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滲出型加齢黄斑変性に対する脈絡膜新生血管の制御及び新たな予後予測因子の検討

東, 惠子 東京大学 DOI:10.15083/0002008274

2023.12.27

概要

審査の結果の要旨
氏名 東

惠子

本研究は滲出型加齢黄斑変性(nAMD)に対し、前半では抗血管内皮増殖因子薬(抗 VEGF
薬)の種類・投与方法による脈絡膜新生血管(CNV)の制御について後ろ向き観察研究で
検討した。後半では pachychoroid neovasculopathy(PNV)の有無で治療反応性や予後を
比較することにより nAMD の新たな予後予測因子を明らかにすべく検討を行い、下記の結
果を得ている。
1.

まず抗 VEGF 薬の種類・投与方法と CNV 制御の関連について後ろ向き観察研究で検討
した。対象はラニビズマブ投与が行われていた nAMD の特殊型であるポリープ状脈絡膜
血管症(PCV)である。CNV の活動性を示す指標として視力、ポリープと CNV を含めた
病変部最大直径(GLD)
、滲出性変化(ポリープの退縮率、網膜下に貯留する滲出液や出
血)に注目した。ラニビズマブ単剤を pro re nata 法(PRN 法:毎月の診察で滲出性変
化が認められた際に抗 VEGF 薬を投与する方法)で投与した場合、2 年後の視力は 85%
の症例で維持されていたが、GLD は全症例で悪化していた。また、82%の症例で滲出性
変化の改善が見られた。このように視力が維持されているにも関わらず GLD 拡大傾向
や滲出性変化の増悪がみられる現象は、ラニビズマブへの耐性が一因として考えられ、
PRN 法によるラニビズマブ単独療法には限界があることが判明した。ラニビズマブで耐
性を認めた症例をアフリベルセプトに変更し、投与方法も Treat & Extend 法(TAE 法:
変化が認められなければ投与を続けながら投与間隔を広げていく方法)に変更したと
ころ、さらに 1 年間視力が維持され、GLD は全例で縮小していた。アフリベルセプト切
り替え後 1 年の長期効果ならびに GLD を用いた有効性を評価した報告は、我々の報告
が初めてであり、この結果、抗 VEGF 薬ならびに投与方法の変更により GLD の拡大を抑
制することが可能であることを明らかにした。

2.

次に、抗 VEGF 薬投与前後の脈絡膜の構造変化と治療効果の関連性について後ろ向き
観察研究を行い、新たに指摘されてきた PNV と治療効果に関連する因子について検討
した。対象は初発や再発の nAMD で、ラニビズマブもしくはアフリベルセプトを投与し
た症例を PNV の有無で 2 群に分けて検討した。PNV 治療効果判定には網膜下に滲出液が
貯留した状態(wet macula)か滲出液が消失した状態(dry macula)への改善や視力の
改善を指標にした。PNV を認めない症例では管腔面積の変化、治療前 CNV の大きさ、抗
VEGF 薬投与ならびにその種別が dry macula に関連した因子として考えられた。同様に
管腔面積の変化、治療前 CNV の大きさ、抗 VEGF 薬投与ならびにその種別は視力改善に
関連した因子にもなっていた。また、これらの脈絡膜血管の管腔構造は 1 か月という比

較的短期間で変化することも明らかになった。一方、PNV を認める症例では治療効果と
関連ある因子は抽出されなかった。この結果から、両群の治療においては管腔面積の変
化が認められていることから脈絡膜血管の反応が異なること、PNV を認める症例では抗
VEGF 薬投与が無効であることから病態形成に VEGF 以外の因子関わっており、その制御
には抗 VEGF 薬以外の治療法も考慮する必要があると考えられた。
3.

これらの結果を踏まえ、PNV に対する抗 VEGF 薬と PDT 併用療法の有効性について後
ろ向き観察研究を行った。PDT は正常組織に大きな障害を与えることなく、低いエネル
ギーで新生血管を選択的に治療することが可能で、nAMD に有効性が認められている治
療法である。しかし、頻回に PDT を行うことは正常な脈絡膜血管を含めた正常組織に影
響を及ぼし、網膜色素上皮細胞を萎縮させることが証明されている。この併用療法を初
発 PCV 症例に行い、その後、抗 VEGF 薬を PRN 法で投与継続した症例を対象にして PNV
の有無と治療効果に関連する因子を検討した。PNV を認める症例は PNV を認めない症例
に比べ、3 年間の経過観察で視力が改善し、初回再発までの期間が長かった。また、PRN
法に基づく抗 VEGF 薬投与回数が少なく、脈絡膜の厚さとも関連していた。これらの結
果から、抗 VEGF 薬と PDT 併用療法は PNV を認める症例では、PNV を認めない症例より
も長期に視力を維持し、脈絡膜の厚さが過度に菲薄化せずに制御できていたと考えら
れた。本検討では nAMD に PNV を合併している症例には初回治療に PDT と抗 VEGF 薬を
併用することで正常脈絡膜組織への影響を最小限にし、治療効果が維持されることを
明らかにした。

以上の結果より、nAMD への治療は新しい分類である PNV を含めた病態生理学的な形態
学的分類を考慮した上で、治療方法や投与方法を最適化することで、より良好な病態制御
が期待できることが示唆された。本研究で得られた知見は、新たな病態概念を元に nAMD
の予後予測因子を新たに明らかとしたものであり、臨床所見や病態に基づいた個別化医療
の確立の土台となる基盤的な研究と考えられる。
よって本論文は博士(医学)の学位請求論文として合格と認められる。

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