P Value
a
Adjusted OR (95% CI)
P Value
.31
Reference 2.1 (0.3–14.5)
.46
.04*
Reference 13.0 (2.1–80.1)
.006*
.02*
Reference 3.1 (0.5–18.2)
.21
.16
Reference 0.3 (0.04–1.9)
.19
.97 .56
Reference 0.2 (0.02–2.1) 1.2 (0.17–8.4)
.18 .18
.05*
Reference 14.2 (1.4–145.6)
.02*
.03*
Reference 20.5 (2.8–147)
.003*
.06*
Reference 8.3 (1.2–56.2)
.03*
IOP ¼ intraocular pressure; OR ¼ odds ratio. Asterisk indicates statistically significant P value. a Adjusting for age of diagnosis of uveitis, type of uveitis, anterior chamber cells, anterior chamber flare, prior ocular surgery, band keratopathy, oral corticosteroid use, and legal blindness at presentation.
years (OR, 7.2; 95% CI, 0.9–57.0; P ¼ .06). Furthermore, eyes with evidence of increased disease severity including other structural ocular complications, such as posterior synechiae, were more likely to present with hypotony. The majority of eyes with hypotony at presentation (57.1%, n ¼ 8) had inflammation in the vitreous or posterior pole. These eyes were 17 times more likely to have hypotony (aOR, 16.9; 95% CI, 1.2–238; P ¼ .04) when compared with eyes with isolated anterior uveitis. Eyes with panuveitis (35.7%, n ¼ 5) were 13 times more likely to present with hypotony (OR, 13.3; 95% CI, 3.5–51.3, P < .001), and eyes with intermediate uveitis (21.4%, n ¼ 3) were 6.7 times more likely to present with hypotony (OR, 6.7; 95% CI, 1.5–30.0; P ¼ .01) compared with eyes with anterior uveitis. Eyes with active disease as _1þ were more defined by anterior chamber (AC) flare > likely to present with hypotony (OR, 3.8; 95% CI, 1.0– 14.0; P ¼ .04) or low IOP (OR, 2.9; 95% CI, 1.0–8.5; 116
P ¼ .04); however, this risk factor was not statistically significant in the multivariate model. Hypotony was associated with poor vision at presentation. The majority of hypotonous eyes (85.7%, n ¼ 12) were legally blind (aOR, 7.6; 95% CI, 0.9–65.3; P ¼ .06), and the rest (14.3%, n ¼ 2) had visual acuity impairment _20/50 but >20/200). No eyes with hypotony at presenta(< tion had visual acuity of 20/40 or better, whereas 77.5% (n ¼ 141) of nonhypotonous eyes had visual acuity of 20/ 40 or better at presentation. Four out of 14 hypotonous eyes at presentation had no follow-up visit. Over a median follow-up period of 11.5 years, 5 out of 10 hypotonous eyes at presentation showed no change in their visual acuity at the end of the follow-up period. Four eyes showed worsening of visual acuity (including 3 eyes with no light perception [NLP]), and only 1 eye showed slight improvement in vision from light perception (LP) to count finger (CF).
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FIGURE 1. Kaplan-Meier estimate of development of hypotony (intraocular pressure <5) during follow-up in eyes with juvenile idiopathic arthritis–associated uveitis that were event-free at presentation.
