Ebenezer Daniel

Cyclosporine for Ocular Inflammatory Diseases

PURPOSE To evaluate the clinical outcomes of cyclosporine treatment for noninfectious ocular inflammation. DESIGN Retrospective cohort study. PARTICIPANTS A total of 373 patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to use cyclosporine 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 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 6 months and 51.9% by 1 year gained sustained, complete control of inflammation over at least 2 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 < or = 10 mg/day) was achieved by 22.1% by 6 months and 36.1% within 1 year. Toxicity led to discontinuation of therapy within 1 year by 10.7% of the population. Patients aged more than 55 years were more than 3-fold more likely to discontinue therapy because of toxicity than patients aged 18 to 39 years. Doses of 151 to 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 seem to offer a therapeutic advantage. CONCLUSIONS Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151 and 250 mg/day. Although cyclosporine was tolerated by the majority of patients, toxicity was more frequent with increasing age; alternative agents may be preferred for patients aged more than 55 years.

Baseline Predictors for One-Year Visual Outcomes with Ranibizumab or Bevacizumab for Neovascular Age-related Macular Degeneration

OBJECTIVE To determine the baseline predictors of visual acuity (VA) outcomes 1 year after treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). DESIGN Cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). PARTICIPANTS A total of 1105 participants with neovascular AMD, baseline VA 20/25 to 20/320, and VA measured at 1 year. METHODS Participants were randomly assigned to ranibizumab or bevacizumab on a monthly or as-needed schedule. Masked readers evaluated fundus morphology and features on optical coherence tomography (OCT). Visual acuity was measured using electronic VA testing. Independent predictors were identified using regression techniques. MAIN OUTCOME MEASURES The VA score, VA score change from baseline, and ≥3-line gain at 1 year. RESULTS At 1 year, the mean VA score was 68 letters, mean improvement from baseline was 7 letters, and 28% of participants gained ≥3 lines. Older age, larger area of choroidal neovascularization (CNV), and elevation of retinal pigment epithelium (RPE) were associated with worse VA (all P<0.005), less gain in VA (all P<0.02), and a lower proportion gaining ≥3 lines (all P<0.04). Better baseline VA was associated with better VA at 1 year, less gain in VA, and a lower proportion gaining ≥3 lines (all P<0.0001). Predominantly or minimally classic lesions were associated with worse VA than occult lesions (66 vs. 69 letters; P=0.0003). Retinal angiomatous proliferans (RAP) lesions were associated with more gain in VA (10 vs. 7 letters; P=0.03) and a higher proportion gaining ≥3 lines (odds ratio, 1.9; 95% confidence interval, 1.2-3.1). Geographic atrophy (GA) was associated with worse VA (64 vs. 68 letters; P=0.02). Eyes with total foveal thickness in the second quartile (325-425 μm) had the best VA (P=0.01) and were most likely to gain ≥3 lines (P=0.004). Predictors did not vary by treatment group. CONCLUSIONS For all treatment groups, older age, better baseline VA, larger CNV area, predominantly or minimally classic lesion, absence of RAP lesion, presence of GA, greater total fovea thickness, and RPE elevation on optical coherence tomography were independently associated with less improvement in VA at 1 year. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Mycophenolate Mofetil for Ocular Inflammation

PURPOSE To evaluate mycophenolate mofetil as a single noncorticosteroid immunosuppressive treatment for noninfectious ocular inflammatory diseases. DESIGN Retrospective cohort study. METHODS Characteristics of patients with noninfectious ocular inflammation treated with mycophenolate mofetil at 4 subspecialty clinics from 1995 to 2007 were abstracted by expert reviewers in a standardized chart review of every eye at every visit. Main outcomes measured were control of inflammation, corticosteroid-sparing effects, and discontinuation of mycophenolate mofetil (including the reasons for discontinuation). Survival analysis was used to estimate the incidence of outcomes, and to identify risk factors for each. RESULTS Among 236 patients (397 eyes) treated with mycophenolate mofetil monotherapy, 20.3%, 11.9%, and 39.8% had anterior uveitis, intermediate uveitis, and posterior uveitis or panuveitis respectively; 14% had scleritis; 7.6% had mucous membrane pemphigoid; and 6.4% had other ocular inflammatory diseases. By Kaplan-Meier estimation, complete control of inflammation--sustained over consecutive visits spanning at least 28 days--was achieved in 53% and 73% of patients within 6 months and 1 year respectively. Systemic corticosteroid dosage was reduced to 10 mg of prednisone or less, while maintaining sustained control of inflammation, in 41% and 55% of patients in 6 months and 1 year respectively. Twelve percent of patients discontinued mycophenolate mofetil within the first year because of side effects of therapy. CONCLUSIONS Given sufficient time, mycophenolate mofetil was effective in managing ocular inflammation in approximately half of the treated patients. Treatment-limiting side effects were observed in 12% of patients and typically were reversible.

