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1.  Exposure to Oral Fluoroquinolones and the Risk of Retinal Detachment: Retrospective Analyses of Two Large Healthcare Databases 
Drug Safety  2014;37:171-182.
Background
A recent Canadian case–control study reported a 4.5-fold increased risk of retinal detachment (RD) during oral fluoroquinolone use. Of the fluoroquinolone-exposed cases, 83 % were exposed to ciprofloxacin. We sought to replicate this finding, and assess whether it applied to all fluoroquinolones.
Methods
In two large US healthcare databases, we performed three case–control analyses: one replicating the recent study; one addressing additional potential confounders; and one that increased sample size by dropping the Canadian study’s requirement for a prior ophthalmologist visit. We also performed a self-controlled case-series (SCCS) analysis in which each subject served as his or her own comparator.
Results
In the replication case–control analyses, the adjusted odds ratios (ORs) for any exposure to fluoroquinolones or ciprofloxacin were approximately 1.2 in both databases, and were statistically significant, and the ORs for current exposure were modestly above 1 in one database, modestly below 1 in the other, and not statistically significant. In the other case–control analyses, the ORs were close to 1. In a post hoc age-stratified case–control analysis, we observed an association of RD with fluoroquinolone exposure among older subjects in one of the two databases. All estimates from the SCCS analyses were below 1.2 and none was statistically significant.
Conclusion
The present study does not confirm the recent Canadian study’s finding of a strong relationship between RD and current exposure to fluoroquinolones. Instead, it found a modest association between RD and current or any exposure to fluoroquinolones in the case–control analyses, and no association in the SCCS analyses.
doi:10.1007/s40264-014-0138-y
PMCID: PMC3936132  PMID: 24526267
2.  Risk Factors for Loss of Visual Acuity among Patients with Uveitis Associated With Juvenile Idiopathic Arthritis: The SITE Study 
Ophthalmology  2012;120(1):186-192.
Purpose
To describe the incidence of and risk factors for visual acuity (VA) loss and ocular complications in patients with juvenile idiopathic arthritis (JIA)-associated uveitis.
Design
Multicenter retrospective cohort study.
Participants
327 patients (596 affected eyes) with JIA-associated uveitis managed at five tertiary uveitis clinics in the United States.
Methods
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study. Demographic and clinical characteristics were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers.
Main Outcome Measures
Loss of VA to 20/50 or to 20/200 or worse thresholds and the development of ocular complications.
Results
At presentation, 240 (40.3%) eyes had a VA of 20/50 or worse; 144 (24.2%) had a VA of 20/200 or worse; 359 (60.2%) had at least one ocular complication. The incidences of VA loss to the 20/50 or worse and 20/200 or worse thresholds were 0.18 and 0.09 per eye-year (EY), respectively; the incidence of developing at least one new ocular complication over follow-up was 0.15/EY (95% confidence interval [CI]: 0.13/EY, 0.17/EY). However, among eyes with uveitis that had no complications at presentation, the rate of developing at least one ocular complication during follow up was lower (0.04/EY, 95% CI: 0.02, 0.06). Posterior synechiae, active uveitis, and prior intraocular surgery were statistically significantly associated with VA to the 20/50 or worse and 20/200 or worse thresholds, both at presentation and during follow-up. Increasing (time-updated) anterior chamber cell grade was associated with increased rates of visual loss in a dose-dependent fashion. Use of immunosuppressive drugs was associated with a reduced the risk of visual loss, particularly for the 20/50 or worse outcome (hazard ratio = 0.40, 95% CI: 0.21, 0.75, P<0.01).
Conclusions
Ocular complications and vision loss were common in our cohort. Increasing uveitis activity was associated with increased risk of vision loss and use of immunosuppressive drugs was associated with reduced risk of vision loss suggesting that control of inflammation and use of immunosuppression may be critical aspects in improving the outcomes of patients with JIA-related uveitis.
doi:10.1016/j.ophtha.2012.07.052
PMCID: PMC3536914  PMID: 23062650
3.  Risk of Hypotony in Non-infectious Uveitis 
Ophthalmology  2012;119(11):2377-2385.
Objective
To describe the risk and risk factors for hypotony in a non-infectious uveitis cohort.
Design
Retrospective cohort study.
Participants
Patients with non-infectious uveitis seen between 1979-2007 at four academic ocular inflammation specialty clinics.
Method
Data were collected by trained, certified, expert reviewers from medical records.
Main Outcome Measures
Hypotony (<5mmHg) and low intraocular pressure (<8mmHg), each sustained for ≥2 visits spanning at least 30 days.