Eyes with a prior history of at least 1 intraocular surgery were statistically significantly more likely to present with hypotony (aOR, 76.3; 95% CI, 1.7–3406, P ¼ .02). Thirteen of 14 hypotonous eyes (92.8%) had undergone cataract surgery prior to presentation, whereas 33 out of 182 eyes (18.3%) without hypotony had undergone cataract surgery at presentation. Subanalysis revealed that 82% of aphakic eyes at presentation had hypotony, vs only 9% of pseudophakic eyes at presentation (x2, P < .0001). Three hypotonous eyes had history of prior glaucoma surgery (2 eyes had trabeculectomy and 1 eye had peripheral laser iridotomy), and there was no significant association with hypotony (OR, 1.9; 95% CI, 0.5–7.3; P ¼ .36). Use of oral corticosteroid at presentation was a strong risk factor for hypotony (aOR, 46.6; 95% CI, 0.9–2297; P ¼ .05) and low IOP (aOR, 14.2; 95% CI, 1.4–145.6; P ¼ .02). Eyes with history of periocular corticosteroid injections were more likely to present with hypotony (aOR 30.7; 95% CI 1.4–669; P ¼ .03) or low IOP (aOR, 20.5; 95% CI, 2.8–147; P ¼ .003). Use of topical glaucoma drops, topical corticosteroids, mydriatic drops, glaucoma drops, or immunosuppressive drugs were not associated with hypotony or low IOP at presentation. INCIDENCE OF OCULAR COMPLICATIONS AMONG EYES WITH JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS AND HYPOTONY/LOW INTRAOCULAR PRESSURE:
Seventy-eight percent of patients were seen in follow-up, and the median follow-up period of these patients was 5.3 VOL. 169
years (range, 2 weeks to 29.7 years). During follow-up, 26 of 137 developed hypotony, with a rate of 0.04 per eyeyear (95% CI, 0.02/EY–0.05/EY, Figure 1), and 38 of 132 eyes developed low IOP (IOP <8 mm Hg) at the rate of 0.06 (95% CI, 0.04/EY–0.08/EY) (Table 3). Although 4 out of 5 eyes with low IOP at presentation developed hypotony for at least 1 visit during follow-up at a rate of 0.48/EY (95% CI, 0.13/EY–1.23/EY), only 1 eye had sustained hypotony. During the follow-up period, some eyes improved in terms of IOP measurements, but the increases in IOP were typically 1–2 mm Hg. Although a small number of eyes had increases in IOP enough to move from the ‘‘hypotony’’ group to the ‘‘low IOP’’ group, no eyes _8 mm Hg improved enough to achieve sustained IOP > (eg, the ‘‘normal IOP’’ group). Of the 26 eyes with newly diagnosed hypotony during follow-up, 12 had a history of recent glaucoma surgery. The median time between glaucoma surgery and development of new hypotony was 0.17 years (range: 1 week to 6.9 years). Among eyes with recent glaucoma surgery during follow-up, 9 eyes had recent tube shunt surgery, 2 eyes had recent trabeculectomy, and 1 eye had history of surgical peripheral iridotomy. The majority of hypotonous eyes had visual impairment or legal blindness at the time of presentation. Among eyes with low IOP at presentation, the incidence rate of visual impairment (worse than 20/50 but better than 20/200) was 0.21/EY (95% CI, 0.01/EY–1.19/EY), vs 0.06/EY _8 mm Hg (95% CI, 0.04/EY–0.08/EY) in eyes with IOP >
