Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Volumetric fluid analysis of fixed monthly anti-VEGF treatment in patients with neovascular age-related macular degeneration

·AIM:To evaluate visual outcomes and changes in fluid after administering monthly anti-vascular endothelial growth factor(VEGF)injections to treat neovascular agerelated macular degeneration(n AMD)with subretinal fluid(SRF)and pigment epithelial detachment(PED).·METHODS:This prospective study included eyes with n AMD previously treated with as-needed anti-VEGF injections.The patients were treated with six monthly intravitreal injections of ranibizumab.Quantitative volumetric segmentation analyses of the SRF and PED were performed.The main outcome measures included best-corrected visual acuity(BCVA),and SRF and PED volumes.·RESULTS:Twenty eyes of 20 patients were included in this study.At the 6-month follow-up,BCVA and PED volume did not change significantly(P=0.110 and 0.999,respectively)but the mean SRF volume decreased from 0.53±0.82 mm3 at baseline to 0.08±0.23 mm3(P=0.002).The absorption rate of the SRF volume was negatively correlated with the duration of previous antiVEGF treatment(P=0.029).Seven of the 20 eyes(35%)showed a fluid-free macula and significant improvement in BCVA(P=0.036)by month 6.·CONCLUSION:Quantifying the SRF can precisely determine the patient’s responsiveness to anti-VEGF treatment of n AMD.

Choroidal neovascularization post macular surgery:a case series

Dear Editor,My name is Georgios Tsokolas and I am currently working as Medical Retina Research Fellow at the Eye Unit of Southampton General Hospital in United Kingdom.

Recent Developments in the Treatment of Wet Age-related Macular Degeneration

Age-related macular degeneration(AMD)is the most common cause of irreversible blindness and visual impairment in individuals over the age of 50 years in western societies.More than 25 million people currently suffer from this illness in the world,with an additional 500000 every year,approximately.It is a multifactorial ocular disease that affects the maculae due to a late-onset progressive neurodegeneration and dysfunction of photoreceptors and retinal pigment epithelium(RPE).There are many subtypes of AMD but basically two broad forms:the nonneovascular(dry,nonexudative)and neovascular(wet,exudative).Exudative AMD is the less common form(about 15%)but tends to progress more rapidly.At the moment,wet AMD is treated primarily on the basis of anti-vascular endothelial growth factor(VEGF)agents,which have led to massive improvement in the prognosis of the disease since they were first introduced.This article focuses on the latest treatment approaches to neovascular AMD.An extensive literature review was performed in order to illustrate the effectiveness of current and future anti-VEGF agents as well as the landmark clinical studies that have been carried out to establish these drugs as a gold standard in the therapy of wet AMD.

Comparison of two different treatment regimens’ efficacy in neovascular age-related macular degeneration in Turkish population—based on real life data-Bosphorus RWE Study Group

