Wong Calvin W, Yang Annie A, Liu Chia-Yang, Watsky Mitchell A, Lu Xiaowen, Le Harrison L, Yee Richard W
Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA.
Ophthalmology, Richard W. Yee, MD PLLC, Houston, USA.
Cureus. 2023 Sep 12;15(9):e45136. doi: 10.7759/cureus.45136. eCollection 2023 Sep.
This two-part study aimed to investigate the therapeutic potential of topical spironolactone in ocular graft-versus-host disease (oGVHD). While off-label use of topical spironolactone has been described in dry eye, its efficacy in managing signs and symptoms of oGVHD remains unstudied. Preclinically, we tested the hypothesis that spironolactone induces corneal lipid synthesis in a mouse model. Clinically, we assessed patient response to spironolactone with a retrospective observational design.
Both immortalized and primary human corneal epithelial cells were stained with oil red O after 9 days of treatment with spironolactone. C57BL/6 mice were dosed thrice daily with one drop in each eye for 18 days. Corneal tissue was stained with oil red O and BODIPY™. Twenty eyes with oGVHD, as defined by the International Chronic oGVHD Consensus Group, were studied. Corneal fluorescein staining, lid margin vascularity, meibomian gland obstruction, meibum turbidity, zone A posterior lid margin vascularity, and oGVHD diagnostic criteria severity grading were compared in a pre-post study. Follow-up times ranged from 7 to 21 weeks, with a median time of 12 weeks. Statistical analysis was done with STATA 17 by fitting data to a non-parametric model.
results showed an increased number and density of oil red O staining granules in the treatment group versus control in both primary and immortalized human corneal epithelium. , results showed translation to the mouse model with increased corneal epithelial BODIPY™ signal compared to untreated control. oGVHD patients had improved lid margin vascularity (= 0.046), corneal fluorescein staining ( = 0.021), and International oGVHD Consensus Group severity scores ( = 0.011) after treatment with topical spironolactone. Minimal adverse effects were noted, the most common being mild stinging lasting less than a minute after instillation.
The improved severity scores, lid margin inflammation, and corneal fluorescein staining after weeks of treatment support the rationale that topical spironolactone may benefit oGVHD. The observed lipid production by the corneal epithelium is thought to contribute to this protective effect against ocular surface erosive disease in oGVHD. A mineralocorticoid receptor antagonist, spironolactone may offer therapeutic benefits in oGVHD while avoiding undesirable side effects of topical or systemic glucocorticoids.
这项分为两部分的研究旨在探讨局部使用螺内酯治疗眼部移植物抗宿主病（oGVHD）的潜力。虽然已有关于局部使用螺内酯治疗干眼症的非标签用药描述，但其治疗oGVHD体征和症状的疗效仍未得到研究。在临床前研究中，我们在小鼠模型中检验了螺内酯可诱导角膜脂质合成的假设。在临床研究中，我们采用回顾性观察设计评估了患者对螺内酯的反应。
用螺内酯处理9天后，对永生化和原代人角膜上皮细胞进行油红O染色。C57BL/6小鼠每天滴眼三次，每次一滴，持续18天。对角膜组织进行油红O和BODIPY™ 染色。研究了20只符合国际慢性oGVHD共识小组定义的oGVHD眼睛。在一项前后对照研究中，比较了角膜荧光素染色、睑缘血管化、睑板腺阻塞、睑脂浑浊、A区睑后缘血管化以及oGVHD诊断标准严重程度分级。随访时间为7至21周，中位时间为12周。使用STATA 17通过将数据拟合到非参数模型进行统计分析。
结果显示，在原代和永生化人角膜上皮中，治疗组油红O染色颗粒的数量和密度均高于对照组。结果表明，与未治疗的对照组相比，小鼠模型中角膜上皮BODIPY™ 信号增加。局部使用螺内酯治疗后，oGVHD患者的睑缘血管化（P = 0.046）、角膜荧光素染色（P = 0.021）和国际oGVHD共识小组严重程度评分（P = 0.011）均有所改善。观察到的不良反应最小，最常见的是滴眼后持续不到一分钟的轻微刺痛。
数周治疗后严重程度评分、睑缘炎症和角膜荧光素染色的改善支持了局部使用螺内酯可能对oGVHD有益的理论依据。角膜上皮观察到的脂质生成被认为有助于对oGVHD中眼表侵蚀性疾病的这种保护作用。作为一种盐皮质激素受体拮抗剂，螺内酯可能在oGVHD中提供治疗益处，同时避免局部或全身糖皮质激素的不良副作用。
