Introduction

Retinal angiomatous proliferation(RAP) is a variant of neovascular age-related macular degeneration (AMD)and has recently been discovered to be

present in approximately 10–15% ofeyes with exudative AMD (Yannuzziet al. 2001). According to Yannuzziet al. (2001), RAP arises from the ret-ina rather than from the choroidalcirculation. Retinal angiomatous pro-

liferation has been reported to havean especially poor prognosis and lim-ited response to treatment (Bottoniet al. 2005; Bressler 2005). Moreover,the fellow eye is at high risk of devel-oping RAP (Gross et al. 2005). Vari-ous treatments for RAP, such asconventional laser photocoagulation(Slakter et al. 2000; Johnson & Glaser2006), photodynamic therapy (PDT)(Boscia et al. 2004; Panagiotidis et al.2006; Silva et al. 2007), surgical ther-apy (Borrillo et al. 2003; Sakimotoet al. 2005; Shiragami et al. 2007) orcombined therapies (Boscia et al.2005; Nakata et al. 2006), have beendiscouraging or showed limited suc-cess with recurrent exudation. Recentstudies showed that combined therapyof intravitreal triamcinolone and PDTeffectively reduced angiographic leak-age and had a positive effect on visualacuity (Freund et al. 2006; van deMoere et al. 2007). However, intravi-treal triamcinolone is associated withthe potential complications of eleva-tion of intraocular pressure, end-ophthalmitis and development ofposterior subcapsular cataract (Spaideet al. 2003; Bhavsar et al. 2007).

More recently, promising resultswith off-label intravitreal bevacizumabhave been reported (Joeres et al. 2007;Meyerle et al. 2007; Ghazi et al.2008). Combined intravitreal bev-acizumab and PDT for RAP had apositive effect on RAP lesions (Saitoet al. 2008). Intravitreal injection ofranibizumab also was effective in the

Intravitreal ranibizumabtreatment of retinal angiomatousproliferation

Christina A. Kramann,1 Kilian Schopfer,1 Katrin Lorenz,1

Isabella Zwiener,2 Bernhard M. Stoffelns1 and Norbert Pfeiffer1

1Department of Ophthalmology, University Medical Center Mainz, JohannesGutenberg University, Mainz, Germany2Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI),University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany

ABSTRACT.

Purpose: To determine the efficacy of intravitreal injections of ranibizumab in

the treatment of retinal angiomatous proliferation (RAP) in neovascular age-

related macular degeneration.

Methods: Retrospective, consecutive case series of 26 eyes (26 patients) trea-

ted with intravitreal injections of 0.5 mg ranibizumab for RAP. Patients

received intravitreal injections at monthly intervals during upload phase for a

3-month period.

Results: Mean visual acuity before treatment was 0.75 ± 0.38logMAR

(mean ± SD, n = 26). In the upload phase, mean visual acuity improved

4 weeks after the initial injection to 0.6 ± 0.37logMAR (n = 26) and to

0.53 ± 0.34logMAR (n = 26) 4 weeks after the third monthly intravitreal

injection of ranibizumab. The mean optical coherence tomography (OCT) cen-

tral foveal thickness reduced from 345 ± 55 lm at baseline to 215 ± 87 lm

at 3 months. In the maintenance phase, mean visual acuity after 6 months was

0.66 ± 0.38logMAR (n = 12) and 0.7 ± 0.37logMAR after 9 months

(n = 6). The mean OCT central foveal thickness was 259 ± 59 lm (n = 13)

at 6 months and 280 ± 127 lm (n = 6) at nine-month follow-up.

Conclusion: Intravitreal ranibizumab resulted in an improvement of visual acu-

ity 4 weeks after the first injection but was more pronounced after 3 months.

A reduction in leakage and OCT central foveal thickness was seen 3 months

after the commencement of treatment.

Key words: age-related macular degeneration – intravitreal injection – Lucentis – ranibizumab –

retinal angiomatous proliferation

Acta Ophthalmol.ª 2010 The Authors

Journal compilation ª 2010 Acta Ophthalmol

doi: 10.1111/j.1755-3768.2010.01952.x

Acta Ophthalmologica 2010

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treatment of RAP in a case review offour consecutive patients (Lai et al.2007).