HYPOTONY IN JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS
117
118 TABLE 3. Incidence Rate of Ocular Complications Among Eyes With Juvenile Idiopathic Arthritis–Associated Uveitis and Hypotony (<5 mm Hg) or Low Intraocular Pressure (<8 mm Hg) at Presentation
Total (n ¼ 153)
Outcome
AMERICAN JOURNAL OF OPHTHALMOLOGY
Visual acuity loss Low vision (20/50 to 20/200) Legal blindness (20/200 or worse) Structural complications Ocular hypertension (IOP > 21 mmHg) Glaucomatous damage _0.2 increase in CDR) (> Hypotony (IOP <5 mm Hg) Low IOP (IOP <8 mm Hg) Cataract Intraocular surgeries Any glaucoma procedurec Trabeculectomy Tube shunt Laser peripheral iridotomy Vitrectomy
Events/ At Risk
Ratea (95% CI)/EY
Low IOP _ But<8 mm (5 mm Hg < Hg, n ¼ 5)
Hypotony (<5 mm Hg, n ¼ 10) Events/ At Risk
Rate (95% CI)/EY
Events/ At Risk
Rate (95% CI)/EY
IOP <8 mm Hg (n ¼ 15) Events/ At Risk
Rate (95% CI)/EY
_8 mm Hg (n ¼ 138)b IOP > Events/ At Risk
Rate (95% CI)/EY
Incidence Rate Ratio _8 <8 vs > (95% CI)
P Value
29/113 24/126
0.06 (0.04–0.09) 0/0 0.04 (0.02–0.06) 0/1
N/A 0
1/2 1/3
0.21 (0.01–1.19) 0.15 (0.00–0.84)
1/2 1/4
0.21 (0.01–1.19) 0.12 (0.00–0.67)
28/111 23/122
0.06 (0.04–0.08) 0.04 (0.02–0.57)
3.7 (0.1–22.3) 3.1 (0.1–19.3)
.13 .16
41/93
0.11 (0.08–0.15) 0/6
0
2/3
0.36 (0.04–1.29)
2/9
0.03 (0.00–0.09)
39/84
0.13 (0.09–0.18)
0.2 (0.02–0.8)
.004*
24/97
0.05 (0.03–0.07) 0/1
0
2/3
0.08 (0.01–0.29)
2/4
0.06 (0.01–0.21)
22/93
0.05 (0.03–0.07)
1.3 (0.1–5.1)
.34
26/137 38/132 35/78
0.04 (0.02–0.05) N/A 0.06 (0.04–0.08) N/A 0.27 (0.21–0.33) 0/0
N/A N/A N/A
4/5 N/A 2/2
0.48 (0.13–1.23) 4/5 N/A N/A 3.64 (0.44–13.13) 2/2
0.48 (0.13–1.23) 22/132 0.03 (0.02–0.05) 15.6 (3.9–45.8) <.001* N/A 38/132 0.06 (0.04–0.08) N/A N/A 3.64 (0.44–13.13) 25/76 0.112 (0.08–0.16) 32.3 (3.7–126) .001*
0 0 0 0 0.02 (0.00–0.09)
2/5 0/4 2/4 0/5 2/4
0.12 (0.01–0.43) 0 0.12 (0.01–0.43) 0 0.21 (0.03–0.74)
0.02 (0.00–0.06) 0 0.02 (0.00–0.06) 0 0.04 (0.01–0.13)
27/143 0.03 (0.02–0.5) 7/149 0.01 (0.00–0.02) 23/149 0.03 (0.02–0.04) 5/145 0.005 (0.00–0.01) 17/145 0.02 (0.01–0.03)
0/10 0/10 0/10 0/9 1/7
CDR ¼ cup-to-disc ratio; IOP ¼ intraocular pressure. Asterisk indicates statistically significant P value. a Rate is events occurring in affected eyes per eye-year (EY) at risk. b Considered as the reference group. c Defined as trabeculectomy, tube shunt, and/or laser peripheral iridotomy.
2/15 0/14 2/14 0/14 3/11
