Lotilaner Ophthalmic Solution 0.25% for Demodex Blepharitis: Randomized, Vehicle-Controlled, Multicenter, Phase 3 Trial (Saturn-2).

PURPOSE: To evaluate the safety and efficacy of lotilaner ophthalmic solution 0.25% compared with vehicle for the treatment of Demodex blepharitis. DESIGN: Prospective, randomized, double-masked, vehicle-controlled, multicenter, phase 3 clinical trial. PARTICIPANTS: Four hundred twelve patients with Demodex blepharitis were assigned randomly in a 1:1 ratio to receive either lotilaner ophthalmic solution 0.25% (study group) or vehicle without lotilaner (control group). METHODS: Patients with Demodex blepharitis treated at 21 United States clinical sites were assigned either to the study group (n = 203) to receive lotilaner ophthalmic solution 0.25% or to the control group (n = 209) to receive vehicle without lotilaner bilaterally twice daily for 6 weeks. Collarettes and erythema were graded for each eyelid at screening and at all visits after baseline. At screening and on days 15, 22, and 43, 4 or more eyelashes were epilated from each eye, and the number of Demodex mites present on the lashes was counted with a microscope. Mite density was calculated as the number of mites per lash. MAIN OUTCOME MEASURES: Outcome measures included collarette cure (collarette grade 0), clinically meaningful collarette reduction to 10 collarettes or fewer (grade 0 or 1), mite eradication (0 mites/lash), erythema cure (grade 0), composite cure (grade 0 for collarettes as well as erythema), compliance with the drop regimen, drop comfort, and adverse events. RESULTS: At day 43, the study group achieved a statistically significant (P < 0.0001) higher proportion of patients with collarette cure (56.0% vs. 12.5%), clinically meaningful collarette reduction to 10 collarettes or fewer (89.1% vs. 33.0%), mite eradication (51.8% vs. 14.6%), erythema cure (31.1% vs. 9.0%), and composite cure (19.2% vs. 4.0%) than the control group. High compliance with the drop regimen (mean ± standard deviation, 98.7 ± 5.3%) in the study group was observed, and 90.7% of patients found the drops to be neutral to very comfortable. CONCLUSIONS: Twice-daily treatment with lotilaner ophthalmic solution 0.25% for 6 weeks generally was safe and well tolerated and met the primary end point and all secondary end points for the treatment of Demodex blepharitis compared with vehicle control. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Bevacizumab in High-Risk Corneal Transplantation: A Pilot Multicenter Prospective Randomized Control Trial.

PURPOSE: To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation. DESIGN: Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil. PARTICIPANTS: Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft. METHODS: Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks. MAIN OUTCOME MEASURE: The 52-week endothelial immune rejection rate. RESULTS: Ninety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis. CONCLUSIONS: In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.

Effect of Autologous Serum Eye Drops on Corneal Haze after Corneal Cross-linking.

SIGNIFICANCE: Corneal haze remains a frequent post-operative finding in patients undergoing corneal cross-linking. It has been shown that autologous serum tears promote epithelial healing and reduce post-operative pain; however, the role in the prevention of corneal haze has not been reported. PURPOSE: This study aimed to compare the effect of autologous serum tears versus preservative-free artificial tears on the prevention and resolution of post-cross-linking corneal haze. METHODS: A retrospective cohort study was conducted in a sample population from one surgeon at a tertiary eye center from 2016 to 2019. Seventy-six eyes of consecutive patients who underwent cross-linking were included. Records were reviewed for corneal Scheimpflug densitometry values and maximum keratometry, epithelial healing time, and the use of either autologous serum tears or preservative-free artificial tears. Corneal densitometry values, expressed in standardized grayscale units (GSU), were recorded for the anterior 150-µm corneal stroma and in the 0.0 to 2.0 mm and 2.0 to 6.0 mm zones. RESULTS: Forty-four eyes received autologous serum tears, whereas 32 eyes received preservative-free artificial tears. The baseline GSU of the anterior stromal 0 to 2 mm annulus and the 2 to 6 mm annulus did not significantly differ between groups (P = .50 and P = .40, respectively). There was a statistically significant increase in mean GSU for both anterior 0 to 2 mm and 2 to 6 mm zones between baseline and 1 month (P < .001) and 3 months (P < .001). When comparing the two groups, no statistically significant difference was found post-operatively between the mean GSU at 1 month for the anterior 0 to 2 mm (P = .38) nor the 2 to 6 mm zone (P = .12), or for the third month (P = .60 and P = .44, respectively). CONCLUSIONS: Using Scheimpflug densitometry, we did not find a significant difference in the post-cross-linking corneal haze at 1 and 3 post-operative months between patients who use autologous serum tears and those who use preservative-free artificial tears.

