Landmark Literature

One of the distinguishing features of ophthalmology as a field of medicine is the speed at which things can change. Innovation is driven by the medical profession but is also powered by high impact research that offers clinicians reliable data. Without research, innovation is unavoidably slowed, new knowledge doesn’t come to light as quickly and doctors don’t have the latest knowledge at their fingertips.

After another year where the headlines have been full of both news about breakthroughs and problems in healthcare systems worldwide, it is vital to have a clear sense of the state of the field. With that in mind, we gather some of the leading researchers and experts in the world of ophthalmology to offer their thoughts on the landmark literature of the last twelve months. Here’s the research which has shaped the field and offers valuable insight into where ophthalmic research might be headed into the year to come.

Jugnoo Rahi, Professor of Ophthalmic Epidemiology and Consultant Ophthalmologist, Chair of the Academic and Research Committee of the Royal College of Ophthalmologists (RCOphth) and Director of the Vision and Eyes Group at Great Ormond Street Institute of Child Health.
 

My aim with my choices is to draw readers attention to literature that they might not have noted but which, in my opinion, addresses some of the key issues relating to health in general. These key pieces of academic literature are all reviews or reports of some sort  – i.e. the carefully evidenced and rigorously synthesized work that people often forget is critical to changing practice or policy on a large scale.

Landmark Paper: P. Rajpurkar, et al., “AI in health and medicine”, Nat Med 28, 31, (2022), PMID: 35058619.

This article offers a summary of a two-year long tracking of the developments in medical AI. This is important for ophthalmologists to give some close attention, as there has been much interest in our field about the potential of AI to transform imaging, treatment and diagnostics. However, this paper shows that beyond the hype there is much work to be done to realize the potential to improve healthcare and outcomes for all. Despite the excitement, there remain serious technical and ethical issues from the availability of data to the now well-covered problems of racial bias that still have to be addressed.

Landmark Paper: JD Sachs et al., “The Lancet Commission on lessons for the future from the COVID-19 pandemic” Vol 400, 1224, (2022) PMID 36115368.

At this point it may feel like there is little more to say about the impact of the COVID-19 pandemic but the Lancet Commission on the topic is unequivocally correct in describing it as a profound tragedy and a massive global failure on multiple levels. It is impossible to overstate the impact of the COVID-19 pandemic – not just in terms of simple infection numbers but the knock-on effects that go all the way from global healthcare infrastructure to the impact of long COVID. This report sets out the lessons learned that we must not ignore about global health collaboration and pandemic preparedness if we are to avoid repeating the same struggles in the future.

Landmark Paper: M. Romanello, et al., “The 2022 report of the Lancet Countdown on health and climate change: health at the mercy of fossil fuels,” Vol 400, 1619, (2022) PMID: 36306815.

It’s hard to avoid the fact that we are living in a time of multiple crises, all of which impact healthcare in a variety of complex and interlocking ways. This report is detailed and makes the links between anthropogenic climate change and serious consequences for health and wellbeing on a global level painfully clear. Increases in dengue fever, heat related death and the conditions for vibrio pathogens to develop are all directly linked to climate change. There is emerging evidence about the risks to ocular health e.g. associations between air pollution and its impact on specific eye conditions. Furthermore, ophthalmic surgery can often be very resource intensive, producing a lot of waste and previous research has shown the cataract surgery has a relatively high carbon footprint. We all have our part to play, and ophthalmology is no different. One of our biggest challenges is making sure our treatment pathways are getting good outcomes for our patients and helping safeguard the environment.

Landmark Paper: N. Halasa, M.D., et al, “Maternal Vaccination and Risk of Hospitalization for Covid-19 among Infants,” N Engl J Med, 387, 109, (2022) PMID: 35731908

Based on a case-control test negative design, this paper assessed the remarkable effectiveness of maternal vaccination during pregnancy against hospitalization for Covid-19 among infants younger than 6 months of age. This paper reminds us of the importance of the link between mothers and children’s health and the often profound impact of antenatal interventions - this applies as much to childhood blindness (one of my own particular research interests) as it does to other areas of health, as exemplified in the World Health Organization’s recently published Package of Eye Care Interventions (PECI) which includes a specific module on children.