Results
During follow-up, 126/6785 (1.86%) developed hypotony at the rate of 0.61%(95% Confidence Interval (CI) 0.50, 0.75%)/eye-year. Cataract surgery was associated with a 7.5-fold risk (adjusted hazard ratio (aHR = 7.51, 95% CI 3.97,14.23) of incident hypotony. Phacoemulsification, the type of cataract surgery associated with the least hypotony risk still was associated with nearly five-fold higher hypotony incidence (aHR =4.87, 95% CI 2.25, 10.55). Increased risk was observed in children (aHR =2.92, 95% CI 1.20, 7.10) with respect to young adults, and duration of uveitis of >5 years (aHR =3.08, 95% CI 1.30, 7.31) with respect to uveitis of <6 month duration. ≥3+ vitreous cells, band keratopathy, exudative retinal detachment, posterior synechia and history of pars plana vitrectomy also were associated with greater hypotony incidence. With respect to anterior uveitis, intermediate uveitis (aHR = 0.17, 95% CI 0.05,0.56) and posterior uveitis (aHR =0.11, 95% CI 0.03,0.45) were associated with lower hypotony risk, whereas panuveitis (aHR=1.25, 95% CI 0.67, 2.35) was similar. Approximately five-sixths (84.1%) of eyes presenting with hypotony had a visual acuity of 20/200 or worse (aOR for visual acuity 20/200 or worse=13.85, 95% CI 7.23, 26.53). Risk factors for prevalent hypotony were similar.
Conclusions
The risk of hypotony is low among eyes with non-infectious uveitis, but is more frequently observed in cases with anterior segment inflammation. Signs of present or past inflammation were associated with higher risk, suggesting excellent inflammatory control may reduce the risk of hypotony. Prior ocular surgery also was associated with higher risk; cataract surgery in particular was associated with much higher risk of hypotony. Lower risk of hypotony with phacoemulsification than alternative cataract surgery approaches suggests the phacoemulsification approach is preferable.
doi:10.1016/j.ophtha.2012.05.032
PMCID: PMC3475753  PMID: 22796306
4.  Methotrexate for Ocular Inflammatory Diseases 
Ophthalmology  2009;116(11):2188-98.e1.
Purpose
To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation.
Design
Retrospective cohort study.
Participants
Patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to add methotrexate as a single, noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007, inclusive.
Methods
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage, route of administration of methotrexate, and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers.
Main Outcome Measures
Control of inflammation, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy.
Results
Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for ≥28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone ≤10 mg/d) was achieved within 6 months among 46.1%, 41.3%, 20.7%, 37.3%, 36.5%, and 50.9%, respectively. Overall, success within 12 months was 66% and 58.4% for sustained control and corticosteroid sparing ≤10 mg), respectively. Methotrexate was discontinued within 1 year by 42% of patients. It was discontinued owing to ineffectiveness in 50 patients (13%); 60 patients (16%) discontinued because of side effects, which typically were reversible with dose reduction or discontinuation. Remission was seen in 43 patients, with 7.7% remitting within 1 year of treatment.
Conclusions
Our data suggest that adding methotrexate to an anti-inflammatory regimen not involving other noncorticosteroid immunosuppressive drugs is moderately effective for management of inflammatory activity and for achieving corticosteroid-sparing objectives, although many months may be required for therapeutic success. Methotrexate was well tolerated by most patients, and seems to convey little risk of serious side effects during treatment.
Financial Disclosure(s)
The authors have no proprietary or commercial interests in any of the materials discussed in this article.
doi:10.1016/j.ophtha.2009.04.020
PMCID: PMC3785935  PMID: 19748676
5.  Risk of corticosteroid-induced hyperglycemia requiring medical therapy among patients with inflammatory eye diseases 
Ophthalmology  2012;119(8):1569-1574.
Objective
To identify the incidence and risk factors for corticosteroid-induced hyperglycemia requiring medical therapy among patients with inflammatory eye diseases.
Design
Retrospective cohort study.
Participants
Patients with ocular inflammation followed at five United States tertiary centers who initially were neither diabetic nor taking hypoglycemic medications.
Methods
Eligible patients who used oral corticosteroids during follow-up were identified and followed longitudinally for initiation of hypoglycemic medication over one year after beginning corticosteroids. The remaining eligible patients were followed for one year after their initial visit. Survival analysis was used to calculate the risk of hyperglycemia requiring medical therapy, and to identify potential risk factors.
Main Outcome Measures
Initiation of hypoglycemic medications.
Results
Among 2,073 non-diabetic patients treated with oral corticosteroids, 25 (1.21%) initiated hypoglycemic therapy compared with 5 (0.19%) of 2,666 patients not treated with oral corticosteroids (relative risk (RR) = 4.39, 95% Confidence Interval (CI) = 1.68 – 11.5). Relative risk tended to be higher in association with higher initial doses (For initial doses <40 mg of prednisone/day, RR=3.23, 95% CI: 1.08–9.64; for initial prednisone dose ≥40 mg/day, RR=5.51, 95% CI: 2.01–15.1). Other risk factors for the initiation of hypoglycemic therapy included older age (RR (per each additional 10 years) = 1.46, 95% CI = 1.15 – 1.85, p = 0.002) and African-American race (RR = 2.94, 95% CI = 1.34 – 6.43, p = 0.007).
