Journal of Retina 2016;1(2):85-93 ORIGINAL ARTICLE ISSN 2508-1926 망막혈관종성증식에서유리체강내라니비주맙과애플리버셉트주입술후맥락막두께변화의비교 Comparison of the Changes in Subfoveal Choroidal Thickness after Intravitreal Ranibizumab and Aflibercept Injections in Retinal Angiomatous Proliferation 안소은, 양헌, 전혜민, 김상원, 윤희성 Soh-Eun Ahn, Heon Yang, Hye Min Jeon, Sang Won Kim, Hee Seong Yoon 성모안과병원 Sungmo Eye Hospital, Busan, Korea Purpose: To compare changes in choroidal thickness after intravitreal ranibizumab and aflibercept injections in patients with retinal angiomatous proliferation (RAP). Methods: This study involved 39 eyes (21 ranimizumab-treated eyes, 18 aflibercept-treated eyes) of 36 patients who received either intravitreal ranibizumab or aflibercept injection for the first time and followed up for more than 6 months. Subfoveal choroidal thickness was measured before intravitreal injection and at 3 and 6 months after intravitreal injection to determine any significant change in subfoveal chorioidal thickness over time in each treatment group. The relevant changes at each time point were measured to compare differences between the treatment groups. Central macular thickness and the best corrected visual acuity were measured and compared. Results: Choroidal thickness at 3 and 6 months after injection was significantly lower than that before injection in both the ranibizumab and aflibercept groups (p < 0.001, in all). The changes in choroidal thickness were 17.7 ± 10.9 μm and 13.0 ± 11.0 μm at 3 and 6 months after ranibizumab injection, respectively, and 24.5 ± 12.5 μm and 18.3 ± 11.1 μm at 3 and 6 months after aflibercept injection, respectively. These results show that although no significant differences were observed according to injection type at 3 months, the aflibercept group exhibited a significantly greater decrease at 6 months (p = 0.094, 0.043). The best corrected visual acuity in the two groups was significantly improved for up to 6 months after the injection compared with before the injection, and the central macular thickness also significantly decreased. There was no significant difference in visual improvement and central macular thickness decrease between the two groups. Conclusions: The results confirmed that both of these two drugs significantly decreased the subfoveal choroidal thickness in patients with RAP