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Purpose: To provide preliminary data regarding the safety and efficacy of high-dose intravenous daclizumab (Zenapax; Roche Inc, Nutley, New Jersey, USA) therapy for the treatment of juvenile idiopathic arthritis (JIA)-associated active anterior uveitis.Design: Interventional case series; open-label prospective, phase II pilot study.Methods: Six patients were recruited into the study and received daclizumab therapy at doses of 8 mg/kg at baseline, 4 mg/kg at week 2, and 2 mg/kg every 4 weeks thereafter, for a total of 52 weeks. The study was done at the National Eye Institute between June 29, 2005 and July 9, 2008. The primary outcome was a two-step decrease in inflammation grade assessed at week 12. Primary safety outcome was assessed at weeks 2 and 4. The ocular inflammation was assessed according to the Standardization of Uveitis Nomenclature criteria.Results: Four of the 6 participants achieved two-step reduction in anterior chamber cells according to Standardization of Uveitis Nomenclature Working Group grading scheme for anterior chamber cells 12 weeks into the study and met the primary efficacy endpoint. One additional patient responded to reinduction whereas 1 patient failed reinduction and was considered an ocular treatment failure. Visual acuity improved from a mean of 68 Early Treatment Diabetic Retinopathy Study letters in the worse eye to a mean of 79.6 letters (2 Snellen lines). Three participants were terminated before 52 weeks: First, because of a rash possibly induced by daclizumab; Second, because of ocular treatment failure; and Last, because of uncontrolled systemic manifestations of JIA.Conclusion: High-dose intravenous daclizumab can help reduce active inflammation in active JIA-associated anterior uveitis; however, patients need to be monitored for potential side effects. Larger randomized trials are needed to better assess treatment effect and safety. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the incidence, remission, and relapse of post-surgical cystoid macular edema (PCME) following cataract surgery in inflammatory eye disease., Methods: A total of 1859 eyes that had no visually significant macular edema prior to cataract surgery while under tertiary uveitis management were included. Standardized retrospective chart review was used to gather clinical data. Univariable and multivariable logistic regression models with adjustment for inter-eye correlations were performed., Results: PCME causing VA 20/50 or worse was reported in 286 eyes (15%) within 6 months of surgery. Adults age 18-64 years as compared to children (adjusted odds ratio [aOR] = 2.42, for ages 18 to 44 years and aOR = 1.93 for ages 45 to 64 years, overall P = .02); concurrent use of systemic immunosuppression (conventional aOR 1.53 and biologics aOR = 2.68, overall P = .0095); preoperative VA 20/50 or worse (overall P < .0001); cataract surgery performed before 2000 (overall P = .03) and PMCE in fellow eye (aOR = 3.04, P = .0004) were associated with development of PCME within 6 months of cataract surgery. PCME resolution was seen in 81% of eyes at 12 months and 91% of eyes at 24 months. CME relapse was seen in 12% eyes at 12 months and 19% eyes at 24 months., Conclusions: PCME occurs frequently in uveitic eyes undergoing cataract surgery; however, most resolve within a year. CME recurrences likely are due to the underlying disease process and not relapses of PCME., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD)., Design: Phase 1, open-label, single-center, first-in-human clinical study., Participants: Adult patients (≥50 years of age) with GA secondary to AMD in the study-treated eye (treated eye) with Snellen best-corrected visual acuity of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm 2 (2-8 disc area), and best-corrected visual acuity of 20/800 or better in fellow, nontreated eye were included., Methods: Patients (n = 17) were enrolled sequentially into low-dose (3.56 × 10 10 viral genome/eye; n = 3), intermediate-dose (1.07 × 10 11 viral genome/eye; n = 3), and high-dose (3.56 × 10 11 viral genome/eye; n = 11) cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months., Main Outcome Measures: Safety and tolerability outcomes included assessment of ocular and nonocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate., Results: Baseline patient characteristics were consistent with the disease under study, and all enrolled patients demonstrated foveal center-involved GA. JNJ-81201887 was well-tolerated across all cohorts, with no dose-limiting AEs. No serious or systemic AEs related to study intervention occurred. Overall, 5 of 17 patients (29%) experienced 5 events of mild ocular inflammation related to study treatment; examination findings in all resolved, and AEs resolved in 4 of 5 patients after topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. Geographic atrophy lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0 through 6 to 0.056 mm at months 18 through 24., Conclusions: All 3 studied doses of JNJ-1887 showed a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Birdshot chorioretinopathy is an inflammatory eye condition strongly associated with MHC-I allele HLA-A29. The striking association with MHC-I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16 positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express CD8A which is involved in MHC-I recognition on target cells, display gene signatures indicative of high cytotoxic activity (GZMB, PRF1 and ISG15), and signaling through NK cell receptor CD244 (SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identifies a population of CD8 bright CD244 bright NK cells, which rapidly declines to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8 bright CD244 bright NK cells in birdshot chorioretinopathy., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: The purpose of this study was to report an unusual case of pseudoxanthoma elasticum presenting with an inflammatory phenotype associated with atypical and rapidly progressive subretinal fibrosis., Methods: This was an observational case report., Results: A patient with a history of pseudoxanthoma elasticum presented with rapidly progressive subretinal fibrosis, particularly in the left eye, over the course of one year. The patient was noted at presentation to have intraocular inflammation, outer retinal attenuation, multifocal choroiditis-like lesions, and intraretinal fluid (in the absence of obvious clinical or angiographic signs of exudative choroidal neovascular membranes). An ocular inflammatory phenotype was diagnosed, and the patient was treated with a combination of local steroids and systemic corticosteroids/immunomodulatory agents. After initiation of these agents, the patient demonstrated functional and structural improvement, with partial outer retinal reconstitution, decreased intraretinal fluid, and lack of further progression of subretinal fibrosis., Conclusion: This report describes an inflammatory phenotype of pseudoxanthoma elasticum associated with severe and atypical subretinal fibrosis. This case expands upon the currently known spectrum of inflammatory phenotypes associated with pseudoxanthoma elasticum. Treatment with corticosteroids or immunomodulatory treatment should be considered in similar cases.

Background: Fungal endophthalmitis is an intraocular infection that rarely develops in immunocompetent individuals., Case: A 35-year-old healthy, immunocompetent male presented with a 1-week history of pain and redness in the left eye. Visual acuity was 20/50. Dilated fundus examination revealed focal chorioretinitis in the posterior pole with associated vitritis, suspicious for a fungal etiology. He was started empirically on oral voriconazole and valacyclovir. A comprehensive systemic workup returned negative. Inflammation worsened and a diagnostic vitrectomy was performed which revealed Candida dubliniensis . The dose of oral voriconazole was increased, and intravitreal voriconazole and amphotericin B injections were added for refractory disease. Treatment response was gauged by fungal pillar height on optical coherence tomography. Eight months of oral voriconazole and 68 intravitreal antifungal injections were required to achieve complete regression and a final visual acuity of 20/20., Conclusion: Candida dubliniensis endophthalmitis can affect immunocompetent individuals and require a prolonged treatment course.

