Anti-vascular endothelial growth factor drug treatment of diabetic macular edema: the evolution continues

Diabetic mellitus is the leading cause of blindness in working aged patients in developing nations. Due to the buildup of abnormal metabolites from several overactive biochemical pathways, chronic hyperglycemia causes oxidative stress in the retina which upregulates vascular endothelial growth factor (VEGF). Together with other growth factors and metabolites, VEGF causes endothelial cell proliferation, vasodilation, recruitment of inflammatory cells, and increased vascular permeability, leading to breakdown of the blood-retinal barrier. This allows trans-cellular exudation into the interstitial space resulting in diabetic macular edema (DME). For over 3 decades the standard treatment for DME has been laser photocoagulation. Though laser reduces the incidence of vision loss by 50%, few eyes with diffuse edema experience improved vision. This has led physicians to use the VEGF-binding drugs pegaptanib, ranibizumab, and aflibercept, each of which has been approved for the treatment of exudative macular degeneration, and bevacizumab which is commonly used off-label for a variety of chorioretinal disorders. Intravitreal administration of each drug frequently causes rapid improvement of DME with sustained improvement in vision through 2 years. Though these drugs significantly outperform laser photocoagulation over treatment periods of 1 year of less, the advantages appear to lessen when trials approach 2 years. Further studies to better determine relative efficacies of anti-VEGF drugs and laser photocoagulation are continuing.     

Aflibercept exhibits VEGF binding stoichiometry distinct from bevacizumab and does not support formation of immune-like complexes

Anti-vascular endothelial growth factor (VEGF) therapies have improved clinical outcomes for patients with cancers and retinal vascular diseases. Three anti-VEGF agents, pegaptanib, ranibizumab, and aflibercept, are approved for ophthalmic indications, while bevacizumab is approved to treat colorectal, lung, and renal cancers, but is also used off-label to treat ocular vascular diseases. The efficacy of bevacizumab relative to ranibizumab in treating neovascular age-related macular degeneration has been assessed in several trials. However, questions persist regarding its safety, as bevacizumab can form large complexes with dimeric VEGF₁₆₅, resulting in multimerization of the Fc domain and platelet activation. Here, we compare binding stoichiometry, Fcγ receptor affinity, platelet activation, and binding to epithelial and endothelial cells in vitro for bevacizumab and aflibercept, in the absence or presence of VEGF. In contrast to bevacizumab, aflibercept forms a homogenous 1:1 complex with each VEGF dimer. Unlike multimeric bevacizumab:VEGF complexes, the monomeric aflibercept:VEGF complex does not exhibit increased affinity for low-affinity Fcγ receptors, does not activate platelets, nor does it bind to the surface of epithelial or endothelial cells to a greater degree than unbound aflibercept or control Fc. The latter finding reflects the fact that aflibercept binds VEGF in a unique manner, distinct from antibodies not only blocking the amino acids necessary for VEGFR1/R2 binding but also occluding the heparin-binding site on VEGF₁₆₅.     

Corticosteroid Use for Diabetic Macular Edema: Old Fad or New Trend?

Diabetic retinopathy is the leading cause of blindness in working age individuals in developed countries. Most cases of diabetes related vision loss result from breakdown of the blood-retinal barrier with resultant diabetic macular edema (DME). For over 30 years, laser photocoagulation has been the standard therapy for DME, but most eyes do not experience significant improvements in visual acuity. Intravitreal injections of drugs that inhibit the action of vascular endothelial growth factor (VEGF) lead to gains in vision, but can be expensive and need to be repeated frequently. In addition to VEGF-mediated breakdown of the blood-retinal barrier, recent evidence suggests that inflammation plays an important role in the development of DME. Recognizing this, physicians have injected steroids into the vitreous and developers have created sustained release implants. Intravitreal injections of triamcinolone acetonide lead to rapid resolution of macular edema and significant short-term improvements in visual acuity, but unfortunately, visual acuities diminish when treatment is continued through 2 years. However, intravitreal triamcinolone remains an attractive treatment option for eyes that are pseudophakic, scheduled to undergo cataract surgery, resistant to laser photocoagulation, or require urgent panretinal photocoagulation for proliferative retinopathy. In controlled trials, intraocular implants that slowly release dexamethasone and fluocinolone show promise in reducing macular edema and improving visual acuity. The high incidences of drug related cataracts and glaucoma, however, require that corticosteroids be used cautiously and that patients be selected carefully. The increasing number of patients with DME, the burgeoning cost of medical care and the continuing development of intravitreal steroids suggest that the use of these agents will likely increase in coming years.     