AIM: To compare two different anti-vascular endothelial growth factor(anti-VEGF) treatment regimens'-a priori pro re nata(PRN) and PRN regimen following^(th)e loading phaseanatomical and functional results in neovascular agerelated macular degeneration(n AMD) patients. METHODS: Totally 544 n AMD patients followed and treated with aflibercept(n=135) and ranibizumab(n=409)at 9 different centers between 2013 and 2015 were enrolled into^(th)is retrospective multicenter study. Patients with initial best corrected visual acuity(BCVA) interval of 1.3-0.3(log MAR) and a minimum follow-up of 12 mo were included. Patients under two different regimens-a priori pro re nata(1+PRN) or 3 consecutive intravitreal injections followed by a PRN regimen(3+PRN)-were compared in BCVA at 3^(th), 6^(th) and 12^(th) months, and in central macular^(th)ickness(CMT) at 6^(th) and 12^(th) months. The total study group, intravitreal ranibizumab(IVR) and intravitreal aflibercept(IVA) groups were evaluated separately. RESULTS: The mean CMT decreased in^(th)e 1+PRN(n=101) regimen from 407 to 358 and 340 μm and in^(th)e 3+PRN(n=443) group from 398 to 318 and finally to 310 μm at months 6 and 12, respectively. Anatomically,^(th)e CMT reduction at 6^(th) month(48.5 vs 76.4;P<0.05) was statistically significant in favor of 3+PRN group. BCVA changed in 1+PRN group from 0.77 to 0.78, 0.75 and 0.75;in 3+PRN group from 0.81 to 0.69, 0.72, and 0.76 at months 3, 6, and 12, respectively. Visual gain was statistically better in 3+PRN group at 3^(th) month(-0.01 vs 0.12;P<0.001). In IVR group, CMT reduction was in greater in 3+PRN at 6^(th)(44 vs 72) and 12^(th) month(61 vs 84), but statistically insignificant. The 3+PRN group revealed statistically better visual results at 3^(th) month(-0.02 vs 0.11, P<0.05). In IVA group, although statistically insignificant, CMT reduction(61 vs 89, 6^(th) month;85 vs 97, 12^(th) month) and visual gain(0.02 vs 0.16;0.02 vs 0.14;0.05 vs 0.11) was found in favor of 3+PRN group at all visits.CONCLUSION: The loading dose of anti-VEGF treatments in n AMD leads to significantly better anatomical and functional results, regardless of the agent, specially in early follow-up interval.

Assessment of the long-term visual and anatomical outcomes of ranibizumab to treat neovascular age-related macular degeneration

AIM： To investigate the long-term visual and anatomical outcomes of patients who underwent intravitreal ranibizumab monotherapy to treat neovascular age-related macular degeneration（AMD） and followed-up for at least 2 y.METHODS： A total of 74 eyes of 74 patients who underwent ranibizumab monotherapy for neovascular AMD were included in this retrospective study.RESULTS： The average patient age was 72.1±6.5（range, 57-85）y, the average follow-up time 46.2±13.1（range, 24-75）mo, and the average number of visits 24.1±9.5（range, 8-48）. The mean number of injections in year 1 was 4.5, 1.6 in year 2, 0.9 in year 3, 0.4 on year 4, and 0.1 in the following years. Within the entire follow-up period, the mean number of injections was 7.6±4.4（range, 2-21）. The mean visual acuity was 48.1±15（range, 15-76） letters at baseline and 45.7±19（range, 7-75） at year 5. The mean central macular thickness was 303±78（range, 178-552） μm at baseline and 251±51（range, 138-359） μm at year 5. Scars developed in 47（63.5%） eyes at the end of the follow-up period, and atrophy was evident in 6（8.1%） eyes.CONCLUSION： Ranibizumab monotherapy can stabilize visual acuity for a mean period of 4 y in patients with neovascular AMD.

Choroidal structural changes determined by the binarization method after intravitreal aflibercept treatment in neovascular age-related macular degeneration

AIM:To assess the choroidal structural alterations after intravitreal injection of aflibercept in neovascular agerelated macular degeneration(n AMD).METHODS:Fifty eyes with treatment-naive n AMD were evaluated at baseline,3^(rd),and 12^(th) month.Fifty eyes of 50 healthy subjects were also included as controls.Choroidal thickness(CT)was measured in the subfoveal region.Total circumscribed choroidal area(CA),luminal area(LA),stromal area(SA),and choroidal vascularity index(CVI)was calculated using Image J.RESULTS:At baseline,subfoveal CT was increased in n AMD patients compared to controls(P=0.321).Eyes with n AMD had a significantly increased total circumscribed CA and SA(P=0.041,0.005,respectively).The CVI was decreased(P=0.038).In the 3^(rd) month,the subfoveal CT,LA,and CVI revealed a decrease(P=0.005,P=0.039,0.043,respectively).In the 12th month,subfoveal CT,LA,and CVI were decreased in comparison to baseline measures(P<0.001,0.006,0.010,respectively).CONCLUSION:Significant structural alterations are found after intravitreal aflibercept treatment during the 12-month follow-up,in particular at the third month,in eyes with n AMD.