Objective: To characterize changes in the retinal microvasculature in eyes with birdshot chorioretinopathy (BCR) using OCT angiography (OCTA)., Design: Retrospective, observational, single center., Subjects: Twenty-eight patients (53 eyes) with BCR and 59 age-matched controls (110 eyes)., Methods: En face OCTA images of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) of each eye were assessed for the presence of microvascular abnormalities and used to measure the vessel and foveal avascular zone (FAZ) areas. A longitudinal analysis was performed with a representative cohort of 23 BCR eyes (16 patients) at baseline and at a 2-year time point., Main Outcome Measures: Whole-image vessel density (VD, %), extrafoveal avascular zone (extra-FAZ) VD (%), and FAZ area (%) were calculated and compared between control and BCR eyes. The frequency of microvascular abnormalities in BCR eyes was recorded., Results: In the SCP, increased intercapillary space and capillary loops were common features present on OCTA images. Whole-image and extra-FAZ VD were lower in the BCR group compared with controls ( P < 0.0001 [SCP and DCP]). Foveal avascular zone area was enlarged in BCR eyes ( P  = 0.0008 [DCP]). Worsening best-corrected visual acuity was associated with a decrease in whole-image and extra-FAZ VD in the SCP ( P  < 0.0001 for both) and the DCP ( P < 0.005 for both). Multivariable analysis, with vessel analysis parameters as outcomes, demonstrated that increasing age, increasing disease duration, lower central subfield thickness, and treatment-naive eyes (compared with those on only biologics) were associated with a significant decrease in both DCP whole-image and extra-FAZ VD. Increasing disease duration was associated with a significant decrease in both SCP whole-image and extra-FAZ VD. Longitudinal analysis demonstrated no significant difference in any vessel analysis parameters except for an increase in DCP FAZ area., Conclusions: Our results demonstrate a significant a decrease in VD in BCR eyes and an association on multivariable analysis with disease duration. Quantifying VD in the retinal microvasculature may be a useful biomarker for monitoring disease severity and progression in patients with BCR. Further studies with extended longitudinal follow-up are needed to characterize its utility in monitoring disease progression and treatment response., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: To evaluate the utility of ultrawide-field fluorescein angiography (UWFFA) in patients with anterior uveitis by investigating the detection of retinal vascular leakage (RVL) and the subsequent implications on disease diagnosis and management., Study Design/materials and Methods: Patients, who were referred to the National Eye Institute (NEI) for evaluation of anterior uveitis and underwent UWFFA imaging at the initial visit, were included in this study. The electronic medical records of eligible patients were reviewed. The UWFFA images were assessed for severity of retinal vascular leakage, presence of macular leakage, and optic disc leakage by a two-grader system, and intergrader agreement was calculated using the κ-value. Patients with altered diagnoses and management attributable to UWFFA results were noted., Results: A total of 93 eyes of 63 patients were included in the study. Of 93 eyes, 31 (33.3%) eyes had RVL on UWFFA, with 26 (28.0%) eyes and 5 (5.4%) eyes showing mild and moderate-severe RVL, respectively. Twenty-five (26.9%) eyes showed macular leakage, and 7 (7.5%) eyes showed optic disc leakage. The κ-values ranged from 0.85 - 0.87 indicating excellent intergrader agreement. Of the 31 eyes with RVL, the diagnosis was changed to anterior/intermediate uveitis for 9 (29.0%) eyes and to panuveitis for 4 (12.9%) eyes. Systemic treatment was escalated in 5 patients., Conclusion: Our results suggest that UWFFA imaging is useful in detecting subclinical posterior involvement in patients with anterior uveitis. Moreover, UWFFA results in altered diagnosis and treatment approaches in a portion of patients., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To evaluate the incidence of visually significant posterior capsule opacification (PCO with visual acuity ≤20/50) and the incidence of Nd:YAG laser capsulotomy in the year following cataract surgery for uveitic eyes., Method: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study using a standardized chart review process., Results: Among 1,855 uveitic eyes of 1,370 patients who had undergone cataract surgery, visually significant PCO occurred in 297 eyes (16%), and YAG laser capsulotomy was done in 407 eyes (22%) within the first year following surgery. Higher odds of developing 20/50 visual acuity attributed to PCO were noted in children and young adults compared with adults older than 65 years of age (overall p = 0.03). Poorer preoperative visual acuity (overall p = 0.0069) and postoperative inflammation (odds ratio [OR] = 1.83; 95% CI, 1.37-2.45; p < 0.0001) were associated with PCO incidence. In multivariable analysis, risk factors for YAG laser capsulotomy were younger age groups compared with those older than 65 years of age at the time of surgery (adjusted OR [aOR] = 1.90-2.24; 95% CI, 1.90-2.24; overall p = 0.0007), female sex (aOR = 1.37; 95% CI, 1.03-1.82; p = 0.03), postoperative active inflammation (aOR = 165; 95% CI, 1.27-2.16; overall p < 0.0001), extracapsular cataract extraction compared with phacoemulsification (aOR = 1.70; 95% CI, 1.17-2.47; overall p < 0.0001), and insertion of an intraocular lens (aOR = 4.60; 95% CI, -2.29-9.25; p < 0.0001). Black race was associated with lower YAG laser capsulotomy incidence than Whites (aOR = 0.36; 95% CI, 0.24-0.52; overall p < 0.0001)., Conclusions: Vision-reducing (≤20/50) PCO is common, occurring in about one sixth of uveitic eyes within 1 year of cataract surgery; a higher number (22%) of eyes underwent YAG laser capsulotomy within the first year. Age and postoperative inflammation following cataract surgery are the variables most associated with the incidence of visually significant PCO and YAG laser capsulotomy., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background/aims: To evaluate the efficacy of intravitreal aflibercept for UME (uveitic macular)., Methods: A retrospective review of records of patients that received aflibercept for UME from January 2017 to August 2022 was conducted. The primary outcomes were mean change in visual acuity (VA) and central subfield thickness (CST) 6 and 12 months from the start of aflibercept treatment., Results: A total of 16 eyes of 12 patients were included. Indications for treatment included eyes that had previously demonstrated a history of elevated intraocular pressure secondary to a steroid response ( n  = 10) or a history of non-response or partial response to local corticosteroids ( n  = 6). Fifteen eyes (94%) demonstrated a reduction in CST after their initial injection. At 6-months, mean VA gain was 2.6 ± 7.7 letters ( p  = 0.24) from a mean VA of 67.8 ± 10.7 letters at baseline and mean CST improved by 97.6 ± 113.5 μm ( p = 0.004) from 458.6 ± 123.1 μm at baseline. Fourteen eyes had 12-months of follow up and received a median of 4 injections over 12 visits. The mean VA at 12-months remained stable compared to baseline (mean change of -1.4 ± 12.5 letters ( p  = 0.87)) while the CST improved by a mean of 90.9 ± 114.6 μm ( p = 0.053) compared to baseline., Conclusion: Intravitreal aflibercept injections resulted in reduced central subfield thickness at all time-points. It appears to be an effective treatment alternative for UME, particularly for patients who are not responsive to local corticosteroids or who have contraindications to corticosteroid treatment.