25/128 0.03 (0.02–0.05) 0.5 (0.1–1.9) 7/128 0.01 (0.00–0.02) 0 21/135 0.03 (0.02–0.04) 0 5/131 0.006 (0.00–0.01) 0 14/134 0.02 (0.01–0.03) 2.4 (0.4–8.7)
.16 N/A N/A N/A .09*
SEPTEMBER 2016
FIGURE 2. Kaplan-Meier (KM) estimate of development of legal blindness (visual acuity 20/200 or worse) during follow-up in eyes that were hypotony-free at presentation. The dashed line represents the KM estimate for eyes that stayed hypotony-free during followup, and the constant line refers to eyes with new hypotony during follow-up.
at presentation (incidence rate ratio, 3.7; 95% CI, 0.1– 22.3, P ¼ .13). The incidence of legal blindness (20/200 or worse) was 0.12/EY in the eyes with low IOP (95% CI, 0.00/EY–0.67/EY) and 0.04/EY (95% CI, 0.02/EY–0.06/ _8 mm Hg (incidence rate ratio, EY) in the eyes with IOP > 3.1; 95% CI, 0.1–19.3, P ¼ .16) (Figure 2). RISK FACTORS FOR DEVELOPMENT OF HYPOTONY DURING FOLLOW-UP: Univariate Cox regression analysis
demonstrated that eyes with panuveitis (HR, 9.7; 95% CI, 3.2–29.1, P < .001), prior intraocular surgery (HR, 2.4; 95% CI, 1.1–5.5, P ¼ .03), any structural ocular complications (defined as posterior synechiae, band keratopathy, cataract, glaucoma, optic disc edema, epiretinal membrane, or choroidal neovascularization; HR, 77.9; _3þ (HR, 2.5; 95% CI, 1.9–33.6, P ¼ .005), AC cell > _1þ (HR, 3.8; 95% 95% CI, 1.0–6.7, P ¼ .04), AC flare > CI, 1.6–9.0, P ¼ .003), visual impairment (HR, 7.4; 95% CI, 2.9–18.9, P ¼ .04), legal blindness (HR, 2.9; 95% CI, _3 corticosteroid 1.0–7.9, P ¼ .04), and treatment with < drops per day (HR, 3.0; 95% CI, 1.2–7.9, P ¼ .02) at presentation were more likely to develop hypotony during follow-up. Patients who were receiving immunosuppressive therapy at presentation were statistically significantly less likely to develop hypotony during follow-up (HR, 0.1; 95% CI, 0.02–1.0, P ¼ .05) (Table 4, Figure 3). After adjustment for statistically significant risk factors from the crude analysis, panuveitis remained associated with hypotony (aHR, 43.14; 95% CI, 3.27–569; P ¼ .004), as VOL. 169
did oral corticosteroid treatment (aHR, 28.95; 95% CI, _3þ AC cell or 3.14–267.37, P ¼ .003), presenting with > flare (aHR, 25.6; 95% CI, 4.53–144.93, P < .001), treating with lower dose of corticosteroid drops (aHR, 7.32; 95% CI, 1.34–39.9, P ¼ .02), presence of posterior synechiae (aHR, 5.89; 95% CI, 1.28–26.91, P ¼ .02), and visual impairment (aHR, 4.23; 95% CI, 1.01–17.69, P ¼ .05) at presentation (Table 5). In contrast, treatment with immunosuppressive drug therapy was associated with lower rates of hypotony (aHR, 0.02; 95% CI, 0.00–0.10, P ¼ .002). Use of time-updated analyses for AC cell or flare and treatment with topical or oral corticosteroids or immunosuppressive drug therapy did not alter the results observed in the multivariable analysis (data not shown).
