Does Dry Eye Disease Severity Impact Efficacy of Varenicline Solution Nasal Spray on Sign and Symptom Treatment Outcomes?

SIGNIFICANCE: There is a clinical necessity for dry eye disease treatments that perform across a broad range of presenting patient severities. Varenicline solution nasal spray (VNS), a unique cholinergic agonist ocular surface-sparing nasal spray therapy, demonstrated significant improvement in both signs and symptoms of dry eye disease in subjects with mild, moderate, and severe symptoms as the clinical studies enrolled a more real-world patient population. PURPOSE: This study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease. METHODS: An analysis of integrated data from two randomized clinical trials, ONSET-1 (NCT03636061) and ONSET-2 (NCT04036292) (vehicle control [VC], n = 294; VNS 0.03 mg, n = 308), was performed. Adults 22 years or older with dry eye disease, Ocular Surface Disease Index score of ≥23, corneal fluorescein staining score of ≥2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) of ≤10 mm (no restrictions on Eye Dryness Score [EDS]) were included in this study. Efficacy was evaluated using analysis of covariance among pre-specified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 vs. >5) and EDS (<60 vs. ≥60). Consistency of effect was evaluated by interaction tests. RESULTS: No treatment-subgroup interactions were observed for all end points ( P > .05). The odds of achieving a ≥10-mm improvement in STS for VNS versus VC for patients with baseline STS ≤5 and >5 were 3.4(95% confidence interval, 2.0 to 5.6) and 2.3(1.3 to 4.0) and for EDS of <60 and ≥60 were 3.4(1.9 to 6.1) and 2.5(1.5 to 4.0). Least-squares mean treatment/VC differences in change from baseline in EDS for patients with baseline STS ≤5 or >5 were -7.4(95% confidence interval, -12.5 to -2.4) and -2.8(-8.7 to 3.1); EDS of <60 and ≥60 were -2.9(-8.3 to 2.5) and -8.1(-13.6 to -2.6). CONCLUSIONS: Compared with VC, VNS improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating consistency of effect regardless of initial presenting severity.

A Phase 3b Study for Management of Ocular Side Effects in Patients with Epidermal Growth Factor Receptor-Amplified Glioblastoma Receiving Depatuxizumab Mafodotin.

INTRODUCTION: The Understanding New Interventions with GBM ThErapy (UNITE) study was designed to assess the effect of prophylaxis for ocular side effects (OSEs) in patients with glioblastoma receiving the antibody-drug conjugate (ADC) depatuxizumab mafodotin. UNITE (NCT03419403) was a phase 3b, open-label, randomized, exploratory study performed at 18 research sites in 5 countries. METHODS: The study enrolled adult patients with epidermal growth factor receptor-amplified, histologically confirmed, newly diagnosed supratentorial glioblastoma or grade IV gliosarcoma, and a Karnofsky Performance Status ≥70, receiving depatuxizumab mafodotin. All patients were administered depatuxizumab mafodotin during concurrent radiotherapy and temozolomide and with adjuvant temozolomide. Ninety patients were to be randomized (1:1:1) to OSE prophylactic treatments with each depatuxizumab mafodotin infusion: (a) standard steroid eye drops, (b) standard steroid eye drops plus vasoconstrictor eye drops and cold compress, or (c) enhanced steroids plus vasoconstrictor eye drops and cold compress. A Corneal Epitheliopathy Adverse Event (CEAE) scale was devised to capture symptoms, grade OSEs (scale of 0-5), and inform ADC dose modifications. The primary endpoint was the frequency of a required change in OSE management due to inadequate control of OSEs, defined as decline from baseline in visual acuity (using logarithm of the minimum angle of resolution [LogMAR] scale) or a Grade ≥3 CEAE event, in the worst eye in the first 8 weeks of treatment; unless otherwise specified, the treatment period refers to both the chemoradiation and adjuvant phases. RESULTS: The UNITE study was stopped early after interim analysis of separate phase III trial showed no difference in survival from depatuxizumab mafodotin. Forty patients were randomized (38 received depatuxizumab mafodotin). Overall, 23 patients experienced inadequate control of OSEs that required change in OSE management within 8 weeks of treatment, with 21 (70.0%) experiencing ≥+0.3 change on LogMAR scale in baseline-adjusted visual acuity and 12 reporting a grade ≥3 CEAE. There were no definitive differences among prophylactic treatments. CONCLUSIONS: The premature cessation of the study precludes definitive conclusions regarding the OSE prophylaxis strategies. No new clinically significant safety findings were noted. Despite these limitations, this study highlights the need for novel assessment tools to better understand and mitigate OSEs associated with ADCs.

