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Purpose This study characterizes the current landscape of uveitis specialists and their practice settings in the United States. Methods An anonymous Internet-based survey with questions pertaining to training history and practice characteristics was distributed via REDCap to the American Uveitis Society and Young Uveitis Specialists listservs. Results Forty-eight uveitis specialists in the United States responded to the survey out of 174 uveitis specialists that identify as practicing in the United States. Twenty-five of 48 respondents (52%) completed an additional fellowship. These additional fellowships ranged from surgical retina (12/25, 48%), cornea (8/25, 32%), and medical retina (4/25, 16%). Two-thirds of uveitis specialists managed their own immunosuppression, while one-third comanaged immunosuppression with rheumatologists. Thirty-three of 48 (69%) maintained a surgical practice. Conclusion This is the first survey of uveitis specialists across the United States to provide understanding into training and practice characteristics. These data will provide insight into career planning, practice building, and assist in resource allocation.

We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population.Retrospective data from 5,530 ...

PurposeTo evaluate the long-term visual acuity (VA) outcome of cataract surgery in inflammatory eye disease.SettingTertiary care academic centres.DesignMulticentre retrospective cohort study.MethodsA total of 1741 patients with non-infectious inflammatory eye disease (2382 eyes) who underwent cataract surgery while under tertiary uveitis management were included. Standardised chart review was used to gather clinical data. Multivariable logistic regression models with adjustment for intereye correlations were performed to evaluate the prognostic factors for VA outcomes. Main outcome measure was VA after cataract surgery.ResultsUveitic eyes independent of anatomical location showed improved VA from baseline (mean 20/200) to within 3 months (mean 20/63) of cataract surgery and maintained through at least 5 years of follow-up (mean 20/63). Eyes that achieved 20/40 or better VA at 1 year were more likely to have scleritis (OR=1.34, pConclusionsOur results suggest that adult and paediatric eyes with uveitis typically have improved VA following cataract surgery and remain stable thereafter for at least 5 years.

Purpose To compare mycophenolate mofetil (MMF) to methotrexate (MTX) as corticosteroid-sparing therapy for ocular inflammatory diseases. Design Retrospective analysis of cohort study data. Methods Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained via medical record review. The study included 352 patients who were taking single-agent immunosuppression with MTX or MMF at 4 tertiary uveitis clinics. Marginal structural models (MSM)-derived statistical weighting created a virtual population with covariates and censoring patterns balanced across alternative treatments. With this methodological approach, the results estimate what would have happened had none of the patients stopped their treatment. Survival analysis with stabilized MSM-derived weights simulated a clinical trial comparing MMF vs MTX for noninfectious inflammatory eye disorders. The primary outcome was complete control of inflammation on prednisone ≤10 mg/day, sustained for ≥30 days. Results The time to success was shorter (more favorable) for MMF than MTX (hazard ratio = 0.68, 95% confidence interval: 0.46-0.99). Adjusting for covariates, the proportion achieving success was higher at every point in time for MMF than MTX from 2 to 8 months, then converges at 9 months. The onset of corticosteroid-sparing success took more than 3 months for most patients in both groups. Outcomes of treatment (MMF vs MTX) were similar across all anatomic sites of inflammation. The incidence of stopping therapy for toxicity was similar in both groups. Conclusions Our results suggest that, on average, MMF may be faster than MTX in achieving corticosteroid-sparing success in ocular inflammatory diseases.

PURPOSE: To report the clinical features, severity, and management of ocular immune-related adverse events (irAEs) in the setting of immune checkpoint inhibitor therapy for metastatic malignancies. METHODS: Retrospective chart review at three tertiary ophthalmology clinics. Electronic medical records were reviewed between 2000 and 2017 for patients with new ocular symptoms while undergoing checkpoint inhibition therapy. RESULTS: Eleven patients were identified. Ocular irAEs ranged from keratoconjunctivitis sicca to Vogt-Koyanagi -Harada-like findings. Average timing of irAEs from starting checkpoint inhibitor therapy was 15.7 weeks. Ocular inflammation was successfully controlled with corticosteroids in most cases, however three patients discontinue treatment as a result of ocular inflammation with decreased visual acuity, two discontinued due to progression of metastatic disease, and one discontinued due to severe systemic irAEs. CONCLUSION: We found a wide spectrum of ocular irAEs associated with immune checkpoint inhibitors. In most cases, ocular AEs did not limit ongoing cancer treatment.