for up to 6 months after the injection, and the intravitreal injection of aflibercept tended to show a greater decrease in subfoveal choroidal thickness than the intravitreal injection of ranibizumab. Keywords: Aflibercept; Optical coherence tomography; Ranibizumab; Retinal angiomatous proliferation; Subfoveal choroidal thickness Address reprint requests to Hee Seong Yoon, MD Sungmo Eye Hospital, #409-1 Haeun-daero, Haeundae-gu, Busan 48064, Korea Tel: 82-51-743-0775, Fax: 82-51-743-0776 E-mail: eyeyoon@naver.com Received: 2016. 10. 7 Revised: 2016. 10. 18 Accepted: 2016. 10. 18 Copyright 2016 The korean retina society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
JOURNAL OF RETINA 서론 망막혈관종성증식은망막-망막혹은망막-맥락막혈관의문합을특징으로하는삼출성나이관련황반변성의한형태로 [1,2], 국내나이관련황반변성기초역학조사에서는약 6.2% 를차지하는것으로나타났다 [3]. 전형적인삼출성나이관련황반변성과비교하였을때, 망막혈관종성증식으로진단된환자는비교적나이가많고양안에서발생하며 [4,5], 드루젠이나거짓드루젠과같은망막의연령관련변성소견이더높은빈도로보고되고있다 [6,7]. 빛간섭단층촬영 (optical coherence tomography, OCT) 의발전으로깊이증강모드 (enhanced depth imaging [EDI] mode) 가개발되면서맥락막층을더욱정교하게평가할수있게되었고 [8,9], 이를통해망막혈관종성증식환자에서특징적으로매우얇은맥락막두께가보임을확인하였다 [6,10]. 일부보고에서는이처럼얇은맥락막에의한관류장애가망막혈관종성증식에서망막내신생혈관의발생에영향을미칠것으로추측하였다 [6]. 한편, 삼출성나이관련황반변성의치료약제로사용되는항혈관내피성장인자 (anti-vascular endothelial growth factor, anti- VEGF) 는유리체강내주사시맥락막층까지침투하여혈관수축효과를나타내고그결과신생혈관의활성도를낮추는것으로알려져있다 [11-13]. 망막혈관종성증식에서도베바시주맙, 라니비주맙을비롯하여최근애플리버셉트에이르기까지약제별로유리체강내주입술후병변의축소및장기적인시력호전과중심망막두께의감소를보인연구결과들을확인할수있다 [14-18]. 하지만망막혈관종성증식환자를대상으로두종류이상의약제효과를비교한논문은많지않으며 [18], 특히맥락막두께변화에미치는영향을비교분석한연구는부족한실정이다. 이에저자들은처음진단된망막혈관종성증식환자에서유리체강내라니비주맙과애플리버셉트주입술후중심하맥락막두께의변화를비교하고, 최대교정시력및중심망막두께의변화도함께확인하고자하였다. 대상과방법 본연구는헬싱키선언에입각한성모안과병원의학연구윤리심의위원회의승인아래진행되었다 ( 승인번호 : 2016-BM-002-01). 2013년 6월부터 2016 년 2월까지본원을내원한망막혈관종성증식환자중에서치료기왕력이없는환자만을후향적차트분석을통해선택하였다. 망막혈관종성증식의진단은안저소견, 형광안저혈관조영및인도시아닌그린혈관조영소견을종합적으로판단하여이루어졌으며특징적인망막-망막혹은망막-맥락막혈관문합이발견되는경우에진단하였다. 그중에서유리체강내라니비주맙 0.5 mg/0.05 ml (Lucentis, Genentech Inc., South San Francisco, CA, USA) 또는애플리버셉트 2.0 mg/0.05 ml (Eylea, Regeneron, New York, NY, USA and Bayer HealthCare, Berlin, Germany) 주입술을시행받고 6개월이상경과관찰이가능했던 36명 39안을대상으로하였다. 주사약제의선택은시술의사의재량에의해이루어졌으며, 진단후 1개월간격으로 3회의주사를시행하고이후에는병변이잔존또는재발하는경우추가치료를하였다. 첫 3회주사후안저검사나빛간섭단층촬영에서망막하액이남아있거나재발한경우, 새로생긴황반출혈, 망막색소상피박리의크기증가와같은병변의활성소견이보일경우추가주사를시행하였다. 심한매체혼탁을동반한경우와 6디옵터이상의고도근시환자, 시력에영향을줄수있는다른질환이나병태를동반한경우본연구에서제외하였다. 맥락막두께에영향을줄수있는레이저시술이나유리체망막수술을시행받은경우또한연구에서제외하였다. 