DISCUSSION HEREIN WE PRESENT OUR FINDINGS OF HYPOTONY AND LOW
IOP in a series of 108 consecutive patients with JIAassociated chronic uveitis observed at a single tertiarycare center over 30 years. Although retrospective data necessitates cautious interpretation owing to its inherent potential biases, we observed a small but significant proportion of patients with hypotony in our cohort. In our study, hypotony was present in 9.3% of patients at presentation. This is comparable to the 1.7%–19% range reported in other cohorts.10,14,15,20 Over a median follow-up period
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119
TABLE 4. Factors Influencing the Risk of Hypotony (<5 mm Hg) and Low Intraocular Pressure (IOP <8 mm Hg) in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Results of Univariate Cox Proportional-Hazards Regressions Hypotony (<5 mm Hg) (n ¼ 137, Events ¼ 26) Variable
Age at presentation (y) <6 6–12 13–18 >18 Age at the time of uveitis diagnosis <4 y 4–9 y >9y Sex Female Male Race White Black Other Duration of uveitis prior to presentation (per year) Duration of uveitis at presentation <6 months 6 months to 2 years >2 years Type of uveitis Anterior Intermediate or AntþInt Panuveitis Ocular surgery history Any intraocular surgery Prior vitrectomy Prior cataract surgery Prior glaucoma surgerya Signs of inflammatory activity Anterior chamber cells Quiet 0.5þ 1þ 2þ 3þ or worse Anterior chamber flare Quiet 1þ 2þ 3þ or worse Structural complications at presentation Any structural complications Posterior synechiae Epiretinal membrane Treatment at presentation Topical corticosteroid drops None 1–3 drops/d >3 drops/d
HR (95% CI)
P Value
Low IOP (<8 mm Hg) (n ¼ 132, Events ¼ 38) HR (95% CI)
P Value
Reference 2.9 (0.8–11.1) 1.3 (0.2–7.7) 3.5 (01.0–12.4)
.11 .79 .05*
Reference 2.7 (0.9–7.7) 1.9 (0.5–6.4) 2.9 (1.0–8.1)
.07 .32 .04*
Reference 1.8 (0.5–6.1) 1.2 (0.3–4.6)
.36 .79
Reference 1.8 (0.6–5.3) 2.5 (0.8–7.5)
.30 .11
Reference 2.5 (1.1–5.6)
.03*
Reference 2.2 (1.1–4.5)
.03
Reference 3.1 (1.2–7.9) 0.7 (0.1–5.0) 1.04 (1.0–1.1)
.02* .69 .006*
Reference 2.1 (0.8–5.5) 3.3 (1.1–9.7) 1.02 (0.99–1.05)
.13 .03 .05
Reference 1.0 (0.3–3.3) 1.4 (0.6–3.5)
.96 .43
Reference 1.0 (0.4–2.8) 1.3 (0.6–2.9)
.99 .44
Reference 0.8 (0.2–3.5) 9.7 (3.2–29.1)
.77 <.001*
Reference 1.4 (0.5–4.0) 7.5 (2.6–21.7)
.50 <.001
2.7 (1.4–5.5) 1.9 (0.5–8.3) 2.1 (0.9–4.6) 4.5 (1.8–11.3)
.005 .35 .07 .001
2.4 (1.1–5.5) 4.9 (1.4–16.6) 2.9 (1.2–6.6) 2.6 (0.9–7.5)
.03* .01* .01* .09
Reference 2.1 (0.7–6.2) 0.9 (0.2–3.2) 1.7 (0.5–6.2) 3.0 (1.0–8.9)
.17 .86 .42 .04*
Reference 2.3 (0.8–6.8) 4.7 (1.8–12.2) 86.5 (13–576)
.14 .001* <.001*
7.9 (1.9–33.6) 2.8 (1.3–6.0) 6.2 (1.8–21.1)
.005* .01* .003*
Reference 3.0 (1.2–7.9) 1.0 (0.4–2.4)
.02* .96
Reference 1.6 (0.6–4.3) 0.6 (0.2–2.0) 3.0 (1.2–7.9) 3.0 (1.2–7.6)
.37 .37 .02 .02
Reference 2.1 (0.9–4.7) 3.3 (1.5–7.3) 215.7 (18.7–2485) 2.8 (1.3–6.2) 2.1 (1.1–4.2) 4.7 (1.4–15.5)
Reference 4.0 (1.7–9.3) 1.0 (0.5–2.1)
.08 .004 <.001 .01 .03 .01
.001 .98 Continued on next page
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TABLE 4. Factors Influencing the Risk of Hypotony (Continued ) Hypotony (<5 mm Hg) (n ¼ 137, Events ¼ 26) Variable
HR (95% CI)
Topical mydriatic drops Topical IOP-lowering drops Oral corticosteroid Immunosuppressive agents Prior priocular corticosteroid injection(s) Visual acuity at presentation 20/40 or better 20/50 to 20/160 20/200 or worse
1.8 (0.7–4.2) 2.3 (0.9–6.3) 2.4 (0.8–6.8) 0.1 (0.02–1.0) 3.3 (1.3–8.3) Reference 7.4 (2.9–18.9) 2.9 (1.0–7.9)
Low IOP (<8 mm Hg) (n ¼ 132, Events ¼ 38)
P Value
HR (95% CI)
P Value
.20 .09 .12 .05* .01*
1.5 (0.7–3.4) 1.8 (0.8–4.3) 3.0 (1.1–7.8) 0.7 (0.3–1.6) 2.3 (1.0–5.0)
.28 .17 .02 .42 .04
<.001* .04*
Reference 3.5 (1.4–8.7) 3.1 (1.3–7.4)
.006 .01
CI ¼ confidence interval; HR ¼ hazard ratio; IOP ¼ intraocular pressure. Asterisk indicates statistically significant P value. a Includes tube, trabeculectomy, peripheral iridotomy, endoscopic cyclophotocoagulation, goniotomy trab, goniotomy.
FIGURE 3. Kaplan-Meier (KM) estimate of development of hypotony during follow-up in eyes that were hypotony-free at presentation. The constant line represents eyes treated with immunosuppressive therapy (IMT) at presentation, and the dashed line represents eyes that had not received IMT at presentation.
