Treatment Impact on the Long-Term Ocular Outcomes in Behçet's-Related Uveitis.

PURPOSE: To examine the demographic characteristics, findings and complication rates in patients with Behçet's uveitis (BU) and to investigate the effect of early biological therapy on the development of complications. METHODS: Medical records of 94 patients with BU were retrospectively reviewed. Demographic data, ocular findings and complications at presentation, complications during follow-up, and treatments received during follow-up were analyzed. Patients who were followed for at least 24 months were divided into two groups according to the time of presentation as Group 1 (between 2009 and 2015) and Group 2 (between 2016 and 2021). Complications at the time of presentation and during follow-up, and treatments were compared. RESULTS: We enrolled 94 patients with a male-to-female ratio of 1.94 with a mean age of 30 ± 12 years. Median follow-up was 58.1(12-163) months. There were 35 patients (66 eyes) in Group 1 and 33 patients (61 eyes) in Group 2. At the time of presentation, end-stage disease, cataract, epiretinal membrane, and optic atrophy were significantly more common in Group 1 than in Group 2 (p < 0.05). A significantly higher proportion of eyes in Group 1 developed macular edema, cataract, epiretinal membrane, and macular atrophy during-follow-up (p < 0.05). Median time to initiation of biological treatment was 17.29 months in Group 1 and 3.33 months in Group 2 (p < 0.001). The overall complication rate was significantly lower in Group 2. CONCLUSIONS: Prognosis of BU is improved after the introduction of biological treatment. Early use of biological agents in BU is effective in decreasing sight-threatening ocular complications.

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.

Drug Retention Time of Immunosuppressive Therapy in Behcet's Uveitis.

PURPOSE: Behcet's Disease is a chronic multisystem vasculitis associated with a blinding uveitis. Few comparative studies exist between conventional disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs in Behcet's uveitis (BU). We therefore used drug retention time (DRT), an accepted surrogate measure of pharmacological efficacy and tolerability, to compare these treatments in patients with BU. METHODS: Retrospective chart review of patients who met the revised International Criteria for Behcet's Disease (ICBD) treated at the Royal Victorian Eye and Ear Hospital, Australia, between 1985-2021. DRT was analysed with Kaplan-Meier plots and defined as total time on drug in the first medication-period for each DMARD in each patient. RESULTS: Forty-eight patients (37 males) with median age of 28.6 years were followed-up for a median of 8.0 years. At initial presentation, half had bilateral disease and median logMAR visual acuity was 0.176 (Snellen 6/9) in 62 uveitic eyes (16 anterior uveitis, 11 intermediate, 2 posterior, and 33 panuveitis). Thirty-three patients met ICBD initially. Prescribed corticosteroid-sparing agents were Cyclosporin (N = 24), Mycophenolate (N = 22), Azathioprine (N = 22), Methotrexate (N = 16), and Adalimumab (N = 15). Median DRT was 14.0, 27.4, 8.3, 24.0, and 52.0 months, respectively. DMARDs were discontinued 116 times and adverse effects (N = 37) were the main reason for cessation. Over time, patients were switched from Cyclosporin to Adalimumab earlier in the disease course due to poorer tolerance of adverse events. CONCLUSION: Adalimumab's drug retention time was found to be similar to and possibly better than cDMARDs in patients with BU, who often suffer from vision-threatening disease at first presentation.

Evaluation and comparison of microperimetry and optical coherence tomography findings in patients with Behçet uveitis.