IMPORTANCE: Diverse, representative enrollment in pivotal clinical trials is vital to sufficiently power subgroup analyses and ensure equity and validity of trial results. OBJECTIVE: To evaluate the racial/ethnic representation, trends, and disparities in clinical trials leading to US Food and Drug Administration (FDA) ophthalmology drug approvals from 2000 to 2020. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from participants in clinical trials of drugs for neovascular age-related macular degeneration (AMD), open-angle glaucoma (OAG), and expanded indications for diabetic retinopathy (DR) from January 1, 2000, to December 31, 2020. Trial data were sourced from FDA reviews, ClinicalTrials.gov, and relevant linked studies. National expected racial/ethnic proportions were sourced from public National Eye Institute prevalence data as well as published rates scaled using US Census Bureau data. MAIN OUTCOMES AND MEASURES: The primary outcome measures were the distribution of and change over time in the racial/ethnic proportion of participants in clinical trials leading to FDA approval of drugs for AMD, OAG, and DR. RESULTS: During the 20-year period, 31 clinical trials were identified for 13 medications with 18 410 participants. The distribution of trial participants was different from the expected trial distribution for most approvals with regard to race/ethnicity (12 drugs) and sex (10 drugs). Compared with the first decade (2000-2010), trials conducted in the second decade (2011-2020) showed increases in enrollment of Asian (odds ratio [OR], 2.30; 95% CI, 1.97-2.68; P

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Purpose: To describe with multimodal imaging a case of post-infectious unilateral outer retinopathy with choroiditis. Methods: Retrospective chart review of a case of a 67-year old male who presented following the onset of viral symptoms with an acute onset outer retinopathy, small vessel leakage on fluorescein angiography, and choroidal involvement evident on indocyanine green angiography and near infrared fundus autofluorescence (NIR-AF). Work up for infectious and autoimmune etiologies was negative. Results: Treatment with IV methylprednisolone followed by high dose oral prednisone resulted in improvement in visual acuity, outer retinal reconstitution and resolution of the choroidal changes. Conclusions: Despite this presentation sharing features with both acute zonal occult outer retinopathy (AZOOR) and multifocal choroiditis (MFC), the case is highly atypical of both entities.

Autoimmune retinopathy (AIR) is a rare immune-mediated retinopathy associated with circulating antiretinal antibodies (ARAs). Other prominent features of AIR include visual field deficits and photoreceptor dysfunction in the setting of progressive unexplained vision loss. The role of inflammation is poorly understood in AIR. Since cytokines play a central role in the initiation and development of inflammation, we evaluated the presence of proinflammatory cytokines and chemokines in AIR patient sera. We demonstrate that IL-6 and CXCL9 are both elevated in AIR patient sera. Moreover, the presence and concentration of these 2 molecules appear to correlate with AIR patient disease severity. This cytokine profile, IL-6 and CXCL9, has been described to participate in a variety of autoimmune and inflammatory diseases. Our study provides support for an activated inflammatory process in AIR and identifies possible mechanisms that can drive autoimmunity in this disease.

Intravitreal injections have become the most commonly performed ophthalmic procedure, transforming modern retina practice. Postinjection endophthalmitis, while rare, remains the most feared potential complication. Prophylaxis measures including topical antisepsis, hand hygiene, gloves, masks, and drapes have all been proposed to help prevent postinjection endophthalmitis; however, there remains significant variation in protocol, given the lack of agreement among retina specialists on which steps are crucial to prevent endophthalmitis. With millions of injections performed annually, collating data have helped us better understand risk factors for endophthalmitis after intravitreal injection. We summarize the consensus guidelines for intravitreal injection technique and comprehensively review the literature on prevention of postinjection endophthalmitis.