일반적으로망막혈관종성증식이아닌전형적삼출성나이관련황반변성이진행하는경우에도망막-맥락막문합이나타날수있는것으로알려져있다 [19]. 이를배제하기위해황반중심에지도모양위축이나원반형반흔이관찰되는경우또는증상발생후 6개월이상경과한경우연구에서제외하였다. 모든환자는내원당시최대교정시력, 안압측정, 굴절검사, 안저검사, 형광안저혈관조영, 인도시아닌그린혈관조영및빛간섭단층촬영을시행하였다. 빛간섭단층촬영은 SD-OCT (CirrusTM HD-OCT 4000, Carl Zeiss Meditec, Dublin, CA, USA) 를사용하였고, 7 이상의신호강도를보이는영상만을분석하였다. 중심하맥락막두께는깊이증강영상 (EDI) 기법으로촬영된고해상도라스터스캔영상에서 Cirrus 소프트웨어에서제공하는직선측정도구 (linear measurement tool) 를이용하여, 중심와바로아래지점에서망막색소상피의외측경계에서부터공막의내측경계까지수직선을그어측정하였다 (Fig. 1) [8,20,21]. 두명의저자 (ASE, YH) 가독립적으로측정하여도출한맥락막두께의평균값을분석에사용하였다. 주사전초기중심하맥락막두께, 주사후 3개월, 6개월째중심하맥락막두께를측정하였고, 각각의시기별중심하맥락막두께의측정자간일치도를분석한결과, 급내상관계수 (intra-class correlation coefficient) 는주사전 0.984 (95% confidence interval [CI]: 0.978 0.988, p<0.001), 주사후 3개월째 0.983 (95% CI: 0.979 0.990, p<0.001), 6개월째 0.987 (95% CI: 0.982 0.991, p<0.001) 로높은신뢰도를보였다. 최대교정시력은 Snellen 시력표를사용하여측정한뒤 logmar로변환하였다. 중심망막두께는 cube scan data로부터계산된 Early Treatment Diabetic Retinopathy Study 영역중에서중심 1 mm 영역의평균망막두께로정의하였다. 약제종류에따라라니비주맙군과애플리버셉트군으로나누고약제그룹별로주사전과비교하여주사후 3개월, 6개월째중심하맥락막두께가의미있는변화를보이는지확인하였다. 86
Ahn SE, et al. 망막혈관종성증식치료후맥락막두께 A B C D Figure 1. Representative images of retinal angiomatous proliferation. (A) Color fundus photography shows retinal hemorrhage, neovascular membrane, and multiple soft drusen. (B) Fluorescein angiography shows retinal-retinal anastomosis (RRA) (arrow). (C) Indocyanine green angiography reveals RRA (arrow). (D) Enhanced depth imaging optical coherence tomography shows subretinal neovascularization membrane above pigment epithelial detachment. Subfoveal choroidal thickness (double-head arrow) was defined as the vertical distance drawn from the outer border of the retinal pigment epithelium to the inner border of the sclera (arrowheads) beneath the very center of the fovea. Table 1. Comparisons of baseline characteristics of 39 eyes (36 patients) with retinal angiomatous proliferation Characteristics Ranibizumab group Aflibercept group p-value Number of eyes (n) 21 18 Age (years) 78.2 ± 3.9 76.9 ± 5.8 0.379 * Sex (male:female) 4:15 5:12 0.706 Hypertension (eyes, %) 9 (42.9) 7 (38.9) 0.802 Diabetes mellitus (eyes, %) 3 (14.3) 3 (16.7) 1.000 Spherical equivalent (D) -0.06 ± 1.5 0.19 ± 1.7 0.762 * Subfoveal choroidal thickness (μm) 164.5 ± 40.4 161.6 ± 39.5 0.989 * BCVA (logmar) 0.61 ± 0.34 0.65 ± 0.29 0.686 * Central macular thickness (μm) 426.2 ± 99.5 409.3 ± 