The SARS-CoV-2 Virus and the Cholinergic System: Spike Protein Interaction with Human Nicotinic Acetylcholine Receptors and the Nicotinic Agonist Varenicline.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the worldwide coronavirus disease 2019 (COVID-19) pandemic. Although the pathophysiology of SARS-CoV-2 infection is still being elucidated, the nicotinic cholinergic system may play a role. To evaluate the interaction of the SARS-CoV-2 virus with human nicotinic acetylcholine receptors (nAChRs), we assessed the in vitro interaction of the spike protein of the SARS-CoV-2 virus with various subunits of nAChRs. Electrophysiology recordings were conducted at α4ß2, α3ß4, α3α5ß4, α4α6ß2, and α7 neuronal nAChRs expressed in Xenopus oocytes. In cells expressing the α4ß2 or α4α6ß2 nAChRs, exposure to the 1 µg/mL Spike-RBD protein caused a marked reduction of the current amplitude; effects at the α3α5ß4 receptor were equivocal and effects at the α3ß4 and α7 receptors were absent. Overall, the spike protein of the SARS-CoV-2 virus can interact with select nAChRs, namely the α4ß2 and/or α4α6ß2 subtypes, likely at an allosteric binding site. The nAChR agonist varenicline has the potential to interact with Spike-RBD and form a complex that may interfere with spike function, although this effect appears to have been lost with the omicron mutation. These results help understand nAChR's involvement with acute and long-term sequelae associated with COVID-19, especially within the central nervous system.

Standard management options for rosacea: The 2019 update by the National Rosacea Society Expert Committee.

In 2017, a National Rosacea Society Expert Committee developed and published an updated classification of rosacea to reflect current insights into rosacea pathogenesis, pathophysiology, and management. These developments suggest that a multivariate disease process underlies the various clinical manifestations of the disorder. The new system is consequently based on phenotypes that link to this process, providing clear parameters for research and diagnosis as well as encouraging clinicians to assess and treat the disorder as it may occur in each individual. Meanwhile, a range of therapies has become available for rosacea, and their roles have been increasingly defined in clinical practice as the disorder has become more widely recognized. This update is intended to provide a comprehensive summary of management options, including expert evaluations, to serve as a guide for tailoring treatment and care on an individual basis to achieve optimal patient outcomes.

Donor, Recipient, and Operative Factors Associated with Graft Success in the Cornea Preservation Time Study.

PURPOSE: To associate donor, recipient, and operative factors with graft success 3 years after Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter, double-masked, randomized clinical trial. PARTICIPANTS: One thousand ninety individuals (1330 study eyes) with a median age of 70 years undergoing DSAEK for Fuchs endothelial corneal dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE; 6% of eyes). METHODS: Eyes undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0 to 7 days (n = 675) or 8 to 14 days (n = 655). Donor, recipient, and operative parameters were recorded prospectively. Graft failure was defined as regraft for any reason, a graft that failed to clear by 8 weeks after surgery, or an initially clear graft that became and remained cloudy for 90 days. Failure in the first 8 weeks was classified further as primary donor failure or early failure, in the absence or presence of operative complications, respectively. Proportional hazards and logistic regression models were used to estimate risk ratios (RR) and 99% confidence intervals (CIs) for graft failure. MAIN OUTCOME MEASURES: Graft success at 3 years. RESULTS: One thousand two hundred fifty-one of 1330 grafts (94%) remained clear at 3 years and were considered successful. After adjusting for PT, tissue from donors with diabetes (RR, 2.35; 99% CI, 1.03-5.33) and operative complications (RR, 4.21; 99% CI, 1.42-12.47) were associated with increased risk for primary or early failure. Preoperative diagnosis of PACE (RR, 3.59; 99% CI, 1.05-12.24) was associated with increased risk for late failure by 3 years after surgery compared with Fuchs dystrophy. Graft success showed little variation among other factors evaluated, including donor age (RR, 1.19 per decade; 99% CI, 0.91-1.56 per decade), preoperative donor endothelial cell density (RR, 1.10 per 500 cells; 99% CI, 0.74-1.63 per 500 cells), graft diameter (RR, 1.22 per 1 mm; 99% CI, 0.39-3.76 per 1 mm), and injector use for graft insertion (RR, 0.92; 99% CI, 0.40-2.10). CONCLUSIONS: Descemet stripping automated endothelial keratoplasty success in the early and entire postoperative period is more likely when the donor did not have diabetes and was without operative complications and in the long-term postoperative period in recipients with Fuchs dystrophy compared with those with PACE. Mechanisms whereby diabetic donors and PACE recipients reduce the rate of graft success after DSAEK warrant further study.

