Optimizing Behçet Uveitis Management: A Review of Personalized Immunosuppressive Strategies.

Behçet uveitis poses significant management challenges, owing to its intricate pathogenesis and the severe prognosis it harbors, frequently culminating in irreversible visual impairment and an elevated risk of blindness. This review synthesizes contemporary insights into personalized immunosuppressive strategies for Behçet uveitis, emphasizing the necessity for a customized approach in recognition of the disease's heterogeneity and the variable responsiveness to treatment. This discourse elaborates on the application, efficacy, and safety profiles of traditional immunosuppressants, highlighting a paradigm shift toward integrative combination therapies aimed at diminishing reliance on glucocorticoids and mitigating their associated adverse effects. This thorough evaluation seeks to enlighten clinical practices and spearhead future investigations aimed at refining the management of Behçet uveitis, championing a personalized, multidisciplinary strategy to amplify therapeutic efficacy and enhance patient quality of life.

Enhanced immunosuppressive capability of mesenchymal stem cell-derived small extracellular vesicles with high expression of CD73 in experimental autoimmune uveitis.

BACKGROUND: Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. METHODS: To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. RESULTS: Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. CONCLUSION: Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.

Decoding Behcet's Uveitis: an In-depth review of pathogenesis and therapeutic advances.

Behcet's disease (BD) is a rare but globally distributed vasculitis that primarily affects populations in the Mediterranean and Asian regions. Behcet's uveitis (BU) is a common manifestation of BD, occurring in over two-thirds of the patients. BU is characterized by bilateral, chronic, recurrent, non-granulomatous uveitis in association with complications such as retinal ischemia and atrophy, optic atrophy, macular ischemia, macular edema, and further neovascular complications (vitreous hemorrhage, neovascular glaucoma). Although the etiology and pathogenesis of BU remain unclear, numerous studies reveal that genetic factors (such as HLA-B51), dysregulated immune responses of both the innate and adaptive immune systems, infections (such as streptococcus), and environmental factors (such as GDP) are all involved in its development. Innate immunity, including hyperactivity of neutrophils and γδT cells and elevated NK1/NK2 ratios, has been shown to play an essential role in this disease. Adaptive immune system disturbance, including homeostatic perturbations, Th1, Th17 overaction, and Treg cell dysfunction, is thought to be involved in BU pathogenesis. Treatment of BU requires a tailored approach based on the location, severity of inflammation, and systemic manifestations. The therapy aims to achieve rapid inflammation suppression, preservation of vision, and prevention of recurrence. Systemic corticosteroids combined with other immunosuppressive agents have been widely used to treat BU, and beneficial effects are observed in most patients. Recently, biologics have been shown to be effective in treating refractory BU cases. Novel therapeutic targets for treating BU include the LCK gene, Th17/Treg balance, JAK pathway inhibition, and cytokines such as IL-17 and RORγt. This article summarizes the recent studies on BU, especially in terms of pathogenesis, diagnostic criteria and classification, auxiliary examination, and treatment options. A better understanding of the significance of microbiome composition, genetic basis, and persistent immune mechanisms, as well as advancements in identifying new biomarkers and implementing objective quantitative detection of BU, may greatly contribute to improving the adequate management of BU patients.

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

Evolution of research in diagnosis and management of uveitis over four decades in India.

Uveitis and its complications are more common in the developing world, in which the condition occurs in up to 714 per 100,000 in the population and accounts for up to 25% of all blindness. In India, the ophthalmic sub speciality of uveitis greatly evolved in the last four decades. In the early decades most of the studies were epidemiological studies. In recent years, more research has been published due to tremendous advancements in clinical diagnosis, laboratory investigations and ancillary test and treatment modalities. In this review article, we did a medline search with key words 'uveitis' and 'India', and selectively incorporated articles showing the evolution of this sub-speciality in India.

[Advancements in research on immune responses associated with adeno-associated virus vector-mediated ocular gene therapy].

Adeno-associated virus (AAV) vectors have been widely employed in gene therapy for ocular and systemic diseases. However, clinical trial outcomes have indicated that gene therapy may trigger severe adverse events associated with immune-inflammatory reactions, thereby impacting the safety and efficacy of gene therapy. The immune-inflammatory reaction induced after gene therapy in the eye is referred to as gene therapy-associated uveitis, which has become a major obstacle limiting the long-term and effective use of ocular gene therapy. This review comprehensively explores four aspects: the immune response mechanisms of gene therapy, ocular manifestations of associated uveitis, factors influencing immune inflammation, and preventive and therapeutic strategies. The aim is to provide insights for the development of safer and more effective ocular gene therapy.