The purpose of this study was todetermine the outcome after intravi-treal injections of ranibizumab in alarger series of patients with RAPlesions in the three-month uploadphase and in the following mainte-nance period.

Methods

We report a consecutive case series of26 eyes (26 patients) with RAPbecause of neovascular macular de-generation treated with intravitrealinjections of ranibizumab (dose 0.5mg in 0.05 ml, Lucentis�; Novar-tis Pharma, Nurnberg, Germany).Patients with RAP stages I-III inwhich intravitreal therapy of rani-bizumab was indicated for the firsttime and completed at least three-month follow-up were evaluated. Thediagnosis of RAP was based on clini-cal and angiographic findings accord-ing to Yannuzzi et al. (2001). Duringthe upload phase in the first 3 months,patients received intravitreal injectionsof ranibizumab at baseline, 1 and2 months, in the following mainte-nance phase in case of progression(vision loss of at least one line, wors-ening of macular oedema of>100 lm, persistence of leakage).

Baseline ocular examinationincluded determination of best cor-rected distance visual acuity [BCVA,EN ISO 8596, BCVA was convertedinto logarithm of the minimum angleof resolution (logMAR) for statisticalanalysis], slit lamp examination, bin-ocular biomicroscopy, fundus col-our photography, optical coherencetomography (OCT) (fast macularthickness acquisition protocol, Stratu-sOCT, Zeiss Jena GmbH, Jena,Germany), fluorescein angiography(FA, HRA II, Heidelberg Engineer-ing, Heidelberg, Germany) and, ifneeded, indocyanine green angiogra-phy (ICGA, HRA II, HeidelbergEngineering, Heidelberg, Germany).

Before therapy, written informedconsent was obtained from all patientsafter the potential risks and benefitsof the intravitreal injections wereexplained in detail.

All patients underwent intravitrealinjections of ranibizumab via parsplana under topical anaesthesia under

strict aseptic conditions. Light percep-tion and intraocular pressure weretested after the injections.

Patients were rescheduled for fol-low-up visits every 4 weeks. Best cor-rected visual acuity, slit lamp andbinocular examination were performedat monthly intervals, and OCT, FAand ICGA were performed at leastevery 3 months.

All eyes completed at least thethree-month follow-up after the firstinjection. None of the patients hadundergone prior treatment or receivedadditional treatment for neovascularAMD during follow-up.

Statistical analysis was performedusing spss statistical software (version14.0, SPSS Inc., Chicago, IL, USA).The primary question was if there wasa difference in visual acuity betweenbaseline and follow-up at 3 months.The significance level was fixed ata = 0.05. All other p-values were con-sidered as explorative.

A paired t-test was performed foranalysis of mean visual acuity at base-line and each follow-up visit. Thechange of central retinal thicknessover time was evaluated using theWilcoxon signed rank test. For eachpaired statistical test, casewise deletionof missing data was performed if avariable had a missing value.

An unpaired t-test was used toassess the influence of RAP stagesI-III on visual acuity and change incentral retinal thickness at the end ofthe upload phase.

Results

Twenty-six eyes of 26 consecutivepatients were included in the study.Patient age ranged from 61–94 years(mean 77 years), 18 patients werewomen. All eyes had 3 or moremonths of follow-up after the firstinjection of ranibizumab (this equals1 month after the third monthly injec-tion in the upload phase). Twelve eyescompleted a 6-month follow-up, andsix eyes completed a 9-month follow-up after the first injection. None ofthe eyes had prior treatment for neo-vascular AMD.

The mean number of intravitrealinjections per eye was 3.46 (range 3–6). Eighteen (69%) eyes received threeinjections, 5 (19%) eyes received fourinjections, 2 (8%) eyes received five

injections and 1 (4%) eye received sixinjections.

At baseline, nine eyes (35%) hadpigment epithelium detachment andseven eyes had a stage I lesion (27%),17 eyes a stage II lesion (65%) andtwo eyes a stage III lesion (8%).