Conclusions
These results suggest that the absolute risk of corticosteroid-induced hyperglycemia that is detected and treated with hypoglycemic therapy in the tertiary ocular inflammation setting is low (an excess cumulative risk on the order of 1% within one year), although on a relative scale it is approximately 4.4-fold higher than in patients not treated with oral corticosteroids. Higher age and African-American race also were risk factors. Physicians who use systemic corticosteroids for ocular inflammatory diseases should be aware of this risk, and should consider surveillance for hyperglycemia among high-risk patients. However, given the low absolute risk, routine laboratory monitoring or referral for monitoring may not be necessary for low risk patients.
doi:10.1016/j.ophtha.2012.01.043
PMCID: PMC3394895  PMID: 22484116
6.  High-Dose Intravenous Corticosteroids for Ocular Inflammatory Diseases 
Purpose
To evaluate the effectiveness and risk of complications of high-dose intravenous pulsed corticosteroids for non-infectious ocular inflammatory diseases.
Methods
Retrospective cohort study. One hundred four eyes of seventy patients who received high-dose intravenous corticosteroids for treatment of active ocular inflammation were identified from five centers. The main outcome measures were control of inflammation and occurrence of ocular or systemic complications within one month after treatment.
Results
Within ≤1 month of starting treatment, 57% of eyes achieved complete control of inflammation (95% confidence interval (CI): 33-83%), improving to 82% when near-complete control was included (95% CI: 61-96%). Most eyes (85%; 95% CI: 70-95%) gained clinically significant improvement in anterior chamber inflammation. One patient developed a colon perforation during treatment. No other major complications were recorded.
Conclusions
Treatment of ocular inflammation with high-dose intravenous corticosteroids resulted in substantial clinical improvement for most cases within one month. Complications of therapy were infrequent.
doi:10.3109/09273948.2011.646382
PMCID: PMC3306126  PMID: 22409561
Corticosteroids; Inflammation; Intravenous; Non-infectious; Uveitis
7.  Risk of Relapse in Primary Acute Anterior Uveitis 
Ophthalmology  2011;118(10):1911-1915.
Purpose
To evaluate the risk of and risk factors for a second episode (relapse) among patients with remitted primary anterior uveitis.
Design
Retrospective cohort study.
Participants
Patients with primary anterior uveitis presenting to one of 4 academic ocular inflammation subspecialty practices achieving remission of the primary episode within 90 days of initial uveitis diagnosis.
Methods
Data were obtained by standardized chart review.
Main outcome measures
Time-to-relapse of anterior uveitis and risk factors for relapse.
Results
102 patients with a first episode of anterior uveitis were seen within 90 days of first-ever uveitis onset and followed for 165 person-years after achieving remission of the initial episode. Most patients were female (60%) and white (78%). Forty patients had a recurrence of anterior uveitis. The incidence of relapse was 24% per person-year (95% Confidence Interval [CI]: 17–33%). At 1.5 years after remission, 61% (95% CI: 48–71%) were still in remission. Younger adults had significantly higher relapse risk than middle-aged adults (hazard ratio [18–35 year-old persons vs. 35–55 year-old persons]=2.7, 95% CI: 1.3–6.0).
Conclusions
Our results suggest that many patients with remitted primary anterior uveitis presenting for tertiary uveitis care will relapse. Age in the young adult range was associated with higher risk of relapse. Given the high relapse risk, management of patients with primary anterior uveitis should include an explicit plan for detecting and managing relapses.
doi:10.1016/j.ophtha.2011.02.044
PMCID: PMC3179829  PMID: 21680024
8.  Suppressor of Cytokine Signaling-1 (SOCS1) Inhibits Lymphocyte Recruitment into the Retina and Protects SOCS1 Transgenic Rats and Mice from Ocular Inflammation 
This study reveals that Suppressor of cytokine signaling-1 mitigates uveitis by inhibiting the infiltration of inflammatory cells into the retina and conferring protection to retinal cells by inhibiting activities of proapoptotic cytokines.
Purpose.
Suppressors of cytokine signaling (SOCS) proteins regulate the intensity and duration of cytokine signals and defective expression of SOCS1 and SOCS3 has been reported in a number of human diseases. The purpose of this study was to investigate the role of SOCS1 in intraocular inflammatory diseases (uveitis) and whether SOCS1 expression is defective in patients with ocular inflammatory diseases.
Methods.
Blood from patients with scleritis or healthy human volunteers was analyzed for SOCS expression by RNase protection assay and RT-PCR. The authors generated SOCS1 transgenic rats and mice (SOCS1-Tg), induced experimental autoimmune uveoretinitis (EAU) by active immunization with interphotoreceptor retinal binding protein or adoptive transfer of uveitogenic T cells, and investigated effects of SOCS1 overexpression on EAU. SOCS1-mediated protection of retinal cells from apoptosis was assessed by annexin V staining.
Results.
Induction of cytokine-induced SH2 protein was comparable between patients and volunteers, whereas 80% of lymphocytes from patients with scleritis failed to induce SOCS1 in response to IL-2. Compared with wild-type littermates, SOCS1-Tg rats/mice developed less severe EAU. Constitutive overexpression of SOCS1 in retina inhibited expression of chemokines (CCL17, CCL20, CXCL9, CXCL10), reduced Th17/Th1 expansion, and inhibited recruitment of inflammatory cells into the retina. The authors also show that SOCS1 protected retinal cells from staurosporine as well as H2O2-induced apoptosis.
Conclusions.