Advances in the treatment of diabetic retinopathy

As the diabetes epidemic in the United States continues to worsen, so too does the prevalence of diabetic retinopathy (DR). DR is divided broadly into nonproliferative and proliferative stages, with or without vision-threatening macular edema. Progression to proliferative DR is associated with vision loss that is often irreparable, and a rapid decline in health-related quality of life. Vascular endothelial growth factor (VEGF)-A is upregulated in the diabetic eye, and has been identified as a key driver of DR pathogenesis. With this perspective, we review the published phase III clinical trial data of anti-VEGF therapies approved for the treatment of DR in the United States. Using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale, in which an improvement of ≥2 steps is considered clinically significant, approximately one-third of patients with DR and macular edema experience this level of improvement after 1 year of treatment with either ranibizumab or aflibercept. The rates of clinically significant DR improvement with ranibizumab could be twice that in the subgroup of patients with moderately severe or severe nonproliferative DR and macular edema. These clinical trial data indicate that intraocular inhibition of VEGF is a rational approach for the management of DR.     

Therapie des diabetischen Makulaödems

Background

Diabetic macular edema (DME) is a common cause of diabetes-related visual impairment that also affects patients of working age. Laser treatment has been the gold standard of DME treatment for decades. The introduction of intravitreal injection therapies, e.?g. anti-VEGF therapy, has widened the range of treatment options. This allows more individualized DME therapy and improves the prognosis for vision.

Objectives

This article aims to provide a short overview of current therapy options and their relevance in DME treatment based on recent studies and treatment recommendations.

Results

VEGF-Inhibitors represent a first-line treatment and are superior to laser treatment when DME affects the fovea. In addition to ranibizumab and aflibercept, bevacizumab is used off-label. High treatment frequencies with an average of seven to nine injections in the 1st year and monthly controls, if possible using optical coherence tomography, are crucial. The number of injections required decreases thereafter. The gain in visual acuity of on average two to three lines demonstrated in studies is usually not achieved in real life due to under-treatment. Intravitreal steroids provide longer treatment effects, but are second choice due to local side effects, mainly cataract and glaucoma. Laser therapy remains an option (1st choice in extrafoveal DME). In special cases, vitrectomy may be indicated.

Conclusions

Modern DME treatment permits individualized therapies based on multimodal diagnostics while taking the patient’s individual situation and wishes into account. However, in order to make effective use of these opportunities , early diagnosis (screening), adequate patient motivation, and appropriate risk factor adjustment are required.

     

Medikamentöse Therapie der diabetischen Retinopathie und Makulopathie

Although the prognosis in diabetic eye complications has improved as a result of better glycemic and blood pressure control as well as advances in the established therapy options of laser coagulation and vitreoretinal surgery, diabetic retinopathy remains the most common cause of blindness among the working population of the industrial nations. Experimental and clinical data indicate that new pharmacological options for pathophysiologically oriented therapy may be effective. Initial experience with intravitreal injection of the glucocorticoid triamcinolone acetonide or vascular endothelial growth factor (VEGF) inhibitors pegaptanib, ranibizumab and bevacizumab have shown that, in the case of diffuse diabetic macular edema, which has been difficult to treat to date, at least a temporary anatomic and partly functional improvement can be achieved. Furthermore, the application of these intravitreal therapy modalities as adjuvants to/after laser coagulation or surgery can be considered in selected cases of focal diabetic macular edema and proliferative diabetic retinopathy. Further prospective trials are needed to answer questions on duration of effect, the need for repeat injections, as well as on side effects.     

Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab

Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.     

Intravitreal anti-VEGF drugs as adjuvant therapy in diabetic retinopathy surgery

The use of intravitreal anti vascular endothelial growth factor (anti-VEGF) drugs such as pegaptanib, ranibizumab and bevacizumab has been widely reported to treat complications such as macular edema and rubeosis. During the past few years they have also been used as an adjuvant therapy to reduce intraocular bleeding during vitrectomy in eyes with proliferative diabetic retinopathy as well as to reduce the occurrence of vitreous haemorrhages in vitrectomized eyes and facilitate glaucoma surgery. In this paper we review the use of anti VEGF drugs in the surgical management of diabetic retinopathy related complications.     

Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy

Vascular endothelial growth factor (VEGF) plays a key role in the development of both proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DMO). In recent years, anti-VEGF agents have emerged as new approaches to the treatment of these devastating diabetic complications. Although Phase III studies in the diabetic population are needed, intravitreal anti-VEGF therapy is currently being used in clinical practice. Intravitreal injection is an effective means of delivering anti-VEGF drugs to the retina. However, this is an invasive procedure associated with potentially serious complications, such as endophthalmitis or retinal detachment, which may be significant for patients requiring serial treatment over many years. In addition, although delivered within the vitreous, anti-VEGF drugs could pass into the systemic circulation, which could potentially result in hypertension, proteinuria, increased cardiovascular events and impaired wound healing. Pegaptanib, ranibizumab and bevacizumab are the currently available anti-VEGF agents. Ranibizumab and bevacizumab block all VEGF isoforms, thus impairing both physiological and pathological neovascularisation. Pegaptanib only blocks the VEGF₁₆₅ isoform, and would therefore seem the best option for avoiding systemic adverse effects in diabetic patients, although this remains to be demonstrated in clinical trials. In this regard, head-to-head studies designed to evaluate not only the efficacy, but also the systemic adverse effects of these drugs in a high-risk population such as diabetic patients are warranted.     

Soluble Mediators of Diabetic Macular Edema: The Diagnostic Role of Aqueous VEGF and Cytokine Levels in Diabetic Macular Edema

Diabetic macular edema (DME) is a significant cause of vision loss and represents an important clinical and public health problem. It is characterized by breakdown of the blood retinal barrier with fluid accumulation in the sub-retinal and intra-retinal spaces. Although several hypotheses exist for the causes of diabetic macular edema, specific molecular mechanisms remain unclear. Current thinking includes the role of vascular endothelial growth factor (VEGF) and inflammatory cytokines in vascular permeability. We review studies showing a relationship between elevated aqueous VEGF, monocyte chemoattractant protein -1, interleukin 6, or interleukin 8 in association with DME and as predictors of DME. The presence of mediators in both the angiogenesis and inflammatory pathways data suggest a multifactorial model for the development of DME. Further studies targeting individual cytokine activity will be important to our understanding of the pathogenesis and treatment.     

糖尿病性黄斑水肿的发病机制与治疗进展

目前全球糖尿病视网膜病变（DR）患者约9300万,其中增殖性DR（PDR）患者1700万,糖尿病性黄斑水肿（DME）患者2100万,威胁视力的DR患者2800万。随着年龄的增长,DME现已成为糖尿病患者视力损害的主要原因。其发病机制尚未明确,研究显示视网膜内、外屏障的破坏等在DME的发生发展中起到重要作用。目前,DME的治疗方法包括传统的激光光凝、糖皮质激素的应用、抗血管内皮生长因子（VEGF）药物的玻璃体腔注射、蛋白激酶C抑制剂的应用、玻璃体手术等,但每种疗法都有其优点和不足。联合治疗重复次数少、疗效高、安全性强,是未来发展的新趋势。本文对老年性DME治疗的国内外研究现状及发展趋势进行综述。     

The laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion: A protocol for systematic review and meta-analysis

Background:At present, laser is regarded as an effective treatment for macular edema secondary to branch retinal vein occlusion. With the breakthrough of anti-vascular endothelial growth factor drugs in ophthalmology clinical research, the intravitreal injection of ranibizumab is widely applied, but both methods have their limitations, so some clinical studies have combined and applied them together. However, the clinical results are inconsistent and controversial, and there is no relevant system evaluation for the laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion now.Objective:Meta analysis is used to analyze and evaluate the effectiveness and safety of the laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion.Method:CNKI, VIP, WANFANG, China Biology Medicine disc, Web of Science, PubMed, Embase, Cochrane Library have used random controlled clinical trial of laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion from the establishment of the database to October 2020. Two researchers conducted independent screening, quality assessment and data extraction for the literatures, and used RevMan5.3 to conduct Meta analysis for the included literatures.Result:The research has evaluated the effectiveness and safety of the laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion through the aspects of the best corrected visual acuity 6 months after operation, macular center thickness and the incidence of adverse reactions such as elevated intraocular pressure, endophthalmitis, vitreous hemorrhage and cataract.Conclusion:Laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion has good effect, and the research has provided reliable evidence for the use of clinical treatment of the laser combined with intravitreal injection of ranibizumab for treatment of macular edema secondary to branch retinal vein occlusion.     