Extracellular Vesicles in Corneal Fibrosis/Scarring.

Communication between cells and the microenvironment is a complex, yet crucial, element in the development and progression of varied physiological and pathological processes. Accumulating evidence in different disease models highlights roles of extracellular vesicles (EVs), either in modulating cell signaling paracrine mechanism(s) or harnessing their therapeutic moiety. Of interest, the human cornea functions as a refractive and transparent barrier that protects the intraocular elements from the external environment. Corneal trauma at the ocular surface may lead to diminished corneal clarity and detrimental effects on visual acuity. The aberrant activation of corneal stromal cells, which leads to myofibroblast differentiation and a disorganized extracellular matrix is a central biological process that may result in corneal fibrosis/scarring. In recent years, understanding the pathological and therapeutic EV mechanism(s) of action in the context of corneal biology has been a topic of increasing interest. In this review, we describe the clinical relevance of corneal fibrosis/scarring and how corneal stromal cells contribute to wound repair and their generation of the stromal haze. Furthermore, we will delve into EV characterization, their subtypes, and the pathological and therapeutic roles they play in corneal scarring/fibrosis.

Extracellular Vesicles Secreted by Corneal Myofibroblasts Promote Corneal Epithelial Cell Migration.

Corneal epithelial wound healing is a multifaceted process that encompasses cell proliferation, migration, and communication from the corneal stroma. Upon corneal injury, bidirectional crosstalk between the epithelium and stroma via extracellular vesicles (EVs) has been reported. However, the mechanisms by which the EVs from human corneal keratocytes (HCKs), fibroblasts (HCFs), and/or myofibroblasts (HCMs) exert their effects on the corneal epithelium remain unclear. In this study, HCK-, HCF-, and HCM-EVs were isolated and characterized, and human corneal epithelial (HCE) cell migration was assessed in a scratch assay following PKH26-labeled HCK-, HCF-, or HCM-EV treatment. HCE cells proliferative and apoptotic activity following EV treatment was assessed. HCF-/HCM-EVs were enriched for CD63, CD81, ITGAV, and THBS1 compared to HCK-EV. All EVs were negative for GM130 and showed minimal differences in biophysical properties. At the proteomic level, we showed HCM-EV with a log >two-fold change in CXCL6, CXCL12, MMP1, and MMP2 expression compared to HCK-/HCF-EVs; these proteins are associated with cellular movement pathways. Upon HCM-EV treatment, HCE cell migration, velocity, and proliferation were significantly increased compared to HCK-/HCF-EVs. This study concludes that the HCM-EV protein cargo influences HCE cell migration and proliferation, and understanding these elements may provide a novel therapeutic avenue for corneal wound healing.

A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease.

PURPOSE: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy. DESIGN: An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator. PARTICIPANTS: Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53). METHODS: After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks. MAIN OUTCOME MEASURES: The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire. RESULTS: CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups. CONCLUSIONS: CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.

Brimonidine Ophthalmic Solution 0.025% for Reduction of Ocular Redness: A Randomized Clinical Trial.