Defective expression of SOCS1 in patients with scleritis, taken together with SOCS1-mediated protection of neuroretinal cells from apoptosis, suggest that SOCS1 has neuroprotective function in the retina, implying that administration of SOCS1 mimetic peptides may be useful in treating uveitis or scleritis.
doi:10.1167/iovs.11-7688
PMCID: PMC3176005  PMID: 21778271
9.  Adverse effects of smoking on patients with ocular inflammation 
Background
To evaluate how smoking affects the time to disease quiescence and time to disease recurrence in patients with ocular inflammation.
Methods
A retrospective cohort study of patients with ocular inflammation who were followed longitudinally and had smoking information available in the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study database.
Results
Among 2676 patients with active ocular inflammation, smokers were more likely to have bilateral ocular disease and poorer visual acuity on presentation compared with non-smokers and previous smokers. In a multivariate analysis, there was no statistically significant difference in the time to disease quiescence between groups. However, the median time to recurrence of ocular inflammation was statistically significantly longer for non-smokers (9.4 months) and for previous smokers (10.7 months) than for current smokers (7.8 months) (p=0.02). The RR of ocular inflammation recurrence was higher for smokers than for non-smokers (adjusted HR=1.19, 95% CI 1.03 to 1.37) and tended towards significance in previous smokers (adjusted HR=1.11, 95% CI 0.93 to 1.35).
Conclusions
Smoking was associated with an increased likelihood of bilateral ocular inflammation and reduced vision upon presentation, and an increased risk of recurrence compared with not smoking. These results suggest that patients with ocular inflammation should be counselled to stop smoking as part of routine management.
doi:10.1136/bjo.2009.174466
PMCID: PMC3227535  PMID: 20606023
11.  Cyclosporine for Ocular Inflammatory Diseases 
Ophthalmology  2010;117(3):576-584.
Purpose
To evaluate the clinical outcomes of cyclosporine treatment for non-infectious ocular inflammation
Design
Retrospective cohort study
Participants
Three hundred seventy-three patients with non-infectious ocular inflammation managed at four tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single non-corticosteroid immunosuppressive agent to their treatment regimen, between 1979-2007 inclusive.
Methods
Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures: Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity.
Results
Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by six months and 51.9% by one year gained sustained, complete control of inflammation over at least two visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone 10 mg/day or less) was achieved by 22.1% by six months and 36.1% within one year. Toxicity led to discontinuation of therapy within one year by 10.7% of the population. Patients over 55 years of age were over 3-fold more likely to discontinue therapy because of toxicity than patients ages 18-39 years. Doses of 151-250 mg/day tended to be more successful than lower doses, and were not associated with a higher discontinuation for toxicity rate; higher doses did not appear to offer a therapeutic advantage.
Conclusion
Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151-250 mg/day. While cyclosporine was tolerated by the majority of patients, toxicity was much more frequent with increasing age; alternative agents may be preferred for patients over 55 years of age.
doi:10.1016/j.ophtha.2009.08.010
PMCID: PMC2830390  PMID: 20031223
12.  Cyclophosphamide for ocular inflammatory diseases 
Ophthalmology  2009;117(2):356.
Purpose
To evaluate the outcomes of cyclophosphamide therapy for non-infectious ocular inflammation.
Design
Retrospective cohort study
Participants
Two hundred fifteen patients with non-infectious ocular inflammation observed from initiation of cyclophosphamide.
Methods
Patients initiating cyclophosphamide, without other immunosuppressive drugs (other than corticosteroids), were identified at four centers. Dose of cyclophosphamide, response to therapy, corticosteroid-sparing effects, frequency of discontinuation and reasons for discontinuation were obtained by medical record review of every visit.
Main Outcome Measures
Control of inflammation, corticosteroid-sparing effects, discontinuation of therapy.
Results
The 215 patients (381 involved eyes) meeting eligibility criteria carried diagnoses of uveitis (20.4%), scleritis (22.3%), ocular mucous membrane pemphigoid (45.6%) or other forms of ocular inflammation (11.6%). Overall, approximately 49.2% (95% confidence interval (CI): 41.7%-57.2%) gained sustained control of inflammation (for at least 28 days) within 6 months, and 76% (95% CI: 68.3%-83.7%) within 12 months. Corticosteroid-sparing success (sustained control of inflammation while tapering prednisone to 10 mg or less among those not meeting success criteria initially) was gained by 30.0% and 61.2% by six and 12 months respectively. Disease remission leading to discontinuation of cyclophosphamide occurred at the rate of 0.32/person-year (95% CI: 0.24 -0.41), and the estimated proportion with remission at or prior to 2 years was 63.1% (95% CI: 51.5%-74.8%). Cyclophosphamide was discontinued by 33.5% of patients within one year because of side effects-usually of a reversible nature.
Conclusions
Our data suggest that cyclophosphamide is effective for the majority of patients for controlling inflammation and allowing tapering of systemic corticosteroids to 10 mg of prednisone or less, although a year of therapy may be needed to achieve these goals. Unlike with most other immunosuppressive drugs, disease remission was induced by treatment in the majority of patients who were able to tolerate therapy. In order to titrate therapy properly and to minimize the risk of serious potential side effects, a systematic program of laboratory monitoring is required. Judicious use of cyclophosphamide appears beneficial for severe ocular inflammation cases where the potentially vision-saving benefits outweigh the substantial potential side effects of therapy, or when indicated for associated systemic inflammatory diseases.
doi:10.1016/j.ophtha.2009.06.060
PMCID: PMC2819575  PMID: 19969366
13.  Hypopyon in patients with uveitis 
Ophthalmology  2009;117(2):366.
