This treatment fills a gap for patients who are unresponsive and/or intolerant to the standard treatments for noninfectious keratitis, such as lubricants, corticosteroids, and immunosuppressants. 

Few treatments are available for this patient population with advanced disease, according to Joseph Grieco, PhD, director of Clinical Development at Mallinckrodt Pharmaceuticals in Bedminster, New Jersey.

Grieco explained that RCI works via its anti-inflammatory and immunomodulatory effects through interaction with melanocortin receptors.


Grieco and his colleagues conducted a multicenter, open-label, phase 4 study to evaluate the efficacy and safety of RCI in patients with refractory severe non-infectious keratitis. 

The primary efficacy endpoint was the proportion of patients with improvements in the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire score by 12 or more points. 

The Visual Analogue Scale (VAS) for burning/stinging and eye discomfort, and corneal fluorescein staining were exploratory endpoints for the study. 

The safety endpoints were the proportion of patients with treatment-emergent or serious adverse effects during the study.

The study included 36 patients (mean age, 63.3 years; 71.4% women; 80% Caucasian). All patients had bilateral keratitis (mean duration, 4.4 years). Patients administered 80 units of RCI twice a week for 12 weeks followed by tapering for 4 weeks.

Grieco explained that the IDEEL symptom bother score at week 12 after the start of treatment showed that 50% of patients had greater than a 12-point improvement, and 52.9% achieved that level of improvement as early as week 2 after treatment initiation.

“The mean changes from baseline in the symptom bother score exceeded the minimal clinically important difference threshold at every evaluation point,” he said.

At the 12-week evaluation, the VAS score indicated that all symptoms improved from baseline, with the most pronounced improvements seen in ocular dryness and discomfort.

Improvements in corneal and conjunctival staining also were seen as soon as 4 weeks after treatment started and were sustained through week 12. 

The mean change went from 5.3 at baseline to -1.0 at week 4 and was sustained to week 12 at -1.1.

A third of patients had an adverse effect during the study, most of which occurred once. The intraocular pressure did not increase.

“The results of this open-label study showed that 80 units of RCI twice weekly for 12 weeks was associated with rapid and sustained improvements in the symptoms of persistent severe noninfectious keratitis that had previously not responded to standard-of-care therapies,” Grieco concluded. 


This article is adapted from Grieco’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual conference. He is an employee of Mallinckrodt Pharmaceuticals. RCI is approved by the FDA for severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, including keratitis.


1. Huang YJ, Galen K, Zweifel B, et al. Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists. J

Articles

Joseph Grieco, PhD, notes that treatment fills a gap for patients who are unresponsive to the standard treatments for noninfectious keratitis. 

Injections offer relief for refractory severe noninfectious keratitis

An experimental study of hemorrhagic shock conducted in rabbits found that during progression of and recovery from shock, the blood flow in the eye shows decreases and increases similar to those seen in the kidney and intestines. 

Noninvasive measurement of the blood flow in the eye may be a new indicator of shock-related organ damage, reported Kento Watanabe, MD, from the Department of Ophthalmology, Toho University School of Medicine, Tokyo, and Tomoaki Shiba, MD, from the Department of Ophthalmology, International University of Health and Welfare Narita Hospital, Funabashi, Chiba, Japan.

While shock is defined as the progression of organ disorders, it is difficult to evaluate using only parameters such as blood pressure. 

Fundus examination is the only examination that facilitates direct observation of an organ’s blood supply, which reflects the true nature of shock. 

Evaluation of the retinal vessels is a valuable resource because they have the same function and structure as the coronary and renal arteries, Watanabe explained.

Watanabe and his colleagues used laser speckle flowgraphy (LSFG) to study the relationship between whole body and ocular blood flow in small- and medium-sized animals and they found previously that the ocular blood flow index obtained using LSFG accurately reflects the blood pressure and cardiac output during shock, and that the ocular blood flow is larger than the rate of decrease in cardiac output (unpublished data).

In the study, shock was induced in 10 New Zealand white rabbits by removing blood at the rate of 1 mL/minute for 30 minutes; the animals were observed for 20 minutes and the blood returned. 

During the period of shock, the mean arterial blood pressure (MAP) was measured in the brachial artery. 

The blood flow in the intestines and kidneys was measured using an ultrasonic blood flow meter at the mesenteric artery and renal artery. LSFG was used to measure the ocular blood flow. 

The mean blur rate (MBR), a blood flow index specific to LSFG, was measured in the retinal vessels and choroid. The rate of change of each parameter was compared with the baseline value before the blood was removed.

The investigators found that the MBR in the retinal vessels and choroid, the intestinal and renal blood flow, and the MAP decreased significantly as the blood was removed and recovered nearly to the baseline value when the blood was returned. 