of 5.3 years, 26 of 137 at-risk eyes in this series developed hypotony at the rate of 0.04/EY, which is similar to the rate reported for pediatric uveitis patients (0.03/EY)21 and the rate reported for JIA-associated uveitis patients within the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study (0.028/EY).15 However, this rate was 6.7-fold higher than that reported among all noninfectious uveitis patients (adults and children) enrolled in the VOL. 169
SITE study (0.006/EY).15 Because all these reports are based on retrospective data from tertiary uveitis clinics, the risk of hypotony may be lower in general ophthalmology clinics following patients with JIA uveitis. Interestingly, the rate of hypotony in this study is lower than that reported in our previous report (0.09/EY).11 This finding may reflect that the risk of and the type of ocular complications change through the course of the disease,2,22 or may
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TABLE 5. Factors Influencing the Risk of Hypotony (<5 mm Hg) and Low Intraocular Pressure (<8 mm Hg) in Patients With Juvenile Idiopathic Arthritis–Associated Uveitis: Results of Multivariate Cox Proportional-Hazards Regressionsa Hypotony (<5 mm Hg) (n ¼ 137, Events ¼ 26) Variable
Sex Female Male Race White Others Duration of uveitis at presentation <6 months 6 months to 2 years >2 years Type of uveitis Anterior Intermediate or anterior/intermediate Panuveitis Anterior chamber cells/flare Quiet or <1 1þ 2þ 3þ or worse History of intraocular surgeryb Posterior synechiae Treatment at presentation Topical corticosteroid drops None 1–3 drops/day >3 drops/day Oral corticosteroid Immunosuppressive agents Visual acuity at presentation 20/40 or better 20/50 to 20/200 20/200 or worse
HR (95% CI)
P Value
Low IOP (<8 mm Hg) (n ¼ 132, Events ¼ 38) HR (95% CI)
P Value
Reference 2.78 (0.51–15.19)
.24
Reference 4.31 (1.46–12.74)
.008*
Reference 2.94 (0.71–12.13)
.14
Reference 2.89 (1.00–8.37)
.05*
Reference 1.11 (0.21–5.76) 2.31 (0.44–12.06)
.90 .32
Reference 0.97 (0.28–3.31) 0.67 (0.20–2.22)
.96 .51
Reference 0.06 (0.00–1.02) 43.14 (3.27–569.30)
.05* .004*
Reference 1.61 (0.29–9.00) 4.05 (0.54–30.34)
.59 .17
Reference 2.68 (0.76–9.42) 0.42 (0.04–4.35) 25.62 (4.53–144.93) 1.22 (0.20–7.33) 5.89 (1.28–26.91)
.12 .46 <.001* .83 .02*
Reference 0.94 (0.36–2.46) 5.42 (0.87–33.72) 13.94 (4.22–46.08) 7.14 (1.79–28.53) 1.67 (0.55–5.08)
.90 .07 <.001* .005* .37
Reference 7.32 (1.34–39.90) 0.75 (0.18–3.11) 28.95 (3.14–267.37) 0.02 (0.00–0.10)
.02* .69 .003* .002*
Reference 2.61 (0.87–7.83) 0.88 (0.38–2.07) 5.16 (1.13–23.48) 0.60 (0.18–1.91)
.08 .77 .03* .39
Reference 4.23 (1.01–17.69) 2.81 (0.46–17.36)
.05* .26
Reference 2.54 (0.73–8.76) 1.01 (0.22–4.64)
.14 .98
CI ¼ confidence interval; HR ¼ hazard ratio; IOP ¼ intraocular pressure. Asterisk indicates statistically significant P value. a Adjusted for sex, race, duration of uveitis at presentation, type of uveitis, anterior chamber cells/flare, history of intraocular surgery, posterior synechia, treatment regimen (topical corticosteroid, oral corticosteroid, immunosuppressive agents), and visual acuity at presentation. b Includes cataract surgery, vitrectomy, tube trabeculectomy, peripheral iridotomy, endoscopic cyclophotocoagulation, goniotomy.
reflect changes in referral patterns (eg, earlier referral) or more aggressive treatment patterns (eg, earlier institution of immunosuppression or biological therapy earlier). Indeed, the proportion of patients referred to our center already receiving immunosuppressive drug therapy prior to presentation increased 4-fold over of the course of this study (P < .001). After adjustment for potentially confounding factors, risk factors for hypotony at presentation included prior intraocular surgery, inflammation in the posterior segment, prior oral corticosteroid use, and legal blindness at presentation. We also observed an increased risk of low IOP and 122
hypotony in boys, but this was only significant for low IOP in multivariate analysis. Similarly, prior studies have been equivocal regarding whether sex is a risk factor for ocular complications in JIA-associated uveitis, with most data indicating either no sex predilection or a higher risk of complications in boys.23–25 During follow-up, statistically significant risk factors for developing hypotony included clinical characteristics that imply more severe uveitis. Panuveitis, use of oral corticosteroid therapy (eg, only children with the most sightthreatening uveitis receive oral corticosteroids in order to avoid the risk of growth retardation in the majority of