PURPOSE: To evaluate and compare the findings of MP and OCT in patients with inactive Behçet's uveitis (BU). METHODS: Sixty-five eyes of 38 patients were included in this retrospective study. Ophthalmologic examination findings and OCT and MP results were recorded. The relationship between best corrected visual acuity (BCVA), duration of uveitis, central macular thickness (CMT), presence of photoreceptor zone (PZ), and/or retinal pigment epithelium (RPE) damage, macular integrity index, mean threshold and fixation stability was analyzed. RESULTS: There was a positive correlation between BCVA and CMT (p < 0.001). The eyes with PZ and/or RPE damage had significantly lower visual acuity (p < 0.001). There was a negative correlation between BCVA and macular integrity index (p = 0.005). BCVA showed positive correlations with mean threshold and fixation stability [(BCVA vs. mean threshold, p < 0.001), (BCVA vs. P1, p < 0.001), and (BCVA vs. P2, p < 0.001)]. While there was no significant correlation between CMT and macular integrity index (p = 0.08), both mean threshold and fixation stability were significantly positively correlated with CMT [(CMT vs. mean threshold, p = 0.01), (CMT vs. P1, p = 0.008), and (CMT vs. P2, p = 0.005)]. Mean threshold and fixation stability (P1 and P2) were significantly lower in the eyes with PZ and/or RPE damage (p = 0.008, p = 0.02, and p = 0.01, respectively). CONCLUSION: MP showed results consistent with visual acuity and morphological findings by OCT in patients with inactive BU. Although MP is promising for patient follow-up, controlled prospective studies are needed.

Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: A systematic review and meta-analysis.

AIM: This study aims to evaluate the long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha (anti-TNF-α) therapy for patients with Behcet's uveitis (BU) using meta-analysis. METHODS: We searched the Web of Science and PubMed databases for eligible studies up to December 1, 2022. The quality of each identified study was assessed using the Joanna Briggs Institute's case series literature quality assessment tool. Statistical analysis was conducted using Stata 16.0 software with a random-effects model. RESULTS: Twelve studies comprising 1156 patients with BU were included in our analysis. We found that 85.0% of patients achieved ocular inflammation remission after receiving anti-TNF-α treatment, with a 95% confidence interval (CI) ranging from 78.7% to 90.5%. Additionally, 77.4% (95% CI: 57.5%-92.5%) experienced an improvement in visual acuity (VA). Moreover, the pooled dose reduction of glucocorticoids (GCs) was 11.08 mg (95% CI: -13.34 mg to -8.83 mg). Throughout the follow-up period, the cumulative retention rate of the medication was 67.3% (95% CI: 53.7%-79.6%). Serious adverse events occurred in 5.8% (95% CI: 3.1%-8.9%) of cases, with the three most common types being severe infusion or injection reactions (2.7%; 95% CI: 0.8%-5.4%), tuberculosis (1.3%; 95% CI: 0.0%-3.9%), and bacterial pneumonia (1.3%; 95% CI: 0.1%-3.4%). Subgroup analysis revealed that ocular inflammation remission rates were 89.3% (95% CI: 81.2%-95.5%) for adalimumab treatment and 83.7% (95% CI: 75.3%-90.8%) for infliximab treatment. The drug retention rate after adalimumab therapy was 70.3% (95% CI: 62.0%-78.0%) compared to 66.4% (95% CI: 48.6%-82.2%) for infliximab treatment. Furthermore, the incidence of severe infusion or injection reactions was 2.2% (95% CI: 0.1%-5.8%) following adalimumab treatment and 3.5% (95% CI: 0.7%-7.7%) following infliximab treatment. CONCLUSIONS: Anti-TNF-α therapy represents an effective treatment for BU patients with favorable safety profile and high drug retention rate and a potential advantage of adalimumab over infliximab in terms of ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.

4-Octyl Itaconate Inhibits Proinflammatory Cytokine Production in Behcet's Uveitis and Experimental Autoimmune Uveitis.

