Anti-VEGF reduces inflammatory features in macular edema secondary to retinal vein occlusion

INTRODUCTION

Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy,resulting in visual impairment. The incidence of RVO is about 0.5%-1.8% in the general population

. The complications due to RVO include macular edema (RVO-ME), retinal neovascularization with secondary vitreous hemorrhage,neovascular glaucoma,

., which largely impaired the vision of patients. The pathogenesis of RVO-ME is multifactorial.The occluded and damaged blood vessels as well as retinal ischemia can result in local hypoxia with the increased hypoxia inducible factor-1 alpha (HIF-1α), resulting in elevated secretion of vascular endothelial growth factor(VEGF), which could cause vascular hyperpermeability and neovascularization

. Anti-VEGF treatment has been shown to be beneficial to patients with RVO-ME and becomes the first-line therapy in the treatment of RVO-ME

. Besides VEGF, other factors including inflammatory cells and cytokines were also associated with the pathogenesis of RVO-ME.

During the clinical practice, we noticed that the RVOME patients with HRF benefit from anti-VEGF injections,demonstrating the improved visual acuity (VA), reduced central macular thickness (CMT) and HRF number, as well as the decreased non-perfusion area (NPA). Besides the direct anti-VEGF effect, we hypothesized that anti-VEGF reagents might exert anti-inflammatory effect in patients with RVOME. To address this question, we retrospectively reviewed 28 eyes from 28 treatment-na?ve patients, who underwent three consecutive intravitreal injections of anti-VEGF reagents.The VA, CMT, the HRF number, and NPA size before and after intravitreal injections were quantified and compared.

Increasing evidence suggested that hyperreflective foci(HRF) in retina were identified as the active inflammatory cells, especially microglia and macrophages, by using optical coherence tomography (OCT) or optical coherence tomography angiography (OCTA), indicating the inflammatory conditions in retina for patient with RVO-ME. HRF were first mentioned by Coscas

in patients with age-related macular degeneration (AMD) with spectral-domain OCT. Subsequently,HRF have been involved in many retinal diseases, such as RVO, diabetic retinopathy, choroideremia, and other retinal degenerative diseases

. Although its pathogenesis is still debated, HRF likely characterizes a progressive nature of an inflammatory retinal microenvironment.

The intravitreal injection was conducted at the temporal limbus through the eyeball’s pars plana under aseptic conditions in the operating room. Twenty-eight patients received three consecutive intravitreal injections of ranibizumab at the concentration of 0.5 mg/ 0.05 mL (Novartis Pharma Stein AG, Switzerland,

=18) or conbercept at the concentration of 0.5 mg/ 0.05 mL(Chengdu Kang Hong Biotech Co., Ltd., Sichuan Province,China,

=10) with a 30-gauge needle. Each injection interval allowed a variation of 1wk. The participants were treated with three monthly intravitreal injections until the macular edema(ME) was resolved.

1.1 臨床資料 收集2011年1—11月我院門診血清TPPA、RPR均陽(yáng)性需要治療的梅毒患者824例，其中男446例，女378例。男性平均年齡45.8歲，女性平均年齡37.9歲。

SUBJECTS AND METHODS

This study was approved by the Clinical Research Ethical Committee of Shanghai General Hospital affiliated to Shanghai Jiao Tong University (Permits No.2020KY205-2) and adhered to the principles of the Declaration of Helsinki. Informed consents were signed by all the participants.

The present study was a retrospective cohort study,including 28 treatment-na?ve patients, aged 64.2±2.1 years old. The patients were comprised of 14 males (50%) and 14 females (50%). The RVO included 14 BRVO and 14 CRVO.This retrospective study was conducted in the Department of Ophthalmology, Shanghai General Hospital affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai, China between August 26, 2019, and July 30,2020. Participants who received intravitreal injections of anti-VEGF drugs for three months were included in the study. The eyes with any co-existing ocular diseases, including diabetic retinopathy, hypertensive retinopathy, AMD, or uveitis,

.,were excluded.

At the initial examination, comprehensive ophthalmic examinations were performed for every patient, including OCTA, fundus photography, best-corrected visual acuity(BCVA), intraocular pressure and anterior segment evaluation using slit-lamp biomicroscopy. Follow-up examinations were conducted 1wk after each intravitreal injection.