Ocular Sarcoidosis.

Sarcoidosis frequently affects the eye and can do so in many different ways. Sarcoidosis causing uveitis can have distinctive features that facilitate identifying sarcoidosis as the cause of the uveitis. Progress is being made in elucidating ocular sarcoidosis, as for example, by transcriptomics, genetics, therapy, and imaging.

Immunology of Retinitis Pigmentosa and Gene Therapy-Associated Uveitis.

The underlying immune state of inherited retinal degenerations (IRDs) and retinitis pigmentosa (RP) has been an emerging area of interest, wherein the consequences have never been greater given the widespread recognition of gene therapy-associated uveitis (GTU) in gene therapy clinical trials. Whereas some evidence suggests that the adaptive immune system may play a role, the majority of studies indicate that the innate immune system is likely the primary driver of neuroinflammation in RP. During retinal degeneration, discrete mechanisms activate resident microglia and promote infiltrating macrophages that can either be protective or detrimental to photoreceptor cell death. This persistent stimulation of innate immunity, overlaid by the introduction of viral antigens as part of gene therapy, has the potential to trigger a complex microglia/macrophage-driven proinflammatory state. A better understanding of the immune pathophysiology in IRD and GTU will be necessary to improve the success of developing novel treatments for IRDs.

[Intermediate and Posterior Uveitis - Disease entities]. / Intermediäre und posteriore Uveitis ­ Teil 2.

Intermediate and posterior uveitis can have multiple infectious and noninfectious causes, and posterior uveitis in particular is clinically multifaceted. Some entities require prompt initiation of therapy to ensure visual prognosis. This article presents typical characteristics of intermediate and posterior uveitides and explains special features of their treatment.

MiR-223-3p attenuates M1 macrophage polarization via suppressing the Notch signaling pathway and NLRP3-mediated pyroptosis in experimental autoimmune uveitis.

Autoimmune uveitis is an intraocular inflammatory disease with a high blindness rate in developed countries such as the United States. It is pressing to comprehend the pathogenesis of autoimmune uveitis and develop novel schemes for its treatment. In the present research, we demonstrated that the Notch signaling pathway was activated, and the level of miR-223-3p was significantly reduced in rats with experimental autoimmune uveitis (EAU) compared with the level of normal rats. To investigate the relationship between miR-223-3p and Notch signaling, EAU rats received miR-223-3p-carrying lentivirus, miR-223-3p vector-carrying lentivirus (miR-223-3p-N), and γ-secretase inhibitor (DAPT), respectively. The results of Q-PCR, immunological experiments, and flow cytometry analysis all support the hypothesis that both miR-223-3p and DAPT, a Notch signaling pathway inhibitor, had similar inhibitory effects on the EAU pathological process. That is to say, they could both inhibit the activation of the Notch signaling pathway via modulating recombination signal binding protein-Jκ (RBPJ) to restore the polarization imbalance of M/M2 macrophages in EAU rats. In addition, miR-223-3p could also inhibit NLRP3 inflammasome activation and inflammasome-induced pyroptosis in ocular tissues. Taken together, our findings indicate that miR-223-3p serves as an important regulator in M1 macrophage polarization and pyroptosis, thereby alleviating the inflammatory response in uveitis.

Healthcare professionals' views on the most important outcomes for non-infectious uveitis of the posterior segment: A qualitative study.

BACKGROUND: Uveitis comprises a range of conditions that result in intraocular inflammation. Most sight-threatening uveitis falls into the broad category known as Non-infectious Posterior Segment-Involving Uveitis (PSIU). To evaluate treatments, trialists and clinicians must select outcome measures. The aim of this study was to understand healthcare professionals' perspectives on what outcomes are important to adult patients with PSIU and their carers. METHODS: Twelve semi-structured telephone interviews were undertaken to understand the perspectives of healthcare professionals. Interviews were audio recorded, transcribed and thematically analysed. Findings were compared with the views of patients and carers and outcomes abstracted from a previously published systematic review. RESULTS: Eleven core domains were identified as important to healthcare professionals: (1) visual function, (2) symptoms, (3) functional ability, (4) impact on relationships, (5) financial impact, (6) psychological morbidity and emotional well-being (7) psychosocial adjustment to uveitis, (8) doctor / patient / interprofessional relationships and access to health care, (9) treatment burden, (10) treatment side effects, (11) disease control. Healthcare professionals recognised a similar range of domains to patients and carers but placed more emphasis on certain outcomes, particularly in the disease control domain. In contrast the range of outcomes identified via the systematic review was limited. CONCLUSION: Healthcare professionals recognise all of the published outcome domains as patients/carers in the previous publication but with subtly differing emphasis within some domains and with a priority for certain types of measures. Healthcare professionals discussed the disease control and side effects/complications to a greater degree than patients and carers in the focus groups.