4-octyl itaconate (4-OI) is an anti-inflammatory metabolite that activates the nuclear-factor-E2-related factor 2 (NRF2) signaling. In the current work, we investigated whether 4-OI could affect the production of proinflammatory cytokines in Behcet's uveitis (BU) and experimental autoimmune uveitis (EAU). Peripheral blood mononuclear cells (PBMCs) of active BU patients and healthy individuals with in vitro 4-OI treatment were performed to assess the influence of 4-OI on the proinflammatory cytokine production. EAU was induced and used for investigating the influence of 4-OI on the proinflammatory cytokine production in vivo. The flow cytometry, qPCR, and ELISA were performed to detect proinflammatory cytokine expression. NRF2 signaling activation was evaluated by qPCR and western blotting (WB). Splenic lymphocyte transcriptome was performed by RNA sequencing. The NRF2 expression by BU patients-derived PBMCs was lower than that by healthy individuals. After treatment with 4-OI, the proportion of Th17 cells, along with the expression of proinflammatory cytokines (IL-17, TNF-α, MCP-1, and IL-6) by PBMCs, were downregulated, and anti-inflammatory cytokine (IL-10) expression was upregulated, although IFN-γ expression was unaffected. The EAU severity was ameliorated by 4-OI in association with a lower splenic Th1/Th17 cell proportion and increased nuclear NRF2 expression. Additionally, 4-OI downregulated a set of 248 genes, which were enriched in pathways of positive regulation of immune responses. The present study shows an inhibitory effect of 4-OI on the proinflammatory cytokine production in active BU patients and EAU mice, possibly mediated through activating NRF2 signaling. These findings suggest that 4-OI could act as a potential therapeutic drug for the treatment and prevention of BU in the future study.

Proteomic profiling of aqueous humor-derived exosomes in Vogt-Koyanagi-Harada disease and Behcet's uveitis.

Vogt-Koyanagi-Harada (VKH) disease and Behcet's uveitis (BU) are the two major vision-threatening uveitis entities. This study performed the first label-free quantitative proteomics on aqueous humor-derived exosomes from 84 patients with VKH or BU to determine their potential roles. Sixty-five differentially expressed proteins (DEPs) and 40 DEPs were detected in the VKH and BU groups, respectively. GO and KEGG analysis showed that DEPs were mainly enriched in the complement-related pathways. The complement C1q subcomponent subunit B (C1QB) was identified as a key exosomal protein, and its expression was significantly increased by western blotting in both diseases. Additionally, the integrated analysis based on the published scRNA-seq data showed that C1QB-containing exosomes were mainly produced by mononuclear macrophages in the anterior segment tissue. Overall, our proteomic profiling highlights that complement-related pathways may be actively involved in the pathogenesis of these two diseases. These pathways may also serve as treatment targets for both diseases.

Plasma-derived exosomal protein SHP2 deficiency induces neutrophil hyperactivation in Behcet's uveitis.

To investigate the effect of plasma-derived exosomal proteins on neutrophil hyperactivation in Behcet's uveitis (BU), we treated neutrophils from healthy controls with plasma-derived exosomes from active BU patients, and determined the level of neutrophil activation by real-time quantitative PCR (RT-qPCR) and cytokine detection assay. The results revealed that exosomes from active BU patients could activate neutrophils as shown by increasing the expression levels of pro-inflammatory cytokines (IL-17 and IL-6), chemokines (IL-8 and MCP-1), and NETs (MPO and ELANE). Label-free quantitative proteomic analysis of plasma-derived exosomes from patients and healthy controls found a remarkably distinct protein profile and identified differentially expressed proteins (DEPs) between the two groups. The results of GO, KEGG, and GSEA enrichment analysis showed that DEPs were enriched in innate immune-mediated and neutrophil hyperactivation-related signaling pathways. The protein-protein interaction (PPI) analysis determined that SHP2 was a downregulated key hub protein in the exosomes of active BU patients. Knockdown of SHP2 in human neutrophil cell lines (NB4 cells) was shown to promote the secretion of pro-inflammatory cytokines, chemokines, and NETs. The converse effects were observed following SHP2 overexpression. In conclusion, we highlighted a pathogenic role of plasma-derived exosomal SHP2 deficiency in facilitating neutrophil activation and suggested that SHP2 might be an immunoprotective factor in BU pathologic process.

Treatment Adherence Effect on the Visual Acuity of Behçet's Uveitis Patients.