PURPOSE: To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and development of noninfectious uveitis. METHODS: A survey was distributed to uveitis specialists to identify patients who developed uveitis while receiving either PD-1 inhibitors pembrolizumab and nivolumab; PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; or the CTLA-4 inhibitor ipilimumab. RESULTS: Fifteen patients from seven institutions were identified. The most common cancer diagnosis (13/15) was malignant melanoma. Fourteen patients had a new uveitis diagnosis following checkpoint blockade administration (6 anterior uveitis, 6 panuveitis, 1 posterior uveitis, 1 anterior/intermediate combined); one patient developed optic neuritis. Uveitis was diagnosed within 6 months after drug initiation for 11/12 patients (median 63 days). Corticosteroid treatment was effective for most patients, although 2 patients had permanent loss of vision. CONCLUSIONS: Patients on checkpoint inhibitor therapy should be educated to seek care if they develop ocular symptoms, and prompt referral to specialists should be incorporated into oncology protocols.

Purpose: To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and the development of noninfectious uveitis. Methods: A survey was distributed to uveitis specialists to identify patients who developed uveitis while receiving either PD-1 inhibitors pembrolizumab and nivolumab; PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; or the CTLA-4 inhibitor ipilimumab. Results: Fifteen patients from seven institutions were identified. The most common cancer diagnosis (13/15) was malignant melanoma. Fourteen patients had a new uveitis diagnosis following checkpoint blockade administration (six anterior uveitis, six panuveitis, one posterior uveitis, one anterior/intermediate combined); one patient developed optic neuritis. Uveitis was diagnosed within 6 months after drug initiation for 11/12 patients (median 63 days). Corticosteroid treatment was effective for most patients, although two patients had permanent loss of vision. Conclusions: Patients on checkpoint inhibitor therapy should be educated to seek care if they develop ocular symptoms, and prompt referral to specialists should be incorporated into oncology protocols.

Purpose To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery. Observations A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation. Conclusion and Importance This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.

Purpose To describe the role of telemedicine screening for pediatric diabetic retinopathy (DR) and to identify risk factors for pediatric DR. Methods The medical records of a telemedicine program at a tertiary, academic medical center over 17 months were reviewed retrospectively. Patients visiting an academic pediatric endocrinology clinic who met guidelines underwent telescreening. Presence of pediatric DR and risk factors for retinopathy were evaluated. Results The fundus photographs of 852 patients 10-23 years of age were reviewed. Diabetic retinopathy was noted in 51 (6%). Patients with an abnormal screening photograph were compared to patients with diabetes who had normal screening photographs (n = 64). Older age, longer diabetes duration, type 1 diabetes, and higher average glycated hemoglobin (HbA1c) from the year prior to the photograph were associated with increased risk of retinopathy. Of these, longer duration (P = 0.003) and higher average A1c (P = 0.02) were significant after adjusting for sex, race, and age. Conclusions Our telemedicine program found a higher percentage of diabetic retinopathy screening non-mydriatic photographs than prior studies found through standard ophthalmic examinations. In this relatively small sample size, longer duration of disease and higher average A1c were associated with increased risk of having diabetic retinopathy in our study.

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

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 P 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 P = 0.007), LMHs (OR, 10.62; P P = 0.01), and visual impairment (OR, 3.23; P 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.

Purpose Autoimmune retinopathy (AIR) is a retinopathy associated with unexplained vision loss presumably linked to circulating antiretinal antibodies; currently, however, there are no standardized criteria regarding the diagnosis, treatment strategy, or pathogenesis of this disease. The importance of B-lymphocyte immunophenotyping in the classification of AIR is unknown. Methods We utilized 15-color multiparametric flow cytometry to identify aberrations in B cell subsets that may contribute to the pathophysiology of AIR. Luminex cytokine analysis was also performed on plasma samples from AIR patients. Results Significant differences in AIR patients compared to individuals with other inflammatory conditions or healthy donors were found in the B cell memory compartment, including an increase in naive B cells and a decrease in switched and unswitched memory B cells, which correlated with alterations in immunoglobulin secretion. Conclusions These findings suggest that the maturation process of B cells may be impaired and that B cell immunophenotyping may help in understanding disease process in AIR.