Adherence to Hydroxychloroquine Dosing Guidelines by Rheumatologists: An Electronic Medical Record-Based Study in an Integrated Health Care System.

PURPOSE: To study the adherence of rheumatologists to the hydroxychloroquine (HCQ) dosing guidelines established by the American Academy of Ophthalmology in 2011 and 2016. DESIGN: Retrospective review of electronic medical records (EMRs) in an integrated health care system. PARTICIPANTS: All rheumatology patients started on HCQ who were seen by a NorthShore ophthalmologist between the years 2009 and 2016. METHODS: Data on patient weights, height, gender, and HCQ dosage were extracted from the EMR. The recommended maximum starting dose was determined using 2 formulas based on ideal or actual body weight. MAIN OUTCOME MEASURES: The percentage of patients whose dose exceeded the recommended maximum. RESULTS: A total of 554 patients on HCQ were identified. Some 50% of the patients had been placed on excess initial doses according to the 2011 guidelines, and 47% of the patients had been placed on excess initial doses according to the 2016 guidelines. The introduction of the guidelines had no appreciable effect on HCQ dosing. A separate analysis of all patients currently receiving maintenance HCQ therapy demonstrated excess dosing in 297 of 527 (56%), according to the 2016 guidelines. CONCLUSIONS: Approximately one half of all patients started on HCQ by NorthShore rheumatologists received doses in excess of the recommended maximum, and slightly more than one-half of all patients currently on treatment continue to receive excess doses. Our data suggest that the publication of the consensus guidelines in 2011 had no appreciable effect on HCQ dosing and that transitioning to the 2016 dosing modification is unlikely to change this outcome unless additional steps are taken to improve adherence.

Matching-adjusted indirect comparison of phase 3 clinical trial outcomes of OC-01 (varenicline solution) nasal spray and lifitegrast 5% ophthalmic solution for the treatment of dry eye disease.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a methodology for cross-study comparisons after adjusting for baseline characteristic imbalances. It is a comparative analytical approach used across therapeutic areas absent head-to-head trial outcomes. OBJECTIVE: To compare the efficacy of OC-01 (varenicline solution) 0.03 mg nasal spray (OC-01 VNS) to lifitegrast 5% ophthalmic solution on tear production and patient-reported eye dryness in patients with dry eye disease (DED) using data from phase 3 clinical trials via MAIC analysis. METHODS: Individual patient data (IPD) from the phase 3 registrational trial of OC-01 VNS and aggregate data from 2 phase 3 trials of lifitegrast in the publicly available XIIDRA New Drug Application were used. Using unanchored MAIC methods, IPD were weighted on clinically relevant baseline variables (age, race, sex, baseline Schirmer's test score [STS], and Eye Dryness Score [EDS]) to produce weighted OC-01 VNS datasets matched to the same lifitegrast datasets' variables. Least-squares (LS) mean change from baseline (CFB) in STS for OC-01 VNS was calculated using the identical analysis of covariance model and covariates used to calculate the same values for lifitegrast in the XIIDRA New Drug Application and was then compared. LS mean EDS (based on a 100- point Visual Analogue Scale) was compared via analysis of covariance in the weighted OC-01 VNS and lifitegrast datasets. OC-01 VNS at 2 and 4 weeks compared to lifitegrast data at 2 and 6 weeks. RESULTS: Data from 511 subjects (n = 260 treated; 251 vehicle control [VC]) in the OC-01 VNS phase 3 trial, 588 (n = 293 treated, 295 VC) in the lifitegrast phase 3 OPUS-1 trial, and 718 (n = 358 treated, 360 VC) in the lifitegrast phase 3 OPUS-2 trial were analyzed. The LS mean STS CFB for OC-01 VNS at 2 and 4 weeks was significantly greater than that for lifitegrast at 2 and 6 weeks in OPUS-1 and OPUS-2 (P < 0.0001 for all comparisons). The LS mean EDS CFB for OC-01 VNS at 2 and 4 weeks was significantly greater than that for lifitegrast at 2 and 6 weeks in OPUS-1 (P < 0.0001 for both comparisons) and at 4 weeks vs lifitegrast at 6 weeks in OPUS-2 (P < 0.0001). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produced significantly greater improvement in mean STS and comparable or greater improvement in EDS compared with lifitegrast in phase 3 trials. These findings suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with lifitegrast for the treatment of DED within the conditions of the analysis methodology. DISCLOSURES D White is a consultant for Oyster Point Pharma, Inc. L Hendrix, M Macsai, and A Gibson are employees and shareholders for Oyster Point Pharma, Inc. L Sun was an employee of COEUS, Clinical Research at the time of study conduct and received funding from Oyster Point Pharma, Inc. I Tam is an employee of COEUS, Clinical Research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc was involved in the study design, data collection, data analysis, and preparation of the manuscript and is the manufacturer/licensee of OC-01 (varenicline solution) nasal spray. Oyster Point Pharma, Inc., sponsored the phase 3 OC-01 (varenicline solution) clinical study from which analysis data were obtained.