HIF inhibitors for ischemic retinopathies and cancers: options beyond anti-VEGF therapies

Aberrant activation of the hypoxia inducible factor (HIF) pathway causing overexpression of angiogenic genes, like vascular endothelial growth factor (VEGF), is one of the underlying causes of ocular neovascularization (NV) and metastatic cancer. Consistently, along with surgical interventions, a number of anti-VEGF agents have been approved by FDA for the treatment of ocular neovascular diseases. These anti-VEGF agents, like ranibizumab/lucentis, have revolutionized the treatment in the past decade. However, substantial vision improvement is observed only in a subset of age-related macular degeneration patients receiving ranibizumab. Further, all current therapies are associated with limitations and side effects. For example, surgeries cause tissue destruction and inflammation while anti-VEGF therapies are expensive, require repeated administration, and offer temporary relief from vascular leakage. These factors impose significant cost and treatment burdens to both the patient and society. With an aging population in most western countries with a continually increasing number of patients on lifelong treatment for these retinal diseases, the focus of ocular drug development for neovascular diseases will be to improve efficacy while reducing treatment costs. Blocking the HIF pathway, a major regulator of ocular NV and cancer, offers an appealing therapeutic strategy. Therefore, this review summarizes HIF inhibitors that have been recently evaluated for the treatment of different cancers and ischemic retinopathies.     

Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are the most common microvascular complications of diabetes. DR is a leading cause of blindness, and DN is a major cause of end-stage renal diseases. Diabetic macular edema (DME) resulting from increased vascular permeability in the retina and retinal neovascularization (NV) represent two major pathological changes in DR and are the primary causes of vision loss in diabetic patients. Previous studies have shown that angiogenic factors such as vascular endothelial growth factor (VEGF) play a key role in the development of DME and retinal NV. Studies in recent years have demonstrated that a number of endogenous angiogenic inhibitors are present in the normal retina and counter act the effect of VEGF in the regulation of angiogenesis and vascular permeability. Decreased levels of angiogenic inhibitors in the vitreous and retina have been found in diabetic patients and diabetic animal models. The decreased levels of angiogenic inhibitors shift the balance between angiogenic factors and angiogenic inhibitors and consequently, lead to the development of DME and retinal NV. Recently, we have found that these angiogenic inhibitors are expressed at high levels in the normal kidney and are down-regulated in diabetes. Moreover, these inhibitors inhibit the activity of VEGF and TGF-beta, two major pathogenic factors of DN. Therefore, decreased levels of these angiogenic inhibitors in diabetes may be associated with pathologies of DN. This review will summarize recent progress in these fields and therapeutic approaches to use angiogenic inhibitors for the treatment of diabetic complications.     

Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema

Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.     

Ranibizumab in neovascular age-related macular degeneration

Neovascular age-related macular degeneration (AMD) is a visually devastating condition resulting from choroidal neovascularization and secondary photoreceptor loss. Ranibizumab and bevacizumab are medications that target vascular endothelial growth factor (VEGF). While other therapies have demonstrated some ability to reduce the risk of losing vision from neovascular AMD, most patients continue to lose some degree of central visual acuity. There is growing evidence that intravitreal administration of ranibizumab and bevacizumab is effective in significantly improving the visual acuity in patients with neovascular age-related macular degeneration.     

Posterior subtenon and intravitreal triamcinolone acetonide for diabetic macular edema