Recomendaciones SER sobre el tratamiento de la uveítis / SER recommendations for the treatment of uveitis

Objetivo: Elaborar recomendaciones basadas en la evidencia disponible y el consenso de expertos para el manejo terapéutico de los pacientes con uveítis no infecciosas, no neoplásicas y no asociadas a enfermedad desmielinizante. Métodos: Se identificaron preguntas clínicas de investigación relevantes para el objetivo del documento, reformuladas en formato PICO (paciente, intervención, comparación, outcome o desenlace) por un panel de expertos seleccionados en base a su experiencia en el área. Se realizó una revisión sistemática de la evidencia, graduándose de acuerdo a los criterios Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Subsecuentemente, se formularon las recomendaciones. Resultados: Se seleccionaron tres preguntas PICO, referentes a uveítis anteriores, no anteriores y complicadas con edema macular. Se formularon un total de 19 recomendaciones con base en la evidencia encontrada y/o en el consenso de expertos. Conclusiones: Se presenta el primer documento oficial de la Sociedad Española de Reumatología de recomendaciones para el tratamiento de las uveítis. Pueden aplicarse directamente al sistema sanitario español como herramienta de ayuda y homogenización terapéutica.(AU)

Objective: To develop evidence-based expert-consensus recommendations for the management of non-infectious, non-neoplastic, non-demyelinating disease associated uveitis. Methods: Clinical research questions relevant to the objective of the document were identified, and reformulated into PICO format (patient, intervention, comparison, outcome) by a panel of experts selected based on their experience in the field. A systematic review of the available evidence was conducted, and evidence was graded according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Subsequently, recommendations were developed. Results: Three PICO questions were constructed referring to uveitis anterior, non-anterior and complicated with macular edema. A total of 19 recommendations were formulated, based on the evidence found and/or expert consensus. Conclusions: Here we present the first official recommendations of the Spanish Society of Rheumatology for the treatment of non-infectious and non-demyelinating disease associated uveitis. They can be directly applied to the Spanish healthcare system as a tool for assistance and therapeutic homogenisation.(AU)

SER recommendations for the treatment of uveitis.

OBJECTIVE: To develop evidence-based expert-consensus recommendations for the management of non-infectious, non-neoplastic, non-demyelinating disease associated uveitis. METHODS: Clinical research questions relevant to the objective of the document were identified, and reformulated into PICO format (patient, intervention, comparison, outcome) by a panel of experts selected based on their experience in the field. A systematic review of the available evidence was conducted, and evidence was graded according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Subsequently, recommendations were developed. RESULTS: Three PICO questions were constructed referring to uveitis anterior, non-anterior and complicated with macular edema. A total of 19 recommendations were formulated, based on the evidence found and/or expert consensus. CONCLUSIONS: Here we present the first official recommendations of the Spanish Society of Rheumatology for the treatment of non-infectious and non-demyelinating disease associated uveitis. They can be directly applied to the Spanish healthcare system as a tool for assistance and therapeutic homogenisation.

[Chinese expert consensus on the clinical diagnosis and treatment of Behcet's uveitis (2023)].

Behcet's disease is a chronic and recurrent multisystemic inflammatory disease, and its etiology and pathogenesis are not completely clarified. Behcet's uveitis is one of the common types of uveitis with the highest rate of untreatable blindness among various uveitis entities in China. The blindness in patients with Behcet's uveitis is commonly caused by retinal vascular occlusion, retinal atrophy and optic nerve atrophy. Early diagnosis and treatment are essential to preserve and improve visual function in these patients. To provide general guidance and reference in the diagnosis and treatment of Behcet's uveitis, consensus opinions have been developed through an extensive investigation on this disease by the experts in the Uveitis and Ocular Immunology Group of Chinese Ophthalmologist Association and the Ocular Immunology Group of Ophthalmology Society of Chinese Medical Association.

Use of Biologics and Stem Cells in Equine Ophthalmology.