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_3þ AC cell or flare, presence of pospatients), presence of > terior synechiae, and visual impairment at presentation all were associated with the risk of subsequent hypotony. Although all levels of anterior chamber inflammation at presentation were associated with subsequent hypotony, multivariate analysis showed this association to be statisti_3þ AC cell or flare, suggesting that cally significant for > the most severe levels of inflammation are associated with hypotony. However, even moderate inflammation still may be harmful, as suggested by the univariate analyses. A history of intraocular surgery, especially cataract surgery or vitrectomy, was associated with hypotony both at presentation and during follow-up. However, this association was not statistically significant for incident hypotony after adjustment for other factors. The increase in the risk of hypotony after cataract surgery was less than that reported by the SITE research group for patients with noninfectious uveitis (aHR ¼ 7.5); however, this cohort contained both children and adults.15 Therefore the difference could be attributable to disparate responses of the eyes to cataract surgery within different age groups, or could be a result of longer uveitis duration among adult patients in the SITE cohort. Hypotony is a known side effect of cataract surgery in nonuveitic eyes through different mechanisms: wound leak, not apparent on slit-lamp examination but diagnosed through ultrasound biomicroscopy26,27; inadvertent cyclodialysis clefts28,29; rotation of IOL haptic into a cyclodialysis cleft30; and the haptic of the IOL causing ciliochoroidal irritation.31 Hypotony occurs in uveitic eyes after cataract surgery for similar reasons. As the researchers in the SITE research group suggested,
cataract development usually occurs in patients with more severe uveitis, which can drive both the incidence of cataract requiring surgery and the incidence of hypotony.15 The majority of hypotonous eyes (12 of 14) were legally blind at the time of presentation to our clinic. Developing new hypotony during follow-up also was associated with poor visual outcome. During follow-up, eyes with IOP <8 had worse visual acuity outcomes than those eyes without hypotony, thus underscoring the importance of avoiding the development of hypotony. Fortunately, use of immunosuppressive drug therapy was associated with a substantial decrease in the rate of developing hypotony even after adjustment for potential confounding. This finding further underscores the importance of early and aggressive treatment with immunosuppressive drug therapy in JIA-associated uveitis and agrees with other published studies demonstrating the utility of immunosuppression in improving the clinical and visual outcomes of patients with JIA-related uveitis.12,13,32,33 In conclusion, hypotony is a severe complication of longstanding inflammation in eyes with JIA-associated uveitis. The presence of panuveitis, oral corticosteroid treatment, baseline visual impairment, severe intraocular inflammation, and posterior synechiae were associated with greater risk of developing hypotony during follow-up. Developing new hypotony was associated with poor visual outcome. In contrast, the use of immunosuppressive therapy was associated with significantly lower risk of hypotony, suggesting that early diagnosis and referral, as well as appropriate inflammatory control with immunosuppressive drug therapy, may reduce risk of hypotony in JIA-associated uveitis.
FUNDING/SUPPORT: SUPPORTED IN PART BY THE KIDS UVEITIS RESEARCH AND EDUCATION (KURE) FUND AT THE WILMER EYE Institute, Baltimore, Maryland. Financial disclosures: Jennifer E. Thorne: Funding from NEI, Allergan; Advisory Board Member for AbbVie and Xoma; Consultant for Gilead. The following authors have no financial disclosures: Ahmadreza Moradi, Inna G. Stroh, Ashvini K. Reddy, Dana M. Hornbeak, Theresa G. Leung, and Bryn M. Burkholder. All authors attest that they meet the current ICMJE criteria for authorship.
REFERENCES 1. Foster CS. Diagnosis and treatment of juvenile idiopathic arthritis-associated uveitis. Curr Opin Ophthalmol 2003; 14(6):395–398. 2. Vitale AT, Graham E, de Boer JH. Juvenile idiopathic arthritis-associated uveitis: clinical features and complications, risk factors for severe course, and visual outcome. Ocul Immunol Inflamm 2013;21(6):478–485. 3. Heiligenhaus A, Heinz C, Edelsten C, et al. Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors. Ocul Immunol Inflamm 2013;21(3):180–191. 4. Kanski JJ, Shun-Shin GA. Systemic uveitis syndromes in childhood: an analysis of 340 cases. Ophthalmology 1984; 91(10):1247–1252.
