Sapna Gangaputra

Effects of medical therapies on retinopathy progression in type 2 diabetes.

BACKGROUND We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

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.

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.

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.

Course of Cytomegalovirus Retinitis in the Era of Highly Active Antiretroviral Therapy: Five-Year Outcomes

PURPOSE To describe the 5-year outcomes of patients with cytomegalovirus (CMV) retinitis and AIDS in the era of highly active antiretroviral therapy (HAART). DESIGN Prospective, multicenter, observational study. PARTICIPANTS A total of 503 patients with AIDS and CMV retinitis. METHODS Follow-up every 3 months with medical history, ophthalmologic examination, laboratory testing, and retinal photographs. Participants were classified as having previously diagnosed CMV retinitis and immune recovery (CD4+ T cells ≥ 100 cells/μl), previously diagnosed retinitis and immune compromise, and newly diagnosed CMV retinitis (diagnosis <45 days before enrollment). MAIN OUTCOME MEASURES Mortality, retinitis progression (movement of the border of a CMV lesion ≥ ½ disc diameter or occurrence of a new lesion), retinal detachment, immune recovery uveitis (IRU), and visual loss (< 20/40 and ≥ 20/200). RESULTS Overall mortality was 9.8 deaths/100 person-years (PY). Rates varied by group at enrollment from 3.0/100 PY for those with previously diagnosed retinitis and immune recovery to 26.1/100 PY for those with newly diagnosed retinitis. The rate of retinitis progression was 7.0/100 PY and varied from 1.4/100 PY for those with previously diagnosed retinitis and immune recovery to 28.0/100 PY for those with newly diagnosed retinitis. The rate of retinal detachment was 2.3/100 eye-years (EY) and varied from 1.2/100 EY for those with previously diagnosed retinitis and immune recovery to 4.9/100 EY for those with newly diagnosed retinitis. The rate of IRU was 1.7/100 PY and varied from 1.3/100 PY for those with previously diagnosed retinitis and immune recovery at enrollment to 3.6/100 PY for those with newly diagnosed retinitis who subsequently experienced immune recovery. The rates of visual loss to < 20/40 and to ≤ 20/200 were 7.9/100 EY and 3.4/100 EY, respectively; they varied from 6.1/100 EY and 2.7/100 EY for those with previously diagnosed retinitis and immune recovery to 11.8/100 EY and 5.1/100 EY for those with newly diagnosed retinitis. Although the event rates tended to decline with time, in general, at no time did they reach zero. CONCLUSIONS Despite the availability of HAART, patients with AIDS and CMV retinitis remain at increased risk for mortality, retinitis progression, complications of the retinitis, and visual loss over a 5-year period. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Periocular Corticosteroid Injections in Uveitis: Effects and Complications

PURPOSE To evaluate the benefits and complications of periocular depot corticosteroid injections in patients with ocular inflammatory disorders. DESIGN Multicenter, retrospective cohort study. PARTICIPANTS A total of 914 patients (1192 eyes) who had received ≥ 1 periocular corticosteroid injection at 5 tertiary uveitis clinics in the United States. METHODS Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained at every visit via medical record review by trained reviewers. MAIN OUTCOME MEASURES Control of inflammation, improvement of visual acuity (VA) to ≥ 20/40, improvement of VA loss attributed to macular edema (ME), incident cataract affecting VA, cataract surgery, ocular hypertension, and glaucoma surgery. RESULTS Among 914 patients (1192 eyes) who received ≥ 1 periocular injection during follow-up, 286 (31.3%) were classified as having anterior uveitis, 303 (33.3%) as intermediate uveitis, and 324 (35.4%) as posterior or panuveitis. Cumulatively by ≤ 6 months, 72.7% (95% CI, 69.1-76.3) of the eyes achieved complete control of inflammation and 49.7% (95% CI, 45.5-54.1) showed an improvement in VA from <20/40 to ≥ 20/40. Among the subset with VA <20/40 attributed to ME, 33.1% (95% CI, 25.2-42.7) improved to ≥ 20/40. By 12 months, the cumulative incidence of ≥ 1 visits with an intraocular pressure of ≥ 24 mmHg and ≥ 30 mmHg was 34.0% (95% CI, 24.8-45.4) and 15.0% (95% CI, 11.8-19.1) respectively; glaucoma surgery was performed in 2.4% of eyes (95% CI, 1.4-3.9). Within 12 months, among phakic eyes initially ≥ 20/40, the incidence of a reduction in VA to <20/40 attributed to cataract was 20.2% (95% CI, 15.9-25.6); cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes (95% CI, 11.1-17.2). CONCLUSIONS Periocular injections were effective in treating active intraocular inflammation and in improving reduced VA attributed to ME in a majority of patients. The response pattern was similar across anatomic locations of uveitis. Overall, VA improved in one half of the patients at some point within 6 months. However, cataract and ocular hypertension occurred in a substantial minority.

Intensive diabetes therapy and ocular surgery in type 1 diabetes.