PURPOSE: This study aimed to explore the relationship between treatment adherence, visual acuity, quality of life (QoL), depression, and anxiety levels in individuals with Behçet's uveitis (BU). METHODS: A total of 55 BU patients and 55 healthy controls completed sociodemographic questionnaires, the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), World Health Organization Quality of Life Questionnaire-BREF version (WHOQOL-BREF), Self-reported Questionnaire About Treatment Compliance, and the Morisky Medication Adherence Scale (MMAS). The scores obtained from these scales were analyzed to assess the relationship between treatment adherence, visual acuity, QoL, depression, and anxiety levels. RESULTS: The results revealed that 36 (65.4%) of the 55 BU patients exhibited depressive symptoms, while 45 (81.8%) of them experienced symptoms of anxiety. Patients with BU demonstrated significantly higher BAI and BDI scores compared to the healthy control group (p < 0.001). Furthermore, the patient group reported lower mean scores across multiple domains of the WHOQOL-BREF questionnaire, including general health, psychological health, social relationships, and environment (p < 0.05). Moreover, a significant association was observed between low treatment adherence and lower values of best-corrected visual acuity (BCVA) (p < 0.05), as well as a higher frequency of uveitis attacks (p = 0.005). CONCLUSION: Poor treatment adherence in BU patients has a negative effect on final visual acuity outcomes. Moreover, BU patients experience lower QoL and higher rates of depression and anxiety compared to the healthy control group. These findings highlight the importance of addressing treatment adherence and psychological well-being in the management of BU.

Retinal thickness profiles in patients with Behçet uveitis during remission / Perfis de espessura da retina em pacientes com uveíte de Behçet durante remissão

ABSTRACT Purpose: The purpose of this study was to evaluate the intraretinal layer thickness in the macular region and its correlation with the duration of uveitis and visual acuity in patients with Behçet uveitis. Methods: In this cross-sectional study, we included 93 eyes of 57 patients with Behçet uveitis and 100 eyes of 50 healthy individuals admitted to a tertiary center from January to September 2017. We performed macular measurements in all subjects via spectral domain-optical coherence tomography (SD-OCT) and divided the retina into layers using automated segmentation software on the SD-OCT device. We then compared layer thicknesses between the patient and control groups and evaluated the correlation between OCT parameters and the duration of uveitis and visual acuity in the patient group. Results: Our records show a mean age of 37.9 ± 10.8 (18-64) years and 37.7 ± 12.2 (21-61) years in the patient and control groups (p=0.821), respectively. Meanwhile, data reveal a mean duration of uveitis of 6.9 ± 4.7 (1-20) years. We found a reduction in the total outer layer thickness in the patient group (p<0.001). However, we did not find a statistically significant difference in the inner retinal layers except in the inner nuclear layer. The duration of uveitis negatively correlated with the outer retinal layer's thickness (correlation coefficient = -0.250). On the other hand, visual acuity positively correlated with the central macular, the total inner layer, and the outer retinal layer thicknesses (correlation coefficients: 0.194, 0.154, and 0.364, respectively). However, the inner nuclear layer negatively correlated with visual acuity. Conclusions: Using retinal segmentation via SD-OCT for follow-ups can help estimate visual loss in patients with Behçet uveitis, which can cause significant changes in intraretinal layers in the macular region.