Masquerade syndromes present to uveitis clinics due to the appearance of inflammatory signs and chronic symptoms that are not responsive to conventional treatment. They are frequently misdiagnosed and treated as refractory inflammatory conditions, which delays appropriate diagnosis and management. This review of literature focuses on the commonly encountered masquerade syndromes and discusses the role of multimodal imaging in addressing these complex clinical presentations. We review the conventional imaging techniques for these patients and discuss emerging technological advances that may help in establishing a diagnosis. We present cases highlighting the utility of multimodal imaging in identifying the etiology.

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 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.

Purpose To investigate the intravisit repeatability of optical coherence tomography angiography (OCTA) in a cohort of uveitis patients. Methods One hundred ten patients were imaged twice per eye, per visit, using the Zeiss Cirrus HD-OCT Model 5000 device. To calculate choriocapillaris flow void area (CC FV) 6 × 6-mm images were used, and 3 × 3-mm images were used to calculate vessel density (VD) and the foveal avascular zone area (FAZ) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Repeatability was measured using Bland-Altman analyses and intraclass correlation coefficients (ICC) with associated coefficient of variation (CV). Results The level of intravisit repeatability differed across indices ranging from moderate to excellent. CC FV had the highest intravisit repeatability with an ICC of 0.980 (95%CI, 0.966-0.989), a CV of 15.9% and Bland-Altman limits of agreement from -0.398 to 0.411 mm2. DCP FAZ had the lowest intravisit repeatability with an ICC of 0.677 (95%CI, 0.510-0.796), a CV of 17.4% and Bland-Altman limits of agreement from -0.395 to -0.355 mm2. Intraoperator repeatability was excellent across all indices. Conclusions This study demonstrates that OCTA is a reliable tool to quantitatively assess specific indices of vascular structure in uveitis patients with good intravisit repeatability. However, the range of variability for each index should be taken into account when evaluating clinically meaningful changes. Translational relevance The repeatability of the metrics we have described has implications in supporting the development of OCTA-derived quantitative assessments of the retinal and choroidal vasculature in uveitis patients as potential imaging biomarkers.

Purpose To compare evaluation by clinical examination with image grading at a reading center for the classification of diabetic retinopathy and diabetic macular edema. Methods Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Family Investigations of Nephropathy in Diabetes (FIND) had similar methods of clinical and fundus photograph evaluation. For analysis purposes, the photographic grading scales were condensed to correspond to the clinical scales, and agreement between clinicians and reading center classification were compared. Results Six thousand nine hundred and two eyes of ACCORD participants and 3,638 eyes of FIND participants were analyzed for agreement (percent, kappa) on diabetic retinopathy on a 5-level scale. Exact agreement between clinicians and reading center on diabetic retinopathy severity category was 69% in ACCORD and 74% in FIND (kappa 0.42 and 0.65). Sensitivities of the clinical grading to identify the presence of mild nonproliferative retinopathy or worse were 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. Diabetic macular edema agreement in 6,649 eyes of ACCORD participants and 3,366 eyes of FIND participants was similar (kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify diabetic macular edema were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively. Conclusion The results support the use of clinical information for defining broad severity categories but not for documenting small-to-moderate changes in diabetic retinopathy over time.

Background: It is unclear whether HIV-related factors modify risk of hypertension (HTN). In a cohort of patients with AIDS, the authors determined HTN incidence and prevalence and assessed associated traditional, HIV-specific, and retinal vasculature factors. Methods: Prospective observational cohort included 2390 patients with AIDS (1998-2011). Univariate analysis was used to assess the impact of traditional- and AIDS-related risk factors for HTN prevalence and incidence. Multivariate regression analyses were used to evaluate the adjusted impact of these factors. Results: Hypertension prevalence was 22% (95% confidence interval [CI] 21%-24%) and was associated with traditional HTN risk factors (age, black race, and higher weight) as well as diabetes, hyperlipidemia, time since AIDS diagnosis, and higher CD4 counts. Hypertension incidence was 64.1 per 1000 person-years (95% CI 58.7/1000-69.9/1000). Age, race, weight, and diabetes were associated with incident HTN but HIV-specific factors were not. Conclusions: Hypertension, a prevalent cardiovascular risk factor in patients with AIDS, is associated with traditional and metabolic risk factors.

