Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.

Predictive Association of Pre-Operative Defect Areas in the Outer Retinal Layers With Visual Acuity in Macular Hole Surgery.

Purpose: The purpose of this study was to develop methods to model the external limiting membrane (ELM) and ellipsoid zone (EZ) within the elevated cuff surrounding a macular hole (MH) to determine if the predicted size of the defect in these layers after virtual flattening was associated with the actual postoperative defect and best-corrected visual acuity (BCVA). Methods: Patients were included who had undergone successful MH surgery. The defects in the ELM and EZ after virtual flattening were modeled using in-house software. Main outcomes were postoperative defects in ELM and EZ at 2 months and BCVA at 12 months. Results: Fifty-eight patients were included. BCVA improved from 0.87 (0.31) logMAR pre-operatively to 0.26 (0.21) at 12 months (P < 0.001). For both the ELM and EZ, the predicted virtually flattened pre-operative defects were associated with the actual postoperative defects at 2 months (R2 = 0.33, P < 0.01 and R2 = 0.50, P < 0.01, respectively). There was a significant association of BCVA at 12 months (adjusted R2 = 0.85) with the pre-operative modeled area of the defect in the ELM (P < 0.01) and to a lesser extent with the defect in the EZ (P < 0.01) and base of the MH (P < 0.01). Conclusions: Virtually flattening of the pre-operative defect in the ELM provides important predictive information of visual acuity. Incorporation of tools into commercially available optical coherence tomography (OCT) devices to facilitate such measurements would provide the clinician with important prognostic information. Translational Relevance: We have developed methodology that can potentially be used to predict the postoperative state of the outer retinal layers and the associated visual outcome in patients undergoing surgery for MH.

Clinical outcomes in Caucasian patients with polypoidal choroidal vasculopathy.

PURPOSE: To describe treatment outcomes in a cohort of Caucasian patients with polypoidal choroidal vasculopathy (PCV). METHODS: Clinical charts from 48 eyes of 45 Caucasian patients with PCV were retrospectively reviewed. All cases were diagnosed with indocyanine green angiography. Best corrected visual acuity (BCVA) and optical coherence tomography (OCT) imaging were analyzed at baseline and final follow-up. RESULTS: Eyes were treated with a combination of verteporfin photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) (n = 24), or PDT monotherapy (n = 9), or anti-VEGF monotherapy (n = 8), or no treatment (n = 7). Aflibercept was the anti-VEGF agent in 30 out of 32 eyes. Sixteen out of 24 eyes in the combination treatment group received initial PDT at diagnosis. All treatments led to stabilization of BCVA at final visit with a trend for better visual acuity in the anti-VEGF monotherapy group. There was a substantial reduction in central retinal thickness associated with resolution of subfoveal fluid and improvement in retinal pigment epithelial detachment in all treatment groups. BCVA and OCT findings remained stable in eyes which received no treatment. The use of PDT was associated with 0.5 fewer intravitreal injections per annum, which was not statistically significant. CONCLUSIONS: In the largest series of Caucasian patients with PCV presented to date, anti-VEGF monotherapy, PDT, or their combination preserved visual acuity and improved subfoveal exudative changes. Combination treatment was not superior to anti-VEGF monotherapy.

Polypoidal choroidal vasculopathy: a common type of neovascular age-related macular degeneration in Caucasians.

AIMS: To describe the prevalence of polypoidal choroidal vasculopathy (PCV) in a Caucasian population with neovascular age-related macular degeneration (NAMD). METHODS: All patients referred to a city AMD service over a 2-year period underwent imaging including Indocyanine Green Angiography at baseline. A panel of experts confirmed the patients with NAMD and diagnosed the lesion type including PCV. The proportion of Caucasian patients with PCV was identified. Two authors independently reviewed clinical imaging and recorded data of patients with PCV on lesion characteristics. Further information including treatments received and visual acuity at different time points was analysed. RESULTS: A total of 492 patients were diagnosed with NAMD during the 2-year study period. Of these patients, 204 had occult lesions (41.5%). PCV was identified in 45 patients (22.1% of occult NAMD and 9.1% of all NAMD). 23 patients received anti-vascular endothelial growth factor (VEGF) monotherapy, 8 received verteporfin photodynamic therapy (PDT) monotherapy and the remaining 14 patients were managed with combined PDT and anti-VEGF treatment. CONCLUSIONS: The prevalence of PCV in Caucasians is higher than previously reported. Indocyanine Green Angiography should be a standard investigation for all new patients with NAMD, particularly those with occult NAMD, to avoid missing this important subset.

Use of Staurenghi lens angiography in the management of posterior uveitis.

PURPOSE: Retinal vasculitis is an important component of posterior uveitis. It may be difficult to detect either clinically or with conventional angiography. We assessed the role of Staurenghi lens angiography (SLA) in the diagnosis and management of patients with posterior uveitis. METHODS: A total of 26 patients attending the St Paul's Eye Unit uveitis clinic with posterior uveitis underwent wide-angle (150 degree) retinal angiography with the Heidelberg Retina Angiograph 2 Scanning Laser Ophthalmoscope using the Staurenghi SLO 230 contact lens. We determined the percentage of patients in whom this imaging modality assisted in diagnosing and quantifying the extent of vasculitis, planning treatment or monitoring disease activity. RESULTS: Staurenghi lens angiography assisted in diagnosing and quantifying the extent of vasculitis in 62% of patients, and in planning laser photocoagulation or immunosuppression titration in 62% of patients and enhanced disease monitoring in 35% of patients. In 31% of cases, SLA revealed vasculitis that was not evident clinically. CONCLUSION: Staurenghi lens angiography is a valuable tool in the management of patients with posterior uveitis and can be used for the diagnosis, treatment and follow-up of these patients.