At baseline, mean logMAR BCVA(EN ISO 8596) was 0.75 ± 0.38(mean ± SD, n = 26). During theupload phase, after the first injection ofranibizumab, visual acuity improved to0.6 ± 0.37 (p = 0.014, n = 26), afterthe first three injections of ranibizumabin 3-month follow-up, mean logMARBCVA further statistically significantlyimproved to 0.53 ± 0.34 (p = 0.002,n = 26). In the maintenance period,at the 6-month follow-up, availablefor 12 eyes, mean logMAR BCVAwas 0.66 ± 0.38 (p = 0.793) and 0.7± 0.37logMAR (p = 0.922 n = 6)9 months after the initial ranibizumabinjection (Fig. 1).

The BCVA in five eyes (19%)improved by three or more lines at4 weeks, 20 eyes (77%) had stablevisual acuity and one eye (4%) had adecreased BCVA of three or morelines at 4 weeks. At three-month fol-low-up, eight eyes (31%) hadincreased BCVA compared to baselineby three or more lines, 17 eyes (65%)had stable BCVA and one eye (4%)had decreased BCVA of three or morelines. At 6 months, four eyes (33%)improved by three or more lines com-pared to baseline, six eyes (50%) hadstable BCVA and two eyes (17%) hada decreased BCVA of three or morelines. At nine-month follow-up,BCVA improved one eye (17%) bythree or more lines, four eyes (67%)had stable BCVA and one eye (17%)had a decreased BCVA of three ormore lines (Fig. 2).

The reduction in mean centralfoveal thickness was largest in the first3 months during upload phase, meanOCT central foveal thicknessimproved from 345 ± 55 lm at base-line to 215 ± 87 lm at 3 months(p < 0.001, n = 26). In the mainte-nance phase, mean OCT centralfoveal thickness was 259 ± 59 lm(p = 0.001, n = 13) at 6 months and280 ± 127 lm (p = 0.31, n = 6) atnine-month follow-up after the initialranibizumab injection (Fig. 3).

The change in visual acuity wasrelated to the stage of the RAP lesionat month 3. Eyes with RAP stage II

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showed the most improvement ofBCVA (unpaired t-test, p = 0.017)compared to baseline compared toeyes with RAP stage I.

The change in central foveal retinalthickness at month 3 compared tobaseline was also more pronounced ineyes with RAP II (mean 155.2 lmreduction) compared to eyes withRAP I (mean 110.8 lm reduction);this was not statistically significant(unpaired t-test, p = 0.191).

Because of the small number of eyeswith RAP stage III (n = 2), the statis-tical tests did not have the power todetect differences in change in BCVAor change in central foveal thicknesscompared to baseline.

No ocular or systemic adverseevents were observed during theupload or maintenance period.

Discussion

Retinal angiomatous proliferation is acommon subtype of AMD. In con-trast to choroidal neovascularization(CNV) in AMD, the angiomatousproliferation originates from the retinaand extends posteriorly into the subre-tinal space.

In 2001, three different stages wereidentified by Yannuzzi et al. (2001):intraretinal neovascularization instage I, subretinal neovascularizationin stage II and CNV with a vascula-rized pigment epithelium detachmentand retinal-choroidal anastomosisin stage III (Yannuzzi et al. 2001).Recently, the term ‘Type 3 neovascu-larization’ was introduced to empha-size the intraretinal location of thevascular complex and to distinguishneovascularization in RAP from theGass CNV Type 1 and Type 2 ana-tomical classification (Freund et al.2008).

Retinal angiomatous proliferationhas been identified to have a poorprognosis, and therapy appears to bemost challenging, as most of theestablished treatments for exudativeAMD have limited success for RAP(Slakter et al. 2000; Borrillo et al.2003; Boscia et al. 2004, 2005; Sakim-oto et al. 2005; Johnson & Glaser2006; Nakata et al. 2006; Panagiotidiset al. 2006; Shiragami et al. 2007;Silva et al. 2007).