OC-01 (Varenicline Solution) Nasal Spray for the Treatment of Dry Eye Disease Signs and Symptoms in Subjects with Autoimmune Disease: Integrated Data from ONSET-1 and ONSET-2.

Purpose: We evaluate the treatment effect of OC-01 (varenicline solution) nasal spray (VNS) in dry eye disease (DED) subjects from two randomized trials who self-reported autoimmune disease (AID). Patients and Methods: Post hoc subgroup analysis of subjects reporting a history of AID from the integrated OC-01 VNS 0.03 or 0.06 mg and vehicle control (VC) treatment groups of the ONSET-1 and ONSET-2 trials. Mean change in Schirmer test with anesthesia score (STS, mm) and Eye Dryness Score (EDS) from baseline to 28 days was compared between OC-01 VNS and VC groups. Consistency of treatment effect in subjects with and without AID was evaluated using treatment-subgroup interaction terms in ANCOVA models for mean changes from baseline STS and EDS, and in a logistic regression model for proportion achieving ≥10 mm STS improvement. Results: Of the 891 participants, 31 reported comorbid AID. In all models, the treatment-subgroup interaction terms were not significant (p>0.05), indicating consistency of therapeutic effect of OC-01 VNS in subjects with and without AID. In subjects with AID, the treatment difference for STS was 11.8 mm and -9.3 for EDS and difference for proportion of subjects with ≥10 mm STS improvement was 61.1%. The most common adverse event was sneeze (82-84%), graded as mild by 98% of subjects. Conclusion: OC-01 VNS demonstrated consistency in improving both tear production and patient-reported symptoms in subjects with AID, consistent with pivotal ONSET-1 and 2 trial results. Further investigation is warranted, and results may further support use of OC-01 VNS for DED in AID patients.

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Pilot study for the detection of early exudative age-related macular degeneration with optical coherence tomography.

BACKGROUND: Optical coherence tomography (OCT) provides microscopic retinal images. Optical coherence tomography is noninvasive, using light waves to produce detailed retinal images. Here, we investigate the ability of OCT to detect early choroidal neovascularization in age-related macular degeneration. METHODS: Seventy-nine patients, diagnosed with nonexudative macular degeneration in one eye and exudative macular degeneration in the other were enrolled in this prospective, observational, nonrandomized study. Participants underwent examination (visual acuity, intraocular pressure, biomicroscopy, and ophthalmoscopy) followed by OCT in the study eye (nonexudative macular degeneration eye) every 3 months for 2 years. If examination did not show choroidal neovascularization, but OCT images raised suspicion, patients were reexamined in 4 weeks to 6 weeks and/or fluorescein angiography was performed. Visual acuity, OCT anomaly detected, and time between OCT and fluorescein angiography detection were examined. RESULTS: Fifteen (19%) patients developed exudative macular degeneration, as confirmed by fluorescein angiography, in the study eye. Four additional patients showed potential exudative macular degeneration on OCT only. Of the 15 patients who developed exudative macular degeneration, 13 had disease progression identified on OCT before examination and/or fluorescein angiography showed changes. Subretinal pigment epithelium fluid was the most common OCT anomaly, with development of sub-/intraretinal fluid also visible. CONCLUSION: Optical coherence tomography could be a powerful screening tool for patients with age-related macular degeneration at high risk for developing choroidal neovascularization.