Purpose: To evaluate the long-term visual acuity (VA) outcome of cataract surgery in inflammatory eye disease., Setting: Tertiary care academic centres., Design: Multicentre retrospective cohort study., Methods: A 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., Results: Uveitic 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, p<0.0001) or anterior uveitis (OR=2.2, p<0.0001), VA 20/50 to 20/80 (OR 4.76 as compared with worse than 20/200, p<0.0001) preoperatively, inactive uveitis (OR=1.49, p=0.03), have undergone phacoemulsification (OR=1.45 as compared with extracapsular cataract extraction, p=0.04) or have had intraocular lens placement (OR=2.13, p=0.01). Adults had better VA immediately after surgery, with only 39% (57/146) paediatric eyes at 20/40 or better at 1 year., Conclusions: Our 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., Competing Interests: Competing interests: JTR: AbbVie (consultant); Gilead (consultant); Janssen (consultant); Eyevensys (consultant); UpToDate (author/royalties); Pfizer (financial support); Novartis (consultant); Roche (consultant); Alcon Research Institute (financial support); Horizon (financial support and consultant); Revolo (consultant); Neoleukin (consultant); Affibody (consultant); Celgene-Bristol Myers (Data Monitoring Committee); Eli Lilly (Clinical Endpoints Committee). GL-C: AbbVie (consultant, lecture fees); Allergan (grant support); Mallinckrodt (consultant, grant support); Sanofi (grant support, lecture fees). ES: Eyevensys (consultant); Santen (consultant); EyeGate (consultant, financial support); AbbVie (consultant, financial support); Clearside (consultant, financial support); EyePoint (consultant, financial support). SGa: Merit CRO (consultant); NEI (grant support); RPB (grant support). SGr: Olleyes (grant support). JT: AbbVie (consultant); ADVISE/MERIT, NEI (grant support); Gilead (consultant); Roche (consultant); Tarsier Pharma (equity owner); UpToDate (consultant). JHK: Gilead (consultant); Betaliq (equity owner); Tarsier Pharma (equity owner)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To present current expert practice patterns and to formulate a consensus for the management of HSV and VZV AU by uveitis specialists worldwide., Methods: A two-round online modified Delphi survey with masking of the study team was conducted. Responses were collected from 76 international uveitis experts from 21 countries. Current practices in the diagnosis and treatment of HSV and VZV AU were identified. A working group (The Infectious Uveitis Treatment Algorithm Network [TITAN]) developed data into consensus guidelines. Consensus is defined as a particular response towards a specific question meeting ≥75% of agreement or IQR ≤ 1 when a Likert scale is used., Results: Unilaterality, increased intraocular pressure (IOP), decreased corneal sensation and diffuse or sectoral iris atrophy are quite specific for HSV or VZV AU from consensus opinion. Sectoral iris atrophy is characteristic of HSV AU. Treatment initiation is highly variable, but most experts preferred valacyclovir owing to simpler dosing. Topical corticosteroids and beta-blockers should be used if necessary. Resolution of inflammation and normalisation of IOP are clinical endpoints., Conclusions: Consensus was reached on several aspects of diagnosis, choice of initial treatment, and treatment endpoints for HSV and VZV AU. Treatment duration and management of recurrences varied between experts., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Aims: To present current practice patterns in the diagnosis and management of Cytomegalovirus anterior uveitis (CMV AU) by uveitis experts worldwide., Methods: A two-round modified Delphi survey with masking of the study team was performed. Based on experience and expertise, 100 international uveitis specialists from 21 countries were invited to participate in the survey. Variation in the diagnostic approaches and preferred management of CMV AU was captured using an online survey platform., Results: Seventy-five experts completed both surveys. Fifty-five of the 75 experts (73.3%) would always perform diagnostic aqueous tap in suspected CMV AU cases. Consensus was achieved for starting topical antiviral treatment (85% of experts). About half of the experts (48%) would only commence systemic antiviral treatment for severe, prolonged, or atypical presentation. The preferred specific route was ganciclovir gel 0.15% for topical treatment (selected by 70% of experts) and oral valganciclovir for systemic treatment (78% of experts). The majority of experts (77%) would commence treatment with topical corticosteroid four times daily for one to two weeks along with antiviral coverage, with subsequent adjustment depending on the clinical response. Prednisolone acetate 1% was the drug of choice (opted by 70% of experts). Long-term maintenance treatment (up to 12 months) can be considered for chronic course of inflammation (88% of experts) and those with at least 2 episodes of CMV AU within a year (75-88% of experts)., Conclusions: Preferred management practices for CMV AU vary widely. Further research is necessary to refine diagnosis and management and provide higher-level evidence., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression., Design: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression., Participants: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer., Methods: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study., Main Outcome Measures: Overall mortality and CM., Results: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration., Conclusions: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. All rights reserved.)

Ophthalmic manifestations and tissue tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in association with coronavirus disease 2019 (COVID-19), but the pathology and cellular localization of SARS-CoV-2 are not well characterized. The objective of this study was to evaluate macroscopic and microscopic changes and investigate cellular localization of SARS-CoV-2 across ocular tissues at autopsy. Ocular tissues were obtained from 25 patients with COVID-19 at autopsy. SARS-CoV-2 nucleocapsid gene RNA was previously quantified by droplet digital PCR from one eye. Herein, contralateral eyes from 21 patients were fixed in formalin and subject to histopathologic examination. Sections of the droplet digital PCR-positive eyes from four other patients were evaluated by in situ hybridization to determine the cellular localization of SARS-CoV-2 spike gene RNA. Histopathologic abnormalities, including cytoid bodies, vascular changes, and retinal edema, with minimal or no inflammation in ocular tissues were observed in all 21 cases evaluated. In situ hybridization localized SARS-CoV-2 RNA to neuronal cells of the retinal inner and outer layers, ganglion cells, corneal epithelia, scleral fibroblasts, and oligodendrocytes of the optic nerve. In conclusion, a range of common histopathologic alterations were identified within ocular tissue, and SARS-CoV-2 RNA was localized to multiple cell types. Further studies will be required to determine whether the alterations observed were caused by SARS-CoV-2 infection, the host immune response, and/or preexisting comorbidities., (Copyright © 2023 American Society for Investigative Pathology. All rights reserved.)

Purpose: To estimate the incidence/risk factors for cataract in noninfectious anterior uveitis., Design: Retrospective multicenter cohort study (6 US tertiary uveitis sites, 1978-2010)., Methods: Data were harvested by trained expert reviewers, using protocol-driven review of experts' charts. We studied cataract incidence-newly reduced visual acuity worse than 20/40 attributed to cataract; or incident cataract surgery-in 3923 eyes of 2567 patients with anterior uveitis., Results: Cataract developed in 507 eyes (54/1000 eye-years, 95% CI 49-59). Time-updated risk factors associated with cataract included older age (≥65 vs <18 years: adjusted hazard ratio [aHR] 5.04, 95% CI 3.04-8.33), higher anterior chamber cell grade (P(trend)=0.001), prior incisional glaucoma surgery (aHR 1.86, 95% CI 1.10-3.14), band keratopathy (aHR 2.23, 95% CI 1.47-3.37), posterior synechiae (aHR 3.71, 95% CI 2.83-4.87), and elevated intraocular pressure ≥30 vs 6-20 mm Hg (aHR 2.57, 95% CI 1.38-4.77). Primary acute (aHR 0.59, 95% CI 0.30-1.15) and recurrent acute (aHR 0.74, 95% CI 0.55-0.98) had lower cataract risk than chronic anterior uveitis. Higher-dose prednisolone acetate 1%-equivalent use (≥2 drops/day) was associated with >2-fold higher cataract risk in eyes with anterior chamber cell grades 0.5+ or lower but was not associated with higher cataract risk in the presence of anterior chamber cells of grade 1+ or higher., Conclusions: Cataract complicates anterior uveitis in ∼5.4/100 eye-years. Several fixed and modifiable risk factors were identified, yielding a point system to guide cataract risk minimization. Topical corticosteroids only were associated with increased cataract risk when anterior chamber cells were absent or minimally present, suggesting their use to treat active inflammation (which itself is cataractogenic) does not cause a net increase in cataract incidence., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To report the use of combination intravitreal pharmacotherapy using anti-vascular endothelial growth factor (VEGF) and short and long-term corticosteroid implants for the treatment of retinal vasoproliferative tumors (VPT) associated with intermediate uveitis., Methods: Retrospective chart review of patients with VPT secondary to idiopathic intermediate uveitis that underwent combination intravitreal pharmacotherapy at a single center was performed. Multimodal imaging including ultrawide field color fundus photography, ultrawide field fluorescein angiography, and optical coherence tomography obtained before and after treatment were reviewed., Results: Four eyes of 4 patients were treated with multiple injections of a combination of aflibercept, dexamethasone, and fluocinolone acetonide implants for VPT associated with intermediate uveitis. All 4 patients had improvement in visual acuity, intraocular inflammation, central macular thickness, and retinal vascular leakage, as well as regression of the VPT and reduction in lesion leakage on follow-up., Conclusion: Combination intravitreal anti-VEGF and corticosteroid implants may be a useful approach for the treatment of intermediate uveitis-associated VPTs and can lead to both functional and structural improvement., Competing Interests: Conflict of interest: None.