由于種子千粒重低籽粒瘦弱，幼苗頂土能力差，為了保證全苗，在播前精細(xì)整地，足墑下種，適當(dāng)淺播，深3厘米左右。

Retinal microvasculature was visualized by using the RTVue XR Avanti OCT system (Optovue, Inc., Fremont, CA, USA),and the quantification was carried out using the manufacturer’s AngioVue software. The scanning was centered on the fovea with an area of 6×6 mm

.

CMT measured with OCTA was calculated as the average retinal thickness in a 1-mm-diameter circular region centered at the fovea which was automatically analyzed by OCTA.

To observe the efficacy of two different anti-VEGF reagents,we sub-grouped the patients and analyzed the effect based on ranibizumab and conbercept injections. In Table 2, for ranibizumab treatment, the VA increased in RVO (1.4±0.1

0.6±0.1,

=18,

<0.05), BRVO (1.2±0.2

0.3±0.1,

=8,

<0.05), and CRVO (1.6±0.2

0.9±0.2,

=10,

<0.05);and for conbercept treatment, the VA was increased in RVO(1.7±0.2

1.0±0.1,

=10,

<0.05), BRVO (1.7±0.3

0.8±0.2,

=6,

<0.05), and CRVO (1.7±0.1

1.2±0.2,

=4,

<0.05).No significant difference has been found in term of VA improvement for each sub-group between ranibizumab and conbercept treatment.

The NPA was outlined manually in enface image of the superficial capillary plexus (SCP) with 6×6 mm

scanning area in OCTA and analyzed automatically with the OCTA auto-segmentation software. The SCP was segmented as 3 μm below the internal limiting membrane and 15 μm below the inner plexiform layer.

The data were analyzed by using the IBM SPSS Statistics 21 software. All values are presented as a number or mean±standard deviation. The VA was expressed as the logarithm of the minimum angle of resolution (logMAR).A paired

-test was employed to compare BCVA, the number of HRF, and NPA between the baseline and after 3 consecutive monthly anti-VEGF injections. A

-value less than 0.05 was determined as statistically significant difference.

RESULTS

CMT is a sensitive parameter to evaluate RVO-ME. In our study, the CMT reduced significantly after anti-VEGF injections (Table 1 and Figure 2),RVO (460±34.0

268.8±12.0 μm,

=28,

<0.05), BRVO(413±47

255±11 μm,

=14,

<0.05), and CRVO (512±47

283±22 μm,

=14,

<0.05).

目前，隨著我國(guó)社會(huì)主義發(fā)展進(jìn)程的不斷推進(jìn)，以電網(wǎng)改造工作為主的建設(shè)內(nèi)容逐漸被列為我國(guó)重要的議事日程當(dāng)中。且國(guó)家電網(wǎng)在智能電網(wǎng)戰(zhàn)略部署的督導(dǎo)作用下，形成重點(diǎn)加強(qiáng)區(qū)域電網(wǎng)建設(shè)、提高中低壓配電網(wǎng)智能化運(yùn)行水平的改造體系。另外，在先進(jìn)技術(shù)的協(xié)調(diào)作用下，我國(guó)終端遠(yuǎn)程通訊技術(shù)基本上得到進(jìn)一步優(yōu)化，利于提升農(nóng)網(wǎng)系統(tǒng)的自動(dòng)化建設(shè)水平。由此可以看出，實(shí)行電網(wǎng)改造工作對(duì)于我國(guó)電網(wǎng)建設(shè)進(jìn)程而言，具有多么重要的意義[1]。

BCVA improved significantly from baseline to the final follow-up, and the mean change of BCVA was -0.8±0.1 for RVO group (Table 1). Figure 1 demonstrated the changes of VA before and after the treatment. After three consecutive injections of anti-VEGF reagents, the VA significantly increased in all three groups, RVO (1.5±0.1

0.8±0.1,

=28,

<0.05), BRVO (1.4±0.2

0.6±0.1,

=14,

<0.05), and CRVO (1.6±0.1

1.0±0.2,

=14,

<0.05).