SIGNIFICANCE: The α2-adrenergic receptor agonist brimonidine has been reported to induce conjunctival blanching in cataract, strabismus, laser refractive, and filtration procedures. Clinicians are often faced with red eyes with no apparent underlying pathology. Low-dose brimonidine reduced ocular redness in such subjects with efficacy maintained over 1 month and negligible rebound redness. PURPOSE: The aim of this study was to evaluate the safety and efficacy of brimonidine tartrate ophthalmic solution 0.025% for the treatment of ocular redness. METHODS: In this single-center, double-masked, phase 3 clinical trial, adult subjects with baseline redness of more than 1 unit in both eyes (0- to 4-unit scale) were randomized 2:1 to brimonidine 0.025% or vehicle. A single dose was administered in-office (day 1); thereafter subjects instilled treatment four times a day for 4 weeks, with clinic visits on days 15, 29, and 36 (7 days post-treatment). Efficacy end points included investigator-evaluated redness 5 to 240 minutes post-instillation on day 1 (primary); investigator-evaluated change from baseline 1, 360, and 480 minutes post-instillation on day 1, and 1 and 5 minutes post-instillation on days 15 and 29; total clearance of redness, and subject-assessed redness. Safety/tolerability measures included adverse events, rebound redness, and drop comfort. RESULTS: Sixty subjects were randomized (n = 40 brimonidine, n = 20 vehicle). Investigator-assessed redness was lower with brimonidine versus vehicle over the 5- to 240-minute post-instillation period (mean [SE], 0.62 [0.076] vs. 1.49 [0.108]; P < .0001) and at each time point within that period (P < .0001). At 1, 360, and 480 minutes post-instillation, respectively, the mean differences (95% confidence interval) between treatments were -0.73 (-1.05 to -0.41), -0.57 (-0.84 to -0.29), and -0.39 (-0.67 to -0.10), respectively. No tachyphylaxis was evident with brimonidine on days 15 and 29, and minimal rebound redness was observed following discontinuation. Adverse events were infrequent, and brimonidine was rated as very comfortable. CONCLUSIONS: Brimonidine 0.025% appeared safe and effective for reduction of ocular redness, with an 8-hour duration of action, no evidence of tachyphylaxis, and negligible rebound redness.

A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease.

PURPOSE: To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD). DESIGN: Phase 1/2 prospective, randomized, double-masked clinical trial. PARTICIPANTS: Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled. METHODS: Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen. MAIN OUTCOME MEASURES: Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI). RESULTS: After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04). CONCLUSIONS: Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids.

Latanoprost-Eluting Contact Lenses in Glaucomatous Monkeys.

PURPOSE: To assess the ability of latanoprost-eluting contact lenses to lower the intraocular pressure (IOP) of glaucomatous eyes of cynomolgus monkeys. DESIGN: Preclinical efficacy study of 3 treatment arms in a crossover design. PARTICIPANTS: Female cynomolgus monkeys with glaucoma induced in 1 eye by repeated argon laser trabeculoplasty. METHODS: Latanoprost-eluting low-dose contact lenses (CLLO) and high-dose contact lenses (CLHI) were produced by encapsulating a thin latanoprost-polymer film within the periphery of a methafilcon hydrogel, which was lathed into a contact lens. We assessed the IOP-lowering effect of CLLO, CLHI, or daily latanoprost ophthalmic solution in the same monkeys. Each monkey consecutively received 1 week of continuous-wear CLLO, 3 weeks without treatment, 5 days of latanoprost drops, 3 weeks without treatment, and 1 week of continuous-wear CLHI. On 2 consecutive days before initiation of each study arm, the IOP was measured hourly over 7 consecutive hours to establish the baseline IOP. Two-tailed Student t tests and repeated-measures analysis of variance were used for statistical analysis. MAIN OUTCOME MEASURES: Intraocular pressure. RESULTS: Latanoprost ophthalmic solution resulted in IOP reduction of 5.4±1.0 mmHg on day 3 and peak IOP reduction of 6.6±1.3 mmHg on day 5. The CLLO reduced IOP by 6.3±1.0, 6.7±0.3, and 6.7±0.3 mmHg on days 3, 5, and 8, respectively. The CLHI lowered IOP by 10.5±1.4, 11.1±4.0, and 10.0±2.5 mmHg on days 3, 5, and 8, respectively. For the CLLO and CLHI, the IOP was statistically significantly reduced compared with the untreated baseline at most time points measured. The CLHI demonstrated greater IOP reduction than latanoprost ophthalmic solution on day 3 (P = 0.001) and day 5 (P = 0.015), and at several time points on day 8 (P < 0.05). CONCLUSIONS: Sustained delivery of latanoprost by contact lenses is at least as effective as delivery with daily latanoprost ophthalmic solution. More research is needed to determine the optimal continuous-release dose that would be well tolerated and maximally effective. Contact lens drug delivery may become an option for the treatment of glaucoma and a platform for ocular drug delivery.

Collagen cross-linking of the Boston keratoprosthesis donor carrier to prevent corneal melting in high-risk patients.

