Global collaboration is the cornerstone of scientific advancement. Frontiers in Ophthalmology has organized a series of special edition Research Topics, with the goal of highlighting the latest advancements in Inflammatory Eye Diseases across the globe, showcasing the academic excellence and high-quality work of internationally recognized researchers. These collections aim to shed light on the recent progress made across the entire breadth of the Inflammatory Eye Disease field and reflect on the future challenges faced by researchers across borders. This Research Topic will focus specifically on contributions to the field from Europe researchers.

MIOS - Retina and Inflammation

University of Siena

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Frontiers in Ophthalmology

Inflammatory Eye Diseases

Global Excellence in Inflammatory Eye Diseases: Europe

Transcending geographical limitations, global collaboration is the very foundation of scientific progress, with collective efforts forging new pathways of knowledge. (<a href="#B1">1</a>, <a href="#B2">2</a>) Exhibiting a steadfast commitment to collaborative pursuits, Frontiers in Ophthalmology has meticulously compiled a special edition Research Topic that highlights the latest advancements in Inflammatory Eye Diseases from all corners of the globe. A Research Topic featuring internationally acclaimed researchers, this showcase of academic prowess exemplifies the collaborative spirit that is integral to modern scientific exploration.Within the extensive sphere of Inflammatory Eye Diseases, European researchers have contributed significantly. This Research Topic provides a unique view of the advancements in this field from a specific region, with a nuanced perspective. It emphasizes the close-knit nature of the scientific community, where scholars from various origins contribute. Pushing the boundaries of knowledge in unison, people converge to collectively address challenges.In this handpicked Research Topic, the first article offers a detailed overview of biologic remedies for Uveitis triggered by Juvenile Idiopathic Arthritis (JIA-U) (<a href="https://doi.org/10.3389/fopht.2022.954901">Dini et&nbsp;al.</a>). This all-encompassing review, published on August 15, 2022 in Frontiers in Ophthalmology, presents a map that steers through the complex treatment situation for JIA-U, which is notably challenging, especially in the pediatric population. The authors leave no stone unturned by deeply exploring the effects of cytokine blockers and cell-targeted therapies, providing subtle perspectives into how healthcare improvements are reshaping the future of JIA-U’s prognosis. As a comprehensive source for researchers and practitioners alike, this review is an essential tool, setting the path for continuing research and therapeutic interventions.Moving to the second article, an original research piece published on June 2, 2023, the focus shifts to a meticulous examination of risk factors for the development of macular edema in children with uveitis (<a href="https://doi.org/10.3389/fopht.2023.1134077">Friling et&nbsp;al.</a>). This retrospective study, involving 150 pediatric patients, represents a significant contribution to our understanding of pediatric uveitis. The authors clearly identify key factors influencing the onset of macular edema, shedding light on the complexity of this condition. This research not only increases our understanding of pediatric uveitis but also underscores the critical importance of early detection and vigilant follow-up to improve patient outcomes. The implications of these findings extend beyond the confines of the article influencing practice in clinical settings and laying grounds towards better care for patients.In the realm of case reports, the third article stands as a unique and compelling contribution (<a href="https://doi.org/10.3389/fopht.2023.1131674">Saban et&nbsp;al.</a>). Published on July 3, 2023, this case report details a successful treatment approach for cytomegalovirus retinitis. The administration of cytomegalovirus-specific cytotoxic T lymphocytes (CTL) represents a promising advancement in immunotherapy, suggesting potential alternatives for scientific exploration and therapeutic applications. This singular case not only showcases the potential of personalized treatments but also underscores the dynamic nature of treatment strategies, particularly in the context of hematopoietic cell transplantation. This report holds significance not only for its individual implications but also for its potential to pave the way for further explorations into personalized immunotherapeutic interventions.Navigating the contemporary landscape, the fourth article addresses a concern that has emerged in the wake of global events – herpetic anterior uveitis following COVID-19 vaccinations (<a href="https://doi.org/10.3389/fmed.2023.1242225">Ott et&nbsp;al.</a>). (<a href="#B3">3</a>) Published on September 22, 2023, this article presents a case series, providing a thorough exploration of the temporal relationship between vaccination and herpetic eye disease. The authors delve into the intricacies of this relationship, posing critical questions regarding potential risks that warrant further investigation. In the backdrop of the ongoing global vaccination efforts, this article assumes heightened relevance, urging the scientific community to explore deeper into the potential implications of vaccinations on ocular health.Concluding this rich and diverse Research Topic is a mini-review that delves into the future potential of CAR-Treg cell therapies in treating ocular autoimmune conditions (<a href="https://doi.org/10.3389/fopht.2023.1184937">Abraham et&nbsp;al.</a>). (<a href="#B4">4</a>) Published on April 18, 2023, this mini-review takes readers on a journey through the proliferating field of cell therapy for ocular autoimmune conditions. Focusing on Chimeric Antigen Receptor modified T cell (CAR-T) therapy, the authors articulate the potential application of this cutting-edge approach in treating ophthalmic conditions. The mini-review not only synthesizes existing knowledge but also serves as a launchpad for discussions surrounding future strategies in applying CAR-Treg therapy in the treatment of ophthalmic conditions.In essence, this Research Topic on Inflammatory Eye Diseases serves as a comprehensive tapestry woven by the collaborative efforts of European researchers. Each article contributes a thread to this intricate weave, offering unique insights and perspectives that collectively advance our understanding of these diseases. As we navigate the complex terrain of eye diseases, this Research Topic exemplifies the power of global collaboration, pushing the boundaries of knowledge and paving the way for innovations that hold the promise of improved patient outcomes.CF: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. MDS: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Global excellence in inflammatory eye diseases: Europe