3.1 建立良好的護(hù)患關(guān)系 良好的護(hù)患關(guān)系是醫(yī)護(hù)活動(dòng)順利開(kāi)展的必要條件，患者的依從性常與護(hù)患關(guān)系有著密切的聯(lián)系［6］。融洽的護(hù)患關(guān)系可產(chǎn)生良好的心理氣氛和情緒反應(yīng)，促使患者遵循治療方案。如果護(hù)患間沒(méi)有充分的交流，沒(méi)有形成良好的信任關(guān)系，就難以促使患者建立良好的服藥依從性。因此，護(hù)士應(yīng)針對(duì)老年人的特點(diǎn)，并結(jié)合其知識(shí)層次和性格，進(jìn)行有效的溝通交流，建立良好的護(hù)患關(guān)系。

The HRF number was manually counted in the whole retina within a 6-mm diameter centered on the fovea using a foveaspanning horizontal B-scan. HRF in OCTA was defined as a discrete and well-circumscribed dot-shaped lesion of equal or higher reflectivity than the retinal pigment epithelium (PRE)band. The maximal diameter of HRF was limited within the 20 to 50 μm range in order to exclude small counting noise signals(less than 20 μm) and prevent large hyperreflective clumps,such as hard exudates. Poor-quality images with a signal strength index less than 4/10 were excluded. The quantification of HRF was conducted independently by two experienced physicians.

The baseline clinical features of 28 eyes were shown in Table 1. The participants are comprised of 14 females (50%) and 14 males (50%). The mean age of patients was 64.2±2.1 years old, ranging from 50 to 78 years old, with 63.2±2.5 years old for BRVO and 64.8±3.4 years old for CRVO. The RVO included both BRVO (50%,

=14)and CRVO (50%,

=14). All participants underwent three consecutive monthly injections of ranibizumab (18 patients)or conbercept (10 patients). Eight patients with BRVO and 10 patients with CRVO were injected with ranibizumab; and 6 patients with BRVO and 4 patients with CRVO were injected with conbercept. The mean interval between baseline and final follow-up was 108.1±8.7 (range 56-240)d.

For ranibizumab treatment group, the CMT decreased in RVO(506±38

284±17 μm,

=18,

<0.05), and CRVO (578±46

290±29 μm,

=10,

<0.05; Table 2). As for conbercept treatment groups, the CMT decreased in RVO (399±61

242±12 μm,

=10,

<0.05; Table 2). No obvious difference for the reduction of CMT was observed for each sub-group between ranibizumab and conbercept treatment.

中國(guó)教師：在大的格局和總體布局當(dāng)中，廣州以校際間均衡、區(qū)域間均衡為目標(biāo)，以好教育為統(tǒng)領(lǐng)，組合拳打得十分精彩，并得到了肯定。教育部《教育現(xiàn)代化進(jìn)程監(jiān)測(cè)評(píng)價(jià)指標(biāo)體系研究》專題組發(fā)布的《全國(guó)15個(gè)副省級(jí)城市教育現(xiàn)代化監(jiān)測(cè)評(píng)價(jià)與比較研究報(bào)告（2015）》顯示，在4個(gè)現(xiàn)代化一級(jí)監(jiān)測(cè)指標(biāo)中，廣州好幾個(gè)綜合排名位居前列，其中教育普及發(fā)展第二、教育條件保障第二、教育質(zhì)量要素第四。那么，接下來(lái)在辦好家門口的學(xué)校方面，有什么好的做法嗎？

就拿最開(kāi)始的喂飯方式來(lái)講，正確的方式是把勺子平行地伸進(jìn)嘴巴，放在寶寶的舌頭上面，讓他自己把嘴唇閉住把食物從勺子上抿下來(lái)。而事實(shí)中，很多喂養(yǎng)者都急于把食物喂進(jìn)去，選擇的方式是更有“效率”地把勺子與嘴巴呈30度角，從上往下地把食物塞進(jìn)去，然后寶寶被動(dòng)地合上嘴巴。

HRF was identified as active macrophages and/or microglia in retina on OCT or OCTA examination. In this study, HRF was shown to be distributed throughout the whole retina, especially in the inner retina. HRF number significantly reduced in RVO(76.5±4.8

47.8±4.3,

=28,

<0.05), BRVO (68.1±5.6

40.6±4.7,

=14,

<0.05), and CRVO (84.9±7.3

55±6.9,

=14,

<0.05), respectively, following anti-VEGF treatment(Table 1 and Figure 3).

