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ENGLISH ABSTRACT
0.05%环孢素与0.1%他克莫司滴眼液治疗慢性oGVHD后患者眼表干眼相关指标及泪液炎症因子比较
马骄
申展
胡博浩
赵英涵
刘姝婉
吴蓉
彭荣梅
洪晶
作者及单位信息
·
DOI： 10.3760/cma.j.cn115989-20221008-00473
Comparison of ocular surface dry eye-related indices and tear cytokine levels in chronic ocular graft-versus-host disease patients after receiving topical treatment of 0.05% cyclosporine and 0.1% tacrolimus eye drops
Ma Jiao
Shen Zhan
Hu Bohao
Zhao Yinghan
Liu Shuwan
Wu Rong
Peng Rongmei
Hong Jing
Authors Info & Affiliations
Ma Jiao
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Shen Zhan
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Hu Bohao
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Zhao Yinghan
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Liu Shuwan
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Wu Rong
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Wu Rong is working at Department of Ophthalmology, Peking University Shenzhen Hospital, Shenzhen 518000, China
Peng Rongmei
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
Hong Jing
Department of Ophthalmology, Peking University Third Hospital, Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing 100191, China
·
DOI： 10.3760/cma.j.cn115989-20221008-00473
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摘要

目的比较0.05%环孢素与0.1%他克莫司滴眼液治疗慢性眼部移植物抗宿主病(oGVHD)后患者眼表干眼相关指标及泪液炎症因子的改变。

方法采用随机对照研究方法，纳入2020年4月至2021年4月于北京大学第三医院眼科确诊为慢性oGVHD的患者60例60眼，采用随机数字表法将患者分为他克莫司组30例30眼和环孢素组30例30眼。他克莫司组主要采用0.1%他克莫司滴眼液点眼，2次/日；环孢素组采用0.05%环孢素滴眼液点眼，4次/日。此外，2个组患眼均采用0.1%氟米龙滴眼液2次/日、小牛血去蛋白提取物眼用凝胶3次/日、0.1%玻璃酸钠滴眼液8次/日点眼，进行抗炎和润滑治疗。用药后1个月随访并依据排除标准筛选患者，最终将他克莫司组21例21眼和环孢素组12例12眼纳入后续研究。分别于治疗前、治疗后1个月对患眼进行检查，主要评价指标包括眼表疾病指数(OSDI)问卷评分、角膜荧光素钠染色评分和泪膜破裂时间(BUT)。采用Luminex芯片法检测患眼治疗前后泪液中白细胞介素(IL)-6、IL-8、IL-17、表皮生长因子(EGF)和肿瘤坏死因子-α(TNF-α)的质量浓度并进行组间比较。

结果他克莫司组和环孢素组治疗前后OSDI差值分别为0.4(－5.6，21.5)和27.2(4.6，45.0)，环孢素组OSDI改善程度明显优于他克莫司组，差异有统计学意义( Z＝－2.547， P＝0.009)。他克莫司组和环孢素组治疗前后角膜荧光素钠染色评分差值分别为5.0(2.5，10.0)分和3.5(－0.5，13.8)分，BUT差值分别为0.0(－3.0，0.0)s和－1.5(－3.0，0.0)s，组间比较差异均无统计学意义( Z＝－0.526、－0.804，均 P>0.05)。他克莫司组与环孢素组治疗前后IL-6、IL-8、IL-17、EGF和TNF-α表达量差值比较，差异均无统计学意义( Z＝－0.487、－0.112、－0.412、－1.085、－1.198，均 P>0.05)。

结论2种药物治疗慢性oGVHD后，患者泪液中各因子含量的改变程度均未见显著差异。慢性oGVHD患者应用0.05%环孢素滴眼液治疗可能比0.1%他克莫司滴眼液有更好的舒适度。

移植物抗宿主病;干眼;泪液;细胞因子;环孢素;他克莫司
ABSTRACT

ObjectiveTo compare ocular surface dry eye-related indexes and tear cytokine level changes in chronic ocular graft-versus-host disease (oGVHD) patients after receiving topical treatment of 0.05% cyclosporine or 0.1% tacrolimus eye drops.

MethodsA randomized controlled study was conducted.A total of 60 chronic oGVHD patients (60 eyes) were recruited at Beijing University Third Hospital from April 2020 to April 2021.The patients were divided into tacrolimus group and cyclosporine group by a random number table, with 30 patients (30 eyes) in each group.Patients in tacrolimus group used 0.1% tacrolimus eye drops (twice a day) and patients in cyclosporine group used 0.05% cyclosporine eye drops (4 times a day).Additionally, 0.1% flumetholon (twice a day), deproteinized calf blood extract (3 times a day), and 0.1% sodium hyaluronate eye drops (8 times a day) were applied for anti-inflammation and lubrication in both groups.Patients were screened according to exclusion criteria after 1-month treatment.Eventually, 21 patients (21 eyes) in tacrolimus group and 12 patients (12 eyes) in cyclosporine group were included for further study.Patients were examined before and 1 month after treatment.The primary evaluation indexes included Ocular Surface Disease Index (OSDI), corneal fluorescein staining scores and tear film break-up time (BUT).Expressions of interleukin (IL)-6, IL-8, IL-17, epidermal growth factor (EGF), and tumor necrosis factor-α (TNF-α) in tears were detected before and after treatment using Luminex chip.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Peking University Third Hospital (No.M2020489).Written informed consent was obtained from each subject before any medical examination.