The rates of change at the end of the period of blood removal were as follows: MAP, 69.4%; kidney, 43.5%; intestine, 54.8%; MBR of the retinal vessels, 42.3%; and MBR of the choroid, 55.5%.

The rates of change between the MBR of the retinal vessels and kidney and between the MBR of the choroid and intestine were similar, and no significant difference was observed. 

The MBR of the retinal vessels and MBR of the choroid were significantly positively correlated with the MAP (r = 0.87, 0.73), renal blood flow (r = 0.66, 0.59), and intestinal blood flow(r = 0.84, 0.61).

“In this study, the ocular blood flow reflected the blood flow in the kidneys and intestines,” the authors concluded. “The key takeaway point is that non-invasive ocular blood flow measurement using LSFG may be a new indicator of shock-related organ damage.”

This article is adapted from Watanabe’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

Non-invasive ocular blood flow measurement using laser speckle flowgraphy may be a new indicator of shock-related organ damage, investigators report. 

Researchers target ocular blood flow, systemic organ blood flow in hemorrhagic shock

Dr Christopher Starr of Weill Cornell Medicine, discusses an overview of his virtual ARVO 2021 presentation regarding dry eye disease flares, including a rapid readout assessment of 10 years' worth of world literature to analyze studies in which the inflammatory disease's condition are categorized.

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Dr Christopher Starr discusses key points from his virtual ARVO 2021 presentation regarding dry eye disease flares, including a rapid readout assessment of 10 years' worth of world literature to analyze studies in which the inflammatory disease's condition are categorized.

Looking at 10 years of dry eye disease flares

Dr. Michael Mbagwu, of the VA Palo Alto Health Care System; Byers Ophthalmic Innovations Fellow, Byers Eye Institute, Stanford University Medical School, speaks on the highlights of his virtual 2021 ARVO presentation regarding the development of an algorithm tool that links patient imaging to their clinical data, specifically within the American Academy of Ophthalmology's (AAO) IRIS Registry. 

Dr. Michael Mbagwu speaks on the highlights of his virtual 2021 ARVO presentation regarding the development of an algorithm tool that links patient imaging to their clinical data, specifically within the AAO IRIS Registry.  

Linking patient imaging to AAO IRIS Registry clinical data

Dr Theodore Leng medical advisor at Verana Health and director of clinical translational research, Byers Eye Institute, Stanford University School of Medicine, discusses the highlights from his presentation on "AAO IRIS Registry Data Replicates VIEW 1 and VIEW 2 Clinical Trial Outcome Data," in which the first replications using real-world data of a phase 3 trial was utilized, during the virtual 2021 ARVO meeting. 

Dr Theodore Leng discusses the highlights from his presentation on "AAO IRIS Registry Data Replicates VIEW 1 and VIEW 2 Clinical Trial Outcome Data," during the virtual 2021 ARVO meeting. 

Looking at real-world trial data replication outcomes of AAO IRIS Registry data 

Dr. Daniel F. Kiernan, a vitreoretinal surgeon at The Eye Associates, Sarasota, Florida, discusses the highlights of his 2021 ARVO virtual presentation on the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on optical coherence tomography (OCT) testing following vitreoretinal surgery.

Dr. Daniel F. Kiernan discusses key findings of a clinical study analyzing the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on OCT testing following vitreoretinal surgery.

Clinical results analyze dexamethasone implant effect on macular thickness

The understanding of the epidemiology, natural history, causal mechanisms, and treatments for diabetic retinopathy (DR) has evolved dramatically over recent decades. 

The staggering statistics underscore the importance of this progress considering that by 2040, an estimated 642 million patients will be affected by diabetes globally. Importantly, 7.3 million are undiagnosed and a third of the population is pre-diabetic, which, as Lloyd Paul Aiello, MD, PhD, noted, is a less recognized problem.

Aiello is a professor in the Department of Ophthalmology at Harvard Medical School, and director, Beetham Eye Institute, Joslin Diabetes Center, Boston.


“The percentages of diagnosed, undiagnosed, and total diabetes among adults increase dramatically with age, in some cases more than 7-fold between ages 18-44 and 65 and older,” Aiello said. “The incidence of diagnosed diabetes increases about 2-fold after age 40.”

Aiello explained further that about 20% of the US population over 65 years are projected to have diabetes by 2035. Diabetes currently is the seventh leading cause of death in the US.”

Black, non-Hispanic, and Hispanic populations have higher prevalence rates of diabetes than white, non-Hispanics. While diabetes about 20 years ago was far more prevalent in the southern US, it is now highly prevalent nationwide, with the rates having increased from 1.5%-6.9% in 2004 to 12.2%-33.0% currently.