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration

Age related macular degeneration （AMD） is a complex progres- sive neurodegenerative disease causing blindness in 30-35 million people worldwide. It affects the macula region of the retina leading to severe vision loss and legal blindness in individuals 〉 50 years of age （Wong et al., 2014）. The precise aetiology of AMD is unknown but smoking, age and genetic factors are major risk factors for AMD predisposition （Ding et al., 2009）. The genetic basis of AMD is well described with a recent study from the International AMD gene consortium （IAMDGC） reporting 52 genetic variants across 34 loci associated with the risk of AMD pathogenesis and explaining more than 50% of the genetic heritabilitv of the disease （Fritsche et al., 2016）.

Intravitreal aflibercept in neovascular age-related macular degeneration previously treated with ranibizumab

AIM：To report the change in visual acuity and central macular thickness（CMT）following treatment with intravitreal aflibercept injections in patients with neovascular agerelated macular degeneration（n AMD）with suboptimum response to ranibizumab.METHODS：This was a retrospective study. The inclusion criteria were patients with n AMD who responded poorly to ranibizumab. Patients then received either 3 consecutive aflibercept injections followed by pro re nata（PRN）treatment or PRN alone. Primary endpoints were mean change in bestcorrected visual acuity（BCVA）and CMT at 12 mo. Secondary endpoints were number of injections and adverse events.RESULTS：Forty-nine eyes from 49 patients met the inclusion criteria and completed 12-month follow up on aflibercept. Thirty-eight eyes received 3 consecutive aflibercept injections followed by PRN treatment and 11 eyes received PRN injections alone. At 12 mo,mean BCVA improved by one letters（log MAR 0.56±0.31 to 0.54±0.34）and mean CMT decreased from 303.9±82.1 to 259.2±108.3 μm.Four percent of eyes gained 15 letters or more,6% lost more than 15 letters and the remaining 90% had stable BCVA. The mean number of aflibercept injections was 6.There was one case of infectious endophthalmitis.CONCLUSION：Intravitreal aflibercept in patients with n AMD with a previous suboptimal response to ranibizumab resulted in an anatomical improvement in macular appearance at 12 mo without a corresponding improvement in visual acuity.

6-weekly bevacizumab versus 4-weekly ranibizumab for neovascular age-related macular degeneration:a 2-year outcome

AIM： To compare visual acuity and central macular thickness（CMT） changes in neovascular age-related macular degeneration patients treated with either 6weekly bevacizumab regimen or 4 weekly ranibizumab on an as required basis.·METHODS： Patients made an informed choice between bevacizumab 1.25 mg or ranibizumab 0.5 mg. The selected treatment was administered in the first 3 visits.Bevacizumab patients were followed-up 6 weekly and ranibizumab 4 weekly. Retreatment criteria was based on the reduction of 〉5 letters in the best-corrected visual acuity（BCVA）, the presence of retinal fluid on optical coherence tomography（OCT） or new retinal haemorrhage.·RESULTS： Visual acuity at 2y bevacizumab patients gained 7. 0 letters and ranibizumab 9. 2（ P = 0. 31, 95 %CI-6.4 to 2.0）. At 2y 86% of bevacizumab and 94%ranibizumab patients had not lost 15 letters or more（P =0.13）. Mean CMT decreased at 2y bevacizumab by 146 μm,ranibizumab 160 μm（P =0.72）. Mean number of injections was at 2y bevacizumzb 11.9, ranibizumab 10.3（P =0.023）.· CONCLUSION： Bevacizumab 6 weekly on an as required basis was not demonstrably non-inferior to ranibizumab 4 weekly pro re nata（prn） in terms of BCVA and change in CMT. In the bevacizumab group, one more injection was required in the second year compared to the ranibizumab group.