Landmark Paper: World Health Organization, Package of Eye Care Interventions (2022) 
Available at http://bit.ly/3X8AObf

Given our work with the Vision and Eyes Group, this report from the World Health Organization is my final choice. My colleague Dr Lola Solebo and I had the privilege of being the UK members of the international expert group that developed the pediatric ophthalmology module. The aim of the PECI is to offer advice to policy-makers and technical decision-makers in low- and middle-income countries to integrate eye care into the packages and policies of their health services. The numbers around global vision issues are deeply shocking, with this report estimating a billion people with visual impairment that could be prevented or has yet to be addressed. Service providers within low and middle income countries can use the PECI to plan and implement eye care interventions in their service programmes; and the donor and development agencies can use it as a blueprint for eye care programmes.

Anat Loewenstein, Vice Dean of the Faculty of Medicine and Sidney Fox Chair of Ophthalmology at Tel Aviv University, Chairman of Ophthalmology at Sourasky Medical Center and Director of the department of Ophthalmology at Tel Aviv Medical Centre
 

When I was asked for the landmark literature of the last year I looked first of all for papers which reported on evidence based level one studies. Namely, on multicenter, randomized clinical trials. It is not that there is not important information in different kinds of trials, or other kinds of academic research but rather, I believe that such information has the potential to change the way we treat patients.

I think that the TENAYA and LUCERNE(1), ALOFT (2), Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema (3) and post hoc analysis of the FILLY study (4) were the most influential studies published this last year.

The common thread in these studies is that they represent advancement for both retina patients and physicians and have the potential to alleviate some of the disease management burden. The TENAYA and LUCERNE studies demonstrate the potential durability of faricimab – a novel treatment for AMD, which can be implemented in the future using the personalized treatment interval regimen – and this is something which can be utilized in our daily clinical practice. Since most patients were fluid free for 2-4 months without the need for additional treatment, we are heading towards a more durable and personalized method of care.

As for the ALOFT Study, it shows that monitoring at home can be feasible and also has the potential to alleviate treatment burden by using AI for fluid localization and quantification, thus improving clinical decision making processes. If we implement this model into clinical practice, early diagnosis and treatment for AMD will be within our reach and this can only help patients to manage this all-too-debilitating disease. The study establishes the feasibility of a new digital model for health, with three points of care –  the patient’s home, the physician’s clinic and a monitoring center, for the management of macular degeneration.

Diabetic Macular Edema is another major cause of visual loss. Until today we mainly looked at pivotal trials which investigated the efficacy and safety of one drug given for the duration of the trial, comparing it to the standard of care. In the real world, due to limited resources all over the world, many health systems request initiation of treatment with bevacizuab and then switching to a registered drug only upon non optimal response. This very commonly used regimen was never studied for safety and efficacy. This study proves that such a regimen has results similar to those achieved with the regiment studied in the pivotal trial.

As for the post hoc analysis of the FILLY study, results showed that pegcetacoplan has the potential to slow geographic atrophy progression. The progression from iRORA to cRORA is slowed down when using this drug and it gives GA patients much-needed new hope for treatment for this debilitating disease – a hope which was virtually nonexistent since treatment was previously limited to observation.

The studies I chose all offer possible solutions: A digital health model using home monitoring being able to preserve visual acuity at the time of conversion to neovascular disease and at the end of follow up is a new way to manage our patients with possible favorable outcomes, a model that we did not appreciate earlier.

The new trials looking at longer treatment duration offer a reduced burden for the patients, physicians and the system with resultant better compliance and, of course, results. The ability to use bevacizumab and then switch provides reassurance to a regimen commonly used and the ability to lower costs.

The new treatment for GA has been developing rapidly over the last year with several treatment options arising; I look forward to seeing the phase 3 DERBY and OAKS publications and the revolution in GA care due to these new treatments. In the meantime, the outcomes are being presented at international meetings all over the world along with press releases. Hopefully, phase 3 outcomes will be published over the year to come.

All of these have the potential to really improve the management of our patients.

The state of research in ophthalmology looks promising and the combination of home monitoring and durable therapy has wide ranging possible applications. I am sure that in the future we will see a novel model where patients are treated with durable drugs and monitored from their own home for disease activity. This approach will allow more precise retreatment decisions and longer intervals for those who are suitable for it. In addition to home monitoring among nAMD patients, I can imagine there is a strong possibility of combining home monitoring for GA patients, for instance conversion from iRORA to cRORA from the patient's home thus alleviating management and facilitating the most suitable clinical decisions. I think my choices prove that we are blessed with many new treatment options. We have better, more personalized ways to treat our patients, and I look forward with keen interest to seeing the results of similar trials in other diseases such as RVO.