Matching-adjusted indirect comparison of phase 3 clinical trial outcomes: OC-01 (varenicline solution) nasal spray and cyclosporine a 0.05% ophthalmic emulsion for the treatment of dry eye disease.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when head-to-head studies have not been performed. OBJECTIVE: To compare the efficacy of OC-01 varenicline nasal spray (OC-01 VNS) 0.03 mg to cyclosporine A (CsA) 0.05% ophthalmic emulsion on tear production in patients with dry eye disease based on data from the respective phase 3 clinical trials using the MAIC technique. METHODS: Individual patient data were drawn from the phase 3 registry trial of OC-01 VNS; aggregate data were drawn from 2 phase 3 trials of CsA in the publicly available New Drug Application for CsA 0.05% ophthalmic emulsion (RESTASIS). Using unanchored MAIC methods, the individual patient data were weighted based on 4 clinically relevant baseline variables (age, race, sex, and baseline Schirmer test score [STS]) to produce a weighted OC-01 VNS dataset matched to the key demographics of the CsA dataset. Least-squares mean change from baseline in STS for OC-01 VNS was calculated using the identical analysis of variance model used to calculate the same value for CsA in the RESTASIS New Drug Application, which were then compared. Proportions of subjects with improvement of 10 mm or more from baseline in STS were compared in the weighted OC-01 VNS and CsA dataset. Time points available for comparisons were CsA trials at 3 and 6 months and OC-01 data at 2 and 4 weeks. RESULTS: Data from 511 subjects in the OC-01 VNS phase 3 trial and 585 in the CsA phase 3 trials were analyzed. The least-squares mean STS change from baseline for OC-01 VNS at 2 and 4 weeks was significantly higher than that for CsA at 3 and 6 months (P < 0.0001 for all comparisons). Mean STS improvements were approximately 6-7 mm for OC-01 VNS and approximately 1 mm for CsA. The proportion of subjects with improvement of 10 mm or more from baseline in STS was significantly higher for OC-01 VNS (50.2%) than CsA (11.7 and 17.1% in the 2 CsA studies; P < 0.0001 for both comparisons). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produces significantly greater improvement in mean STS and results in significantly greater numbers of patients with substantial improvement in STS (percentage ≥ 10 mm) compared with CsA. Together, absent more robust data from head-to-head trials, findings may suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with CsA for the treatment of dry eye disease within conditions of the analysis methodology. DISCLOSURES: Dr Visco was a consultant for Novartis, Allergan, and Oyster Point, Inc. Ms Hendrix and Drs Macsai and Gibson are employees and shareholders for Oyster Point Pharma, Inc. Drs Sun and Tam participated in clinical research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc sponsored the Phase 3 OC-01 (varenicine solution) clinical study from which analysis data are obtained.

OC-01 (Varenicline Solution) Nasal Spray Demonstrates Consistency of Effect Regardless of Age, Race, Ethnicity, and Artificial Tear Use.