PurposeTo report a case series of herpetic uveitis following COVID-19 vaccinations.</sec>MethodsDemographic, clinical and treatment-related data of herpetic anterior uveitis cases was collected at five tertiary eye hospitals between January 2021 and June 2022. A retrospective database review at one of the centers comparing the number of cases of herpetic eye disease before and after the introduction of COVID-19 vaccination was performed as well.</sec>ResultsTwenty-four patients (9 female, 15 male) with a mean age of 54 years (range 28–83 years) were diagnosed with herpetic uveitis, reporting an onset of symptoms 3–42 days after the first, second or third dose of COVID-19 vaccination. Median time between vaccination and onset of herpetic eye disease was 10 days (mean 12.7 ± 10.15 days) days. The administered vaccines were BNT162b2, mRNA-1273, BBIBP-CorV and Ad26.COV2.S. The cases included 11 HSV, 10 VZV and 1 CMV anterior uveitis, 2 were not further specified. There was an equal number of first episodes (n = 12, 50%) and recurrent episodes (n = 12, 50%). Response to established regimens was generally good. The retrospective database review revealed the exact same incidence of herpetic uveitis during the pandemic and ongoing vaccination compared to prior SARS-CoV-2.</sec>ConclusionThis report includes 24 cases of herpetic anterior uveitis in a temporal relationship to various COVID-19 vaccines. This study supports the potential risk of herpetic eye disease following COVID-19 vaccines, but proof of a direct, causal relationship is missing.</sec>

Purpose: To report a case series of herpetic uveitis following COVID-19 vaccinations.Methods: Demographic, clinical and treatment-related data of herpetic anterior uveitis cases was collected at five tertiary eye hospitals between January 2021 and June 2022. A retrospective database review at one of the centers comparing the number of cases of herpetic eye disease before and after the introduction of COVID-19 vaccination was performed as well.Results: Twenty-four patients (9 female, 15 male) with a mean age of 54 years (range 28–83 years) were diagnosed with herpetic uveitis, reporting an onset of symptoms 3–42 days after the first, second or third dose of COVID-19 vaccination. Median time between vaccination and onset of herpetic eye disease was 10 days (mean 12.7 ± 10.15 days) days. The administered vaccines were BNT162b2, mRNA-1273, BBIBP-CorV and Ad26.COV2.S. The cases included 11 HSV, 10 VZV and 1 CMV anterior uveitis, 2 were not further specified. There was an equal number of first episodes (n = 12, 50%) and recurrent episodes (n = 12, 50%). Response to established regimens was generally good. The retrospective database review revealed the exact same incidence of herpetic uveitis during the pandemic and ongoing vaccination compared to prior SARS-CoV-2.Conclusion: This report includes 24 cases of herpetic anterior uveitis in a temporal relationship to various COVID-19 vaccines. This study supports the potential risk of herpetic eye disease following COVID-19 vaccines, but proof of a direct, causal relationship is missing.