141.7 0.587 * Stage (eyes, %) 1.000 Stage 1 4 (19.0) 3 (16.7) Stage 2 14 (66.7) 12 (66.7) Stage 3 3 (14.3) 3 (16.7) Pigment epithelial detachment (eyes, %) 11 (52.4) 10 (55.6) 0.843 Values are presented as mean ± SD or n (%). BCVA = best corrected visual acuity; logmar = logarithm of the minimum angle of resolution. * p-value by Mann-Whitney U-test; p-value by Fisher s exact test; p-value by χ 2 test. 또한시기별로주사전과주사후중심하맥락막두께의차이를계산한변화량이두약제간에차이를보이는지확인하였다. 주사전맥락막두께가두꺼울수록큰변화량을보일수있다는가능성을염두에두고초기맥락막두께를기준으로한변화율을도출한후두약제간의차이를분석하였다 ( 맥락막두께변화율 [%] = 맥락막두께변화량 [μm] / 주사전맥락막두께 [μm] 100). 최대교정시력과중심망막두께도약제그룹별로주사전과비교하여주사후 3개월, 6개월째의미있는변화를보이는지확인하고, 두약제간에변화량의차이를보이는지비교하였다. 통계분석은 SPSS software version 18.0 (SPSS Inc., Chicago, IL, USA) 을사용하였다. 각각의약제그룹내에서주사전과주사후 3개월, 6개월째중심하맥락막두께, 최대교정시력, 중심망막두께의변화는 repeated measures analysis of variance를이용 하여유의성을확인하였고, 약제종류에따른두그룹별비교는연속형변수의경우 Mann-Whitney U test, 범주형변수의경우카이제곱검정또는 Fisher s exact test를이용하였다. p-value가 0.05보다작은경우를통계적으로유의한것으로간주하였다. 결과 전체대상군은총 36명 39안으로라니비주맙군이 21안, 애플리버셉트군이 18안이었다. 주사약제별로연령, 성별, 진단당시굴절력, 최대교정시력, 중심망막두께및중심하맥락막두께를 Table 1에제시하였으며초기중심하맥락막두께를포함한주사전특성에서두군간에유의한차이는보이지않았다. 87
JOURNAL OF RETINA 라니비주맙군의경우, 주사전중심하맥락막두께 164.5 ± 40.4 μm에서주사후 3개월째 146.8 ± 38.9 μm, 6개월째 151.5 ± 39.4 μm로주사전과비교하여주사후유의한맥락막두께의감소를보였다 (p<0.001, in both). 애플리버셉트군에서도주사전맥락막두께 161.6 ± 39.5 μm에서주사후 3개월째 137.1 A B C ± 37.6 μm, 6개월째 143.6 ± 36.2 μm로유의한맥락막두께의감소를보였다 (p<0.001, in both) (Fig. 2). 두약제모두평균적으로첫주사후 3개월째에비해 6개월째중심하맥락막두께가두꺼워지는양상을보였다 (Fig. 2, 3). 중심하맥락막두께의변화량및변화율은주사전과비교하여주사후 3개월째, 라니비주맙군에서 17.7 ± 10.9 μm, 11.0 ± 6.2% 가감소하고, 애플리버셉트군에서 24.5 ± 12.5 μm, 15.4 ± 8.0% 가감소하였으며애플리버셉트군에서보다큰감소를보였으나두군간의통계학적으로유의한차이는없었다 (p=0.094, 0.083, respectively). 주사후 6개월째는라니비주맙군에서 13.0 ± 11.0 μm, 8.0 ± 6.1% 가감소하고, 애플리버셉트군에서 18.3 ± 11.1 μm, 11.2 ± 6.0% 가감소하였으며애플리버셉트군이라니비주맙군에비해유의하게큰감소를보였다 (p=0.043, in both) (Table 2). 3개월째누적주사횟수는 3번으로두군에서동일하였고, 6개월째누적주사횟수는라니비주맙군이 3.24 ± 0.44회, 애플리버셉트군이 3.11 ± 0.32회로두군간의유의한차이는없었다 (p=0.512). 첫 3회치료후추가주사가필요했던경우를비교하였을때도라니비주맙군이 5안 (23.8%), 애플리버셉트군이 2안 (11.1%) 으로두군간의유의한차이는없었다 (p=0.418) (Table 3). 라니비주맙군의경우, 최대교정시력 (logmar) 은주사전, 주사후 3개월, 6개월째각각 0.61 ± 0.34, 0.41 ± 0.26, 0.40 ± 0.21이었으며, 같은시기에측정된중심망막두께는각각 426.2 ± 99.5 μm, 214.1 ± 34.1 μm, 215.2 ± 28.9 μm였다. 주사후 3개월, 6개월째최대교정시력은주사전과비교하여유의하게호전되었으며, 중심망막두께역시유의하게감소한결과를보였다 (p<0.001, in all). 