OBJECTIVE: To examine the clinical relevance and pathophysiology of Boston keratoprosthesis (B-KPro)-related corneal keratolysis (cornea melt) and to describe a novel method of preventing corneal melt using ex vivo crosslinked cornea tissue carrier. METHODS: A review of B-KPro literature was performed to highlight cases of corneal melt. Studies examining the effect of corneal collagen cross-linking (CXL) on the biomechanical properties of corneal tissue are summarized. The use of crosslinked corneal tissue as a carrier to the B-KPro is illustrated with a case. RESULTS: Corneal melting after B-KPro is a relatively rare event, occurring in 3% of eyes during the first 3 years of postoperative follow-up. The risk of post-KPro corneal melting is heightened in eyes with chronic ocular surface inflammation such as eyes with Stevens-Johnson syndrome and mucous membrane pemphigoid. This chronic inflammation results in high tear levels of matrix metalloproteinases, the enzymes responsible for collagenolysis and corneal melt. Crosslinked corneal tissue has been shown to have stiffer biomechanical properties and to be more resistant to degradation by collagenolytic enzymes. We have previously optimized the technique for ex vivo corneal CXL and are currently studying its impact on the prevention of corneal melting after B-KPro surgery in high-risk eyes. Crosslinked carrier tissue was used in a 52-year-old man with familial aniridia and severe post-KPro corneal melt. The patient maintained his visual acuity and showed no evidence of corneal thinning or melt in the first postoperative year. CONCLUSION: Collagen crosslinking was previously shown to halt the enzymatic degradation of corneal buttons ex vivo. This study demonstrates the safety and potential benefit of using crosslinked corneal grafts as carriers for the B-KPro, especially in eyes at higher risk of postoperative melt.

Relaxing descemetotomy: microscope-integrated OCT-guided technique for acute corneal hydrops.

Introduction: 3 cases are used to illustrate the technique of Descemet membrane (DM) relaxing incisions followed by air descemetopexy for the management of patients with acute corneal hydrops. Patients and Clinical Findings: In each case, anterior-segment optical coherence tomography (OCT) demonstrated taut DM detachments and hydrops was refractory to conservative medical management and intracameral air injection. Diagnosis Intervention and Outcomes: To facilitate the reapproximation of DM and potentiate corneal deturgescence, intraoperative OCT-guided descemetotomy was performed with bent surgical scissors and a bent 30-gauge needle. Subsequent air descemetopexy was successful, and DM reattachment was maintained postoperatively. Corneal edema improved in all patients relatively rapidly postoperatively. Conclusions: Relaxing descemetotomy with air descemetopexy may be useful in cases of acute corneal hydrops with taut DM detachments that are unresponsive to air tamponade alone.

Development and Characterization of a Photocrosslinkable, Chitosan-Based, Nerve Growth Factor-Eluting Hydrogel for the Ocular Surface.

Purpose: Recombinant human nerve growth factor (rhNGF; cenegermin-bkbj, OXERVATE) is the first and only U.S. Food and Drug Administration-approved treatment for moderate to severe neurotrophic keratopathy. The aim of this study was to determine the feasibility of incorporating a version of rhNGF in a mucoadhesive hydrogel capable of sustained drug release to the ocular surface. Methods: Hydrogels loaded with rhNGF were synthesized by conjugating chitosan with azidobenzoic acid (Az-Ch), adding rhNGF, and exposing the solution to ultraviolet (UV) radiation to induce photocrosslinking. Az-Ch hydrogels were evaluated for physical properties and rhNGF release profiles. Cytocompatbility of Az-Ch was assessed using immortalized human corneal limbal epithelial (HCLE) cells. TF1 erythroleukemic cell proliferation and HCLE cell proliferation and migration were used to assess the bioactivity of rhNGF released from Az-Ch hydrogels. Results: Az-Ch formed hydrogels in <10 seconds of UV exposure and demonstrated high optical transparency (75-85 T%). Az-Ch hydrogels exhibited good cytocompatibility with no demonstratable effect on HCLE cell morphology or viability. rhNGF was released gradually over 24 hours from Az-Ch hydrogels and retained its ability to induce TF1 cell proliferation. No significant difference was observed between rhNGF released from Az-Ch and freshly prepared rhNGF solutions on HCLE cell proliferation or percent wound closure after 12 hours; however, both were significantly better than control (P < 0.01). Conclusions: rhNGF-loaded Az-Ch hydrogels exhibited favorable physical, optical, and drug-release properties, as well as retained drug bioactivity. This drug delivery system has the potential to be further developed for in vivo and translational clinical applications. Translational Relevance: Az-Ch hydrogels may be used to enhance rhNGF therapy in patients with NK.