For ranibizumab treatment, the number of HRF decreased in RVO (83.8±6.7

55.8±5.8,

=18,

<0.05), and CRVO(90.7±9.3

66.7±6.7,

=10,

<0.05; Table 2). As for conbercept treatment group, the number of HRF decreased in RVO (64.9±4.5

33.0±2.2,

=10,

<0.05; Table 2). No significant difference for HRF reduction was detected among three groups between ranibizumab and conbercept treatments.

NPA reflected the non-perfusion of retinal capillaries due to transient occlusion of leukocyte in retinal blood vessels or permanent dropout of retinal capillaries forming acellular capillaries. To see whether or not anti-VEGF reagent could reduce NPA, we compared the NPA before and after three consecutive injections. As shown in Table 1, there was slightly increase of NPA for CRVO (10.4±1.4 mm

) than BRVO (8.9±1.0 mm

), but no significant difference, in the defined macular region (6×6 mm

) at baseline. After anti-VEGF treatment, we observed gradual reduction of NPA after three consecutive injections in patients with RVO, 8.9±1.0 mm

(baseline), 8.5±1.0 mm

(after 1

injection), 8.1±1.0 mm

(after 2

injection), and 7.4±1.0 mm

(after 3

injection), although no significant difference was observed (Figure 4).

To see the effect of different anti-VEGF reagents on NPA, we analyzed and compared their effect on the changes of NPA.The data showed that, in ranibizumab and conbercept treatment group, NPA decreased in RVO, BRVO, and CRVO (Table 2)but with no significant difference. No obvious change was shown in NPA reduction between ranibizumab and conbercept treatments.

DISCUSSION

With an estimated 16 million patients worldwide, RVO become one of the most common retinal vascular diseases in adults

. In our study, the VA improved and the CMT decreased significantly in patients with RVO-ME after anti-VEGF treatments. The HRF also decreased significantly,accompanied with progressive reduction of NPA after three consecutive anti-VEGF treatments. This study indicated that retinal inflammation might play a contributory role in the pathogenesis of RVO-ME.

The pathogenesis of RVO-ME is complicated, in which ischemia and hypoxia plays essential roles in the formation of RVO-ME. Ischemia and hypoxia could stabilize HIF-1α and leads to elevated secretion of VEGF and other down-stream targets. In human, VEGF family contains five members,including VEGF-A (usually named as VEGF), VEGF-B,VEGF-C, VEGF-D, as well as placental growth factor (PGF).Both VEGF and PGF play important roles in the formation of ME through inducing the breakdown of blood-retinal barrier (BRB). Besides, the inflammation is considered as a key player in RVO. Previous studies reported that several inflammatory factors, other than VEGF and PGF, contributed to the pathogenesis of RVO-ME, including angiotensin II,interleukin (IL)-1β, IL-6, IL-8, basic fibroblast growth factor(bFGF), monocyte chemoattractant protein 1 (MCP-1), and PGF,

. Through binding VEGF receptors (VEGFR) on endothelial cells, VEGF and PGF induced the up-regulation of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, enhancing the leukocyte adhesion to the vessel wall,thus leading to leukostasis, retinal non-perfusion and BRB breakdown. Chronic inflammation will result in acellular capillaries, aggregating the retinal hypoxia. VEGF and PGF also facilitate the proliferation and activation of microglia and macrophage through VEGFR. The HRF on OCT or OCTA mainly refers to the inflammatory cells in retina, such as microglia and macrophages. These inflammatory cells,including leukocytes, will release pro-inflammatory factors,causing BRB breakdown, ME, neuronal damage, and visual deterioration

.

We hypothesized that anti-VEGF reagents, by antagonizing VEGF and/or PGF, blocked the activation of VEGFR both on endothelial cells and inflammatory cells (microglia,macrophage, and leukocyte,

.), thus down-regulated adhesion molecules of endothelial cell and deactivated the inflammatory cells as well as the inflammatory factor release. In this way, the leukostasis was alleviated and NPA was improved,and the HRF also decreased by anti-VEGF treatment, indicating an anti-inflammatory effect of anti-VEGF reagents.