Background/aims: To establish a consensus in the nomenclature for reporting optical coherence tomography angiography (OCTA findings in uveitis., Methods: The modified Delphi process consisted of two rounds of electronic questionnaires, followed by a face-to-face meeting conducted virtually. Twenty-one items were included for discussion. The three main areas of discussion were: wide field OCTA (WF-OCTA), nomenclature of OCTA findings and OCTA signal attenuation assessment and measurement. Seventeen specialists in uveitis and retinal imaging were selected by the executive committee to constitute the OCTA nomenclature in Uveitis Delphi Study Group. The study endpoint was defined by the degree of consensus for each question: 'strong consensus' was defined as >90% agreement, 'consensus' as 85%-90% and 'near consensus' as >80% but <85%., Results: There was a strong consensus to apply the term 'wide field' to OCTA images measuring over 70° of field of view, to use the terms 'flow deficit' and 'non-detectable flow signal' to describe abnormal OCTA flow signal secondary to slow flow and to vessels displacement respectively, to use the terms 'loose' and 'dense' to describe the appearance of inflammatory choroidal neovascularisation, and to use the percentage of flow signal decrease to measure OCTA ischaemia with a threshold greater than or equal to 30% as a 'large area'., Conclusions: This study sets up consensus recommendations for reporting OCTA findings in uveitis by an expert panel, which may prove suitable for use in routine clinical care and clinical trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy., Design: Single-center observational case study., Participants: Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included., Methods: Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing., Main Outcome Measures: Visual acuity, electrophysiology, fluorescein angiography, and OCT findings., Results: Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33-5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography., Conclusions: Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Published by Elsevier Inc.)

Importance: Tumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the association between ADAs and treatment response in patients with noninfectious uveitis (NIU) is not well understood., Objective: To assess the frequency of ADAs and their association with drug levels and clinical response in patients with NIU treated with adalimumab or infliximab., Design, Setting, and Participants: This retrospective cross-sectional study included patients diagnosed with NIU who received adalimumab or infliximab and underwent testing for serum drug level and ADAs at the National Eye Institute from September 2017 to July 2021., Exposures: Serum drug level testing with reflex testing for ADA levels was performed., Main Outcomes and Measures: The main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU., Results: Of 54 patients included in the study, 42 received adalimumab (mean [SD] age, 43.6 [19.6] years; 25 [59.5%] female) and 12 received infliximab (mean [SD] age, 42.7 [20.4] years; 7 [58.3%] male). In the adalimumab group, mean (SD) drug level was 9.72 (6.82) μg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients). Mean drug level was lower in those with ADAs compared with those without ADAs (mean [SD], 2.8 [2.6] μg/mL vs 13.6 [5.2] μg/mL; difference: 10.8 μg/mL; 95% CI, 8.3-13.2 μg/mL; P < .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (mean [SD], 11.0 [7.3] μg/mL vs 6.8 [4.5] μg/mL; difference: -4.2 μg/mL; 95% CI, -8.7 to 0.2 μg/mL; P = .06). Multivariable modeling showed that a 1-arbitrary unit increase in ADAs was associated with a -0.02 μg/mL (95% CI, -0.01 to -0.34 μg/mL) difference in mean drug level (P < .001). Favorable clinical response was associated with a threshold drug level above 2.7 μg/mL or an antibody level below 15.2 μg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) μg/mL, and no ADAs were detected., Conclusions and Relevance: In this study, 35.7% of adalimumab-treated patients with NIU had ADAs. The presence of ADAs was associated with lower drug levels, and higher ADA levels were associated with increased risk of TNFi treatment failure. Although limited by the retrospective design, our results suggest that therapeutic drug monitoring may be considered among patients experiencing therapy failure to help exclude ADAs as a potential cause of treatment failure.

Background: Coronavirus disease 2019 (COVID-19) systemic symptoms and sequelae have been studied extensively, but less is known about the characterization, duration, and long-term sequelae of ocular symptoms associated with COVID-19 infection. The purpose of this study was to analyze the frequency, spectrum, and duration of ocular symptoms in participants with COVID-19 infection treated in inpatient and outpatient settings., Methods: A retrospective electronic survey was distributed to NIH employees and the public who reported testing positive for SARS-CoV-2. The anonymous survey collected information on demographics, past ocular history, systemic COVID-19 symptoms, and ocular symptoms., Results: A total of 229 (21.9% male and 78.1% female, mean age 42.5 ± 13.9) survey responses were included. Ocular symptoms were reported by 165 participants with a mean of 2.31 ± 2.42 symptoms. The most commonly reported ocular symptoms were light sensitivity (31.0%), itchy eyes (24.9%), tearing (24.9%), eye redness (24.5%), and eye pain (24.5%). Participants with ocular symptoms had a higher number of systemic symptoms compared to participants without ocular symptoms (mean 9.17 ± 4.19 vs 6.22 ± 3.63; OR: 1.21; 95% CI: 1.11 - 1.32; p < 0.001). Ocular symptoms were more common in those who reported a past ocular history compared to those who did not (81.8% vs 67.1%; OR: 2.17; 95% CI: 1.08 - 4.37; p = 0.03). Additionally, the onset of ocular symptoms occurred most frequently at the same time as systemic symptoms (47.5%), and 21.8% reported symptoms lasting ≥ 14 days., Conclusions: Ocular surface-related symptoms are the most frequent ocular manifestations, and systemic disease severity is associated with the presence of ocular symptoms. Additionally, our results show that ocular symptoms can persist post-COVID-19 infection. Further work is needed to better understand ocular symptoms in COVID-19 and long-term sequelae., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: Conflicts of interest HBN has received grant support from AbbVie, consulting fees from 23andMe, AbbVie, and DAVA Oncology, and advisory board fees from Boehringer Ingelheim, all related to hidradenitis suppurativa. DMS and HBN have received grant support from the National Psoriasis Foundation. RGM has received grant support from SOBI, Novartis, Regeneron, and Lilly under US Federal Government Cooperative Research and Development Agreements. DCP, MO, MM, JT, HNS, SMS, SM, AADJ, THM, AD, RKR, ZD, NNM and EWC have no conflicts of interest to report.

Purpose: To evaluate the risk factors associated with clinically important intraocular pressure (IOP) elevation with topical difluprednate treatment in patients with non-infectious uveitis., Design: Retrospective cohort study., Methods: Fifty-four eyes of 54 patients with non-infectious uveitis treated with topical difluprednate at the current institution were included. Demographics and clinical characteristics of uveitis patients were collected. The main outcome measure was development of clinically important IOP elevation defined as IOP ≥21 mmHg and an increase of ≥10 mmHg from baseline., Results: A clinically important IOP elevation was observed in 17 patients (31.5%). The mean time to clinically important IOP elevation was 7.4±4.8 weeks (range 3-19). Statistically significant risk factors for incident clinically important IOP elevation were being a child (adjusted hazard ratio [aHR] 7.85 [95% CI 1.48-41.56], P = .02) and concurrent use of systemic steroids (aHR 5.31 [95% CI 1.18-24.00], P = .03). Patients with concurrent systemic corticosteroids developed clinically important IOP elevation earlier than those without systemic corticosteroid (mean 5.7±3.4 [range 3-14] vs 10.4±5.7 [range 4-19] weeks, P = .05). Incident IOP ≥30 mmHg occurred in 7 patients (13.0%). All patients responded well to the cessation of difluprednate and/or use of topical antiglaucomatous agents and no eyes required glaucoma surgery., Conclusions: This study demonstrated that clinically important IOP elevation is common in uveitis patients with topical difluprednate treatment. Children and patients with concurrent systemic corticosteroids are at substantial risk of developing clinically important IOP elevation., (Published by Elsevier Inc.)