Herpetic anterior uveitis following COVID-19 vaccines: a case series

PurposeWe hereby describe a case of persistent cytomegalovirus (CMV) viremia and retinitis following allogeneic hematopoietic cell transplantation (HCT) that was successfully treated with infusion of CMV-specific cytotoxic T lymphocytes (CTL) despite previous treatment with Epstein Bar Virus (EBV) -specific CTL, which occurred 5 months earlier.</sec>ObservationsFollowing several anti- viral medication treatment trials that failed to eradicate the infectious process, the patient was treated with infusions of CMV-CTL from a biobank of cryopreserved virus-specific cells. Shortly after the first infusion, a remarkable response was noted. A few days after the second infusion, the retinitis resolved completely. No recurrence was noted at the one-year follow-up, and there was no evidence of GVHD.</sec>Conclusions and importanceThe case is unique for two reasons: use of virus-specific CTL for an indication of CMV retinitis; and successive administration, in the same patient, of third-party virus-specific CTL to treat two different infections (Epstein-Barr virus and cytomegalovirus) on two separate occasions following hematopoietic cell transplantation.</sec>

Purpose: We hereby describe a case of persistent cytomegalovirus (CMV) viremia and retinitis following allogeneic hematopoietic cell transplantation (HCT) that was successfully treated with infusion of CMV-specific cytotoxic T lymphocytes (CTL) despite previous treatment with Epstein Bar Virus (EBV) -specific CTL, which occurred 5 months earlier.Observations: Following several anti- viral medication treatment trials that failed to eradicate the infectious process, the patient was treated with infusions of CMV-CTL from a biobank of cryopreserved virus-specific cells. Shortly after the first infusion, a remarkable response was noted. A few days after the second infusion, the retinitis resolved completely. No recurrence was noted at the one-year follow-up, and there was no evidence of GVHD.Conclusions and importance: The case is unique for two reasons: use of virus-specific CTL for an indication of CMV retinitis; and successive administration, in the same patient, of third-party virus-specific CTL to treat two different infections (Epstein-Barr virus and cytomegalovirus) on two separate occasions following hematopoietic cell transplantation.

Case Report: Cytomegalovirus-specific T-lymphocyte infusion for resistant cytomegalovirus retinitis

AimTo determine the risk factors for macular edema (ME) in children with uveitis.</sec>MethodsA retrospective study was conducted of 150 pediatric patients (264 eyes) with uveitis attending 2 tertiary medical centers. Data were collected from the medical files on demographics, type of uveitis, etiology, clinical findings, treatment, and time to development of ME. Risk factors for the development of ME were identified.</sec>ResultsME developed in 63 eyes (23.9%) over a mean period of 15.3 ± 2.95 months from diagnosis of uveitis, at a rate of 0.08 eyes per eye-year. On univariate analysis, risk factors for the development of ME were the non-anterior location of the inflammation (p=0.002), band keratopathy (p <0.0001), posterior synechiae (p=0.003), cataract (p=0.002), and vision impairment at presentation (p <0.0001). On multivariate analysis, non-anterior uveitis, which includes intermediate, pan, and posterior-uveitis, and vision impairment retained significance as independent risk factors of ME.</sec>ConclusionWithin the pediatric population with uveitis, non-anterior location is associated with the highest risk of ME, followed by the presence of complications, such as band keratopathy and posterior synechiae. These findings indicate a need for close follow-up in children with uveitis for early detection of ME.</sec>