RESUMO Objetivo: Avaliar a espessura das camadas intraretinianas na região macular e sua relação com a duração da uveíte e acuidade visual em pacientes com uveíte de Behçet. Métodos: Este estudo transversal incluiu 93 olhos de 57 pacientes com uveíte de Behçet e 100 olhos de 50 indivíduos saudáveis que foram admitidos em um hospital terciário entre janeiro de 2017 e setembro de 2017. As medições maculares foram realizadas com tomografia de coerência óptica de domínio espectral (SD-OCT) em todos os pacientes. A retina foi dividida em camadas usando software de segmentação automatizado no dispositivo SD-OCT. As espessuras da camada foram comparadas entre os pacientes e os grupos controle. No grupo de pacientes, foi avaliada a correlação entre os parâmetros obtidos na OCT e a duração da uveíte e acuidade visual. Resultados: A média de idade foi de 37,9 ± 10,8 (18-64) no grupo de pacientes e 37,7 ± 12,2 (21-61) no grupo controle (p=0,821). A duração média da uveíte foi de 6,9 ± 4,7 (1-20) anos. A espessura total das camadas externas no grupo de pacientes foi reduzida (p<0,001). Uma diferença estatisticamente significativa não foi encontrada nas camadas internas da retina, exceto na camada nuclear interna. Uma correlação negativa foi detectada entre a duração da uveíte e a espessura da camada externa da retina (coeficiente de correlação = -0,250). Uma correlação positiva significativa foi detectada entre a acuidade visual e a espessura macular central bem como a espessura total das camadas internas e externas da retina (coeficientes de correlação 0,194; 0,154 e 0,364, respectivamente). A camada nuclear interna foi negativamente correlacionada com a acuidade visual. Conclusões: A uveíte de Behçet pode causar alterações significativas nas camadas intraretinianas na região macular. A segmentação da retina com SD-OCT pode ser útil para acompanhamentos e para estimar a perda visual em pacientes com uveíte de Behçet.

Advances in pathogenesis and treatment of ocular involvement in Behcet's disease.

Behcet's disease (BD) is a chronic multi-systemic disease characterized by relapsing-remitting oral ulcers, genital ulcers, ocular inflammatory involvements, and numerous other systemic features. Ocular involvements are quite common in BD and may cause severe tissue damage and potentially blindness. Even though the pathogenesis of BD remains ambiguous, growing evidences have shown that genetic factors, environmental triggers and immunological abnormalities play significant roles in its development and progression. Novel biotherapies targeting IFN-γ, TNF-α and interleukins have been used in recent years. In this review, we mainly pay attention to the ocular involvement of BD, and discuss the current understanding of mechanisms and advances in therapeutic approaches, especially novel biologics. Finally, we discuss the management in patients with pregnancy.

Are optical coherence tomography and fluorescein angiography comparable for detection of macular edema in Behçet uveitis?

PURPOSE: To investigate the role and agreement of spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography (FA) for macular edema (ME) diagnosis in Behçet uveitis (BU). METHODS: Eyes with ME detected by SD-OCT and/or FA were enrolled. Type of ME by SD-OCT and grade of macular leakage (ML) by FA were investigated. Eyes were divided into three groups according to the agreement of tests. Three groups and factors that could affect the compatibility of tests were statistically analyzed. RESULTS: Sixty-one eyes of 61 patients were included. Both imaging methods detected ME in 42.6% of eyes (group 1). In 47.5% of eyes, ME was revealed by OCT (group 2). The remaining 9.8% of the eyes had ME, detected only by FA (group 3). Grade 2 ML by FA was more common in group 1 (p = 0.01). The grade of ML by FA was similar in groups 2 and 3. In group 2, most of the eyes showed diffuse ME by OCT (p < 0.001). Epiretinal membrane was detected more frequently in group 3 (p = 0.005). Duration and activity of uveitis were similar between groups. CONCLUSION: SD-OCT was able to detect ME in 90% of the eyes with BU. Duration and activity of uveitis were not related to the compatibility of imaging methods.

Shaping the Future of Behçet's Uveitis Management: A Comprehensive Review of Efficacy, Challenges, and Prospects of Biologic Therapies.

Behçet's uveitis (BU), a vision-threatening manifestation of Behçet's disease, poses substantial management challenges due to its chronic, relapsing nature and potential for vision loss. This review explores the role of biologic therapies in the treatment of BU, providing a comprehensive overview of their effectiveness, drawbacks, and future possibilities. Traditionally, management has relied heavily on corticosteroids and conventional immunosuppressants. However, their long-term use is frequently associated with systemic side effects and insufficient control of ocular inflammation. Biologic therapies, particularly TNF-alpha inhibitors like infliximab and adalimumab, have emerged as effective alternatives, offering better disease control and a more favorable safety profile. We critically evaluated these agents, noting their clinical efficacy in reducing inflammatory flares and preserving visual acuity. Despite their benefits, several issues remain. Accessibility, cost, and lack of long-term safety data limit their widespread use. Additionally, individual variability in treatment response necessitates personalized therapeutic strategies. Recent research has shown promise in addressing these challenges, with the emergence of novel biologic agents and personalized medicine approaches. In summary, biologic therapies represent a paradigm shift in BU management, contributing to better patient outcomes. Yet, there are significant challenges to be overcome. As we move forward, continued research, development of novel biologic agents, and a precision medicine approach will shape the future landscape of BU treatment.