Purpose: To evaluate OC-01 [varenicline solution nasal spray (VNS)] tear production and symptom outcomes in patients with dry eye disease by age, gender, race, ethnicity, and artificial tear use status. Patients and Methods: Adults ≥22 years of age diagnosed with dry eye disease, with Ocular Surface Disease Index score ≥23, corneal fluorescein staining score ≥2 in ≥1 region or ≥4 for all regions, and baseline Schirmer Test Score (STS) ≤10 mm, with no restrictions on eye dryness score (EDS). Efficacy was assessed using integrated data from ONSET-1 and ONSET-2 [vehicle control (VC), n=294; OC-01 VNS 0.03 mg, n=308]. Subgroups included age (≤55, 56-65, >65 years), gender (male, female), race (White, Black or African American), ethnicity (Hispanic or Latino, Not Hispanic or Latino), and artificial tear use (yes, no). Analysis of covariance models, with the covariates treatment, study site, and baseline severity measures, were used to calculate treatment-VC differences. Consistency of effect among subgroups was evaluated by conducting interaction tests. Results: Consistency of treatment effect across subgroups was observed for all endpoints, with P value for all treatment-subgroup interaction terms >0.05. For % of patients with ≥10mm improvement in STS and least squares (LS) mean change from baseline in STS and EDS, there was improvement in tear production across demographic group categories. Artificial tear use did not change STS or EDS outcomes with OC-01 VNS. Conclusion: OC-01 VNS improved tear production and patient-reported symptom outcomes across a broad range of patients by age, gender, race, and ethnicity, and regardless of artificial tear use status at baseline. OC-01 VNS demonstrated a consistent benefit across an extensive range of patients with dry eye disease.

Standard management options for rosacea, part 1: overview and broad spectrum of care.

The standard management options were developed by a consensus committee and review panel of 26 experts to assist in providing optimal patient care based on the standard classification and grading systems for rosacea that were developed to perform research; analyze results and compare data from different sources; and provide a common terminology and reference for the diagnosis, treatment, and assessment of results in clinical practice. We discuss standard management options for rosacea in 2 parts: (1) overview and broad spectrum of care, and (2) options according to subtype. The options are considered provisional and may be expanded and updated as appropriate. Managing the various potential signs and symptoms of rosacea calls for consideration of a broad spectrum of care, and a more precise selection of therapeutic options may become increasingly possible as the mechanism of action of therapies are more definitively established.

Standard management options for rosacea, part 2: options according to subtype.

The standard management options were developed by a consensus committee and review panel of 26 experts to assist in providing optimal patient care based on the standard classification and grading systems for rosacea that were developed to perform research; analyze results and compare data from different sources; and provide a common terminology and reference for the diagnosis, treatment, and assessment of results in clinical practice. We discuss the standard management options for rosacea in 2 parts: (1) overview and broad spectrum of care, and (2) management options according to subtype. The menu of options is considered provisional and may be expanded and updated as appropriate. Managing the various potential signs and symptoms of rosacea calls for consideration of a broad spectrum of care, and a more precise selection of therapeutic options may become increasingly possible as the mechanisms of action of therapies are more definitively established.

Use of Topical Rho Kinase Inhibitors in the Treatment of Fuchs Dystrophy After Descemet Stripping Only.

PURPOSE: Fuchs corneal dystrophy (FD) is a common cause of endothelial keratoplasty. Recently, a series of FD cases treated with Descemet stripping only (DSO) demonstrated recovery of the central endothelium without transplantation of donor cells. Ripasudil, a rho kinase inhibitor, has been shown to promote corneal endothelial wound healing in animal models. This study prospectively evaluated the use of ripasudil in patients undergoing DSO for FD. METHODS: Enrolled patients underwent DSO with or without cataract surgery, performed by 1 surgeon. On the first postoperative day, patients were assigned to topical ripasudil 0.4% (Glanatec) 4 times a day for 2 months or no ripasudil and followed up monthly for the first 6 months and then at 9 and 12 months after surgery. Endothelial cell density (ECD) and pachymetry were evaluated at each postoperative visit. RESULTS: Eighteen patients were enrolled, including 8 women and 1 man in each group. Overall, patients who underwent DSO with ripasudil recovered vision more quickly (4.6 vs. 6.5 weeks, P < 0.01). In addition, the ripasudil group had a statistically significantly higher average ECD at 3, 6, and 12 months. The patients in the DSO observation group had a 10% decrease in peripheral ECD when comparing counts before surgery with counts 12 months after surgery (P < 0.05). In the DSO ripasudil group, there was no significant difference between peripheral ECD at preoperative baseline versus 12 months after surgery. CONCLUSIONS: DSO with topical rho kinase inhibitors may be an alternative treatment for patients with FD and a peripheral ECD greater than 1000 cells/mm.

Prelamellar Dissection Donor Corneal Thickness Is Associated With Descemet Stripping Automated Endothelial Keratoplasty Operative Complications in the Cornea Preservation Time Study.