애플리버셉트군의경우, 최대교정시력 (logmar) 은주사전, 주사후 3개월, 6개월째각각 0.65 ± 0.29, 0.43 ± 0.16, 0.43 ± 0.17 이었으며, 같은시기에측정된중심망막두께는각각 409.3 ± 141.7 μm, 197.4 ± 23.7 μm, 199.8 ± 21.6 μm였다. 주사후 3개월, 6개월째최대교정시력은주사전과비교하여유의하게호전되었으며, 중심망막두께역시유 Table 2. Comparison of subfoveal choroidal thickness changes between patients treated with ranibizumab and those treated with aflibercept Figure 2. Six-months changes in subfoveal choroidal thickness, best corrected visual acuity, and central macular thickness in eyes with retinal angiomatous proliferation that were treated with ranibizumab (closed blue diamond, blue line) or aflibercept (closed red square, red line), according to the follow-up period. (A) Subfoveal choroidal thickness after injection was significantly lower than that before injection in both the ranibizumab and aflibercept groups. (B) Best corrected visual acuity in the two groups was significantly improved after the injection compared with before the injection, and (C) central macular thickness also significantly decreased. * p < 0.05 by repeated measures analysis of variance (ANOVA). Ranibizumab group Aflibercept group p-value * 3 months (μm) 17.7 ± 10.9 24.5 ± 12.5 0.094 3 months (%) 11.0 ± 6.2 15.4 ± 8.0 0.083 6 months (μm) 13.0 ± 11.0 18.3 ± 11.1 0.043 6 months (%) 8.0 ± 6.1 11.2 ± 6.0 0.043 Values are presented as mean ± SD unless otherwise indicated. * p-value by Mann-Whitney U-test; Amount of change from baseline value at each follow-up time; Percentage of change from baseline value at each follow-up time. 88
Ahn SE, et al. 망막혈관종성증식 치료 후 맥락막두께 A D B E C F Figure 3. Representative cases of retinal angiomatous proliferation treated with ranibizumab (left column) or aflibercept (right column). (A) A 77-year-old male patient was treated with ranibizumab. Subfoveal choroidal thickness (SFCT) (double-head arrow) at baseline was 176 μm. (B) After three monthly injections, SFCT (double-head arrow) was decreased to 133 μm. (C) He had no recurrence during the 6-months follow-up period. SFCT (double-head arrow) was rethickened to 161 μm. (D) A 74-year-old female patient was treated with aflibercept. SFCT (double-head arrow) at baseline was 174 μm. (E) After three monthly injections, SFCT (double-head arrow) was decreased to 125 μm. (F) He had no recurrence during the 6-months follow-up period. SFCT (double-head arrow) was measured to 137 μm. Table 3. Six-months results for treatment