Gut microbial signatures and their functions in Behcet's uveitis and Vogt-Koyanagi-Harada disease.

BACKGROUND: A number of public metagenomic studies reveal an association between the gut microbiome and various immune-mediated diseases including Behcet's uveitis (BU) and Vogt-Koyanagi-Harada disease (VKH). Integrated-analysis and subsequent validation of these results could be a potentially powerful way to understand the microbial signatures and their functions in these two uveitis entities. METHODS: We integrated the sequencing data of our previous metagenomic studies on two major uveitis entities, BU and VKH as well as four other publicly available immune-mediated diseases datasets, including Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA), Crohn's disease (CD) and Ulcerative Colitis (UC). Alpha-diversity and beta-diversity analysis were used to compare the gut microbiome signatures between both uveitis entities and other immune-mediated diseases and healthy controls. Amino acid homology between microbial proteins and a uveitogenic peptide of the interphotoreceptor retinoid-binding protein (IRBP)161-180 was investigated using a similarity search in the NCBI protein BLAST program (BLASTP). Enzyme-linked Immunosorbent Assay (ELISA) was performed to evaluate the cross-reactive responses of experimental autoimmune uveitis (EAU)-derived lymphocytes and BU patients-derived peripheral blood mononuclear cells (PBMCs) against homologous peptides. The area under the curve (AUC) analysis was used to test the sensitivity and specificity of gut microbial biomarkers. RESULTS: Depleted Dorea, Blautia, Coprococcus, Erysipelotrichaceae and Lachnospiraceae as well as enriched Bilophila and Stenotrophomonas were identified in BU patients. An enriched Alistipes along with a lower level of Dorea were observed in VKH patients. A peptide antigen (SteTDR) encoded by BU specifically enriched Stenotrophomonas was identified to share homology with IRBP161-180. In vitro experiments showed that lymphocytes from EAU or PBMCs from BU patients reacted to this peptide antigen as shown by the production of IFN-γ and IL-17. Addition of the SteTDR peptide to the classical IRBP immunization protocol exacerbated EAU severity. Gut microbial marker profiles consisted of 24 species and 32 species respectively differentiated BU and VKH from each other as well as from the other four immune-mediated diseases and healthy controls. Protein annotation identified 148 and 119 specific microbial proteins associated with BU and VKH, respectively. For metabolic function analysis, 108 and 178 metabolic pathways were shown to be associated with BU and VKH, respectively. CONCLUSIONS: Our study revealed specific gut microbial signatures and their potentially functional roles in BU and VKH pathogenesis that differ significantly from other immune-mediated diseases as well as healthy controls.

Interferon-α2a induces CD4+ T cell apoptosis and suppresses Th1/Th17 responses via upregulating IRF1-mediated PDL1 expression in dendritic cells from Behcet's uveitis.

Recombinant interferon-α2a (IFNα2a) has been widely used in the treatment of Behcet's uveitis (BU). However, the mechanism underlying its effects remains poorly understood. In this study, we investigated its effect on dendritic cells (DCs) and CD4+ T cells, which are essential for the development of BU. Our results showed that the expression of PDL1 and IRF1 was significantly decreased in DCs from active BU patients, and IFNα2a could significantly upregulate PDL1 expression in an IRF1-dependent manner. IFNα2a-treated DCs induced CD4+ T cells apoptosis and inhibited the Th1/Th17 immune response in association with reduced secretion of IFN-γ and IL-17. We also found that IFNα2a promoted Th1 cell differentiation and IL-10 secretion by CD4+ T cells. Finally, a comparison of patients before and after IFNα2a therapy revealed that the frequencies of Th1/Th17 cells significantly decreased in association with remission of uveitis after IFNα2a therapy. Collectively, these results show that IFNα2a could exert its effects by modulating the function of DCs and CD4+ T cells in BU.