High A1c, blood pressure, and cholesterol, are well-known risks.

“A concern is that less than 20% of diabetic adults control these risk factors adequately and more than 75% do not adhere to minimal activity guidelines,” he said.


DR is one of the most common complication, with a prevalence of 49%; however, there is hope, because the cases of global blindness actually decreased slightly in Western Europe and high-income areas of North America possibly because of nationwide diabetic retinopathy screening programs in the UK, improved glycemic control, and better therapies,

Decreases in diabetic macular edema (DME),

 proliferative diabetic retinopathy (PDR), retinopathy progression, clinically significant ME, and visual impairment have occurred.

 Evaluation of about 15,000 patients at the Joslin Clinic showed a median best-corrected visual acuity (VA) of 20/20 and 92% had 20/40 or better.

In addition to improved diabetes care, treatment rates and better therapies also are credited for improved outcomes. Treatment with panretinal photocoagulation (PRP), which prevents about 98% of blindness when patients were treated in a timely fashion, increased substantially.

Anti-vascular endothelial growth factor (VEGF) therapy was a huge leap forward4 and is evolving as a viable alternative to PRP for PDR. Ranibizumab (Avastin, Genentech) was non-inferior to PRP, provided better vision during the first 2 years post-treatment and better mean visual field outcomes, and decreased chances of vitrectomy and developing DME.

Anti-VEGF therapy has been extremely effective for DME with study data now over 5 years.

 The major anti-VEGF drugs are all beneficial with somewhat similar efficacy except in certain subpopulations.



Supplementation with deferred/prompt laser treatment helped maintain VA gains, and 56% never needed any laser over the 5-year study.

Interestingly, while a number of anti-VEGF injections are needed in early treatment, far fewer are needed later on to maintain the visual gains.

A new therapeutic option is treatment of non-PDR. The Panorama Study

 showed high percentages of patients with 2 or more steps of improvement, lower rates of worsening in DR severity, and fewer vision-threatening complications from baseline with anti-VEGF therapy compared with sham.

In addition, the development of sophisticated imaging modalities is changing evaluation and treatment modalities and how diabetes-related eye disease is screened in the community.

A major hurdle for DR is the lack of patient awareness, which is a substantial contributor to non-adherence to eye care guidelines and poor outcomes, Aiello emphasized. 

Retinal imaging is the best way to view almost the retinal surface with some devices now showing nearly the entire retina in a single image. Hand-held imaging devices are evolving and will likely help monitoring of patients in underserved areas.

The future of DR care may include several exciting new research areas. One is retinal binding protein 3 that may protect against many aspects of DR.

In addition, there are pathways that do not depend on VEGF, and artificial intelligence and deep learning that are already entering the clinical arena.

This article is adapted from Aiello’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

1. Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ Open 2014;4:e004015. Doi: 10.1136/bmjopen-2013-004015.

2. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: The twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology 2009;116:497-503.

3.Klein R, Klein BEK. Are individuals with diabetes seeing better? a long-term epidemiological perspective. Diabetes 2010; 59:1853-60. https://doi.org/10.2337/db09-1904.

4. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. A randomized clinical trial. JAMA 2015;314:2137-46.

5. The Diabetic Retinopathy Clinical Research Network, Elman MJ, 

 RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77.

6. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372:1193-203.

7. Wykoff CC. Intravitreal aflibercept for moderately severe to severe non-proliferative diabetic retinopathy (NPDR): 2-year outcomes of the phase 3 PANORAMA Study. Data presented at: Angiogenesis, Exudation and Degeneration Annual Meeting; February 8, 2020; Miami, FL.

8. Yokomizo H, Maeda Y, Park K, et al. Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy. Sci Transl Med 2019;11:eaau6627. doi: 10.1126/scitranslmed.aau6627

During a presentation at the ARVO virtual meeting, Lloyd Paul Aiello, MD, PhD, explains that a key hurdle for diabetic retinopathy is the lack of patient awareness, which is a substantial contributor to non-adherence to eye care guidelines and poor outcomes.

Diabetes and DR: Making progress in the global epidemic

This image is a pre-treatment photo of the fundus. (Image courtesy of Friederike Kortuem, MD, MSc)

Reviewed by Friederike C. Kortuem, MD, MSc

Treatment with voretigene neparvovec-rzyl (Luxturna, Novartis) resulted in a short-term change in the foveal morphology in a 15-year-old girl with visual impairment that included nyctalopia and decreased visual acuity (VA) in early childhood, according to Friederike Kortuem, MD, MSc, from Eye Clinic Tübingen, University of Tübingen, Tübingen, Baden-Württemberg, Germany.