of retinal angiomatous proliferation using either ranibizumab or aflibercept Ranibizumab group Aflibercept group p-value* 3 months -0.21 ± 0.26-0.23 ± 0.17 0.626* 6 months -0.22 ± 0.23-0.22 ± 0.19 0.770* 3 months 212.0 ± 88.0 211.9 ± 126.5 0.945* 6 months 211.0 ± 90.2 209.5 ± 124.5 0.945* 3.24 ± 0.44 3.11 ± 0.32 0.512* 5 (23.8) 2 (11.1) 0.418 logmar change from baseline CMT changes from baseline (μm) Number of anti-vegf injections Number of eyes required 4th injection (%) Values are presented as mean ± SD unless otherwise indicated. logmar = logarithm of the minimum angle of resolution; CMT = central macular thickness; anti-vegf = anti-vascular endothelial growth factor. * p-value by Mann-Whitney U-test; p-value by Fisher s exact test. 89
JOURNAL OF RETINA 의하게감소한결과를보였다 (p<0.001, in all) (Fig. 2). 두약제군을서로비교하였을때, 주사후 3개월, 6개월째최대교정시력의변화정도및중심망막두께의감소정도는유의한차이를보이지않았다 (Table 3). 고찰 망막혈관종성증식은다른유형의삼출성나이관련황반변성에비해보다얇은맥락막두께를보이며, 맥락막위축의발생률이높은질환이다 [6,22,23]. 망막혈관종성증식을유리체강내항혈관내피성장인자단일요법으로치료한최근연구결과들은시력및해부학적인호전이장기간유지될수있음을보여주었으나 [14-18], Grunwald et al. [24,25] 의연구결과에따르면맥락막위축의발생을촉진시킬수있는것으로알려져있다. Mrejen et al. [26] 은이러한맥락막위축의발생이망막혈관종성증식에서지속적인치료에도불구하고시력악화가발생하는이유일것으로추측하였다. 한편 Kim et al. [27] 은망막혈관종성증식에서치료후경과관찰중에맥락막두께가증가되는현상이관찰되며이는재발과관련된소견임을보고하였다. 이처럼망막혈관종성증식환자의진단및치료에있어서맥락막두께를확인하고변화를관찰하는것은중요한부분임을알수있다. 유리체강내 anti-vegf 주사가맥락막두께에미치는영향에관하여서는다양한연구결과가있어왔다. 특히 OCT의발전으로 EDI mode가개발되면서맥락막층을더욱정교하게평가할수있게되어관련연구들이활발하게진행되었다 [13,28-30]. 망막혈관종성증식환자를대상으로한맥락막두께관련연구로 Kim et al. [27] 의연구를꼽을수있는데, 중심하맥락막두께와망막혈관종성증식병변아래맥락막두께가주사후 3개월까지는유의하게감소하지만 1년까지는그상태가유지되지못함을보고하였다. 저자들은초기 3회주사후 as-needed 방식에준한치료를시행한것이이러한맥락막두께의재증가현상에영향을미쳤을것으로보고, 망막혈관종성증식도다른유형의삼출성나이관련황반변성과마찬가지로맥락막조직이 anti-vegf 치료에민감하게반응함을시사하였다 [28,29]. 본연구에서도두가지약제모두주사후 3개월까지는주사전과비교하여유의하게중심하맥락막두께를감소시킴을확인하였다. 주사후 6 개월째는 3개월째에비해서는두께가증가하는양상을보였으나여전히주사전과비교하여서는유의한감소를보였다. 추가적으로 6개월이후에중심하맥락막두께가어떻게변화하는지확인하는것도중요할것으로보이며, 6개월째중심하맥락막두께의증가를보인군과감소를보인군을비교하여이후재발이나맥락막위축발생과의연관성을알아보는것도의미가있을것으로생각된다. 망막혈관종성증식에서중심하맥락막두께관련하여두약제 를비교한결과는 Kim et al. [31] 의연구에서찾아볼수있었다. 전체삼출성나이관련황반변성환자를대상으로라니비주맙과애플리버셉트주사후 3개월째중심하맥락막두께에대한효과를비교하고하위유형을분류하여망막혈관종성증식에서의결과도보고하였다. 라니비주맙은 8.8 ± 8.1 μm, 애플리버셉트는 13.6 ± 13.1 μm의맥락막두께감소를보였으며, 애플리버셉트군에서보다큰감소경향을보이나통계적으로유의한차이는아니었다. 비교적적은안수가이러한결과에영향을미쳤을것으로저자들은판단하고있다. 본연구에서도주사후 3개월째애플리버셉트군에서보다큰맥락막두께감소경향을보이나통계적으로유의한차이는보이지않았다. 주사후 6개월째는이러한경향이보다두드러지게나타나며통계적으로유의한차이를보였다. 