PURPOSE: To identify donor and recipient factors, including eye bank tissue observations, predictive of operative complications in the Cornea Preservation Time Study. METHODS: One thousand three hundred thirty study eyes undergoing Descemet stripping automated endothelial keratoplasty for Fuchs dystrophy or pseudophakic/aphakic corneal edema were randomized to receive a donor cornea with preservation time (PT) of 0 to 7 days (N = 675) or 8 to 14 days (N = 655). Donor factors included demographics, prelamellar corneal and postlamellar lenticule dissection thickness, central endothelial cell density, and tissue processing time. Recipient factors included demographics, intraocular pressure, and glaucoma medications or surgery (trabeculectomy, laser trabeculoplasty). Eye bank observations included donor tissue folds, pleomorphism/polymegethism, and endothelial cell abnormalities. Possible tissue-related operative complications were recorded including difficult donor lenticule unfolding and positioning. Multivariable logistic regression with backward selection was used to identify statistically significant (P < 0.01) associations between factors and operative complications. RESULTS: The only factor predictive of operative complications [58 (4.4%) of 1330 surgeries] was prelamellar dissection donor corneal thickness (P = 0.002). For every 50 µm of donor corneal thickness prior to lamellar dissection, operative complication odds increased by 40% (odds ratio [99% confidence interval (CI)]: 1.40 [1.06-1.83]) adjusting for PT and whether the epithelium was on or off. The estimated mean prelamellar dissection donor corneal thickness for PT 0 to 7 days was 537 µm (99% CI: 516 µm-558 µm) compared with 567 µm (99% CI: 546 µm-588 µm) for PT 8 to 14 days (P < 0.001). CONCLUSIONS: Thicker donor tissue (prelamellar dissection) is associated with operative complications and should be considered in tissue selection for Descemet stripping automated endothelial keratoplasty lenticule preparation.

Incidence and Outcomes of Positive Donor Rim Cultures and Infections in the Cornea Preservation Time Study.

PURPOSE: To assess donor rim culture results and outcomes of ocular infections in the Cornea Preservation Time Study (CPTS). METHODS: Donor corneal rim cultures were optional. Donor characteristics were assessed for association with positive cultures using the Fisher exact test and Poisson regression analyses. Incidence rates of ocular infections were estimated, and 95% confidence intervals were calculated. RESULTS: Cultures were performed in 784 (58.9%) of the 1330 cases. For the 0 to 7-day versus 8 to 14-day preservation time groups, respectively, positive fungal growth occurred in 10 of 397 (2.5%) versus 5 of 387 (1.3%) corneas (P = 0.30), whereas positive bacterial cultures occurred in 6 of 397 (1.5%) versus 4 of 387 (1.0%) corneas (P = 0.75). Surgeon-prepared tissue remained a significant risk for positive fungal cultures [relative risk (RR) of surgeon- versus eye-bank-prepared, 2.85; 95% CI (1.02-7.98)], whereas younger donors [RR per year of age, 0.96; 95% CI (0.93-1.00)] and accidental death donors [RR of accident versus disease, 3.71; 95% CI (1.36-10.13)] were at a greater risk for positive bacterial cultures. Fungal infection (Candida glabrata) developed in 1 (6.7%) of 15 recipients with a positive fungal culture, and no recipient infections occurred with positive bacterial culture. With one additional fungal keratitis (Candida albicans) and one bacterial endophthalmitis (E. coli) with no rim culture performed, a total of 2 of 1330 eyes (0.15%) developed fungal and 1/1330 eyes (0.08%) developed bacterial postkeratoplasty infections. CONCLUSIONS: A longer preservation time was not associated with a higher rate of positive donor rim cultures. The overall rate of infection across the entire cohort was low.

Factors Associated With Graft Rejection in the Cornea Preservation Time Study.