PURPOSE
To evaluate the risk of and risk factors for hypopyon among patients with uveitis, and to evaluate the risk of visual changes and structural complications following hypopyon.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Patients with uveitis at four academic ocular inflammation subspecialty practices.
METHODS
Data were ascertained by standardized chart review.
MAIN OUTCOME MEASURES
Prevalence and incidence of hypopyon, risk factors for hypopyon, and incidence of visual acuity changes and of structural ocular complications following hypopyon.
RESULTS
Among 4,911 patients with uveitis, 41 (8.3/1000) cases of hypopyon were identified at the time of cohort entry. Of these, 2,885 initially free of hypopyon were followed over 9,451 person-years, during which 81 (2.8%) developed hypopyon (8.57/1000 person-years). Risk factors for incident hypopyon included Behçet’s disease (adjusted relative risk (RR)=5.30, 95% confidence interval (CI): 2.76–10.2), diagnosis of a spondyloarthropathy (adjusted RR=2.86, 95% CI: 1.48–5.52), and HLA-B27 positivity (adjusted RR=2.04, 95% CI: 1.17–3.56). Patients with both a spondyloarthropathy and HLA-B27 tended to have higher risk than either factor alone (crude RR=4.39, 95% CI: 2.26–8.51). Diagnosis of intermediate uveitis (+/− anterior uveitis) was associated with a lower risk of hypopyon (with respect to anterior uveitis only, adjusted RR=0.35, 95% CI: 0.15–0.85). Hypopyon incidence tended to be lower among patients with sarcoidosis (crude RR=0.22, 95% CI: 0.06–0.90; adjusted RR=−0.28, 95% CI: 0.07–1.15). Post-hypopyon eyes and eyes not developing hypopyon had a similar incidence of band keratopathy, posterior synechiae, ocular hypertension, hypotony, macular edema, epiretinal membrane, cataract surgery, or glaucoma surgery. Post-hypopyon eyes were more likely than eyes which not developing hypopyon to gain 3 lines of vision (crude RR=1.54, 95% CI: 1.05–2.24) and were less likely to develop 20/200 or worse visual acuity (crude RR=0.41, 95% CI: 0.17–0.99); otherwise visual outcomes were similar in these groups.
CONCLUSIONS
Hypopyon is an uncommon occurrence in patients with uveitis. Risk factors included Behçet’s disease, HLA-B27 positivity, and diagnosis of a spondyloarthropathy. Intermediate uveitis cases (+/− anterior uveitis) had lower risk of hypopyon than other forms of uveitis. On average, post-hypopyon eyes were no more likely than other eyes with uveitis to develop structural ocular complications or lose visual acuity.
doi:10.1016/j.ophtha.2009.07.025
PMCID: PMC2819583  PMID: 20006905
14.  Quality of Life in Sarcoidosis: Comparing the Impact of Ocular and Non-ocular Involvement of the Disease 
Ophthalmic epidemiology  2010;17(4):217-224.
Purpose
To compare the differences in vision and health-related quality of life (HRQOL) of individuals with ocular and non-ocular sarcoidosis; and to examine the impact of specific demographic and clinical factors on the noted differences.
Methods
A cross-sectional study using non-randomized prospective cohort was conducted at the National Eye Institute (protocol number: 06-EI-0239, NCT00379275) from August 31, 2006 until November 15, 2007. Each participant completed vision and HRQOL questionnaires, the Sarcoidosis Health Questionnaire (SHQ) and the National Eye Institute Visual Function Questionnaire (NEI-VFQ), along with a demographic/environmental exposure survey. Clinical data were collected through an ophthalmic exam as part of the research protocol.
Results
The study enrolled 75 biopsy-proven and 20 clinically presumed sarcoidosis participants which were divided into two cohorts, ocular (N = 60) and non-ocular groups (N = 35). The ocular group had significantly lower (P < 0.01) total NEI-VFQ scores compared to the non-ocular group. Multiple linear regression analysis showed that participants with ocular sarcoidosis who had an annual household income of < $50,000 (P < 0.01) had significantly lower total SHQ scores while participants with ocular sarcoidosis whose visual acuity was 20/100 or worse had significantly lower total NEI-VFQ scores (P = 0.03).
Conclusions
Ocular involvement impacts both overall and vision-related quality of life among sarcoidosis patients. Lower economic status appears to have a significant impact on the quality of life of sarcoidosis patients. Assessment of visual function and general health status provide pertinent information for individuals with sarcoidosis and should be included in their care to assess burden of their disease on their quality of life.
doi:10.3109/09286586.2010.483754
PMCID: PMC2994064  PMID: 20642344
Health-related quality of life; Vision-related quality of life; Ocular sarcoidosis; Pulmonary sarcoidosis; Burden of disease
16.  High-dose Daclizumab for the Treatment of Juvenile Idiopathic Arthritis–Associated Active Anterior Uveitis 
American journal of ophthalmology  2009;148(5):696-703.e1.