이는애플리버셉트가라니비주맙에비해맥락막두께를더많이감소시키며 [31], 애플리버셉트의효과가라니비주맙에비해보다오래지속된다는이전연구결과들과비슷한맥락에서이해할수있을것으로보인다 [32,33]. 초기중심하맥락막두께를고려하여맥락막두께의변화율을비교하였을때도마찬가지의결과를보였다. Kim et al. [31] 의연구에서는삼출성나이관련황반변성을세가지하위유형으로분류하고그중한유형으로서망막혈관종성증식을주사후 3개월까지살펴본반면, 본연구에서는망막혈관종성증식만을대상으로보다장기간인주사후 6개월까지의경과를보았다는데의의가있다. 또한변화량뿐만아니라초기맥락막두께를고려한변화율까지상세히기술하였다. 라니비주맙과애플리버셉트를비교하였을때, 주사후중심하맥락막두께감소에있어서는차이를보였지만총투여횟수는유의한차이를보이지않았다. 망막혈관종성증식에서맥락막두께와병변의활성도및재발과의연관성에대해서는아직명확한결론이내려져있지않은상태이다. Kim et al. [27] 은망막혈관종성증식에서치료후경과관찰중에맥락막두께가증가되는현상이재발과관련된소견임을보고하였으나, Maruko et al. [34] 은맥락막두께의변화가재발과연관되어있지않다고보고하였다. 맥락막두께가병변의활성도와강한상관관계를보이는결절맥락막혈관병증이나중심장액성맥락망막병증과는망막혈관종성증식이병태생리적인측면에서차이를보이기때문인것으로보이며, 망막혈관종성증식에서맥락막두께변화와활성도및재발과의관계를논하기위해서는보다많은연구결과들이필요할것으로보인다. 본연구에서도첫 3회주사후 3개월경과시점까지는두약제사이에재발률및추가주사횟수가유의한차이를보이지않았지만, 맥락막두께의증가가재발에선행한다는가정하에두약제사이의맥락막두께감소차이가이후재발률과어떠한연관성을보일지에대해서는추가적인연구가필요할것이다. 최대교정시력과중심망막두께변화관련하여서는 Kim et al. [18] 의연구와비슷한결과를보였다. 저자들은망막혈관종성증 90
Ahn SE, et al. 망막혈관종성증식치료후맥락막두께 식을대상으로 6 개월추적관찰한결과라니비주맙과애플리버 셉트모두시력을개선하고중심망막두께를줄이는데만족할 만한효과를보였으며 6 개월동안의시력변화정도와중심망막 두께감소정도는두약제사이에통계적으로유의한차이가없 었다고보고하였는데, 본연구에서도마찬가지의결과를보여 두약제모두망막혈관종성증식을치료하는데있어서주사후 6 개월까지는좋은효과를기대할수있으며시력호전이나중심 망막두께변화에있어서는특정약제가더우위에있지않다는 것을뒷받침해주었다. 본연구는후향적인단면연구법에의한분석이고, 경과관찰 기간이 6 개월로짧았다는점에서제한점이있다. Small sample size 에서오는통계적인문제점도배제하기힘들다. 약제선택에 있어서기준이되는지침이부재하였다는것또한큰제한점이 다. 담당의사의재량에의해약제가선택되었고이에따른변수 가작용하였을것으로보인다. 또한맥락막두께에영향을미칠 수있는요소들이충분히보정되지않았다. 기존보고에따르면 맥락막두께는일중변동, 굴절력, 안축장, 고혈압및당뇨의유 무와연관되어있다 [35-38]. 초기특성비교에서굴절력, 고혈압, 당뇨의유무가두군간에유의한차이를보이지않음을확인하 였지만, 후향적단면연구인관계로모든요인들이통제될수는 없었다. 마지막으로맥락막두께측정의경우두께를측정하는 객관적인소프트웨어의부재로주관적인측정법에의해연구가 진행되었다는한계점을갖는다. 그러나이미발표된문헌과같 은방법을사용하여두명의저자가측정하였고측정자간신뢰 도가높았다는점에서주관성으로인한한계를어느정도보완 하였다고판단된다. 라니비주맙과애플리버셉트주사후맥락막두께의감소는신 생혈관의활성도와연관되어있는맥락막모세혈관과투과성의 감소를반영한다는측면에서긍정적인반응으로볼수있으나, 한편으로는맥락막의순환장애와위축을유발하여망막색소상 피와망막외층간의결합력에원치않는악영향을미칠수있다 는측면에서치료시주의를기울일필요성이있다. 구조적인호 전뿐만아니라기능적인호전의여부가실제환자를치료함에 있어서중요하기때문이다. 본연구를통해망막혈관종성증식 에서유리체강내주입술시행전후로라니비주맙군과애플리버 셉트군모두주사후 6 개월까지효과적으로중심하맥락막두께 를감소시키고, 애플리버셉트군에서라니비주맙군에비해보다 큰감소량을보임을확인하였으며, 추후이러한경향이재발또 는맥락막위축의발생, 시력예후등에어떠한영향을미칠지 에대한연구또한매우중요할것으로보인다. Conflicts of interest There are no conflicts of interest. References 1. Yannuzzi LA, Negrão S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21:416-34. 2. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina 2008;28:201-11. 3. Park KH, Song SJ, Lee WK, et al. The results of nation-wide registry of age-related macular degeneration in Korea. J Korean Ophthalmol Soc 2010;51:516-23. 