Bilateral viral retinitis in a patient with immune deficiency because of purine nucleoside phosphorylase deficiency.

BACKGROUND: Progressive retinal outer necrosis is a devastating viral necrotizing retinitis, which affects predominantly immunocompromised patients. We report a case in which the ocular findings led to a search for an underlying immune deficiency, established as congenital purine nucleoside phosphorylase deficiency. METHODS: Retrospective, interventional case report. RESULTS: We describe the clinical features and management of the disease. CONCLUSION: This is the first report of bilateral varicella zoster virus retinitis with underlying purine nucleoside phosphorylase deficiency. It highlights the importance of thorough investigation in apparent immunocompetent patients presenting with viral retinitis, as this may indicate an undiagnosed primary immunodeficiency.

Paraneoplastic exudative retinal detachment associated with adenocarcinoma of the lung.

PURPOSE: To report a case of bilateral paraneoplastic exudative retinal detachment (ERD) associated with asymptomatic adenocarcinoma of the lung. METHODS: Case report. RESULTS: A 47-year-old man presented with bilateral ERD accompanied by anterior and posterior segment inflammation. Extensive investigations for local and systemic causes of ERD were unrewarding. Only when computed tomography scanning of the thorax was performed were enlarged thorax lymph nodes demonstrated and revealed biopsy-proven adenocarcinoma. CONCLUSIONS: Paraneoplastic phenomena should be considered in patients presenting with ERD. Ocular paraneoplastic pathologies may be the initial manifestation of an underlying malignancy.

Glycaemic control and control of risk factors in diabetes patients in an ophthalmology clinic: what lessons have we learned from the UKPDS and DCCT studies?

PURPOSE: The Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study (UKPDS) have studied glycaemic control as well as other risk factors in preventing the progression of diabetic end-organ disease, including diabetic retinopathy. We wished to determine to what extent a cross-section of diabetes patients attending our eye clinic met the targets laid down by recent landmark studies. METHODS: We prospectively assessed 44 consecutive diabetes patients attending outpatient clinics for assessment of diabetic retinopathy. Each patient had HbA1c levels, serum cholesterol and blood pressure checked. A proforma was completed for each patient. RESULTS: Of the 44 patients studied, 11 had type 1 diabetes mellitus (DM) and 33 had type 2 DM (11 insulin-dependent DM [IDDM], 22 non-insulin-dependent DM [NIDDM]). The mean age of type 1 DM patients was 43 years; that of type 2 DM patients was 62 years. Five of 11 (46%) type 1 DM patients had poorly controlled diabetes (HbA1c > 9%) compared with four of 33 (12%) type 2 DM patients. Overall, 27 of 44 (62%) patients were on antihypertensive medication. The prevalence of poorly controlled blood pressure (> 150/85 mmHg treated; > 160/90 mmHg untreated) was 16 of 44 (36%) patients overall, and was higher for type 2 DM patients (13/33, 39%) than for type 1 DM patients (3/11, 27%). Random serum cholesterol levels > 5.2 were found in 10 of 44 (23%) patients overall (4/11 [36%] type 1 and 6/33 [18%] type 2 DM patients). CONCLUSIONS: Control of HbA1c, hypertension and hypercholesterolaemia can slow progression of retinopathy and other DM end-points. Many of our patients were poorly controlled in terms of these risk factors. More attention should be addressed to these primary preventative factors in the management of diabetes patients.

Mycophenolate mofetil as an immunosuppressive agent in refractory inflammatory eye disease.

PURPOSE: The aim of this study was to assess the role of mycophenolate mofetil (MMF) in refractory inflammatory eye disease. METHODS: Retrospective, noncomparative, interventional case series of all patients commenced on MMF between 1999 and 2005 for refractory inflammatory eye disease at St Paul's Eye Unit (Liverpool, UK). Main outcome measures noted were control of inflammation, steroid-sparing effect, and adverse effects of MMF therapy. RESULTS: Ten (10) patients (2 with sarcoid, 2 with intermediate uveitis, 1 with Vogt-Koyanagi Harada (VKH) syndrome, 1 with ankylosing spondylitis, 1 with juvenile chronic arthritis (JCA), and 3 with scleritis) who were unresponsive or intolerant to previous therapy and/or as a steroid-sparing agent, received 2-3 g of MMF per day for a mean period of 40.5 months (range, 3-67). Nine (9) patients had a favorable response, with diarrhea and insomnia being the main side-effects. MMF had to be withdrawn in 1 patient because of side-effects and in another because of active arthropathy (with stable uveitis). Average number of relapses was reduced from 3.1 per patient per year to 0.8 per patient per year (P < 0.005). A steroid-sparing effect was achieved in all patients. Visual acuity improved in 8 patients. CONCLUSIONS: MMF appears to be a safe and effective second- or third-line adjunct/alternative immunosuppressant in these difficult cases and works well in combination with cyclosporin A, tacrolimus, and antitumor necrosis factor (TNF) agents. It has potential as a firstor second-line agent and can be considered at a dose of 3 g/day in refractory cases.