Landmark Paper: JS. Heier, et al., “Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomized, double-masked, phase 3, non-inferiority trials”. Lancet. 2022 Feb PMID: 35085502.

Landmark Paper: M. Mathai, et al.,” Analysis of the Long-term Visual Outcomes of ForeseeHome Remote Telemonitoring: The ALOFT Study.” Ophthalmol Retina (2022) PMID: 35483614.

Landmark Paper: CD. Jhaveri, et al.,“Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema,” N Engl J Med. PMID: 35833805.

Landmark Paper: MG. Nittala, et al., “Association of Pegcetacoplan With Progression of Incomplete Retinal Pigment Epithelium and Outer Retinal Atrophy in Age-Related Macular Degeneration: A Post Hoc Analysis of the FILLY Randomized Clinical Trial,” JAMA Ophthalmol. 2022 PMID: 35113137.

Ningli Wang, Director, Beijing Tongren Eye Center, President of the Asian Academy of Ophthalmology and Dean of the School of Ophthalmology at Capital Medical University.
 

I have two principal choices for studies that I believe show promising results for a wide range of settings. As global eye care needs increase, ophthalmologists are rightly ever-more concerned with not just treating our individual patients, but in managing health issues on a population level.  New technologies and concerted efforts from national health care structures have enormous potential for implementing novel and effective approaches to disease screening, management and prevention.

Landmark Paper: L. Hanruo, et al “Economic evaluation of combined population-based screening for multiple blindness-causing eye diseases in China: a cost-effectiveness analysis,” Lancet Glob Health. (2023) PMID: 36702141.

This is the first study to analyze the cost-effectiveness of multiple ophthalmic disease screening based on real-world data and a temporally explicit Markov model in a developing country with large economic heterogeneity from a societal perspective. This study showed that a population screening programme for multiple blinding eye diseases was likely to be highly cost-effective in both rural and urban China. All three screening strategies (non-telemedicine screening, non-AI telescreening and AI telescreening) met the criterion of a highly cost-effective health intervention. In addition, it revealed that annual AI screening in both rural and urban areas in China was the optimal screening strategy.

The results suggested that routine screening of multiple blinding eye diseases could be highly cost-effective in China, which provides robust economic evidence for informed policymaking regarding its large-scale promotion. Moreover, the results indicated that novel screening strategies, such as utilizing AI-based tools, could achieve even greater cost-effectiveness in population screening. These novel screening approaches could play a unique role in high-quality eye care delivery and improve the equity and accessibility of eye health resources. More importantly, they can serve as a feasible example for other countries, especially LMICs with similar settings or epidemiological features.

Landmark Paper: SM Li, et al., “Effect of Text Messaging Parents of School-Aged Children on Outdoor Time to Control Myopia: A Randomized Clinical Trial,” JAMA Pediatr, 176, 1077, (2022), PMID: 36155742

Based on a randomized clinical trial, this paper assessed the remarkable effectiveness of SMS text messages to parents to increase light exposure and time outdoors in school-aged children and provide effective myopia control. This paper reminds us of the importance of school-based increases in time outdoors within the school program, perhaps during lunch breaks, may be necessary to increase time outdoors on school days. The findings suggest that using text message reminders to parents offers improved control of myopia in school-aged children and should be considered as a cost effective tool for use with large populations and over large geographic areas.

Joan W. Miller, Chair of Ophthalmology at Mass Eye and Ear, Massachusetts General Hospital and Ophthalmologist-in-Chief at Brigham and Women’s Hospital; and Chair, Department of Ophthalmology at Harvard Medical School.
 

Given my interests in retinal disease, my choices are designed to bring attention to just a few of the exciting innovations that have occurred in this area of ophthalmic medicine. Our ever increasing knowledge about the genetic roots of so many ophthalmological diseases offers incredible potential not just for early detection and management of disease but unique and targeted therapies for so many patients.

Landmark Paper: M. Margeta et al., “Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in Glaucoma,” Immunity 55, 1627, (2022) PMID: 35977543

A team of scientists at Mass Eye and Ear and Brigham and Women’s Hospital demonstrated that the APOE4 gene variant—known to increase the risk of Alzheimer’s but decrease risk of glaucoma in humans—functions by blocking a disease cascade that leads to the destruction of retinal ganglion cells in glaucoma. Since glaucoma remains a blinding disease for millions of people around the world, these findings provide insight into the role of genetic variants, and the promise of translation to a treatment for patients.