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.

Cyclophosphamide for ocular inflammatory diseases

PURPOSE To evaluate the outcomes of cyclophosphamide therapy for noninfectious ocular inflammation. DESIGN Retrospective cohort study. PARTICIPANTS Two hundred fifteen patients with noninfectious ocular inflammation observed from initiation of cyclophosphamide. METHODS Patients initiating cyclophosphamide, without other immunosuppressive drugs (other than corticosteroids), were identified at 4 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, and 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%) gained sustained control of inflammation 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 6 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 before 2 years was 63.1% (95% CI, 51.5%-74.8%). Cyclophosphamide was discontinued by 33.5% of patients within 1 year because of side effects, usually of a reversible nature. CONCLUSIONS The data suggest that cyclophosphamide is effective for most patients for controlling inflammation and allowing tapering of systemic corticosteroids to 10 mg prednisone or less, although 1 year of therapy may be needed to achieve these goals. Unlike with most other immunosuppressive drugs, disease remission was induced by treatment in most patients who were able to tolerate therapy. 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 seems to be 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.

Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials.

OBJECTIVE To describe the effects of treatment for 1 year with ranibizumab or bevacizumab on macular morphology and the association of macular morphology with visual acuity (VA) in eyes with neovascular age-related macular degeneration (AMD). DESIGN Prospective cohort study within a randomized clinical trial. PARTICIPANTS Participants in the Comparison of Age-related Macular Degeneration Treatments Trials. METHODS Participants were assigned randomly to treatment with ranibizumab or bevacizumab on a monthly or as-needed schedule. Optical coherence tomography (OCT), fluorescein angiography (FA), color fundus photography (FP), and VA testing were performed periodically throughout 52 weeks. Masked readers graded images. General linear models were applied to evaluate effects of time and treatment on outcomes. MAIN OUTCOME MEASURES Fluid type and location and thickness by OCT, size, and lesion composition on FP, FA, and VA. RESULTS Intraretinal fluid (IRF), subretinal fluid (SRF), subretinal pigment epithelium fluid, and retinal, subretinal, and subretinal tissue complex thickness decreased in all treatment groups. A higher proportion of eyes treated monthly with ranibizumab had fluid resolution at 4 weeks, and the difference persisted through 52 weeks. At 52 weeks, there was little association between the presence of fluid of any type (without regard to fluid location) and the mean VA. However, at all time points, eyes with residual IRF, especially foveal IRF, had worse mean VA (9 letters) than those without IRF. Eyes with abnormally thin (<120 μm) or thick (>212 μm) retinas had worse VA than those with normal thickness (120-212 μm). At week 52, eyes with larger neovascular lesions or with foveal scar had worse VA than eyes without these features. CONCLUSIONS Anti-vascular endothelial growth factor (VEGF) therapy reduced lesion activity and improved VA in all treatment groups. At all time points, eyes with residual IRF had worse VA than those without. Eyes with abnormally thin or thick retinas, residual large lesions, and scar also had worse VA. Monthly ranibizumab dosing yielded more eyes with no fluid and an abnormally thin retina, although the long-term significance is unknown. These results have important treatment implications in eyes undergoing anti-VEGF therapy for neovascular AMD. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis: The systemic immunosuppressive therapy for eye diseases study

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 A total of 327 patients (596 affected eyes) with JIA-associated uveitis managed at 5 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 eyes (40.3%) had a VA of ≤20/50, 144 eyes (24.2%) had a VA of ≤20/200, and 359 eyes (60.2%) had at least 1 ocular complication. The incidences of VA loss to the ≤20/50 and ≤20/200 thresholds were 0.18 and 0.09 per eye-year (EY), respectively; the incidence of developing at least 1 new ocular complication over follow-up was 0.15/EY (95% confidence interval [CI], 0.13-0.17). However, among eyes with uveitis that had no complications at presentation, the rate of developing at least 1 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 and ≤20/200 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 risk of visual loss, particularly for the ≤20/50 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. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Methods for Identifying Long-Term Adverse Effects of Treatment in Patients with Eye Diseases: The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study