Surgical treatment for neovascularized retinal pigment epithelial detachment in age -related macular degeneration

Dear Sir, I am Dr. Hui Li, from the Department of Ophthalmology of Shanghai Tenth People’s Hospital Affiliated to Tongji University in Shanghai, China. I write to report a case of neovascularized pigment epithelial detachment (PED) successfully treated with vitrectomy. PED associated occult choroidal neovascular membrane, so called vascularized PED [1] , is a special subtype of neovascular age-related macular degeneration with poor

Changes on optical coherence tomography angiography and fluorescein angiography in eyes with neovascular age-related macular degeneration

AIM:lo evaluate the changes on optical coherence tomography angiography(OCTA) and fluorescein angiography(FA) and their correlation in neovascular agerelated macular degeneration(nAMD) before and after intravitreal aflibercept injections(IAIs).METHODS:In 43 treatment-na?ve patients with nAMD,choroidal neovascularization(CNV) in OCTA were morphologically and quantitatively analyzed before and after IAIs to determine whether they are correlated with leakage on FA or not.By combining CNV in OCTA and leakage in FA,lesions were characterized as three types:L+C+(with both CNV and leakage),L-C+(with CNV but without leakage),or L+C-lesion(with leakage outside CNV).RESULTS:Before IAI,while 27 eyes had L+C+lesion only,16 eyes had both L+C+and L-C+lesions simultaneously.Tiny capillaries and anastomosis in CNV were more developed in L+C+lesion,at 86.0% and58.1%,respectively,relative to 9.3% and 9.3% in L-C+lesions(P<0.001).After IAIs in 33 eyes,tiny capillaries and anastomosis were decreased in the lesions with cessation of leakage on FA(P<0.001 and P=0.001,respectively).In quantitative analysis,neovascularization length and numbers of junctions and endpoints were also significantly decreased.CONCLUSION:Leakage on FA is associated with CNV morphology in OCTA and remained so after IAls.Therefore,by carefully assessing the morphological and quantitative changes of CNV in OCTA before and after treatment,activity of nAMD is expected even though CNV on OCTA is not completely matched with fluorescein leakage.

Bevacizumab versus ranibizumab for neovascular agerelated macular degeneration: a Meta-analysis

AIM: To systematically compare the efficacy and safety of off-label bevacizumab versus licensed ranibizumab intravitreal injections as well as monthly regimen versus pro re nata [PRN(as needed)] regimen in the treatment of neovascular age-related macular degeneration(n AMD).METHODS: Relevant publications were identified through automatically retrieve of database and manually retrieving. The methodological quality of studies included was assessed using the Jadad score and the risk-of-bias assessment. The efficacy estimates were measured by the weight mean difference(WMD) for the improvement of best-corrected visual acuity(BCVA) and central retinal thickness(CRT) reduction. The safety estimates were measured by odds ratios(OR) for adverse events rates. Statistical analysis was conducted by Revman 5.2.7.RESULTS: Seven studies were included in the Metaanalysis. There were no statistically significant differences between bevacizumab and ranibizumab in BCVA at 1 and 2y(P =0.37, P =0.18, respectively),However, both drugs has better BCVA given monthly than given as needed at 1 and 2y(P 【0.05). The results demonstrated the mean decrease in CRT was less in bevacizumab group than ranibizumab group at 1y(P 【0.05),while the difference was not significant at 2y(P =0.24).Treatment monthly gained much more decrease in CRT at 1 and 2y(P 【0.005).There were no differences between drugs in the rates of death, arterial thrombotic events and venous thrombotic events(P =0.41, P =0.55, P =0.10,respectively), while the rates of medical dictionary for regulatory activities(Med DAR) system organ class events and ≥1 systemic serious adverse events were higher in bevacizumab group than ranibizumab group(P 【0.05).But the incidences of death, arterial thrombotic events,venous thrombotic events, Med DAR system organ class events as well as ≥1 systemic serious adverse events were not statistically different between both treatment regimens of monthly and as needed(P =0.14, P =0.76,P =0.73, P =0.12, P =0.11, respectively).· CONCLUSION: Bevacizumab was equivalent to ranibizumab for BCVA, however bevacizumab tended to gain less decrease in CRT and had higher rates of serious adverse events. Compared with treatment as needed, treatment monthly showed superior efficacy in BCVA improvement and CRT reduction, while the rates of adverse events were similar in the two dosing regimens.