Contact lenses as novel tear fluid sampling vehicles for total RNA isolation, precipitation, and amplification.

The tear fluid is a readily accessible, potential source for biomarkers of disease and could be used to monitor the ocular response to contact lens (CL) wear or ophthalmic pathologies treated by therapeutic CLs. However, the tear fluid remains largely unexplored as a biomarker source for RNA-based molecular analyses. Using a rabbit model, this study sought to determine whether RNA could be collected from commercial CLs and whether the duration of CL wear would impact RNA recovery. The results were referenced to standardized strips of filtered paper (e.g., Shirmer Strips) placed in the inferior fornix. By performing total RNA isolation, precipitation, and amplification with commercial kits and RT-PCR methods, CLs were found to have no significant differences in RNA concentration and purity compared to Schirmer Strips. The study also identified genes that could be used to normalize RNA levels between tear samples. Of the potential control genes or housekeeping genes, GAPDH was the most stable. This study, which to our knowledge has never been done before, provides a methodology for the detection of RNA and gene expression changes from tear fluid that could be used to monitor or study eye diseases.

Long-Term Outcomes of 6-Week Treatment of Lotilaner Ophthalmic Solution, 0.25%, for Demodex Blepharitis: A Noninterventional Extension Study.

PURPOSE: The aim of this study was to evaluate the long-term outcomes of lotilaner ophthalmic solution, 0.25%, in the treatment of Demodex blepharitis. METHODS: This observational, extension study included patients with Demodex blepharitis (N = 239) who completed the Saturn-1 study and presented for the day 180 visit. All participants were assessed at days 180 and 365 after the initiation of 6-week treatment with the study drug or its vehicle. RESULTS: The proportion of patients with 0 to 2 collarettes (grade 0) was significantly higher in the study group (N = 128 patients) than in the control group (N = 111 patients) (39.8% vs. 2.7% at day 180 and 23.5% vs. 2.9% at day 365; P < 0.0001). Similarly, the proportion of patients with ≤10 collarettes (collarette grade 0-1) in the study group was significantly higher than in the control group (70.3% vs. 18.0% at day 180 and 62.6% vs. 21.9% at day 365; P < 0.0001). In the study group, erythema continued to improve even after completion of the 6-week lotilaner treatment. No serious ocular adverse events were observed in the study group, and there was 1 treatment-related ocular adverse event in the study group, which was considered mild. CONCLUSIONS: After 6-week treatment with lotilaner ophthalmic solution, 0.25%, for Demodex blepharitis, no long-term concerns were observed during 1 year of follow-up. A high proportion of patients with 0 to 2 collarettes (grade 0) or ≤10 collarettes (collarette grade of 0 or 1) was observed throughout 1 year of follow-up, indicating that the efficacy of lotilaner ophthalmic solution, 0.25%, against Demodex blepharitis may last well after completion of therapy.

Suppression of Neovascularization by Topical and Subconjunctival Bevacizumab After High-Risk Corneal Transplantation.

Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation. Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial. Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus. Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks. Main Outcome Measures: Vessel and invasion area of vessels in the corneal graft and host beds. Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients. Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retention of the Boston keratoprosthesis type 1: multicenter study results.

OBJECTIVE: To report the retention rate of the Boston keratoprosthesis type 1 and to identify risk factors for keratoprosthesis loss. DESIGN: Cohort study. PARTICIPANTS: A total of 300 eyes of 300 patients who underwent implantation of the Boston keratoprosthesis type I device between January 2003 and July 2008 by 19 surgeons at 18 medical centers. METHODS: Forms reporting preoperative, intraoperative, and postoperative parameters were prospectively collected and subsequently analyzed at a central data collection site. MAIN OUTCOME MEASURES: Keratoprosthesis retention. RESULTS: A total cumulative number of 422 life-years of device implantation are included in this analysis. The average duration of follow-up was 17.1 ± 14.8 months, with a range of 1 week to >6.1 years. Ninety-three percent of the 300 Boston keratoprosthesis implants were retained at their last follow-up, corresponding to a retention time of 396 patient-years or 1.42 years/keratoprosthesis. The probability of retention after 1 year and 2 years was 94% and 89%, respectively. During the study period, 21 (7%) eyes failed to retain the device; the reasons for keratoprosthesis loss include sterile keratolysis (9), fungal infections (8), dense retroprosthetic membranes (3), and bacterial endophthalmitis (1). Multivariate analysis demonstrated 3 independent risk factors for keratoprosthesis loss: autoimmune cause (hazard ratio [HR], 11.94; 95% confidence interval [CI], 3.31-43.11), ocular surface exposure requiring a concomitant tarsorrhaphy (HR, 3.43; 95% CI, 1.05-11.22), and number of prior failed penetrating keratoplasties (HR, 1.64; 95% CI, 1.18-2.28). CONCLUSIONS: The Boston keratoprosthesis type 1 seems to be a viable option for eyes that are not candidates for penetrating keratoplasty (PK). Ocular surface disease due to an autoimmune cause demonstrated the lowest retention rate. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