Regenerative therapy and biologics have the promise to treat equine ocular surface diseases, including corneal ulceration or immune-mediated keratitis, or intraocular diseases such as uveitis. The use of blood-derived products such as serum or platelet-rich plasma, mesenchymal stem cells, or amniotic membrane grafts may be beneficial for the treatment of ulcerative and chronic keratitis in horses. Furthermore, the use of stem cells or gene therapy has promise for the treatment of Intraocular diseases such as equine recurrent uveitis by providing efficacious, practical, and long-term therapy for these blinding diseases.

Challenges and management of childhood noninfectious chronic uveitis.

INTRODUCTION: Childhood uveitis is a sight-threatening condition, because if not properly recognized and treated can lead to several ocular complications and blindness. It represents a real challenge not only from an etiologic/diagnostic point of view, but also for management and therapy. AREAS COVERED: In this review we will discuss the main etiologies, the diagnostic approach, risk factors associated to childhood noninfectious uveitis (cNIU), and the difficulties in eye examination in childhood. Moreover, we will discuss the treatment of cNIU in terms of therapeutic choice, timing of initiation, and withdrawal. EXPERT OPINION: Identification of specific diagnosis is mandatory to prevent severe complications, thus a thorough differential diagnosis is essential. Pediatric eye examination may be extremely challenging due to the scarce collaboration, but novel techniques and biomarkers will help in identifying low grade of inflammation, eventually modifying long-term outcomes. Once identified the appropriate diagnosis, recognition of children who may benefit of a systemic treatment is crucial. What, When, and how long are the key questions to address in this field. Current evidence and future results of ongoing clinical trials will help in driving treatment. A proper ocular screening, not only in the context of systemic disease, should be discussed by experts.

The Large Hellenic Study of Uveitis: Diagnostic and Therapeutic Algorithms, Complications, and Final Outcome.

PURPOSE: The purpose of this study is to present the diagnostic and therapeutic algorithms, complications, and final outcome in the management of uveitic patients at a tertiary academic referral center. DESIGN: Observational study. METHODS: Analysis of the archives of 6191 uveitic patients at the Ocular Inflammation Service of the Department of Ophthalmology of the University Hospital of Ioannina in Greece from 1991 to 2020. RESULTS: During the 30 years of the study, the diagnostic ability climbed from 45.43% (1991-1995) to 73.4% (2016-2020). This improvement was linked to several factors including the increase in the number of diagnostic paracenteses for the analysis of intraocular fluids, the range and quality of laboratory blood tests, the multimodal ophthalmic imaging, the proper use of nonophthalmic imaging, and the multidisciplinary approach. The degree of uveitis-related complications was related to the severity and cause of inflammation, the recurrence rate, inappropriate treatment, and the prolonged or initially inactive inflammation. The 3 most common complications included cataract, macular edema, and glaucoma. Apart from the modern treatments and surgical techniques, the 3-month preoperative control of inflammation played a critical role in the surgical outcomes. The percentage of patients with a successful outcome increased from 72% (2001-2005) to 90.50% (2016-2020). The center's experience, prompt referral, patient's compliance, and regular follow-ups are associated with a better outcome. The analysis of the results allowed the development of diagnostic and therapeutic algorithms. CONCLUSIONS: Developing diagnostic and therapeutic algorithms allows for the efficient management of uveitis, leading to better visual outcome and therefore a better quality of life.

Uveitis Registries - A Digital Tool for Patient Care, Education, Research, and Collaboration.

PURPOSE: Clinical registries are increasingly important in research and clinical advancement. This review explores and compares current uveitis registries and recommends future directions on how uveitis registries can complement one another for synergistic effect and benefit. METHODS: From a systematic search, 861 citations were screened for longitudinal, non-interventional, and multicenter uveitis-specific registries. Additional registries were identified via consultations with uveitis experts. Characteristics of all registries were analyzed and compared. RESULTS: Four registries were identified: Treatment Exit Options for Non-infectious Uveitis, AutoInflammatory Disease Alliance International Registry, Ocular Autoimmune Systemic Inflammatory Infectious Study, and Fight Uveitis Blindness!. Despite certain differences, these registries have the overarching goal of collecting large quantities of real-world, high-quality patient data to improve the understanding of uveitis. CONCLUSION: The four uveitis registries share similar goals and collect clinical data from overlapping geographical regions. There is vast potential for collaboration, including data sharing to further augment datasets for analysis.