To identify the incidence and risk factors for corticosteroid-induced hyperglycemia requiring medical therapy among patients with inflammatory eye diseases.Retrospective cohort study.Patients with ocular inflammation followed at 5 United States tertiary centers that initially were neither diabetic nor taking hypoglycemic medications.Eligible patients who used oral corticosteroids during follow-up were identified and followed longitudinally for initiation of hypoglycemic medication over 1 year after beginning corticosteroids. The remaining eligible patients were followed for 1 year after their initial visit. Survival analysis was used to calculate the risk of hyperglycemia requiring medical therapy and to identify potential risk factors.Initiation of hypoglycemic medications.Among 2073 non-diabetic patients treated with oral corticosteroids, 25 (1.21%) initiated hypoglycemic therapy compared with 5 of 2666 patients (0.19%) not treated with oral corticosteroids (relative risk [RR], 4.39; 95% confidence interval [CI], 1.68-11.5). The RR tended to be higher in association with higher initial doses (for initial doses40 mg of prednisone per day: RR, 3.23; 95% CI, 1.08-9.64; for initial prednisone dose ≥40 mg/d: 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).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 1 year), although on a relative scale it is approximately 4.4-fold higher than in patients not treated with oral corticosteroids. Older 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.

To evaluate the effectiveness and risk of complications of high-dose intravenous pulsed corticosteroids for noninfectious ocular inflammatory diseases.Retrospective cohort study in which 104 eyes of 70 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 1 month after treatment.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.Treatment of ocular inflammation with high-dose intravenous corticosteroids resulted in substantial clinical improvement for most cases within 1 month. Complications of therapy were infrequent.

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

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. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

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.

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.Advantages and disadvantages of potential study designs for evaluating rare, late-occurring events are reviewed, and the SITE Cohort Study approach is presented.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 approximately 9,250 ocular inflammation patients at five tertiary centers over up to 30 years. Mortality and cause-specific mortality outcomes over approximately 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.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.

A 4-week-old boy with left ptosis, anisocoria, and a mass on his left hand was diagnosed with Horner syndrome. The diagnosis precipitated a work-up for a possible malignant etiology. Magnetic resonance imaging demonstrated enlarged left cervical and axillary lymph nodes. A biopsy of the hand lesion confirmed embryonal rhabdomyosarcoma, but a biopsy of the axillary lymph node was negative. Mechanical pressure by noncancerous enlarged lymph nodes is hypothesized to cause the Horner syndrome.

To describe the clinical outcomes of ocular syphilis.Retrospective chart review.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.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.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.

The vitreous occupies four fifths of the volume of the eyeball and consists of collagen fibers and hyaluronic acid. These components maintain a clear matrix with viscoelastic properties resulting in outward mechanical forces responsible for retinal attachment. Anatomically, the vitreous can be divided into vitreous base, core, and cortex. The vitreous cortex envelopes the core, with attachments to all its contiguous structures, such as the vitreous base, the lens, parafovea, margin of optic nerve, and major retinal blood vessels. Anchoring fibrils grow from the inner layer of the vitreous cortex into the internal limiting membrane of the retina forming the vitreoretinal interface. Diffusion of molecules can occur through this interface in a unilateral direction providing a pathway for intravitreal drug delivery.