2021 Survey of Keratoplasty Postoperative Steroid Management.

PURPOSE: The aim of the study is to investigate US-based ophthalmologists' preferred corneal transplant techniques and postoperative steroid regimen. METHODS: Ophthalmologists attending the 2021 Cornea and Eye Banking Forum and/or Cornea Subspecialty Day were surveyed in person. RESULTS: Ninety-two ophthalmologists with a median of 13 years (range of 1-35; mean of 14.5; ±9.05 mean ± SD) of experience as attending clinicians were surveyed. One hundred percent of the surgeons performed penetrating keratoplasty, which was followed by 96.7% for Descemet stripping endothelial keratoplasty, 90.2% for Descemet membrane endothelial keratoplasty, and 72.8% for deep anterior lamellar keratoplasty. Prednisolone 1% for postoperative care was the preferred choice across all surveyed keratoplasty techniques and postsurgery time intervals. All surgeons reported steroid administration frequency of 4 times a day in the first month and once a day after 12 months postkeratoplasty. To manage ocular hypertension after corneal transplantation, the leading approach was adding a glaucoma medication (44.6%), and beta-adrenergic antagonists were ranked as the most preferred choice by 59 (66.3%) of the respondents. For graft rejection after corneal transplantation, topical steroids (79.8%) were the initial treatment of choice with hourly administration being the most common frequency prescribed (87.4%). Most surgeons either agreed or strongly agreed (78.4%) that a randomized clinical trial evaluating the safety and efficacy of different steroid regimens after corneal transplantation would influence their clinical decision making. CONCLUSIONS: Prednisolone remains the predominantly used steroid across different keratoplasties. Steroid regimens are similar for non-high-risk penetrating keratoplasty, Descemet membrane endothelial keratoplasty, Descemet stripping endothelial keratoplasty, and deep anterior lamellar keratoplasty. To treat graft rejection, surgeons tend to initially add a glaucoma medication than to reduce the potency or frequency of the steroid.

Prospective, Randomized, Multicenter, Double-Masked, Clinical Trial of Corneal Cross-Linking for Boston Keratoprosthesis Carrier Tissue.

PURPOSE: To assess whether cross-linking the carrier donor cornea of the Boston Keratoprosthesis (BKPro) improves retention of the device in participants at high risk for keratolysis. DESIGN: Prospective, double-masked, randomized clinical trial. METHODS: In this multicenter study, 68 adult participants who were scheduled for BKPro implantation were enrolled. Masked participants were randomized to receive either a cross-linked (CXL) or non-cross-linked (non-CXL) donor corneal carrier. The Kaplan-Meier event-free survival was determined by the product-limit method and compared by the log-rank test to examine whether survival curves were different between the CXL and non-CXL groups. The primary outcome of the study was time from surgery to BKPro removal. The secondary endpoint was 12-month retention rate. RESULTS: A total of 68 participants were enrolled and randomized 1:1 to each group. The average age at the time of surgery was 62 (range = 24-89) years, and 42 participants (62%) were male. The overall BKPro retention rate was 70% during a mean follow-up time of 93 (range = 6-201) weeks. Twenty BKPros were removed, 10 in the CXL group and 10 in the non-CXL group, with 18 requiring removal because of sterile keratolysis. There was no difference in the time to removal between the groups during the study (P = .910). At 12 months, there was no significant difference in the retention rate in the CXL group (94%) vs the non-CXL group (82%, P = .150). CONCLUSIONS: In this prospective study, cross-linking of the carrier cornea prior to BKPro implantation did not reduce the incidence of sterile keratolysis or increase device retention among participants at high risk for retention failure.