Although no statistically significant difference was found,we observed the amelioration of NPA in patients with RVO after anti-VEGF treatment (Figure 4). The improved NPA might be due to transient adhesion of leukocyte to endothelial cells

CD11b/ICAM-1 interaction, and anti-VEGF treatment disrupted the interaction between leukocyte and endothelial cells and re-opened the occluded capillaries.Thus we found the gradual improvement of NPA in patients with RVO after anti-VEGF therapy. But for some patients,the initial NPA cannot be identified easily due to massive,intensive hemorrhage obscured the direct observation of non-perfusion in retina. For some NPA caused by capillary dropout, it can be extrapolated that this non-perfusion cannot be alleviated due to the permanent capillary obliteration because anti-VEGF treatment cannot re-vascularize the NPA in a timely manner. So, the patients with RVO are suggested to initiate anti-VEGF treatment as soon as possible to decrease and eliminate the non-perfusion caused by early transient occlusion by leukocytes, and thus avoid permanent capillary dropout (acellular capillaries).There are still some shortcomings in the current research.First, the sample size of this clinical study was comparatively small, that may affect the comparisons. Second, the study was a short-term observation, which needs a long-term followup. Last, OCTA requires consistent cooperation from the patients, and small vibration might make it difficult to perform the comparison among different groups. Therefore, longterm evaluation of the efficacy of anti-VEGF reagents and large sample multi-center studies are needed in the treatment of RVO-ME. Besides OCTA, other multimodal ophthalmic imagings are required for evaluation of RVO-ME before and after the treatment.

李漁(1611－1680)，浙江金華府蘭溪人，初名仙侶，后改名漁，字謫凡，號(hào)笠翁。他是明末清初時(shí)期著名的文學(xué)家、戲劇家、戲劇理論家、美學(xué)家，一生中創(chuàng)作了大量的文學(xué)作品，包括戲曲、小說(shuō)、詩(shī)詞、曲賦等，其中成就最高的是戲曲，他的作品將擬話本小說(shuō)與戲曲藝術(shù)巧妙地融合為一個(gè)整體，創(chuàng)作出《笠翁傳奇十種》《無(wú)聲戲》《十二樓》等優(yōu)秀戲曲作品。

懷揣著對(duì)鄉(xiāng)村教育摯愛(ài)的堅(jiān)定信念，她在泥濘的小路上往返于各村校之間。70多歲的老母親患上了嚴(yán)重的白內(nèi)障，需要做眼球摘除手術(shù)，為了工作，她無(wú)法陪護(hù)在母親的病床前。孩子高考前，她亦沒(méi)有時(shí)間陪伴。

In summary, retinal inflammation plays a critical role in RVO-ME. As detected with OCTA, besides macular edema,HRF and NPA were also observed. In the pathogenesis of RVO-ME, the retina was stressed under ischemia and hypoxia,which stabilized HIF-1α and increased the production of its down-stream targets, including VEGF, PGF, and VEGFR.Through binding VEGFR, VEGF/PGF enhanced the expression of adhesion molecules on endothelial cells, such as ICAM-1 and VCAM-1, which promoted leukostasis, leading to increased NPA

and aggregating the retinal hypoxia.VEGF/PGF also promoted the activation of inflammatory cells

activating VEGFR on above cells, which were observed as increased number of HRF on OCTA. The activated inflammatory cells, such as macrophage and microglia,increased production of the inflammatory factors, such as IL-1β and IL-6, and MCP-1, further aggravating BRB breakdown and macular edema. The increasing NPA and activation of inflammation constitute a vicious cycle in the pathogenesis of RVO-ME. Anti-VEGF treatments, by antagonizing VEGF and/or PGF, breakdown the vicious cycle and ameliorate the inflammation and retinal hypoxia, as proposed in Figure 5.However, the specific mechanisms for anti-VEGF therapy in the reduction of HRF and NPA warrant further investigation to fully elucidate the anti-inflammatory effect of anti-VEGF in RVO-ME treatment.

ACKNOWLEDGEMENTS

Supported by the National Natural Science Foundation of China (No.81970811; No.81970810;No.82171062); Domestic Science and Technology Cooperation Project of Shanghai Municipal Science and Technology Commission (No.21015800700).

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