PURPOSE
To provide preliminary data regarding the safety and efficacy of high-dose intravenous daclizumab (Zenapax; Roche Inc, Nutley, New Jersey, USA) therapy for the treatment of juvenile idiopathic arthritis (JIA)-associated active anterior uveitis.
DESIGN
Interventional case series; open-label prospective, phase II pilot study.
METHODS
Six patients were recruited into the study and received daclizumab therapy at doses of 8 mg/kg at baseline, 4 mg/kg at week 2, and 2 mg/kg every 4 weeks thereafter, for a total of 52 weeks. The study was done at the National Eye Institute between June 29, 2005 and July 9, 2008. The primary outcome was a two-step decrease in inflammation grade assessed at week 12. Primary safety outcome was assessed at weeks 2 and 4. The ocular inflammation was assessed according to the Standardization of Uveitis Nomenclature criteria.
RESULTS
Four of the 6 participants achieved two-step reduction in anterior chamber cells according to Standardization of Uveitis Nomenclature Working Group grading scheme for anterior chamber cells 12 weeks into the study and met the primary efficacy endpoint. One additional patient responded to reinduction whereas 1 patient failed reinduction and was considered an ocular treatment failure. Visual acuity improved from a mean of 68 Early Treatment Diabetic Retinopathy Study letters in the worse eye to a mean of 79.6 letters (2 Snellen lines). Three participants were terminated before 52 weeks: First, because of a rash possibly induced by daclizumab; Second, because of ocular treatment failure; and Last, because of uncontrolled systemic manifestations of JIA.
CONCLUSION
High-dose intravenous daclizumab can help reduce active inflammation in active JIA-associated anterior uveitis; however, patients need to be monitored for potential side effects. Larger randomized trials are needed to better assess treatment effect and safety.
doi:10.1016/j.ajo.2009.06.003
PMCID: PMC2922905  PMID: 19664754
17.  Therapeutic efficacy of intravitreal bevacizumab on posterior uveitis complicated by neovascularization 
Acta ophthalmologica  2008;87(3):349-352.
Purpose
To evaluate the therapeutic effect of intravitreal bevacizumab in patients with uveitis-associated choroidal/retinal neovascularization.
Methods
Two female patients (40 years, 15 years) with posterior uveitis, (one presumed ocular sarcoidosis, one lupus) were evaluated for neovascularization of the posterior segment. Both patients were given a single dose of 1.25 mg intravitreal bevacizumab.
Results
Significant anatomical and functional recovery was evident in both patients within a few weeks.
Conclusion
In selected uveitic patients, bevacizumab may be an option for managing neovascularization.
doi:10.1111/j.1755-3768.2008.01208.x
PMCID: PMC2908182  PMID: 18513266
anti-VEGF; bevacizumab; lupus retinopathy; neovascularization; proliferative retinopathy; sarcoidosis
18.  Ocular disease in patients with ANCA-positive vasculitis 
Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis—the term recently applied to Wegener's granulomatosis—is a rare multi-system inflammation characterized by necrotizing granulomas and vasculitis. We investigated the ocular manifestations of this disease in a group of patients drawn from five inflammatory eye disease clinics across the United States. Of 8,562 persons with ocular inflammation, 59 individuals were diagnosed with ANCA-positive vasculitis; 35 males and 21 females, aged 16 to 96 years, were included in this study. Ocular diagnoses were scleritis (75.0%), uveitis (17.9%), and other ocular inflammatory conditions (33.9%) including peripheral ulcerative keratitis and orbital pseudotumor. Mean duration of ocular disease was 4.6 years. Oral corticosteroids and other systemic immunosuppressive agents were used by 85.7% and 78.5% of patients, respectively. Over time, patients with ANCA-positive vasculitis experienced 2.75-fold higher mortality than other patients with inflammatory eye disease.
doi:10.1007/s12177-009-9044-4
PMCID: PMC2933008  PMID: 20835396
ANCA-positive vasculitis; Wegener's granulomatosis; Eye; Scleritis
19.  Ocular disease in patients with ANCA-positive vasculitis 
Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis—the term recently applied to Wegener's granulomatosis—is a rare multi-system inflammation characterized by necrotizing granulomas and vasculitis. We investigated the ocular manifestations of this disease in a group of patients drawn from five inflammatory eye disease clinics across the United States. Of 8,562 persons with ocular inflammation, 59 individuals were diagnosed with ANCA-positive vasculitis; 35 males and 21 females, aged 16 to 96 years, were included in this study. Ocular diagnoses were scleritis (75.0%), uveitis (17.9%), and other ocular inflammatory conditions (33.9%) including peripheral ulcerative keratitis and orbital pseudotumor. Mean duration of ocular disease was 4.6 years. Oral corticosteroids and other systemic immunosuppressive agents were used by 85.7% and 78.5% of patients, respectively. Over time, patients with ANCA-positive vasculitis experienced 2.75-fold higher mortality than other patients with inflammatory eye disease.
doi:10.1007/s12177-009-9044-4
PMCID: PMC2933008  PMID: 20835396
ANCA-positive vasculitis; Wegener's granulomatosis; Eye; Scleritis
20.  Ocular Inflammation in Behçet’s Disease: Incidence of Ocular Complications and of Loss of Visual Acuity 
American journal of ophthalmology  2008;146(6):828-836.