Speaking at the Association for Research in Vision and Ophthalmology’s virtual 2021 annual meeting, Kortuem point out that visual deterioration generally occurs early in Leber’s congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD), as soon as birth to 5 years of age.

Characteristically, rapid degeneration of the rods and cones, visual field reduction, sluggish or near-absent pupillary responses, photophobia, nystagmus, and nyctalopia can occur. By the 4th decade of life, patients usually are legally blind. 

Subretinal administration of voretigene naparvovec-rzyl in an adeno-associated viral vector was FDA-approved in the US in 2017 and in Germany in 2019 to treat retinal dystrophies caused by bi-allelic RPE65 mutations; RPE65 is involved in the vitamin A restoration cycle in the eye.

The current patient had an RPE65 homozygous mutation. The VA in the right eye at examination was 20/63, and the anterior segment was unremarkable. The retinal examination in that eye showed central macular atrophy, narrowed vessels, and diffuse peripheral atrophy.

Kortuem demonstrated the overall decreased retinal thickness in the right eye.

Clinical examinations included measurement of the best-corrected VA (BCVA), spectral-domain optical coherence tomography (OCT), and adaptive optics retinal imaging.

At baseline, the patient was injected with the gene therapy vector that was successfully positioned between the neural retina and the retinal pigment epithelium. She was evaluated at baseline and then 2 and 5 weeks and 3 months following treatment.

At baseline, compared with healthy individuals of the same age, this patient’s retina was thinner. Kortuem showed that the central fovea had alterations in its layers and the retinal structures were not well demarcated, in contrast to the parafoveal layer with a preserved outer retina and photoreceptors.

As soon as 2 weeks after treatment, the foveal layer started to change. The external limiting membrane was visualized in the fovea.

“The overall disrupted appearance improved,” she pointed out.

After 5 weeks, the layering of the central fovea improved more out to 3 months.

The adaptive optics images obtained at baseline showed a mosaic of disrupted photoreceptor cells, that according to Kortuem, is characteristic of inherited retinal diseases. Following treatment, the superior nasal area appeared partly clear and the cones were identifiable. In the first 5 weeks following treatment, the initially patchy areas seemed to be decreasing over time. These morphologic rescue parameters changed gradually over time and were correlated partly with the improvement in the foveal-mediated vision after the treatment.

Regarding the safety of the treatment, no signs of inflammation were observed.

The cone functionality improved a bit and the patient reported “brighter” vision, which she also reported 5 weeks after surgery. At 3 months after surgery, the objective changes persisted.

The VA remained stable from baseline to week 5 and then improved by 1 line to 20/50. The contrast sensitivity also remained stable over time.

Chromatic pupil campimetry showed a dramatic increase in the central 10 degrees of the pupil from week 2 to week 5 and this improvement persisted to month 3.

“Rapid changes in the photoreceptor morphology seen on OCT and adaptive optics imaging after successful gene therapy in patients with LCA and EORD can be quantifiable at the individual level,” Kortuem concluded.

This article is adapted from Kortuem’s presentation at the Association for Research in Vision and Ophthalmology virtual annual meeting. She has no financial interest in this subject matter.

In a presentation at ARVO, Friederike Kortuem, MD, MSc, explains that treatment with voretigene neparvovec-rzyl led to a short-term change in the foveal morphology in a patient with visual impairment that included nyctalopia and decreased visual acuity in early childhood. 

Treatment with voretigene neparvovec-rzyl results in foveal morphologic changes in LCA 

Dr Michael A. Singer of the Medical Center Ophthalmology Associates in San Antonio, Texas, speaks on the highlights of his presentation focusing on intraocular pressure (IOP) in the PALADIN 24-month data intravitreal steroid (ILUVIEN), presented during ARVO 2021. 

Dr Michael A. Singer speaks on the highlights of his presentation focusing on IOP in the PALADIN 24-month data intravitreal steroid (ILUVIEN).

Focusing on 24-month data of the PALADIN study

Dr Mohamed Abou Shousha and Dr Richard Parrish II both of the University of Miami Health System Bascom Palmer Eye Institute, discuss their ARVO 2021 presentation regarding a study analyzing visual field measurements using the 

 Visual Field Multi-platform application downloaded on two different commercially available augmented reality devices.

Note: Dr Shousha is also CEO and founder of Hero

Dr Mohamed Abou Shousha and Dr Richard Parrish II discuss their ARVO 2021 presentation regarding a study analyzing visual field measurements using the Heru Visual Field Multi-platform application downloaded on two different commercially available augmented reality devices.





Treatment with voretigene neparvovec-rzyl results in foveal morphologic changes in LCA

Focusing on 24-month data of the PALADIN study

Measuring visual fields with cloud-based AI platform