Retinal vascular occlusions in ocular Behçet disease - a comparative analysis.

PURPOSE: The literature on retinal vascular occlusions in Behçet disease (BD) patients is limited. The aim of this study is to thoroughly investigate retinal vascular occlusions among ocular BD patients. METHODS: Retrospective, multicentre case-control study. Three-hundred and three eyes of 175 patients with ocular BD, from 13 hospitals in Israel and Palestine, were included. Patients were assigned into two groups according to the presence of retinal vascular occlusion. Epidemiology, systemic and ocular manifestations, treatments and outcomes were compared between the groups and risk factors for retinal vascular occlusions were identified. RESULTS: One hundred twenty-five patients (71.4%) were male. The mean age at presentation was 28.2 ± 0.86 years. Retinal vascular occlusions were found in 80 eyes of 54 (30.9%) patients, including branch retinal vein occlusion (51.3%), peripheral vessels occlusions (32.5%), central retinal vein occlusion (13.8%) and arterial occlusions (7.5%). Systemic manifestations were similar among both groups. Anterior uveitis was more common in non-occlusive eyes (p < 0.01). Non-occlusive retinal vasculitis (p = 0.03) and ocular complications were more common in occlusive eyes (p < 0.01). Treatments including mycophenolate mofetil, Infliximab or a combination therapy of anti-metabolite and calcineurin inhibitor were more commonly used by occlusive patients (p < 0.05). Occlusive patients underwent more cataract surgeries (p = 0.03). The occlusive group had worse mean best-corrected visual acuity (BCVA) throughout follow-up (p < 0.01). Risk factors for retinal vascular occlusions included male sex and Jewish ethnicity (p < 0.05). CONCLUSION: Retinal vascular occlusions were found in a third of ocular BD patients. Occlusive eyes had a worse prognosis. Risk factors for vascular occlusions were identified.

Ocular Behçet Disease-Clinical Manifestations, Treatments and Outcomes According to Age at Disease Onset.

Behçet disease (BD) is a multisystemic disease that commonly involves the eyes. Although it affects patients in all age groups, data on ocular disease by age of onset are limited. This retrospective, multicenter study aimed to compare epidemiology, systemic and ocular manifestations, treatments and outcomes between three age groups: juvenile (<18 years), adult (18-39 years) and late (≥40 years) disease onset. The study included 175 ocular BD patients (303 eyes) from Israel and Palestine: juvenile-onset (n = 25, 14.3%), adult-onset (n = 120, 68.6%) and late-onset (n = 30, 17.1%). Most patients in all groups were male. Systemic manifestations were similar in all groups. Systemic co-morbidities were more common in late-onset patients. Bilateral panuveitis was the most common ocular manifestation in all patients. Non-occlusive retinal vasculitis, peripheral vessel occlusions, cataract and elevated intraocular pressure were found more commonly among juvenile-onset eyes. Anterior uveitis and macular ischemia were most common among late-onset eyes, while branch retinal vein occlusion was most common in adult and late-onset eyes. All patients were treated with corticosteroids. Methotrexate, immunomodulatory combinations and biologic treatments were more commonly used for juvenile-onset patients. All groups had a similar visual outcome. Our study showed that patients with ocular BD have varied ocular manifestations and require different treatments according to age of disease onset, but visual outcome is similar.

Ten-year follow-up of infliximab treatment for uveitis in Behçet disease patients: A multicenter retrospective study.