Recurrent Keratoconus: Corneal Transplants for Keratoconus Develop Tomographic Ectatic Changes.

PURPOSE: The purpose of this study was to evaluate postoperative Scheimpflug imaging changes during the first 5 years after penetrating keratoplasty (PK) in patients with keratoconus (KC). METHODS: This retrospective, interventional case series includes 31 eyes of 31 patients who underwent their first PK with a history of KC. Postoperative Scheimpflug imaging was performed 3 months after the removal of the last suture (baseline) and then repeated 3 and 5 years after the PK. Demographic data, donor and host trephination diameter, and Scheimpflug imaging (Pentacam HR, Oculus, Germany) parameters indicative of ectasia were analyzed to evaluate postoperative graft changes that occur after PK. RESULTS: The maximal keratometry (Kmax) progressed significantly between baseline (53.5 ± 6.1 D) and postoperative year 3 and year 5 [56.5 ± 6.1 diopter (D) and 58.8 ± 7.9 D, P < 0.001]. Significant changes were also observed for the anterior best fit sphere and posterior best fit sphere ( P < 0.001 for 3 and 5 years compared with baseline). Kmax increased by at least 2 Ds for 74.2% of patients and up to 7 Ds or more for 25.8% of the patients. A significant inverse correlation was observed for host trephine size and progression of Kmax (r = -0.52, P = 0.01), which indicated that larger host trephination size was associated with a smaller increase in postoperative Kmax. CONCLUSIONS: Tomographic graft changes indicative of ectasia were observed within 3 to 5 years after PK in patients with KC. These changes were observed more frequently and sooner after corneal transplants than previously reported.

Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease: The ESSENCE-2 Randomized Clinical Trial.

Importance: Dry eye disease (DED) is a common public health problem with significant impact on vision-related quality of life and well-being of patients. Medications with rapid onset of action and a good tolerability profile remain an unmet need. Objective: To assess efficacy, safety, and tolerability of a water-free cyclosporine ophthalmic solution, 0.1% (CyclASol [Novaliq GmbH]), applied twice daily in DED compared with vehicle. Design, Setting, and Participants: CyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2) was a phase 3, multicenter, randomized, double-masked, vehicle-controlled clinical study conducted from December 5, 2020, to October 8, 2021. Following a 14-day run-in period with an artificial tear administered 2 times per day, eligible participants were randomly assigned 1:1 to the treatment groups. Patients with moderate to severe DED were included in the study. Interventions: Cyclosporine solution vs vehicle administered 2 times per day for 29 days. Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS; 0-15 National Eye Institute scale) and in dryness score (0-100 visual analog scale) at day 29. Conjunctival staining, central corneal fluorescein staining, and tCFS responders were also assessed. Results: A total of 834 study participants were randomly assigned to cyclosporine (423 [50.7%]) or vehicle (411 [49.3%]) groups at 27 sites. Participants had a mean (SD) age of 57.1 (15.8) years, and 609 (73.0%) were female individuals. The majority of participants self-identified in the following race categories: 79 Asian (9.5 %), 108 Black (12.9%), and 635 White (76.1%). Participants treated with cyclosporine solution had greater improvement in tCFS (-4.0 grades) than the vehicle group (-3.6 grades) at day 29 (change [∆] = -0.4; 95% CI, -0.8 to 0; P = .03). The dryness score showed treatment benefits from baseline in both groups: -12.2 points for cyclosporine and -13.6 points for vehicle (∆ = 1.4; 95% CI, -1.8 to 4.6; P = .38). In the cyclosporine group, 293 participants (71.6%) achieved clinically meaningful reductions of 3 grades or higher in tCFS vs 236 (59.7%) in the vehicle group (∆ = 12.6%; 95% CI, 6.0%-19.3%; P < .001). These responders showed greater improvement in symptoms at day 29 including dryness (∆ = -4.6; 95% CI, -8.0 to -1.2; P = .007) and blurred vision (Δ = -3.5; 95% CI, -6.6 to -4.0; P = .03) compared with nonresponders. Conclusions and Relevance: The ESSENCE-2 trial confirmed that treatment with a water-free cyclosporine solution, 0.1%, results in early therapeutic effects on the ocular surface compared with vehicle. The responder analyses suggest that the effect is clinically meaningful in 71.6% of participants in the cyclosporine group. Trial Registration: ClinicalTrials.gov Identifier: NCT04523129.