AIM: To evaluate retroprospectively the clinical consequences of posterior subtenon (PSTT) and intravitreal (IVT) triamcinolone acetonide injections in diabetic macular edema (DME) refractory to conventional grid laser photocoagulation. MATERIAL AND METHODS: Eyes with clinically significant DME refractory to grid laser photocoagulation were assessed for the inclusion in the study. Complete ophthalmic examination with fluorescein angiography (FA) and optic coherence tomography (OCT) were performed before and in the 1st, 3rd, and 6th months of the treatment. The IVT group received 4 mg/0.1 ml and the PSTT group received 20 mg/0.5 ml triamcinolone injection. PSTT but not IVT injection was repeated in case of recurrent edema. IVT was also applied to the eyes with resistant macular edema after PSTT injection (secondary IVT group). RESULTS: There were 85 eyes of 60 patients in the PSTT group and 41 eyes of 35 patients in IVT group. There were 24 eyes in the primary IVT group and 17 eyes in the secondary IVT group. Mean follow-up time was 4.1+/-1.9 and 4.6+/-2.2 months after PSTT and IVT injections, respectively. In the PSTT group, the mean visual acuity increased from 0.19+/-0.18 to 0.22+/-0.19 and the mean central foveal thickness decreased from 413.1+/-117.5 to 312.1+/-103.1 microm (P=.001 and P=.0001, respectively) during the first 3 months. In the IVT group, the mean visual acuity and central foveal thickness were found to be 0.15+/-0.14 and 494.5+/-141.3 microm before the treatment and 0.20+/-0.16 and 288.4+/-88.5 microm 3 months after the treatment, respectively (P=.008 and P=.001, respectively). The effect in central foveal thickness was significantly greater in the primary IVT group than in the PSTT group (P=.002). There was no significant difference with respect to the decrease in the central foveal thickness and increase in visual acuity between the primary and secondary IVT injections (Mann-Whitney U test, P>.05). The steroid effect started to diminish after the 3rd month. The recurrence of macular edema was seen in 7.1% in the PSTT group starting after 3 months. Twenty percent of the eyes in the PSTT group did not respond to the treatment at all and had secondary IVT injections. Significant intraocular pressure increase was found in 8.2% of the PSTT group and in 24.3% of IVT injection. There was one case of pseudomonas endophthalmitis in the IVT group. CONCLUSION: This study is the first study comparing the clinical outcomes of PSTT and IVT injections for the treatment of DME. Both PSTT and IVT injections caused a significant increase in visual acuity and a decrease in central foveal thickness, especially in the short term. The effect was more pronounced in the IVT group; however, PSTT injection also seemed to be a safe and effective technique for the treatment of DME. Further prospective studies are warranted to assess the efficacy and side effects of IVT and PSTT injections for the treatment of DME.     

两种不同方式治疗视网膜分支静脉阻塞继发黄斑水肿的meta分析

目的系统评价激光联合玻璃体腔注射雷珠单抗与单独玻璃体腔注射雷珠单抗治疗视网膜分支静脉阻塞(BRVO)继发黄斑水肿的疗效及安全性。方法通过检索PubMed、CNKI、万方等数据库收集有关治疗BRVO继发黄斑水肿的随机对照试验研究(RCT)。检索时间为建库至2019年5月。采用RevMan 5.3软件对纳入文献进行meta分析。结果共纳入12篇文献,包括1081例患者。meta分析结果显示:与单纯注药组相比,联合治疗组黄斑中心凹厚度(CMT)在随访1、3、6个月时均降低,差异有统计学意义[95%CI(-135.44^-15.54),P<0.001];但对于最佳矫正视力(BCVA)的提高,2组间无统计学差异[95%CI(-1.75~0.80),P>0.05];2组不良反应的发生率无统计学差异[OR=1.50,95%CI(0.97~2.30),P=0.07]。结论激光联合玻璃体腔注射雷珠单抗能够显著降低BRVO继发黄斑水肿患者的CMT,早期疗效优于单纯注药组。但两种方式对于治疗后BCVA的影响及不良反应的发生尚需要大样本的随机对照双盲研究加以验证。     

The combination therapy of subtenon triamcinolone acetonide injection and intravitreal brolucizumab for brolucizumab-related intraocular inflammation

Rationale:Brolucizumab is a novel anti-vascular endothelial growth factor agent with clinical trials demonstrating excellent efficacy for neovascular age-related macular degeneration (AMD) in both visual and anatomic outcomes. However, there is concern of intraocular inflammation (IOI), and we propose concurrent subtenon triamcinolone acetonide (STTA) to prevent IOI.Patient concern:A 73-year-old man was treated with aflibercept for neovascular AMD in his right eye. Despite 11 months of monthly intravitreal aflibercept injections, optical coherence tomography demonstrated persistent exudation. Ten days following his second brolucizumab injection, the patient presented with decreased vision due to vitritis in his right eyeDiagnosis:Brolucizumab-related IOI in neovascular AMD refractory to aflibercept.Interventions:A combination therapy involving of intravitreal brolucizumab and STTAOutcomes:The anti-vascular endothelial growth factor inhibitor was changed back to aflibercept; however, exudation persisted. Therefore, a combination therapy involving STTA (5 mg/0.5 mL) and intravitreal injection of brolucizumab (6.0 mg/0.05 mL) was performed to treat the exudation and as prophylaxis to recurrent IOI. Combination therapy achieved no recurrent IOI and resolution of exudation with 8-week treatment intervals.Lessons:This case might indicate that STTA is not only an optimal treatment option for brolucizumab-related IOI but also a preventive agent for this condition.