In our study, we found that at theend of the upload phase all but one eyehad stable visual acuity. In eight eyes,visual acuity improved by three ormore lines compared to baseline. Thereduction in mean central foveal thick-ness was largest in the first 3 monthsduring upload phase (Fig. 4). Noadverse events were observed.

Antivascular endothelial growthfactor (anti-VEGF) therapy has beenestablished as an effective treatmentfor subfoveal CNV in exudative AMD(Gragoudas et al. 2004; Brown et al.2006; Rosenfeld et al. 2006). Rani-bizumab is an antibody fragmentderived from a murine antibody toVEGF and binds all active isoformsof VEGF, it is approved for the treat-ment of neovascular AMD and intra-vitreal use. Results from large,prospective clinical trials have shownthat intravitreal injections of rani-bizumab can inhibit CNV andimprove visual acuity in approxi-mately 40% of patients (Brown et al.2006; Rosenfeld et al. 2006). Trans-genic mice with increased expressionof VEGF demonstrated new vesselformation proliferation originatingfrom the deep retinal capillary plexus(Tobe et al. 1998). Reports on the effi-cacy of ranibizumab treatment forRAP lesions are limited but the resultsin the use of ranibizumab for RAPlesions so far are promising. In thePrONTO study, Fung et al. (2007)reported that 10 of the 40 patientsincluded had RAP lesions and thatpatients with RAP required a highermean number of intravitreal injectionsof ranibizumab compared to patientswith other types of neovascular CNV.However, in the PrONTO study,visual acuity and OCT outcomes werenot published separately for patientswith RAP lesions, and therefore, effi-cacy of therapy in patients with RAPlesions remained unclear.

Rouvas et al. (2009) treated 13 eyeswith RAP with 3 monthly injectionsof ranibizumab, 13 eyes with PDT fol-lowed by 3 monthly injections of rani-bizumab and 11 eyes with PDT andone injection of 4 mg triamcinolone.Eight eyes in the group treated withranibizumab alone had stable or bet-ter visual acuity at the end of follow-up. They observed a significant trendtowards better functional and anatom-ical results in the PDT and triamcino-lone group (Rouvas et al. 2009).

Fig. 1. Change in best corrected visual acuity (BCVA) (LogMAR) from baseline over time

(baseline, 1, 3, 6 and 9 months follow-up), [at 1 and 3 months n = 26, at 6 months n = 12, at

9 months n = 6; y-axis BCVA (LogMAR) x-axis months of follow-up].

Fig. 2. Percentage of patients with stable best

corrected distance visual acuity (BCVA),

decreased BCVA by three or more lines or

improved BCVA by three or more lines at 1,

3, 6 and 9 months follow-up (at 1 and

3 months n = 26, at 6 months n = 12, at

9 months n = 6; y-axis follow-up after base-

line (months), x-axis percentage of patients).

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Lai et al. (2007) showed that threeinjections of ranibizumab at monthlyintervals for RAP in four consecutivepatients resulted in a gain in visualacuity and reduction in centralmacular thickness. One patient intheir series developed recurrence ofRAP 8 months after commencementof therapy but responded well toretreatment.

Freund et al. (2008) treated threepatients with RAP lesions with a sin-gle injection of intravitreal rani-bizumab that resulted in resolution ofthe intraretinal oedema and neovascu-lar lesion.

Bevacizumab (Avastin; GenentechInc, South San Francisco, CA, USA)is a humanized monoclonal VEGFantibody, which is Food and Drug

Administration approved for intrave-nous use in patients with colorectalcancer.

Meyerle et al. (2007) reported in aretrospective review of consecutivepatients with RAP treated with intra-vitreal bevacizumab during a 3-monthperiod similar short-term visual acuityand anatomical responses comparedto our study. After intravitreal bev-acizumab therapy, at 3-month follow-up, 29.4% (compared to 30.8% in ourseries) had improved visual acuity and64.7% (compared to 65.4% in ourseries) remained stable. Noteworthy oftheir review is the small percentage ofRAP III lesions (Meyerle et al. 2007).This is also the case in our study.