Comparison of OCT and OCTA manifestations among untreated PCV, neovascular AMD, and CSC in Chinese population

AIM: To compare the qualitative and quantitative features among untreated polypoidal choroidal vasculopathy(PCV), neovascular age-related macular degeneration(nv-AMD) and central serous chorioretinopathy(CSC) using optical coherence tomography(OCT) and OCT angiography(OCTA).METHODS: This retrospective study included 16 eyes with thin-choroid PCV, 18 eyes with thick-choroid PCV, 16 eyes with nv-AMD and 17 eyes with CSC, respectively. The indicators were obtained by OCT and OCTA.RESULTS: Sub-foveal choroidal thickness(SFCT) in CSC was thicker compared to other groups(all P<0.05). SFCT in nv-AMD was thicker compared to thin-choroid PCV, but thinner compared with thick-choroid PCV(both P<0.05). As the ratio of thickness of Haller's layer to thickness of SFCT, which of thin-choroid PCV was significantly higher than CSC(P<0.001). Likewise, thick-choroid PCV had significantly higher ratio than nv-AMD(P=0.016) or CSC(P<0.001). There were differences among them in pigment epithelium detachment(PED). The whole-superficial retinal vessel density(RVD), deep RVD and choroidal capillary vessel density(CCVD) in CSC were significantly higher compared to other three groups, respectively(all P<0.05). The whole CCVD in nv-AMD was higher compared to thick-choroid PCV(P=0.032). Cross-sectional local angiographic form was 87.50%, 83.33%, 0 and 35.29% in thin-choroid PCV, thickchoroid PCV, nv-AMD and CSC, respectively. Cross-sectional diffuse angiographic form was 12.50%, 16.67%, 100% and 5.88% in thin-choroid PCV, thick-choroid PCV, nv-AMD and CSC, respectively.CONCLUSION: Combination of OCT and OCTA can effectively observe the significant alterations existed in PCV, CSC and nv-AMD, and there are distinctive differences among them. The pathogenesis is not exactly the same between PCV and nv-AMD, or PCV and CSC.

Molecular structure, pharmacokinetics and clinical evidence of brolucizumab: a narrative review

Macular neovascularization(MNV)is the hallmark of neovascular age-related macular degeneration(nAMD),one of the leading causes of vision loss in the developed world.The current MNV standard of care including frequent intravitreal anti-vascular endothelial growth factor(VEGF)injections,although has revolutionized favorably the treatment,places a substantial burden on patients,caregivers,and physicians.Brolucizumab is a newly developed single-chain antibody fragment that inhibits activation of VEGF receptor 2 with in vitro affinity and potency comparable to commercially-available anti-VEGF agents.Its small molecular weight and its design allow for high solubility and retinal tissue penetration,and improve binding affinity to the target.Also a high clearance rate leading to minimal systemic exposure was observed.Brolucizumab has shown similar gains in visual acuity compared with other anti-VEGF molecules but a higher and earlier resolution of nAMD related fluid,achieving sustained macular dryness with longer mantainance injection interval ranging from 8 to 12 weeks after monthly loading doses.Rare cases of ocular inflammation also including retinal vasculitis and retinal vascular occlusions referred to an immune-mediated reaction posed safety concerns on selected patients and mantainance treatment interval shorter than 8 weeks.The present review summarizes several key points including the molecular structure and pharmacokinetics,the preclinical and clinical evidence of brolucizumab administration evaluating its efficacy,tolerability,and safety,extended dosing regimens and other indications still under clinical investigation.