BACKGROUND The Diabetes Control and Complications Trial (DCCT) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes. METHODS Between 1983 and 1989, a total of 1441 patients with type 1 diabetes in the DCCT were randomly assigned to receive either intensive diabetes therapy or conventional therapy aimed at preventing hyperglycemic symptoms. They were treated and followed until 1993. Subsequently, 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. The self-reported history of ocular surgical procedures was obtained annually. We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies. RESULTS Over a median follow-up of 23 years, 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy (8.9%) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy (13.4%) (P<0.001). After adjustment for DCCT baseline factors, intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P<0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P=0.01). Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction (adjusted risk reduction with intensive therapy, 48%; 95% CI, 23 to 65; P=0.002); 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy, retinal-detachment surgery, or both (adjusted risk reduction, 45%; 95% CI, 12 to 66; P=0.01). The costs of surgery were 32% lower in the intensive-therapy group. The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up. CONCLUSIONS Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.).

The Epidemiology of Vitreoretinal Interface Abnormalities as Detected by Spectral-Domain Optical Coherence Tomography: The Beaver Dam Eye Study

PURPOSE To describe the prevalence and interrelationships of epiretinal membranes (ERMs), vitreomacular traction (VMT), macular cysts, paravascular cysts (PVCs), lamellar macular holes (LMHs), full-thickness macular holes (FTMHs), and visual impairment in a population-based study of older adults. DESIGN Cross-sectional study. PARTICIPANTS There were 1913 participants aged 63 to 102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008-2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD OCT) scans of the macula in at least 1 eye. METHODS The presence of ERMs and other retinal lesions was determined by standardized grading of macular SD OCT scans and photographs of 3 standard fields. MAIN OUTCOME MEASURES Epiretinal membranes, VMT, macular cysts, PVCs, LMHs, FTMHs, and visual impairment. RESULTS By using SD OCT, the prevalence of ERMs (34.1%), VMT (1.6%), macular cysts (5.6%), PVCs (20.0%), LMHs (3.6%), and FTMHs (0.4%) was estimated. The prevalence of macular cysts (P < 0.001), ERMs (P < 0.001), and VMT (P = 0.005) increased with age; the prevalence of PVCs (P = 0.05) decreased with age; and the prevalence of LMHs was not associated with age (P = 0.70). The prevalence of macular cysts, LMHs, and ERMs was higher in eyes with a history of cataract surgery. Macular cysts and ERMs were more common in eyes with retinal diseases, such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment, than in eyes without these conditions. Macular cysts, ERMs, and FTMHs were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR], 3.96; P < 0.0001), PVCs (OR, 1.45, P = 0.007), LMHs (OR, 10.62; P < 0.001), VMT (OR, 2.72, P = 0.01), and visual impairment (OR, 3.23; P < 0.001) were more frequent in eyes with ERMs compared with eyes without ERMs. CONCLUSIONS Epiretinal membranes are associated with macular cysts, PVCs, LMHs, VMT, and visual impairment. Further follow-up will allow better understanding of the natural history of ERMs and VMT and their relationships to the development of macular cysts and LMHs in the aging population.

Clinical Features and Incidence Rates of Ocular Complications in Patients With Ocular Syphilis

PURPOSE To describe the clinical outcomes of ocular syphilis. DESIGN Retrospective chart review. METHODS The charts of patients with ocular syphilis (regardless of human immunodeficiency virus [HIV] status) seen in a uveitis referral center between 1984 and 2014 were reviewed. RESULTS The study included 35 patients (61 eyes). Panuveitis was the most common type of ocular inflammation (28 eyes), independent of HIV status. Thirty-three of 35 patients received systemic antibiotics with 24 patients treated with intravenous (IV) penicillin only. When compared to the HIV-positive patients, HIV-negative patients with ocular syphilis were older (P < .001), were more likely to be female (P = .004), and had poorer visual acuity at presentation (P = .01). During follow-up, the incidence rates of visual impairment were 0.29 per eye-year (EY; 95% confidence interval [CI]: 0.06/EY-0.86/EY) and 0.12/EY (95% CI: 0.01/EY-0.42/EY) among the HIV-negative and the HIV-positive patients, respectively. The incidence of blindness was 0.07/EY (95% CI: 0.009/EY-0.27/EY) and 0.06/EY (95% CI: 0.002/EY-0.35/EY) among the HIV-negative and the HIV-positive patients, respectively. Longer duration of uveitis prior to diagnosis and chorioretinitis in the macula at presentation were associated with ≥ 2 Snellen lines of visual loss (P < .01) and visual acuity loss to 20/50 or worse (P = .03) in HIV-negative patients, respectively. CONCLUSIONS Syphilis is an uncommon cause of ocular inflammation in both HIV-negative and HIV-positive patients. Visual loss and ocular complications were common among HIV-negative patients even with systemic antibiotic treatment. Delay of diagnosis and chorioretinitis in the macula were associated with visual loss in these patients.