Ghazi et al. (2008) also reportedtheir short-term experience with intra-vitreal bevacizumab of RAP. Theyfound stabilization of visual acuityand central retinal thickness after asingle injection for at least 8 weeks,suggesting that an injection frequencyof less than one per month may besufficient (Ghazi et al. 2008).

Wolf et al. (2008) retrospectivelyevaluated 82 eyes with RAP treatedwith intravitreal bevacizumab. Theyreported a significant improvement ofvisual acuity after the upload phase,but a decrease in visual function fiveto twelve months after completion ofthe upload phase (Wolf et al. 2008).In our study, we also found animprovement of visual acuity com-pared to baseline after 9 months inonly in 16.7% compared to 30.77% atthe end of the upload phase. In con-trast to the three and 6 months ana-tomical response, change in centralretinal thickness after 9 months wasnot statistically different to baseline.

The difficulty in treatment of RAPmay be because of the high-flow nat-ure of the lesions, an anastomoticconnection between the retinal andchoroidal circulation and associateddetachment of the retinal pigment epi-thelium. In our series, retreatmentafter the 3-month upload phase wasneeded in 30.8% of patients. Joereset al. (2007) also found in a prospec-tive case series that after intravitrealinjections of bevacizumab in eyes withRAP, a complete occlusion of feedervessels within a three-month periodcould not be achieved.

We found the most improvement ofBCVA and change in central fovealretinal thickness in eyes with RAP II.

Fig. 3. Change in central foveal thickness from baseline over time (baseline, 3, 6 and 9 months

follow-up (at 1 and 3 months n = 26, at 6 months n = 13, at 9 months n = 6; y-axis central

retinal thickness in lm, x-axis months of follow-up).

Fig. 4. Retinal angiomatous proliferation (RAP) lesion in an 88-year-old man at baseline

(upper row). Early and late fluorescein angiography (FA) shows leakage and intraretinal

oedema. Indocyanine green angiography (ICGA) shows the RAP lesion. Optical coherence

tomography (OCT) shows cystoid macular oedema. After three intravitreal injections of rani-

bizumab, at 3-month follow-up (lower row), no leakage on FA can be observed. The hot spot

on ICGA resolved and OCT shows normalization.

Acta Ophthalmologica 2010

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We presume that this might beexplained by the fact that in RAP I,visual function often is only slightlyreduced as it constitutes the earliestmanifestation of RAP. Growth ofretinal vessels in RAP II into the sub-retinal space then leads to a furtherdecrease in visual function and increasein macular oedema. In RAP III eyes,retinal changes are more pronouncedand might be irreversible, because ofthe small percentage of RAP III eyesin our review this cannot be concludedfrom the current observation.

This study has some limitations thatmust be recognized: we had no con-trol group, all eyes completed the3-month follow-up but less than halfof the eyes included in the studycould be evaluated six or 9 monthafter baseline. The short-term resultsobtained with intravitreal ranibizumabin eyes with RAP in this study appearpromising. However, disease recur-rence in the maintenance periodsuggests that patients with RAP mustbe monitored closely to permit earlyretreatment. Our results suggest thatfurther large and long-term prospec-tive randomized studies are needed todetermine the efficacy and safety ofintravitreal ranibizumab treatment ofeyes with RAP and to determine theoptimal dosing strategy.

Acknowledgement

The authors have no commercial, pro-prietary or financial interest in any ofthe products or companies described inthis article. This article has not beenpresented at a meeting. The authorshave not received funding for researchon the topic of this article. The studywas performed at the Department ofOphthalmology, University MedicalCenter Mainz, Johannes GutenbergUniversity, Mainz, Germany.

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Received on August 12th, 2009.

Accepted on April 27th, 2010.

Correspondence:

Christina Kramann, MD

Department of Ophthalmology

University Medical Center Mainz

Johannes Gutenberg University

Langenbeckstrasse 1

55131 Mainz, Germany

Tel: +0049 6131 175741

Fax: +0049 6131 176620

Email: kramann@augen.klinik.uni-mainz.de

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