Introduction: Vitreoretinal lymphoma is a rare ocular cancer with high morbidity and mortality despite treatment. Diagnosis by cytopathology is often delayed, and various molecular and image-based investigations have been developed. Diverse treatments are used, but there is a limited medical evidence to differentiate their effectiveness. We designed an international registry that would collect diagnostic, treatment and outcomes data, to establish new evidence for the management of this cancer., Methods and Analysis: The International Vitreoretinal B-Cell Lymphoma Registry will accrue data retrospectively for individuals aged 18 years or older, diagnosed with new or recurrent vitreoretinal B-cell lymphoma on or after 1 January 2020. A steering committee of subspecialised ophthalmologists identified 20 key clinical data items that describe patient demographics, tissue involvements, diagnostic testing, ocular and systemic treatments and treatment complications, and visual acuity and survival outcomes. Customised software was designed to permit collection of these data across a single baseline and multiple follow-up forms. The platform collects data without identifiers and at 3 month reporting intervals. Outcomes of the project will include: (1) descriptions of clinical presentations, and diagnostic and therapeutic preferences; (2) associations between clinical presentations, and diagnostics and treatments, and between diagnostics and treatments (assessed by ORs with 95% CIs); and (3) estimations of rates of vision loss, and progression-free and overall survival (assessed by Kaplan-Meier estimates)., Ethics and Dissemination: The registry has received Australia-wide approval by a national human research ethics committee. Sites located outside Australia are required to seek local human research ethics review. Results generated through the registry will be disseminated primarily by peer-reviewed publications that are expected to inform clinical practice, as well as educational materials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose of this paper was to develop a deep learning algorithm to detect retinal vascular leakage (leakage) in fluorescein angiography (FA) of patients with uveitis and use the trained algorithm to determine clinically notable leakage changes., Methods: An algorithm was trained and tested to detect leakage on a set of 200 FA images (61 patients) and evaluated on a separate 50-image test set (21 patients). The ground truth was leakage segmentation by two clinicians. The Dice Similarity Coefficient (DSC) was used to measure concordance., Results: During training, the algorithm achieved a best average DSC of 0.572 (95% confidence interval [CI] = 0.548-0.596). The trained algorithm achieved a DSC of 0.563 (95% CI = 0.543-0.582) when tested on an additional set of 50 images. The trained algorithm was then used to detect leakage on pairs of FA images from longitudinal patient visits. Longitudinal leakage follow-up showed a >2.21% change in the visible retina area covered by leakage (as detected by the algorithm) had a sensitivity and specificity of 90% (area under the curve [AUC] = 0.95) of detecting a clinically notable change compared to the gold standard, an expert clinician's assessment., Conclusions: This deep learning algorithm showed modest concordance in identifying vascular leakage compared to ground truth but was able to aid in identifying vascular FA leakage changes over time., Translational Relevance: This is a proof-of-concept study that vascular leakage can be detected in a more standardized way and that tools can be developed to help clinicians more objectively compare vascular leakage between FAs.

Purpose: To present two patients with treatment-naïve posterior segment uveitis with Vogt-Koyanagi-Harada-like features associated with tattoo-related inflammatory skin changes., Methods: Retrospective report of two cases., Results: Using clinical history and multimodal imaging, a diagnosis of posterior segment uveitis with Vogt-Koyanagi-Harada-like features was made in association with tattoo skin changes in both patients., Conclusion: Physicians should be aware that tattoo-associated posterior segment uveitis with Vogt-Koyanagi-Harada-like features can occur.

Purpose: To investigate the utility of optical coherence tomography angiography (OCTA) for the detection of inflammatory choroidal neovascularization (iCNV) and monitoring their response to treatment., Methods: A retrospective review of patients with a diagnosis of uveitis and associated iCNV with active exudation was performed. Active iCNV was determined by spectral domain OCT and/or fluorescein angiogram. Spectral domain OCTA outer retina to choriocapillaris slabs was evaluated for the presence of iCNV. Follow-up OCTA images were qualitatively assessed to determine whether regression of iCNV occurred after treatment., Results: Thirteen eyes of 12 patients were included. The etiologies of uveitis include punctate inner choroidopathy (n = 4), multifocal choroiditis (n = 2), presumed sarcoid uveitis (n = 2), tuberculous choroiditis (n = 1), birdshot chorioretinopathy (n = 1), syphilitic uveitis (n = 1), serpiginous choroiditis (n = 1), and idiopathic panuveitis (n = 1). Inflammatory choroidal neovascularization was detected on en face OCTA in 10 of 13 eyes (76.9%). After iCNV treatment, en face OCTA demonstrated complete regression of iCNV in 5 of 10 eyes (50%), partial regression in 2 of 10 eyes (20%), and no regression in 3 of 10 eyes (30%)., Conclusions: Optical coherence tomography angiography is an effective modality for detecting iCNV and could provide detailed visualization regarding location, morphologic structure, and flow of the iCNV and its response to therapy.

Purpose: Early identification of patients with noninfectious uveitis requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associated proteomic clusters with the need for IMT during the course of the disease., Design: Multicenter cohort study., Participants: Two hundred thirty treatment-free patients with active noninfectious uveitis., Methods: We used aptamer-based proteomics (n = 1305 proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n = 78) of patients and healthy control participants and independently validated our results in another Dutch cohort (n = 111) and a United States cohort (n = 67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use., Main Outcome Measures: Serum protein levels and use of IMT., Results: Network-based analyses revealed a tightly coexpressed serum cluster (n = 85 proteins) whose concentration was consistently low in healthy control participants (n = 26), but varied among patients with noninfectious uveitis (n = 52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomic location of uveitis (hazard ratio, 3.42; 95% confidence interval, 1.22-9.5; P  = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation: r  = 0.57, P  = 0.006). In an independent Dutch cohort (n = 111), we confirmed that patients with relatively high neutrophil count at diagnosis (> 5.2 × 10 9 /L) had a significantly increased chance of requiring IMT during follow-up (hazard ratio, 3.2; 95% confidence interval, 1.5-6.8; P  = 0.002). We validated these findings in a third cohort of 67 United States patients., Conclusions: A serum protein signature correlating with neutrophil levels was highly predictive for IMT use in noninfectious uveitis. We developed a routinely available tool that may serve as a novel objective biomarker to aid in clinical decision-making for noninfectious uveitis., (© 2022 by the American Academy of Ophthalmology.)

