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，在播前精細整地，足墑下種，適當淺播，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).

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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 建立良好的護患關系 良好的護患關系是醫護活動順利開展的必要條件，患者的依從性常與護患關系有著密切的聯系［6］。融洽的護患關系可產生良好的心理氣氛和情緒反應，促使患者遵循治療方案。如果護患間沒有充分的交流，沒有形成良好的信任關系，就難以促使患者建立良好的服藥依從性。因此，護士應針對老年人的特點，并結合其知識層次和性格，進行有效的溝通交流，建立良好的護患關系。

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.

中國教師：在大的格局和總體布局當中，廣州以校際間均衡、區域間均衡為目標，以好教育為統領，組合拳打得十分精彩，并得到了肯定。教育部《教育現……