4. Gross NE, Aizman A, Brucker A, et al. Nature and risk of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Retina 2005;25:713-8. 5. Bottoni F, Massacesi A, Cigada M, et al. Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation. Arch Ophthalmol 2005;123:1644-50. 6. Kim JH, Kim JR, Kang SW, et al. Thinner choroid and greater drusen extent in retinal angiomatous proliferation than in typical exudative age-related macular degeneration. Am J Ophthalmol 2013;155:743-9, 749.e2. 7. Cohen SY, Dubois L, Tadayoni R, et al. Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation. Br J Ophthalmol 2007;91:354-9. 8. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496 500. 9. Mrejen S, Spaide RF. Optical coherence tomography: imaging of the choroid and beyond. Surv Ophthalmol 2013;58:387 429. 10. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness in retinal angiomatous proliferation. Retina 2014;34:1316-22. 11. Peters S, Heiduschka P, Julien S, et al. Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol 2007;143:995-1002. 12. Schraermeyer U, Julien S. Effects of bevacizumab in retina and choroid after intravitreal injection into monkey eyes. Expert Opin Biol Ther 2013;13:157-67. 13. Ünlü C, Erdogan G, Onal Gunay B, et al. Subfoveal choroidal thickness changes after intravitreal bevacizumab therapy for neovascular age-related macular degeneration. Int J Ophthalmol 2015;8:849-51. 14. Cho HJ, Lee TG, Han SY, et al. Long-term visual outcome and 91
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Ahn SE, et al. 망막혈관종성증식치료후맥락막두께 국문초록 망막혈관종성증식에서유리체강내라니비주맙과애플리버셉트주입술후맥락막두께변화의비교 목적 : 망막혈관종성증식환자에서유리체강내라니비주맙과애플리버셉트주입술후중심하맥락막두께의변화를비교하고자한다. 대상과방법 : 처음으로망막혈관종성증식으로진단된후라니비주맙또는애플리버셉트주입술을시행받고 6개월이상경과관찰가능했던 36명 39안 ( 라니비주맙 21안, 애플리버셉트 18안 ) 을대상으로하였다. 첫주사전, 주사후 3개월, 6개월째중심하맥락막두께를측정하여약제군별로시간에따라의미있는변화를보이는지확인하였고, 시기별변화량을측정하여약제에따른차이를비교하였다. 최대교정시력및중심망막두께도함께측정하여비교하였다. 결과 : 라니비주맙군과애플리버셉트군모두주사전중심하맥락막두께와비교하여주사후 3개월, 6개월째통계적으로유의한감소를보였다 (p<0.001, in all). 라니비주맙주사후 3개월, 6개월째변화량은 17.7 ± 10.9 μm, 13.0 ± 11.0 μm, 애플리버셉트주사후변화량은 24.5 ± 12.5 μm, 18.3 ± 11.1 μm로애플리버셉트군에서보다큰변화량을보였으며 3개월째는통계학적으로유의한차이가없었으나 6개월째는유의한차이를보였다 (p=0.094, 0.043). 두군모두에서최대교정시력및중심망막두께는주사전과비교하여주사후 6개월까지유의하게호전되었으며, 호전정도는두군사이에유의한차이를보이지않았다. 결론 : 망막혈관종성증식환자의치료에서두약제모두주사후 6개월까지유의하게중심하맥락막두께를감소시켰고, 애플리버셉트를주사하였을때라니비주맙에비해보다큰맥락막두께감소를보이는경향을확인하였다. 93