Landmark Paper: G. Eraslan et al., Single-nucleus cross-tissue molecular reference maps to decipher disease gene function, Science, 376, 6594, (2022) PMID: 35549429

This paper is a first-of-its-kind cross-tissue atlas derived from an analysis of nuclei from 25 frozen samples from eight tissue types. As previous research has primarily focused on single-cell atlases derived from one particular healthy or diseased tissue, this cross-tissue atlas has the potential to uncover new clues for specific cell types and genes involved in complex diseases, as these are often caused by dysfunction of more than once cell type or tissue. In ophthalmology, the research team is applying similar approaches to primary open-angle glaucoma, and in the future, age-related macular degeneration, with the hope of learning more about these diseases and developing therapies and better strategies for disease prevention.

Landmark Paper: H. Fu et al., “Thrombospondin 1 missense alleles induces extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma,” J Clin Invest, 132, (2022) PMID: 36453543.

Through advanced genome-sequencing technology, the international team of scientists identified a new genetic mutation in thrombospondin-1 (THBS1) that leads to the development of severe cases of childhood glaucoma, a devastating condition that runs in families and can cause blindness in children by 3 years of age. These findings provide important insights into the causes of childhood glaucoma and offer the prospect of targeted therapy.

Pearse A. Keane, Professor of Artificial Medical Intelligence, Institute of Ophthalmology, UCL and Consultant Ophthalmologist, Moorfields Eye Hospital.
 

Landmark Paper: JS Heier JS, et al., “Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomized, double-masked, phase 3, non-inferiority trials,” Lancet, (2022) PMID: 35085502

Landmark Paper: C. Wykoff et al., Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomized, double-masked, phase 3 trials,” Lancet (2022) PMID: 35085503.

Phase three trials are always essential for clinicians to follow, as these trials offer the most potential for directly influencing how we take care of our patients. These are two absolutely pivotal phase 3 trials showing the efficacy and safety of faricimab in the treatment of wet AMD and diabetic macular edema. These papers have already transformed the care of patients with these conditions all around the world, with faricimab being among the first of the second generation anti-VEGF agents which may be better at eliminating retinal fluid and are thus potentially longer acting.

Landmark Paper: Available at http://bit.ly/3I0vL8o

The second thing I would like to highlight is the announcement of the DERBY and OAKS phase 3 trial results. This is top line data which I’m not sure if has been published in a journal yet, but what makes this so important is that the data shows the first potential treatment for patients with geographic atrophy. Over the course of 24 months of treatment the results show a statistically significant improvement in GA lesions along with an excellent safety profile. The three year GALE extension study will extend the research and will hopefully provide more compelling evidence for this new treatment option.

Landmark Paper: B. Babenko et al., Detection of signs of disease in external photographs of the eyes via deep learningNature Biomedical Engineering, 6, 1370, (2022) PMID: 35352000

Finally, I would like to bring some attention to this frankly mind-blowing paper from the Google Brain team. I should stress that the results will need to be independently confirmed but the research team developed a deep learning model to detect the signs of systemic disease just from external photographs of the eye. Focusing on diabetic retinopathy, diabetic macular oedema and poor blood glucose control, the initial result showed extremely promising predictive performance and underscores just how much impact the introduction of AI tools can have on disease management.

Patricia A. D’Amore, Charles L. Schepens Professor of Ophthalmology, Harvard Medical School, and Professor of Pathology at Mass Eye and Ear
 

As a basic scientist and someone who focuses on the retina, my selections are biased in these areas but show some of the innovative work being done in the area of research.

Landmark Paper: Xu Q, et al., “Stress induced aging in mouse eye,”  D. Aging Cell, (2022), PMID: 36397653

This paper is relevant on a number of fronts. It demonstrates that vulnerability to stress  increases with age and is apparent at the level of the transcriptome and DNA methylation.  Moreover, it shows that repeated stress (in the form of elevated intraocular pressure) of a young  retina translates into transcriptomic and epigenomic changes akin to those seen in aging e.g.  stress accelerates aging. This paper is particularly significant in light of a 2020 paper by Lu et  al. (Nature, 2020) which showed that such changes could be reversed by partial epigenetic reprogramming.