Purpose: To evaluate 10-year outcome of infliximab (IFX) treatment for uveitis in Behçet disease (BD) patients using a standardized follow-up protocol. Design: Retrospective longitudinal cohort study. Participants: 140 BD uveitis patients treated with IFX enrolled in our previous study. Methods: Medical records were reviewed for demographic information, duration of IFX treatment, number of ocular attacks before IFX initiation, best corrected visual acuity (VA) at baseline and 1, 2, 3, 4, 5, and 10 years after IFX initiation, uveitis recurrence after IFX initiation and main anatomical site, concomitant therapies, and adverse events (AEs). Main outcome measures: 10-year IFX continuation rate and change in LogMAR VA. Results: Of 140 BD patients, 106 (75.7%) continued IFX treatment for 10 years. LogMAR VA improved gradually after initiation of IFX, and the improvement reached statistical significance from 2 years of treatment. Thereafter, significant improvement compared with baseline was maintained until 10 years, despite a slight deterioration of logMAR VA from 5 years. However, eyes with worse baseline decimal VA < 0.1 showed no significant improvement from baseline to 10 years. Uveitis recurred after IFX initiation in 50 patients (recurrence group) and did not recur in 56 (non-recurrence group). Ocular attacks/year before IFX initiation was significantly higher in the recurrence group (2.82 ± 3.81) than in the non-recurrence group (1.84 ± 1.78). In the recurrence group, uveitis recurred within 1 year in 58% and within 2 years in 74%. Seventeen patients (34%) had recurrent anterior uveitis, 17 (34%) had posterior uveitis, and 16 (32%) had panuveitis, with no significant difference in VA outcome. In addition, logMAR VA at 10 years did not differ between the recurrence and non-recurrence groups. AEs occurred among 43 patients (30.7%), and 24 (17.1%) resulted in IFX discontinuation before 10 years. Conclusions: Among BD patients with uveitis who initiated IFX, approximately 75% continued treatment for 10 years, and their VA improved significantly and was maintained for 10 years. Uveitis recurred in one-half of the patients, but visual acuity did not differ significantly from the patients without recurrence.

Macrophage-like Cells Characterized by En Face Optical Coherence Tomography was Associated with Fluorescein Vascular Leakage in Behçet's Uveitis.

PURPOSE: To investigate the features of macrophage-like cell (MLC) characterized by en face optical coherence tomography (OCT) in Behçet's uveitis (BU). METHODS: The extent of fluorescein vascular leakage (FVL) was graded on a scale of 0-3 (0=none, 1=mild, 2=moderate, 3=severe) for the optic nerve head (ONH), macula and peripheral retina. The 3µm en face OCT slabs on inner limiting membrane of ONH or macular region was used to visualize the MLCs. RESULTS: The MLC densities of BU group in ONH and macular region were significantly higher than the control group (both p<0.001). The ONH and macular MLC density were significantly higher in eyes with higher FVL grade and they were positively correlated with FVL score (all p<0.001). CONCLUSION: MLC density was elevated in Behçet's uveitis and it may serve as a noninvasive indicator for the severity of fluorescein leakage and retinal inflammation in Behcet's uveitis.

Correlation between Widefield Fundus Fluorescein Angiography Leakage Score and Anterior Chamber Flare in Behçet Uveitis.

AIMS: To investigate the correlation between widefield fundus fluorescein angiography (WF-FA) and anterior chamber laser flare photometry (LFP-flare) in Behçet uveitis (BU). METHODS: Patients with BU who underwent Heidelberg WF-FA between March 2016 and March 2018 were included. Demographics, ocular findings, LFP-flare, central macular thickness were retrospectively analyzed. RESULTS: Eighty-six patients (162 eyes) were included. There was a high correlation between WF-FA leakage score and LFP-flare (rho: 0.691, p < .001). For a flare value of 5.75 ph/ms or higher, the sensitivity for predicting angiographic leakage was 70% and the specificity was 94% (AUC: 0.897, p < .001). Flare values that were equal or above 7.6 ph/ms were found to be 100% specific for leakage in the WF-FA. CONCLUSION: A strong correlation was found between WF-FA leakage and LFP-flare in patients with BU. High LFP-flare levels indicate subclinical posterior segment inflammation in clinically inactive BU.