Purpose To identify factors predictive of remission of inflammation in new-onset anterior uveitis cases treated at tertiary uveitis care facilities. Design Retrospective cohort study. Participants Patients seeking treatment at participating academic uveitis clinics within 90 days of initial diagnosis of anterior uveitis. Methods Retrospective cohort study based on standardized chart review. Main Outcome Measures Factors predictive of remission (no disease activity without corticosteroid or immunosuppressive treatments at all visits during a 90-day period). Results Nine hundred ninety eyes (687 patients) had a first-ever diagnosis of anterior uveitis within 90 days before initial presentation and had follow-up visits thereafter. The median follow-up time was 160 days. Systemic diagnoses with juvenile idiopathic arthritis (JIA; adjusted hazard ratio [aHR], 0.38; 95% confidence interval [CI], 0.19–0.74) and Behcet's disease (aHR, 0.10; 95% CI, 0.01–0.85) were associated with a lower incidence of uveitis remission. Cases of bilateral uveitis (aHR, 0.68; 95% CI, 0.54–0.87) and those with a history of cataract surgery before presentation (aHR, 0.51; 95% CI, 0.29–0.87) also had a lower incidence of remission. Regarding clinical findings at the initial visit, a high degree of vitreous cells at initial presentation was associated with a lower incidence of remission (for 1+ or more vs. none: aHR, 0.72; 95% CI, 0.55–0.95). An initial visual acuity of 20/200 or worse, with respect to 20/40 or better, also was predictive of a lower incidence of remission (aHR, 0.52; 95% CI, 0.32–0.86). Conclusions Factors associated with a lower incidence of remission among new-onset anterior uveitis cases included diagnosis with JIA, Behcet's disease, bilateral uveitis, history of cataract surgery, findings of 1+ or more vitreous cells at presentation, and an initial visual acuity of 20/200 or worse. Patients with these risk factors seem to be at higher risk of persistent inflammation; reciprocally, patients lacking these factors would be more likely to experience remission. Patients with risk factors for nonremission of uveitis should be managed taking into account the higher probability of a chronic inflammatory course.

Purpose This study sought to determine the validity of self-report of prior panretinal photocoagulation (PRP) and focal photocoagulation (FP) compared with fundus photography. Design Prospective cohort study. Participants One thousand three hundred sixty-three type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a subset of the 1441 subjects originally enrolled in the multicenter Diabetes Control and Complications Trial. Methods At each annual visit, subjects were asked by EDIC staff whether they had undergone PRP, FP, or both since the last completed annual clinic visit. Fundus photographs were collected from one quarter of the cohort each year and from the entire cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects. Main Outcome Measures The κ, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated. Results For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. For PRP and FP, sensitivities were 90.4% and 74.0%, respectively; specificities were 96.0% and 98.8%, respectively; positive predictive values were 75.9% and 80.3%, respectively; negative predictive values were 98.9% and 98.4%, respectively; and κ values were 0.80 and 0.76, respectively. Risk factors associated with misreporting included prior laser for diabetic retinopathy and prior ocular surgery (each P Conclusions For subjects with type 1 diabetes, in the absence of a clinical examination or fundus photographs, subject self-report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

PURPOSE Studies have used central retinal arteriolar (CRAE) and central retinal venular (CRVE) calibers, measured from images produced with computerized image analysis, to detect risk factors for systemic diseases. The authors explored suboptimal image focus as a possible contributing factor to artificially larger vascular caliber measurements. METHODS From the reading center image collections, 30 digital retinal images were selected for optimum quality. Image analysis software was used to derive nine progressively blurred versions of the originals. IVAN measurement software was used to measure CRAE and CRVE in the original and the blurred series derived from them. To check the adequacy of the simulation, progressively defocused series of images were taken of several volunteers. RESULTS For CRAE, each level of simulated blurring produced a statically significant increase in apparent vessel caliber from the original (P