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5. Kanski JJ. Juvenile arthritis and uveitis. Surv Ophthalmol 1990;34(4):253–267. 6. Holland GN, Stiehm ER. Special considerations in the evaluation and management of uveitis in children. Am J Ophthalmol 2003;135(6):867–878. 7. Edelsten C, Reddy MA, Stanford MR, Graham EM. Visual loss associated with pediatric uveitis in English primary and referral centers. Am J Ophthalmol 2003;135(5):676–680. 8. Angeles-Han ST, Yeh S, Vogler LB. Updates on the risk markers and outcomes of severe juvenile idiopathic arthritisassociated uveitis. Int J Clin Rheumtol 2013;8(1):109–121. 9. Foster CS, Barrett F. Cataract development and cataract surgery in patients with juvenile rheumatoid arthritis-associated iridocyclitis. Ophthalmology 1993;100(6):809–817. 10. Kump LI, Castaneda RA, Androudi SN, Reed GF, Foster CS. Visual outcomes in children with juvenile idiopathic
HYPOTONY IN JUVENILE IDIOPATHIC ARTHRITIS–ASSOCIATED UVEITIS
123
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
arthritis-associated uveitis. Ophthalmology 2006;113(10): 1874–1877. Woreta F, Thorne JE, Jabs DA, Kedhar SR, Dunn JP. Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol 2007;143(4):647–655. Thorne JE, Woreta F, Kedhar SR, Dunn JP, Jabs DA. Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss. Am J Ophthalmol 2007; 143(5):840–846. Gregory AC, Kempen JH, Daniel E, et al. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis. Ophthalmology 2013;120(1): 186–192. Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology 1996; 103(3):375–383. Daniel E, Pistilli M, Pujari SS, et al. Risk of hypotony in noninfectious uveitis. Ophthalmology 2012;119(11): 2377–2385. Yu EN, Paredes I, Foster CS. Surgery for hypotony in patients with juvenile idiopathic arthritis-associated uveitis. Ocul Immunol Inflamm 2007;15(1):11–17. Schubert HD. Postsurgical hypotony: relationship to fistulization, inflammation, chorioretinal lesions, and the vitreous. Surv Ophthalmol 1996;41(2):97–125. Thorne JE, Jabs DA, Peters GB, Hair D, Dunn JP, Kempen JH. Birdshot retinochoroidopathy: ocular complications and visual impairment. Am J Ophthalmol 2005;140(1): 45–51. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140(3):509–516. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology 2009; 116(8):1544–1551. Rosenberg KD, Feuer WJ, Davis JL. Ocular complications of pediatric uveitis. Ophthalmology 2004;111(12):2299–2306.
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22. Zak M, Fledelius M, Pedersen KF. Ocular complications and visual outcome in juvenile chronic arthritis: a 25year follow-up study. Acta Ophthalmol Scand 2003;81(3): 211–215. 23. Sabri K, Saurenmann RK, Silverman ED, Levin AV. Course, complications, and outcome of juvenile arthritis-related uveitis. J AAPOS 2008;12(6):539–545. 24. Ayuso KV, Cate HA, van der Does P, Rothova A, de Boer JH. Male gender as a risk factor for complications in uveitis associated with juvenile idiopathic arthritis. Am J Ophthalmol 2010;149(6):994–999. 25. Moradi A, Amin RM, Thorne JE. The role of gender in juvenile idiopathic arthritis-associated uveitis [Review]. J Ophthalmol 2014;2014:461078. 26. Sicco thoe Schwartzenberg GW, Pavlin CJ. Occult wound leak diagnosed by ultrasound biomicroscopy in patients with postoperative hypotony. J Cataract Refract Surg 2001; 27(4):549–554. 27. Machemer HF, Roters S. Ultrasound biomicroscopy of chronic hypotony after cataract extraction. J Cataract Refract Surg 2001;27(2):327–329. 28. Mushtaq B, Chiang MY, Kumar V, et al. Phacoemulsification, persistent hypotony, and cyclodialysis clefts. J Cataract Refract Surg 2005;31(7):1428–1432. 29. Maffett MJ, O’Day DM. Cyclodialysis cleft following a scleral tunnel incision. Ophthalmic Surg 1994;25(6):387–388. 30. Lee YC, Chung FL, Chen CC. Intraocular pressure and foveal thickness after phacoemulsification. Am J Ophthalmol 2007; 144(2):203–208. 31. Jahn CE. Reduced intraocular pressure after phacoemulsification and posterior chamber intraocular lens implantation. J Cataract Refract Surg 1997;23(8):1260–1264. 32. Paroli MP, Abbouda A, Restivo L, Sapia A, Abicca I, Pivetti Pezzi P. Juvenile idiopathic arthritis-associated uveitis at an Italian tertiary referral center: clinical features and complications. Ocul Immunol Inflamm 2015;23(1): 74–81. 33. Lerman MA, Burnham JM, Chang PY, et al. Response of pediatric uveitis to tumor necrosis factor-a inhibitors. J Rheumatol 2013;40(8):1394–1403.
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