Aim: To determine the risk factors for macular edema (ME) in children with uveitis.Methods: A retrospective study was conducted of 150 pediatric patients (264 eyes) with uveitis attending 2 tertiary medical centers. Data were collected from the medical files on demographics, type of uveitis, etiology, clinical findings, treatment, and time to development of ME. Risk factors for the development of ME were identified.Results: ME developed in 63 eyes (23.9%) over a mean period of 15.3 ± 2.95 months from diagnosis of uveitis, at a rate of 0.08 eyes per eye-year. On univariate analysis, risk factors for the development of ME were the non-anterior location of the inflammation (p=0.002), band keratopathy (p &lt;0.0001), posterior synechiae (p=0.003), cataract (p=0.002), and vision impairment at presentation (p &lt;0.0001). On multivariate analysis, non-anterior uveitis, which includes intermediate, pan, and posterior-uveitis, and vision impairment retained significance as independent risk factors of ME.Conclusion: Within the pediatric population with uveitis, non-anterior location is associated with the highest risk of ME, followed by the presence of complications, such as band keratopathy and posterior synechiae. These findings indicate a need for close follow-up in children with uveitis for early detection of ME.

Risk factors for the development of macular edema in children with uveitis

Ophthalmic autoimmune and autoinflammatory conditions cause significant visual morbidity and require complex medical treatment complicated by significant side effects and lack of specificity. Regulatory T cells (Tregs) have key roles in immune homeostasis and in the resolution of immune responses. Polyclonal Treg therapy has shown efficacy in treating autoimmune disease. Genetic engineering approaches to produce antigen-specific Treg therapy has the potential for enhanced treatment responses and fewer systemic side effects. Cell therapy using chimeric antigen receptor modified T cell (CAR-T) therapy, has had significant success in treating haematological malignancies. By modifying Tregs specifically, a CAR-Treg approach has been efficacious in preclinical models of autoimmune conditions leading to current phase 1-2 clinical trials. This review summarises CAR structure and design, Treg cellular biology, developments in CAR-Treg therapies, and discusses future strategies to apply CAR-Treg therapy in the treatment of ophthalmic conditions.

Ophthalmic autoimmune and autoinflammatory conditions cause significant visual morbidity and require complex medical treatment complicated by significant side effects and lack of specificity. Regulatory T cells (Tregs) have key roles in immune homeostasis and in the resolution of immune responses. Polyclonal Treg therapy has shown efficacy in treating autoimmune disease. Genetic engineering approaches to produce antigen-specific Treg therapy has the potential for enhanced treatment responses and fewer systemic side effects. Cell therapy using chimeric antigen receptor modified T cell (CAR-T) therapy, has had significant success in treating haematological malignancies. By modifying Tregs specifically, a CAR-Treg approach has been efficacious in preclinical models of autoimmune conditions leading to current phase 1-2 clinical trials. This review summarises CAR structure and design, Treg cellular biology, developments in CAR-Treg therapies, and discusses future strategies to apply CAR-Treg therapy in the treatment of ophthalmic conditions.

CAR-Treg cell therapies and their future potential in treating ocular autoimmune conditions

Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease of childhood and uveitis is its most common extra-articular manifestation. JIA-associated uveitis (JIA-U) is one of the main causes of visual impairment in children and represents a major challenge for pediatrician and ophthalmologist, due to its insidious onset and sight-threatening complications. Topical glucocorticoids are the first line of treatment, followed by conventional disease-modifying anti-rheumatic drugs (DMARDs), usually methotrexate (MTX). In recent years, new biological drugs targeting specific molecules involved in disease pathogenesis, have significantly improved the prognosis of the disease, especially for cases refractory to conventional therapies. In this review we discuss the role of biological agents in JIA-U, focusing on cytokine blockers and cell-targeted therapies aimed to control ocular inflammation.

Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease of childhood and uveitis is its most common extra-articular manifestation. JIA-associated uveitis (JIA-U) is one of the main causes of visual impairment in children and represents a major challenge for pediatrician and ophthalmologist, due to its insidious onset and sight-threatening complications. Topical glucocorticoids are the first line of treatment, followed by conventional disease-modifying anti-rheumatic drugs (DMARDs), usually methotrexate (MTX). In recent years, new biological drugs targeting specific molecules involved in disease pathogenesis, have significantly improved the prognosis of the disease, especially for cases refractory to conventional therapies. In this review we discuss the role of biological agents in JIA-U, focusing on cytokine blockers and cell-targeted therapies aimed to control ocular inflammation.