Purpose
To estimate the risk of structural ocular complications and loss of visual acuity in cases of Behçet’s Disease (BD); to evaluate potential risk and protective factors for these events
Design
Retrospective cohort study
Methods
Setting
Five academic center ocular inflammation subspecialty practices
Study Population
A total of 168 consecutive patients with BD-associated ocular inflammation
Procedures
Clinical data on these patients were ascertained by standardized chart review
Outcome Measures
Visual acuity, structural ocular complications of inflammation, intraocular pressure (IOP)
Results
Over a median follow-up of 1.05 years, the incidence of specific structural complications and IOP disturbances were common: the incidence rate of any ocular complication was 0.45/eye-year (EY). Rates of loss of visual acuity to 20/50 or worse and to 20/200 or worse were 0.12/EY and 0.09/EY respectively. Risk factors for loss of visual acuity during follow-up were persistent inflammatory activity, presence of posterior synechiae, presence of hypotony, and presence of elevated IOP. In a time-dependent analysis, current activity of ocular inflammation was associated with an increased risk of loss of visual acuity to 20/50 or worse (RR = 2.45, 95% CI: 1.1–5.5, p = 0.03) and to 20/200 or worse (RR = 2.67, 95% CI: 1.2–5.8, p = 0.01).
Conclusions
Loss of visual acuity and occurrence of ocular complications were common in patients with ocular inflammation associated with Behçet’s Disease, even with aggressive therapy. Ongoing inflammation during follow-up, presence/occurrence of posterior synechiae, hypotony, and elevated IOP were associated with an increased risk of loss of visual acuity.
doi:10.1016/j.ajo.2008.06.019
PMCID: PMC2617769  PMID: 18708181
21.  Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: A critical assessment of the evidence 
American journal of ophthalmology  2008;146(6):802-12.e1.
Purpose
To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting
Design
Focused evidence assessment.
Methods
Relevant publications were identified by MEDLINE and EMBASE queries and reference list searches.
Results
Extrapolation from transplant, rheumatology, skin disease and inflammatory bowel disease cohorts to the ocular inflammation setting suggest that: 1) alkylating agents increase hematologic malignancy risk and cyclophosphamide increases bladder cancer risk, but less so with ≤18 months’ duration of therapy and hydration respectively; 2) calcineurin inhibitors and azathioprine probably do not increase total cancer risk to a detectable degree, except perhaps some other risk factors (uncommon in ocular inflammation patients) might interact with the former to raise risk; 3) Tumor Necrosis Factor (TNF) inhibitors may accelerate diagnosis of cancer in the first 6–12 months, but probably do not increase long-term cancer risk; and 4) changes in risk with methotrexate, mycophenolate mofetil, and daclizumab appear negligible although non-transplant data are limited for the latter agents. Immunosuppression in general may increase skin cancer risk in a sun-exposure dependent manner.
Conclusion
Use of alkylating agents for a limited duration seems justifiable for severe, vision-threatening disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Antimetabolites, daclizumab, TNF-inhibitors, and calcineurin inhibitors probably do not increase cancer risk to a degree that outweighs the expected benefits of therapy. Monitoring for skin cancer may be useful for highly sun-exposed patients. Data from ocular inflammation patients are needed to confirm the conclusions made in this analysis by extrapolation.
doi:10.1016/j.ajo.2008.04.035
PMCID: PMC2614443  PMID: 18579112
cancer; malignancy; methotrexate; azathioprine; cyclosporine; tacrolimus; cyclophosphamide; chlorambucil; etanercept; infliximab; adalimumab; uveitis; scleritis; ocular inflammation
22.  Infliximab for the treatment of active scleritis 
Objective
This study aimed to evaluate the possible safety and effectiveness of infliximab in patients with active scleritis.
Study Design
Prospective, nonrandomized, open-label pilot study (Protocol No. 04-EI-0065).
Participants
Five patients with active anterior scleritis.
Methods
This single-centre, pilot study of infliximab for the treatment of active anterior scleritis was conducted at the National Eye Institute, National Institutes of Health, between 2003 and 2007. Scleritis patients with active disease who had used at least 1 conventional immunosuppressive agent in the past were included. Primary outcome was a 2-step decrease in scleral inflammation within 14 weeks. Patients received infliximab (5 mg/kg) at baseline, at weeks 2 and 6, and every 4 weeks through week 30, after which the infusion interval was increased (week 36, 48).
Results
All patients met the primary outcome by achieving quiescence of their active scleritis by week 14 with no additional immunosuppressives. However, after 14 weeks 1 patient developed new-onset intraocular inflammation that did not respond to reinduction and was terminated from the study. Side effects attributable to infliximab included ear infection with transient decreased hearing, urinary tract infection, lower respiratory tract infection, and facial rash in 1 patient and urinary tract infection, diarrhea, upper respiratory tract infection, nasal congestion and headache, mouth sores, head tremor, and occasional numbness and tingling in extremities in another patient, all of which resolved spontaneously or with appropriate treatment.