Landmark Paper: DC Zysset-Burri, et al., “The role of the gut microbiome in eye diseases,” Progress in Retinal and Eye, 92, (2023) PMID: 36075807

This paper reviews a growing literature that points to the fact that changes in the profile and  function of the microbiome are associated with a number of ocular pathologies – particular examples offered in this paper are age-related macular degeneration, retinal artery occlusion, central serous chorioretinopathy and uveitis . This effect is hypothesized to be the result of communication among the gut microbiome, its metabolites, and the immune system. The discovery of this novel network may provide new therapeutic targets.

Landmark Paper: L Alarcon-Martinez, et al., “Pericyte dysfunction and loss of inter-pericyte tunneling nanotubes promote neurovascular deficits in glaucoma,” Proc Natl Acad Sci U S A. (2022) PMID: 35135877.

Using two-photon imaging and a mouse model of high-pressure glaucoma, this paper reports reduced capillary diameter and impaired blood flow at pericyte locations and showed that inter pericyte tunneling nanotubes are damaged by the elevated pressure with repercussions for the  regulation of blood flow and neurovascular coupling. This adds another important instance of the biological significance of nanotubes. Moreover, as is the case for diabetic retinopathy, it provides evidence that the pericyte is an early target in the pathogenesis of high-pressure glaucoma.

Landmark Paper: S. Karaman et al., “Interplay of vascular endothelial growth factor receptors in organ-specific vessel maintenance,” J Exp Med, (2022) PMID: 35050301.

This paper investigates the role of vascular endothelial growth factor receptors (VEGFR) in the  maintenance of tissue-specific microvasculatures using deletion of the various receptors  (VEGFR1, VEGFR2, and VEGFR3) in postnatal and adult mice. They show that the phenotypes  seen in mice in which VEGFR2 is deleted either postnatally or in the adult are made worse by  the added deletion of VEGFR1 or VEGFR3 in the intestine, kidney, and pancreas whereas this  effect is not seen in the microvasculatures of the liver or kidney glomeruli. Vessel regression  was noted in the liver and the intestine within just a few days of receptor deletion, the  microvessels of the skin and retina remained stable for at least four weeks. These results demonstrate the endothelial transcriptomes and the mechanism of vessel maintenance vary  among tissue mechanisms downstream of VEGFR signaling and suggest non-uniform roles for  the various VEGF receptors in different tissues.
 

Facts and Figures

• Germany: Jost B. Jonas, has a total of 264,323 citations and was cited 21,219 times in 2021.
• USA, Philadelphia. Carol L. Shields has a H-index of 19
• Japan: By 2021, Kazuo Tsubota had recorded over 1,300 publications.
• UK: One of Harminder Dua’s papers has been cited over 850 times.
• Australia: Fiona Stapleton, had their work cited 1645 times in just 2021.
• Iran: Hassan Hasheni has had almost 300 of their papers be cited at least once throughout their entire career.
• Brazil: João M Furtado has 46741 citations since 2018.
• Singapore: Chelvin Sng has published 83 papers between 2002 and 2022.

All figures are taken from the Stanford University data set

The Stanford Data on Ophthalmology
 

Every year, Stanford University releases a publicly available database of the top cited scientists across the world. The aim of the data set is to provide standardized information on citations, self-citation, numbers of papers and numbers of papers which have been cited at least once – as well as a host of other quantitative measurements. On top of this, the data also collects both career long and individual year impact information. The data set is designed to assess impact rather than just productivity and while all citation data should be used judiciously, it does provide a good visualization of the most impactful papers from the scientific community.

As the authors of the original data set highlight, if a certain figure does not appear on the list it is no reflection on the quality of their work. As the Leiden Manifesto pointed out, quantitative measurement should only ever be used to support qualitative expert assessment. It is undeniably important for ophthalmologists to know the patterns in the web of science, made up as it is of references, citations and publications. For that purpose, these metrics are useful, but the best insight into the state of ophthalmological research comes not just from quantitative measures but when this data meets the qualitative experiences of clinicians, researchers and, of course, patients. While academic science rightly puts serious weight on publication and impact we should not lose sight of how this research translates to the human experience of diagnosis, disease management and – hopefully – better eye health for all.

The data on ophthalmology was gathered from the Stanford data set and was compiled by Andrzej Grzybowski, Professor of Ophthalmology, CEO, Foundation for Ophthalmology Development, Poznan, Poland; EVER President-Elect.