Digital cameras for retinal photography have largely replaced film fundus cameras, in part because of the immediate availability of images and the convenience of their storage, reproduction, and transmission. In addition, commercial film production continues to decrease, and film is likely to be unavailable for retinal photography in the future.1 Digital color fundus photography differs in some potentially important aspects from film photography of the fundus. Digital camera systems for retinal photography vary a great deal with respect to how they handle tonal balance and illumination,2 which may result in differences in evaluation of lesions between film and digital photographs.2 This variation presents challenges with respect to evaluating the images of subtle lesions in eyes with diabetic retinopathy (DR) in multicenter clinical trials. If grading of DR severity between film and digital images differs, there may be consequences for study interpretation. For digital ophthalmic images to be suitable for use in clinical trials evaluating treatment of diabetic eye disease, the sensitivity of diagnosing vascular lesions has to be on a par with the gold-standard modified seven-field (7-field) stereoscopic images, as described in the Early Treatment Diabetic Retinopathy Study (ETDRS) report number 10.3 Some currently available digital camera systems include the option of wide-angle image capture at 45° to 60° (4-field wide protocol), versus the 30° to 35° fields used in conventional 7-field imaging protocols for clinical trials of DR.4 Wide-angle photography offers the possibility of imaging an equivalent area of retina with fewer frames, thereby increasing efficiency and exposing the subject to fewer light flashes. Decreasing the number of images also reduces the total file storage requirement, which may be an important consideration for clinical centers and centralized reading centers. Each uncompressed color image, one side of a stereo pair and independent of angle, is approximately 14 megabytes when obtained with a 6-megapixel digital camera system (14 MB × 14 images for modified 7-field and 14 MB × 8 images for 4-field wide). We compared film and digital images from a subset of Diabetic Retinopathy Clinical Research Network (DRCR.net) clinical centers, to determine the extent of agreement between the grading of these images with respect to diabetic retinal disease assessment, including severity of DR, presence and extent of diabetic macular edema (DME), and clinically significant macular edema (CSME). In addition, we evaluated potential differences in the grading of digital 4-field wide-angle photographs versus digital modified 7-field standard photographs relative to traditional 7-field film grading.

To evaluate relationships between retinal vessel caliber, AIDS-related factors, and mortality.Longitudinal, observational cohort study.We evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the Ocular Complications of AIDS (1998-2008). Semi-automated evaluation of fundus photographs (1 eye/participant) determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) at baseline. Multiple linear regression models, using forward selection, identified independent relationships between indices and various host- and disease-related variables.Included were 1250 participants. Mean follow-up for determination of mortality was 6.1 years. Smaller CRAE was related to increased age (P.001) and hypertension (P.001); larger CRAE was related to lower hematocrit (P = .002). Larger CRAE and CRVE were associated with black race (P.001). Larger CRVE was related to smoking (P = .004); smaller CRVE was related to age (P.001) and higher mean corpuscular volume (P = .001). We observed the following relationships with AIDS-associated factors: smaller CRAE and larger CRVE with history of highly active antiretroviral therapy (HAART; P.001); and larger CRAE with lower CD4+ T lymphocyte count (P = .04). We did not identify independent relationships with human immunodeficiency virus RNA blood levels. There was a 12% (95% CI, 2%-21%) increase in mortality risk per quartile of decreasing AVR (P = .02).Variations in retinal vascular caliber are associated with AIDS-specific factors and are markers for increased mortality risk. Relationships are consistent with the hypothesis that the vasculature is altered by known atherogenic effects of chronic HAART or the prolonged inflammatory state associated with AIDS.

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.

Purpose To evaluate the risk of and risk factors for hypopyon among patients with uveitis and to evaluate the risk of visual changes and complications after hypopyon. Design Retrospective cohort study. Participants Patients with uveitis at 4 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 ocular complications after hypopyon. Results Among 4911 patients with uveitis, 41 (8.3/1000) cases of hypopyon were identified at the time of cohort entry. Of these, 2885 initially free of hypopyon were followed over 9451 person-years, during which 81 patients (2.8%) developed hypopyon (8.57/1000 person-years). Risk factors for incident hypopyon included Behcet's disease (adjusted relative risk [RR]=5.30; 95% confidence interval [CI], 2.76–10.2), spondyloarthropathy (adjusted RR=2.86; 95% CI, 1.48–5.52), and human leukocyte antigen (HLA)-B27 positivity (adjusted RR=2.04; 95% CI, 1.17–3.56). Patients with both a spondyloarthropathy and HLA-B27 had a 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 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 Behcet's disease, HLA-B27 positivity, and spondyloarthropathy. Intermediate uveitis cases (± anterior uveitis) had a lower risk of hypopyon. On average, post-hypopyon eyes were no more likely than other eyes with uveitis to develop structural ocular complications or lose visual acuity. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

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 ≤ 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. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.