Conclusions
Infliximab may be considered as a viable option in treating patients with active scleritis; however, patients should be monitored closely for potentially serious side effects.
doi:10.3129/i09-061
PMCID: PMC2771118  PMID: 19506593
infliximab; TNF; scleritis; immunosuppressive therapy
23.  Recalcitrant Granulomatous Sclerouveitis in a Patient with Granulomatous ANCA-associated Vasculitis 
Purpose
To report an unusual case of granulomatous sclerochoroiditis.
Design
Interventional case report.
Methods
A patient with ANCA-associated granulomatous vasculitis presented with nodular necrotizing scleritis, which was recalcitrant to multiple systemic immunosuppressive therapies and progressed to a blind painful eye, which was enucleated.
Results
Histopathology revealed extensive occlusive vasculitis, diffuse T- and B- cellular infiltration, and lymphoid granulomatous formation. Enhanced MHC class II antigens, adhesion molecules, and Fas (CD95) and FasL (CD95L) were detected in the lesion.
Conclusion
Granulomatous sclerochoroiditis with aggressive immune reaction can be a complication of ANCA-associated granulomatous vasculitis.
doi:10.1080/09273940802596500
PMCID: PMC2727553  PMID: 19412867
ANCA-associated granulomatous vasculitis; necrotizing scleritis; sclero-choroiditis; Wegener granulomatosis
24.  Behcet’s Disease- Comparing Three Decades of Treatment Response at the National Eye Institute 
Background
The goal of the present study was to analyze differences in response to treatment of ocular Behcet’s disease (BD) in the 1960’s, 1980’s and 1990’s.
Methods
Medical records of 120 patients with uveitis due to BD followed at the National Eye Institute (NEI), National Institutes of Health, from 1962 to 2004 were reviewed.
Results
All the patients were categorized in 3 groups according to the time of follow-up: first group was followed from 1962 until 1972, second group from 1983 until 1992 and the third group from 1992 through 2004. Snellen visual acuity was converted to logMAR values. The range of values for inflammation was 0.5 (trace), 1 (mild), 2 (moderate) and 3 (severe). There were 45 patients (89 affected eyes) in the 1960’s group, 26 patients (52 eyes) in the 1980’s group and 49 patients (94 eyes) in the most recent group. Statistical analysis showed that the mean logMAR score decreased with each decade. Mean visual acuity in the 1990’s group was significantly better than in the previous decades (p<0.001 for the 1960’s group and p=0.019 for the 1980’s). The mean inflammation score was significantly higher in the 1960’s than in the subsequent decades (p<0.001 both for 1980’s and for the 1990’s).
Interpretation
BD is a severe blinding disorder. There was a definitive trend toward improvement in clinical outcome from the 1960’s to 1990’s. We attribute this trend to the introduction of newer, more potent corticosteroid-sparing agents and targeted therapy.
doi:10.1139/i08-080
PMCID: PMC2707493  PMID: 18711463
25.  Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study 
Context Whether immunosuppressive treatment adversely affects survival is unclear.
Objective To assess whether immunosuppressive drugs increase mortality.
Design Retrospective cohort study evaluating overall and cancer mortality in relation to immunosuppressive drug exposure among patients with ocular inflammatory diseases. Demographic, clinical, and treatment data derived from medical records, and mortality results from United States National Death Index linkage. The cohort’s mortality risk was compared with US vital statistics using standardised mortality ratios. Overall and cancer mortality in relation to use or non-use of immunosuppressive drugs within the cohort was studied with survival analysis.
Setting Five tertiary ocular inflammation clinics.
Patients 7957 US residents with non-infectious ocular inflammation, 2340 of whom received immunosuppressive drugs during follow up.
Exposures Use of antimetabolites, T cell inhibitors, alkylating agents, and tumour necrosis factor inhibitors.
Main outcome measures Overall mortality, cancer mortality.
Results Over 66 802 person years (17 316 after exposure to immunosuppressive drugs), 936 patients died (1.4/100 person years), 230 (24.6%) from cancer. For patients unexposed to immunosuppressive treatment, risks of death overall (standardised mortality ratio 1.02, 95% confidence interval [CI] 0.94 to 1.11) and from cancer (1.10, 0.93 to 1.29) were similar to those of the US population. Patients who used azathioprine, methotrexate, mycophenolate mofetil, ciclosporin, systemic corticosteroids, or dapsone had overall and cancer mortality similar to that of patients who never took immunosuppressive drugs. In patients who used cyclophosphamide, overall mortality was not increased and cancer mortality was non-significantly increased. Tumour necrosis factor inhibitors were associated with increased overall (adjusted hazard ratio [HR] 1.99, 95% CI 1.00 to 3.98) and cancer mortality (adjusted HR 3.83, 1.13 to 13.01).
Conclusions Most commonly used immunosuppressive drugs do not seem to increase overall or cancer mortality. Our results suggesting that tumour necrosis factor inhibitors might increase mortality are less robust than the other findings; additional evidence is needed.
doi:10.1136/bmj.b2480
PMCID: PMC2714688  PMID: 19578087

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