PURPOSE: To identify factors related to graft rejection following Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter randomized clinical trial. METHODS: A total of 1330 eyes of 1090 subjects undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0-7 days (n = 675) or 8-14 days (n = 655) and followed for 3 years. Central endothelial cell density (ECD) was determined by a central image analysis reading center. Multivariable Cox models adjusted for PT, recipient diagnosis, and surgeon effect were used to identify factors associated with rejection. RESULTS: Cumulative probability of definite graft rejection was 3.6% (99% confidence interval 2.5%-5.3%). Younger recipient age was associated with graft rejection (P < .001; hazard ratio: 0.53 [0.33, 0.83] per decade). PT, donor-recipient sex mismatch, recipient diagnosis, recipient race, graft size, discontinuation of topical corticosteroids and immune-modulators, prior immunizations within 3 months, and prior glaucoma surgery were not associated with rejection (P > .01). Among clear grafts with an ECD measurement at baseline and 3 years (n = 913), endothelial cell loss (ECL) was greater in eyes that experienced a rejection episode (n = 27) than in those that did not (n = 886) (48% vs 38%, P = .03). Twelve of 44 eyes (27%) with definite graft rejection subsequently failed, comprising 15% of the 79 failures in the CPTS. CONCLUSIONS: Graft rejection is uncommon after DSAEK and more likely with younger age, in a study cohort mostly > 50 years old. Rejection increases ECL, but it is not a leading cause of DSAEK failure.

Suture technique for Descemet stripping and endothelial keratoplasty.

PURPOSE: To describe a suture technique for Descemet stripping and endothelial keratoplasty (DSEK). METHODS: The technique was performed in 2 eyes of 2 patients with Fuchs endothelial corneal dystrophy. A double-armed 10-0 prolene suture on a CIF-4 needle was used to pull the donor corneal button into the recipient's anterior chamber without the use of forceps to hold the button. The suture was also used to unfold the lenticule in the eye without marking the stroma with gentian violet, to center the lenticule and to secure that in place. RESULTS: No intraoperative problems occurred in either case. The suture technique was successfully used to pull the donor button into the host's eye and to unfold and center the button. Both lenticules were well centered and had minimal corneal edema. At 6 months, the central endothelial loss was 8% in the first case and 10% in the second. CONCLUSION: This suture technique for DSEK avoids the use of forceps and allows less traumatic donor button manipulation. It may be an effective alternative with low endothelial damage; further follow-up will determine the long-term effect on the central endothelial cell count.

Visual outcomes after accommodating intraocular lens implantation.

PURPOSE: To evaluate and compare the visual outcomes and accommodative amplitude in cataract patients after implantation of the Crystalens intraocular lens (IOL) (Eyeonics) versus standard monofocal IOLs. SETTING: Ten clinics in a nationwide multicenter study in the United States. METHODS: A multicenter comparative interventional case series with masked randomized postoperative examination of 224 eyes of 112 patients was performed by a single observer. Patients were divided into 2 groups (56 patients; 112 eyes each) depending on which IOL was implanted (Crystalens or monofocal). Accommodation was measured using 1 objective (dynamic retinoscopy) and 2 subjective methods (defocus and near point of accommodation). Visual acuity measurements were performed under the same conditions with standard visual acuity charts. RESULTS: Uncorrected monocular near vision was significantly better in the Crystalens group than in the standard monofocal group, with 101 of 112 eyes (90%) and 17 of 112 (15%), respectfully, reading J3 or better postoperatively. All 56 Crystalens patients had a binocular uncorrected near visual acuity of J3 or better compared with 16 of 56 (29%) standard monofocal patients. The mean postoperative monocular (0.85 +/- 0.30 [SD] versus 0.70 +/- 0.19, P<.01) and binocular (1.16 +/- 0.17 versus 1.01 +/- 0.14, P<.01) distance uncorrected visual acuities were also better in the Crystalens group than in the control group. All patients in the study achieved a corrected distance visual acuity of 20/20 or better. Measures of accommodation were significantly higher in Crystalens patients than in the monofocal IOL patients (dynamic retinoscopy 2.42 +/- 0.39 diopters [D] versus 0.91 +/- 0.24 D, P<.01; monocular defocus 1.74 +/- 0.48 D versus 0.75 +/- 0.25 D, P<.01; monocular near point of accommodation 9.5 +/- 3.1 inches versus 34.7 +/- 9.8 inches, P<.01). Perceived accommodation (5.79 D) was significantly greater than the measured accommodation (1.96 to 2.42 D) in Crystalens patients (paired t test, P<.01). CONCLUSIONS: The Crystalens IOL provided better uncorrected near and distance visual outcomes than standard monofocal IOLs in all analyses performed. Patients perceived a greater accommodation than measured. Understanding why this occurred could lead to valuable advances in accommodating IOL technology.