Purpose: To estimate the incidence of corneal endothelial transplantation (CET) and identify risk factors among patients with noninfectious ocular inflammation., Design: Retrospective cohort study., Methods: Adult patients attending United States tertiary uveitis care facilities diagnosed with noninfectious ocular inflammation were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Time-to-event analysis was used to estimate the incidence of CET, including penetrating keratoplasty, Descemet stripping endothelial keratoplasty, or Descemet membrane endothelial keratoplasty procedures. The incidence of CET was calculated. Potential risk factors for CET were also evaluated using Cox regression, accounting for correlation between eyes of the same patient., Results: Overall, 14,264 eyes met eligibility criteria for this analysis, with a median follow-up of 1.8 eye-years. The Kaplan-Meier estimated incidence of CET within 10 years was 1.10% (95% CI, 0.68%-1.53%). Risk factors for CET included age >60 years vs <40 years (adjusted hazard ratio [aHR], 16.5; 95% CI, 4.70-57.9), anterior uveitis and scleritis vs other types (aHR, 2.97; 95% CI, 1.46-6.05; and aHR, 4.14; 95% CI,1.28-13.4, respectively), topical corticosteroid treatment (aHR, 2.84; 95% CI, 1.32-6.13), cataract surgery (aHR, 4.44; 95% CI, 1.73-11.4), tube shunt surgery (aHR, 11.9; 95% CI, 5.30-26.8), band keratopathy (aHR, 5.12; 95% CI, 2.34-11.2), and hypotony (aHR, 7.38; 95% CI, 3.14-17.4). Duration of uveitis, trabeculectomy, peripheral anterior synechia, and ocular hypertension had no significant association after multivariate adjustment., Conclusions: In patients with ocular inflammation, CET occurred infrequently. Tube shunt surgery, hypotony, band keratopathy, cataract surgery, and anterior segment inflammation were associated with increased risk of undergoing CET; these factors likely are associated with endothelial cell damage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Regional corticosteroid therapy for noninfectious uveitis is well-established but usage patterns have not been studied extensively. This study aims to assess practice patterns of retina and uveitis specialists regarding their preferences on the use of local corticosteroid therapy., Methods: A 13-question survey was developed regarding the practice patterns of regional corticosteroid use in specific situations and populations. The survey was distributed to both the American Uveitis Society and Macula Society., Results: Responses from 87 ophthalmologists were analyzed. The two most commonly used drugs were the dexamethasone intravitreal implant (Ozurdex®) and posterior sub-tenon's triamcinolone (also known as posterior sub-Tenon's Kenalog, or PSTK). Regional corticosteroids were used more frequently as first-line treatment in more than half of posterior uveitis cases when compared to anterior uveitis (39.1-46.0% vs 10.3%, respectively). Respondents were more willing to use regional corticosteroids in more than half of unilateral uveitis cases than in bilateral cases (54.7% vs 18.6%, respectively). A majority of respondents (67.1%) stated that they would avoid using regional corticosteroids in patients under 8 years old., Conclusions: Our results demonstrate more frequent regional corticosteroid use in posterior segment uveitis, unilateral cases, and avoidance in younger pediatric patients. Overall, the variability in these responses highlights the need for guidelines regarding regional corticosteroid use., (© 2021. The Author(s).)

Purpose: To investigate the longitudinal changes in choroidal vascularity index (CVI) in eyes with active and quiescent intermediate uveitis using enhanced depth imaging optical coherence tomography (EDI-OCT)., Methods: EDI-OCT images of eyes with active and quiescent intermediate uveitis were retrospectively reviewed and binarized using ImageJ software. Choroidal parameters including CVI, total choroidal area (TCA), luminal area (LA), stromal area (SA), and subfoveal choroidal thickness (SCT) were measured and compared between baseline and follow-up visits among eyes with active and quiescent intermediate uveitis., Results: Thirty-eight eyes from 21 patients with active intermediate uveitis and 30 eyes from 17 patients with quiescent intermediate uveitis were included. CVI in eyes with active intermediate uveitis significantly increased from baseline (66.50% ± 3.40%) with resolution of inflammation on follow-up (68.82% ± 3.90%; P < 0.001). In eyes with quiescent intermediate uveitis at baseline eyes, CVI did not significantly change after follow-up (66.34% ± 3.19% to 66.25% ± 3.13%; P = 0.850)., Conclusions: CVI significantly increased when active inflammation in intermediate uveitis resolved while CVI remained unchanged at follow-up in quiescent intermediate uveitis., Translational Relevance: CVI may be a useful noninvasive tool to monitor treatment response in intermediate uveitis. Our findings also highlight the involvement of choroidal vasculature in uveitic eyes without any clinical evidence of choroiditis.

Background: Due to the guarded prognosis of acute retinal necrosis (ARN), it is relevant to develop a strategy to early categorize those patients in a higher risk of worse outcomes. The purpose of this study is to describe clinical features and predictive factors for retinal detachment (RD) in patients with ARN., Methods: Retrospective observational case series of 34 adult patients (38 eyes) with ARN examined between January 2005 and July 2015 in the National Eye Institute (Bethesda, USA), the Department of Ophthalmology, University of Chile (Santiago, Chile), and APEC (CDMX, Mexico)., Results: A total of 16 males and 18 females with a mean age at presentation of 44.5 ± 16.8 years were included. Twenty-seven patients (79.4%) received intravenous acyclovir as first-line treatment, and 7 patients received either oral antiviral (4 patients) or oral plus intravitreal antiviral (3 patients). All subjects were treated with prednisone, with a mean initial dose of 57.7 ± 16.3 mg per day. Seventeen patients (50.0%) developed retinal detachment. An association of retinal detachment with age at onset was observed (p = 0.04), with patients younger than 50 years presenting a higher risk (OR = 14.86, p = 0.0009). Additionally, patients in this higher risk group had more inflammation in both anterior chamber and vitreous (p = 0.04 and 0.03, respectively). No other predictive factor for retinal detachment was found in the present study., Conclusions: RD represents an important complication in patients with ARN. Younger patients may be at higher risk of this complication, possibly secondary to the presence of a higher level of inflammation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To report the prevalence of QuantiFERON-TB Gold (QFT-G) positivity among uveitis patients compared to general population and to evaluate the differences in clinical features of uveitis., Design: Retrospective cohort study., Methods: SETTING: Institutional., Patient Population: 418 consecutive new uveitis patients, regardless of clinical suspicion, were tested for QFT-G., Observation Procedures: Demographics, TB risk factors, clinical characteristics of uveitis were collected., Main Outcome Measures: The frequency of QFT-G positivity among uveitis patients and characteristic clinical features among QFT-G positive patients., Results: QFT-G positivity was found in 60/418 patients with uveitis (14.4%, 95% CI: 11.18 - 18.14) higher than the general US population (5%, 95% CI: 4.2 - 5.8, p<.001). Age, gender and residence were similar between QFT-G positive and negative groups. Uveitis patients with positive QFT-G were more likely to be foreign born or have a recent travel history (OR:5.84; 95% CI: 2.83 - 12.05; p<.001). QFT-G positive patients were more likely to present with granulomatous uveitis (OR 2.90; 95%CI 1.36 - 6.21; p=.006). No significant association was found with specific clinical features such as choroiditis, retinal vasculitis, occlusive vasculitis, and serpiginoid choroiditis (p>.05 for each). Prevalence of TB-uveitis based on treatment response was 1.19%., Conclusions: Our study demonstrates significantly higher prevalence of QFT-G positivity among uveitis patients compared to average US population. Characteristic signs of TB uveitis reported in endemic countries were not seen in this cohort. Implications of higher prevalence of QFT-G positivity among uveitis patients require further investigation., (Published by Elsevier Inc.)