Purpose: To evaluate potential epidemiologic methods for studying long-term effects of immunosuppression on the risk of mortality and fatal malignancy, and present the methodological details of the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study. Methods: Advantages and disadvantages of potential study designs for evaluating rare, late-occurring events are reviewed, and the SITE Cohort Study approach is presented. Results: The randomized, controlled trial is the most robust method for evaluating treatment effects, but long study duration, high costs, and ethical concerns when studying toxicity limit its use in this setting. Retrospective cohort studies are potentially more cost-effective and timely, if records exist providing the desired information over sufficient follow-up time in the past. Case-control methods require extremely large sample sizes to evaluate risk associated with rare exposures, and recall bias is problematic when studying mortality. The SITE Cohort Study is a retrospective cohort study. Past use of antimetabolites, T-cell inhibitors, alkylating agents, and other immunosuppressives is ascertained from medical records of ∼ 9,250 ocular inflammation patients at five tertiary centers over up to 30 years. Mortality and cause-specific mortality outcomes over ∼ 100,000 person-years are ascertained using the National Death Index. Immunosuppressed and non-immunosuppressed groups of patients are compared with each other and general population mortality rates from US vital statistics. Calculated detectable differences for mortality/fatal malignancy with respect to the general population are 22%/49% for antimetabolites, 28%/62% for T-cell inhibitors, and 36%/81% for alkylating agents. Conclusions: Information from the SITE Cohort Study should clarify whether use of these immunosuppressive drugs for ocular inflammation increases the risk of mortality and fatal cancer. This epidemiologic approach may be useful for evaluating long-term risks of systemic therapies for other ocular diseases.

Photographic Assessment of Baseline Fundus Morphologic Features in the Comparison of Age-related Macular Degeneration Treatments Trials

OBJECTIVE To describe the methods used for assessment of baseline fundus characteristics from color photography and fluorescein angiography (FA) in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and to describe the relationship between these characteristics and visual acuity. DESIGN Randomized, masked, multicenter trial. PARTICIPANTS This investigation included 1185 participants of the CATT study. METHODS Baseline stereoscopic color fundus photographs and FAs of participants in the CATT study were assessed at a central fundus photograph reading center by masked readers. Replicate assessments of random samples of photographs were performed to assess intragrader and intergrader agreements. The association of the lesion characteristics with baseline visual acuity was assessed using analyses of variance and correlation coefficients. MAIN OUTCOME MEASURES Intragrader and intergrader reproducibility, visual acuity, and lesion characteristics. RESULTS Intragrader and intergrader reproducibility showed agreements ranging from 75% to 100% and weighted κ values ranging from 0.48 to 1.0 for qualitative determinations. The intraclass correlation coefficients were 0.96 to 0.97 for quantitative measurements of choroidal neovascularization (CNV) area and total area of CNV lesion. The mean visual acuity varied by the type of pathologic features in the foveal center: 64.5 letters (standard error, 0.7 letters) for fluid only, 59.0 letters (standard error, 0.5 letters) for CNV, and 58.7 letters (standard error, 1.3 letters) for hemorrhage (P<0.001). Fibrotic or atrophic scar present in the lesion, but not under the center of the fovea, also was associated with a markedly reduced visual acuity of 48.4 letters (standard error, 2.2 letters; P<0.0001). Although total area of CNV lesion was correlated weakly with visual acuity when all participants were assessed (Spearman correlation coefficient, ρ = -0.16; P<0.001), the correlation was stronger within patients with predominantly classic lesions (ρ = -0.42; P<0.001). CONCLUSIONS These results show that the methodology used for grading CATT fundus images has good reproducibility. As expected, larger total CNV lesion area and pathologic findings such as hemorrhage, fibrosis, and atrophy at baseline are associated with decreased visual acuity.

Smoking as a risk factor for cystoid macular edema complicating intermediate uveitis.

PURPOSE To describe risk factors for the presence of cystoid macular edema (CME) among patients presenting with intermediate uveitis. DESIGN Cross-sectional study. METHODS SETTINGS Single-center, academic practice. STUDY POPULATION Two hundred and eight patients with intermediate uveitis evaluated from July 1, 1984 through September 30, 2006. PROCEDURES Clinical and demographic data were entered retrospectively into a database and analyzed. OUTCOME MEASURES Presence of CME at presentation to our clinic; risk factors for presenting with CME. RESULTS Of the 208 patients, 74% had bilateral intermediate uveitis, yielding 363 affected eyes. Eighty-nine patients (43%) had CME in at least one eye at the time of presentation to our clinic. After controlling for potentially confounding variables including demographics, duration of disease, active intraocular inflammation, history of diabetes mellitus or hypertension, and presence of epiretinal membrane, actively smoking at presentation was associated with a four-fold increased risk of CME at presentation vs never smoking (odds ratio (OR), 3.90; 95% confidence interval (CI), 1.43, 10.66; P = .008). Former smoking also appeared to increase the risk of CME at presentation in the multivariate analysis, but the result was of borderline statistical significance (OR, 1.97; 95% CI, 0.99, 3.94; P = .055). After adjusting for confounding, there was a 4% increased risk of CME at presentation for each cigarette smoked per day (OR, 1.04; 95% CI, 1.01, 1.7; P = .005). CONCLUSIONS CME was a common structural ocular complication observed in our cohort. Current smoking was associated with a dose-dependent increased risk of having CME at the time of presentation to our clinic.