Purpose: To determine the incidence of and predictive factors for cataract in intermediate uveitis., Design: Retrospective cohort study., Methods: Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study, in which medical records were reviewed to determine demographic and clinical data of every eye/patient at every visit at 5 participating US tertiary care uveitis centers. The primary outcome was development of vision-compromising cataract as defined by a decrease in visual acuity to 20/40 or less, or requiring cataract surgery. Survival analysis assessed visually defined cataract to avoid bias due to timing of surgery vis-à-vis inflammatory status., Results: Among 2,190 eyes of 1,302 patients with intermediate uveitis, the cumulative incidence of cataract formation was 7.6% by 1 year (95% confidence interval [CI] = 6.2%-9.1%), increasing to 36.6% by 10 years (95% CI = 31.2%-41.6%). Increased cataract risk was observed in eyes with concurrent anterior uveitis causing posterior synechiae (hazard ratio = 2.68, 95% CI = 2.00-3.59, P < .001), and in eyes with epiretinal membrane formation (hazard ratio = 1.54, 95% CI = 1.15-2.07, P = .004). Higher dose corticosteroid therapy was associated with significantly higher incidence of cataract, especially time-updated use of topical corticosteroids ≥2 times/d or ≥4 periocular corticosteroid injections. Low-dose corticosteroid medications (oral prednisone 7.5 mg daily or less, or topical corticosteroid drops <2 times/d) were not associated with increased cataract risk., Conclusions: Our study found that the incidence of clinically important cataract in intermediate uveitis is moderate. The risk is higher with markers of severity and with higher doses of corticosteroid medications, the latter being potentially modifiable., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population., Methods: Retrospective data from 5,530 noninfectious uveitis patients were abstracted by expert reviewers, and contemporaneous associations of VA with demographic and clinical factors were modeled., Results: Patients were a median of 41 years old, 65% female, and 73% white. Eyes diagnosed ≥5 years prior to cohort entry had worse VA (-1.2 lines) than those diagnosed <6 months prior, and eyes with cataract surgery performed prior to entry had worse VA (-5.9 lines) than those performed during follow-up. Vitreous haze (-4.2 lines for 3+ vs quiet), hypotony (-2.5 lines for ≤5 mm Hg vs 6-23 mm Hg), and CNV (-1.8 lines) all were strongly associated with reduced VA., Conclusion: Factors associated with reduced VA included well-known structural complications, and lack of subspecialty care during cataract surgery.

Introduction : We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population. Methods : Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up. Results : Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each P < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels. Conclusion : Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.

Purpose : To describe the changes seen on optical coherence tomography angiography [OCTA] in patients with PIC following immunosuppressive therapy. Methods : We reviewed serial OCTA scans from five consecutive PIC patients (5 eyes) with at least 3 months of follow-up, who underwent imaging before and after immunosuppressive therapy. Using ImageJ, superficial and deep retinal vasculature were analyzed for vessel area and foveal avascular zone. Choriocapillaris layer was analyzed for flow signal loss. Results : Five out of five patients received an orbital floor triamcinolone acetonide injection as the initial treatment for periods of activity. Mean choriocapillaris (CC) flow void area obtained after immunosuppressive therapy was significantly lower than the mean CC flow void area obtained prior to treatment (Pre-treatment: 0.270 vs Post-treatment: 0.144; p = .0068). In 2 out of 2 patients with longitudinal visual field testing, CC flow voids were spatially associated with visual field defects, and immunosuppressive therapy was associated with reduced CC flow void area and improved visual function. Conclusion : OCTA can detect alterations in choriocapillaris flow. Longitudinal follow-up demonstrates a centripetal restoration of choriocapillaris flow in response to immunosuppressive therapy. OCTA may be a useful adjunct for monitoring and evaluating treatment of PIC.

Purpose : Aims to determine the variability of ffERG measurements in patients with clinically stable birdshot chorioretinopathy (BCR). Methods : Repeatability coefficients (RC) of ffERG amplitudes and implicit times were calculated from 11 BCR patients. Jackknife resampling estimated 95% confidence intervals of each ERG parameter's RC and the percentage change explained by variability alone was calculated. Results : Intra-visit variability in ffERG parameters was lower than inter-visit. Intravisit RCs demonstrated that for intravisit ERG testing, there was less than 30% variation in ERG amplitude for most parameters. For inter-visit ERG testing, a greater than 40% reduction in ERG amplitude may be clinically meaningful for 6 of 8 ERG parameters. Photopic single flash responses have <2 msec of test-retest variability both within and across visits. Conclusions : A 40% reduction in ERG amplitude and/or a delay of >2 msec in the photopic single flash response may be suitable criteria for meaningful change in BCR patients.

Background: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors can cause unique immune-related adverse effects due to non-specific immunological activation. However, less is known about adverse effects of these drugs in the eye., Methods: Two adverse event databases were retrospectively reviewed. The two databases consisted of a routine adverse event database and a serious adverse event database of expeditiously submitted reports. Patients with any malignancy who had ocular adverse events while on PD-1/PD-L1 inhibitor treatment were included. Patients received nivolumab, pembrolizumab, atezolizumab or durvalumab alone or in combination with other anticancer agents per each trial's protocol. Databases were queried up to May 19, 2020., Results: In the routine adverse event database, 272 adverse events from 213 patients were reported and in the serious adverse event reporting database, 59 ocular adverse events from 47 patients were reported. A lower estimate of the prevalance from the routine adverse event database showed 259/7727 patients on study treatment arms reporting ocular adverse events (3.3% prevalence). Excluding trials that do not report lower grade adverse events to the routine adverse event database results in a higher end estimate of 242/3255 patients on study treatment arms reporting ocular adverse events (7.4% prevalence). Ocular events occurred early after drug initiation (routine database: median 6 weeks, IQR 0-16, serious adverse events database: median 11 weeks, IQR 6-21). The median Common Terminology Criteria for Adverse Events grade was grade 1 (mild) (IQR 1-2) and grade 2 (moderate) (IQR 2-3) for the routine database and the serious adverse events database, respectively. In-depth analysis of the serious adverse event reports revealed varying degrees of clinical workup, with 30/47 patients (64%) receiving ophthalmological evaluation and 16/47 (34%) of patients having to delay or discontinue treatment. However, 16/47 (34%) patients experienced resolution and 14/47 (30%) patients experienced at least some improvement., Conclusions: This is one of the largest analyses of ocular adverse events in patients treated with PD-1/PD-L1 inhibitors in the USA. We found ocular adverse events are rare complications of PD-1/PD-L1 inhibitor therapy, can be severe enough to cause treatment discontinuation/delay, and may not always be appropriately evaluated by eye specialists. Standardized plans for ophthalmology evaluation and management of ocular toxicities are needed in studies of patients treated with PD-1/PD-L1 inhibitors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study explored systemic immune changes in 11 subjects with X-linked retinoschisis (XLRS) in a phase I/IIa adeno-associated virus 8 (AAV8)-RS1 gene therapy trial (ClinicalTrials.gov: NCT02317887). Immune cell proportions and serum analytes were compared to 12 healthy male controls. At pre-dosing baseline the mean CD4/CD8 ratio of XLRS subjects was elevated. CD11c + myeloid dendritic cells (DCs) and the serum epidermal growth factor (EGF) level were decreased, while CD123 + plasmacytoid DCs and serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased, indicating that the XLRS baseline immune status differs from that of controls. XLRS samples 14 days after AAV8-RS1 administration were compared with the XLRS baseline. Frequency of CD11b + CD11c + DCc was decreased in 8 of 11 XLRS subjects across all vector doses (1e9-3e11 vector genomes [vg]/eye). CD8 + human leukocyte antigen-DR isotype (HLA-DR) + cytotoxic T cells and CD68 + CD80 + macrophages were upregulated in 10 of 11 XLRS subjects, along with increased serum granzyme B in 8 of 11 XLRS subjects and elevated IFN-γ in 9 of 11 XLRS subjects. The six XLRS subjects with ocular inflammation after vector application gave a modestly positive correlation of inflammation score to their respective baseline CD4/CD8 ratios. This exploratory study indicates that XLRS subjects may exhibit a proinflammatory, baseline immune phenotype, and that intravitreal dosing with AAV8-RS1 leads to systemic immune activation with an increase of activated lymphocytes, macrophages, and proinflammatory cytokines., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Importance: The clinical utility of most antiretinal antibodies (retina antibodies) currently available for testing remains unclear and unproven. Despite this, the presence of retinal antibodies is included in current diagnostic autoimmune retinopathy criteria., Objective: To evaluate the clinical significance of comprehensive retinal antibody evaluations currently offered in North America., Design, Setting, and Participants: In this cross-sectional study, 14 patients without autoimmune retinopathy were recruited into the Mayo Clinic Neuroimmunology Biorepository for this study between January 1, 2019, and October 1, 2019. These serum samples without autoimmune retinopathy were sent in masked fashion to a Clinical Laboratory Improvement Amendments-certified laboratory. Using similar methods, the Mayo Clinic Neuroimmunology Research Laboratory independently assessed the same sample to ascertain reproducibility of the findings., Main Outcomes and Measures: Results of the autoimmune retinopathy and cancer-associated retinopathy panels., Results: Thirteen of 14 (93%; 95% CI, 66%-100%) serum samples tested positive for retinal antibodies, with a median of 5 retinal antibodies (range, 0-8) per patient at the Clinical Laboratory Improvement Amendments-certified laboratory, which provides a specificity of 7% (95% CI, 0%-34%). Confirmatory immunohistochemistry staining in human retina was present in 12 of 14 samples (86%). α-Enolase was found in 9 (64%). The only retinal antibody not present was recoverin. These nonspecific retinal antibody results were replicated at the Mayo Clinic Laboratory on Western blot using pig retina proteins as substrate., Conclusions and Relevance: The presence of retinal antibodies in 93% of the patients without autoimmune retinopathy indicates a lack of specificity and that most detectable retinal antibodies have limited clinical relevance in the evaluation of patients for suspected autoimmune retinopathy. Current retinal antibody testing, other than recoverin, should be interpreted with caution, especially for cases of low clinical suspicion. The poor specificity is important to recognize to prevent the potentially unnecessary commencement of systemic immunosuppressants that may result in significant extraocular adverse effects. Identification of biomarkers that have a high predictive value for inflammatory or autoimmune retinal diseases is needed to move the field forward.

Purpose: Autosomal recessive bestrophinopathy (ARB) and vitelliform macular dystrophy (VMD) are distinct phenotypes, typically inherited through recessive and dominant patterns, respectively. Recessively inherited VMD (arVMD) has been reported, suggesting that dominant and recessive BEST1-related retinopathies represent a single disease spectrum. This study compares adVMD, arVMD, and ARB to determine whether a continuum exists and to define clinical and genetic features to aid diagnosis and management., Methods: One arVMD patient and nine ARB patients underwent standard ophthalmic examination, imaging, electrophysiology, and genetic assessments. A meta-analysis of reported BEST1 variants was compiled, and clinical parameters were analyzed with regard to inheritance and phenotype., Results: Among 10 patients with biallelic BEST1 variants, three novel ARB variants (p.Asp118Ala, p.Leu224Gln, p.Val273del) were discovered. A patient with homozygous p.Glu35Lys was clinically unique, presenting with VMD, including hyperautofluorescence extending beyond the macula, peripheral punctate lesions, and shortened axial-length. A tritan-axis color vision deficit was seen in three of six (50%) of ARB patients. Attempts to distinguish recessively-inherited ARB and dominantly-inherited VMD genotypically, by variant frequency and residue location, did not yield significant differences. Literature meta-analysis with principle component analysis of clinical features demonstrated a spectrum of disease with arVMD falling between adVMD and ARB., Conclusions: This study suggests that arVMD is part of a continuum of autosomal recessive and dominant BEST1-related retinopathies. Detailed clinical and molecular assessments of this cohort and the literature are corroborated by unsupervised analysis, highlighting the overlapping heterogeneity among BEST1-associated clinical diagnoses. Tritan-axis color vision deficit is a previously unreported finding associated with ARB.

Purpose: To investigate the efficacy of biosimilar infliximab compared to that of the originator infliximab for the treatment of chronic non-infectious uveitis., Design: Before-and-after study., Methods: All patients in the Central Norway Health Region between 2007 and 2018 were included. They were switched from originator to biosimilar infliximab therapy from 2014 to 2017. The primary outcome was quiescence of uveitis before and after the switch. All patients were seen every 1-3 months. Visits were binned into 3-month long periods for each patient takingboth medications. Poisson regression analysis was used to estimate the incidence rate ratio (IRR) of quiescence between the 2 treatments., Results: Twenty-nine patients were treated with infliximab. Twenty-three of those patients were switched from originator to biosimilar infliximab. The majority were white (87%), female (92%), and had chronic anterior uveitis (65%). For patients taking the originator and biosimilar drugs, the median treatment duration was38 months (range: 8-131 months) and 15 months (range: 5-55 months), respectively. Concomitant immunosuppressive medications and topical and oral steroids were used similarly during treatment with both originator and biosimilar infliximab. The IRR for quiescence was 0.91 (95% confidence intervals [CI]: 0.7-1.1; P = 0.38), which indicated no statistically significant differences in achieving quiescence after the switch. Also, there were no differences in the incidence rate of flare events with the switch (IRR: 1.04; 95% CI: 0.36-2.98; P = 0.95). IRR adjusted for intraocular surgery was 0.90 (95% CI: 0.7-1.1; P = 0.37)., Conclusions: No evidence of differences in effectiveness were found in comparing biosimilar to originator infliximab in patients with chronic non-infectious uveitis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To provide recommendations for diagnosis of vitreoretinal lymphoma (VRL)., Methods: Literature was reviewed for reports supporting the diagnosis of VRL. A questionnaire (Delphi 1 round) was distributed to 28 participants. In the second round (Delphi 2), items of the questionnaire not reaching consensus (75% agreement) were discussed to finalize the recommendations., Results: Presenting symptoms include floaters and painless loss of vision, vitreous cells organized into sheets or clumps. Retinal lesions are usually multifocal creamy/white in the outer retina. Other findings include retinal lesions with "leopard-skin" appearance and retinal pigment epithelium atrophy. Severe vitreous infiltration without macular edema is the most likely presentation. Diagnostic vitrectomy should be performed. Systemic corticosteroid should be discontinued at least 2 weeks before surgery. An interleukin (IL)-10:IL-6 ratio > 1, positive mutation for the myeloid differentiation primary response 88 gene and monoclonality are indicators of VRL. Multi-modal imaging (optical coherence tomography, fundus autofluorescence) are recommended., Conclusions: A consensus meeting allowed the establishment of recommendations important for the diagnosis of VRL.

Purpose: To assess how often non-infectious anterior scleritis remits and identify predictive factors., Methods: Our retrospective cohort study at four ocular inflammation subspecialty centers collected data for each affected eye/patient at every visit from center inception (1978, 1978, 1984, 2005) until 2010. Remission was defined as inactivity of disease off all suppressive medications at all visits spanning at least three consecutive months or at all visits up to the last visit (to avoid censoring patients stopping follow-up after remission). Factors potentially predictive of remission were assessed using Cox regression models., Results: During 1,906 years' aggregate follow-up of 832 affected eyes, remission occurred in 214 (170 of 584 patients). Median time-to-remission of scleritis = 7.8 years (95% confidence interval [CI]: 5.7, 9.5). More remissions occurred earlier than later during follow-up. Factors predictive of less scleritis remission included scleritis bilaterality (adjusted hazard ratio [aHR] = 0.46, 95% CI: 0.32-0.65); and diagnosis with any systemic inflammatory disease (aHR = 0.36, 95% CI: 0.23-0.58), or specifically with Rheumatoid Arthritis (aHR = 0.22), or Granulomatosis with Polyangiitis (aHR = 0.08). Statin treatment (aHR = 1.53, 95% CI: 1.03-2.26) within ≤90 days was associated with more remission incidence., Conclusions: Our results suggest scleritis remission occurs more slowly in anterior scleritis than in newly diagnosed anterior uveitis or chronic anterior uveitis, suggesting that attempts at tapering suppressive medications is warranted after long intervals of suppression. Remission is less frequently achieved when systemic inflammatory diseases are present. Confirmatory studies of whether adjunctive statin treatment truly can enhance scleritis remission (as suggested here) are needed., (Copyright © 2019. Published by Elsevier Inc.)