ResultsThe OSDI differences between before and after treatment were 0.4(-5.6, 2.5) in tacrolimus group and 27.2(4.6, 45.0) in cyclosporine group, and the OSDI improvement was significantly greater in cyclosporine group than in tacrolimus group ( Z=-2.547, P=0.009).The differences of corneal fluorescein staining scores and BUT between before and after treatment were 5.0(2.5, 10.0) scores and 3.5(-0.5, 13.8) seconds in tacrolimus group, 0.0(-3.0, 0.0) scores and -1.5(-3.0, 0.0) seconds in cyclosporine group, respectively, with no significantly difference between both groups ( Z=-0.526, -0.804; both at P>0.05).The differences of IL-6, IL-8, IL-17, EGF and TNF-α expressions between before and after treatment in tacrolimus group and cyclosporine group were not significantly different ( Z=-0.487, -0.112, -0.412, -1.085, -1.198; all at P>0.05).

ConclusionsAltered levels of all tested cytokines in oGVHD tears are of no significant differences between tacrolimus and cyclos porine treatment.In addition, 0.05% cyclosporine eye drops may be more comfortable than 1% tacrolimus for chronic oGVHD patients.

Graft vs host disease;Dry eye syndromes;Tears;Cytokines;Cyclosporine;Tacrolimus
Hong Jing, Email: mocdef.3ab61104691gnijgnoh
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引用本文

马骄,申展,胡博浩,等. 0.05%环孢素与0.1%他克莫司滴眼液治疗慢性oGVHD后患者眼表干眼相关指标及泪液炎症因子比较[J]. 中华实验眼科杂志,2023,41(10)：980-984.

DOI:10.3760/cma.j.cn115989-20221008-00473

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同种异体造血干细胞移植术(hematopoietic stem cell transplantation，HSCT)是目前治疗多种血液系统恶性肿瘤的有效手段，慢性移植物抗宿主病(graft-versus-host disease，GVHD)是异基因HSCT术后的常见并发症，发生率为30%~70%，主要由供体淋巴细胞受激活攻击宿主靶器官引起 [ 1 , 2 , 3 ]。慢性GVHD主要表现为长期的慢性炎症过程，其表现类似于干燥综合征、类风湿性关节炎等自身免疫性疾病 [ 4 , 5 ]。60%~90%慢性GVHD患者可发生眼部GVHD(ocular GVHD，oGVHD)，造成角结膜组织炎症、泪腺纤维化、睑板腺萎缩等多种眼表组织损害 [ 6 , 7 ]，主要临床症状为眼干、眼红、眼痛、畏光、有异物感等，若不及时治疗可能会发展为角膜炎、角膜溃疡或穿孔，严重者导致视力下降，甚至盲 [ 8 , 9 , 10 ]。目前，oGVHD尚缺乏规范的临床治疗方案，主要治疗原则为润滑眼表和控制炎症，如采用人工泪液、生长因子类药物滴眼液点眼以缓解干眼症状并保护眼表组织的结构完整性和功能，同时局部应用糖皮质激素或联合免疫抑制剂控制慢性炎症过程 [ 11 , 12 , 13 ]。临床实践中发现，大部分患者经过1个月的治疗后干眼及眼表炎症可明显缓解，但部分患者治疗后症状改善不明显，甚至加重。钙调磷酸酶抑制剂他克莫司和环孢素滴眼液是oGVHD常用的免疫治疗药物，然而，由于oGVHD患者发病情况比较复杂，这2种药物所适应的oGVHD患者是否存在差异，以及造成这种差异的潜在机制尚不明确，而针对不同oGVHD患者的具体情况用药对提高疗效具有重要临床意义。慢性oGVHD病理过程受多种免疫细胞及相关炎症因子调节，检测患者泪液中特定的炎症因子是监测慢性oGVHD病情变化、研究相关病理机制的可行方法 [ 14 ]。近年来，随着微量蛋白检测技术的进步，泪液炎症因子检测已成为研究oGVHD的重要手段。多项研究表明，泪液中白细胞介素(interleukin，IL)-2、IL-6、IL-8、IL-10、IL-17、肿瘤坏死因子α(tumor necrosis factor-α，TNF-α)、表皮生长因子(epidermal growth factor，EGF)等含量的改变有助于预测慢性oGVHD的发生，此外IL-6、IL-8、IL-10、TNF-α等炎症因子含量变化程度有助于判断慢性oGVHD的严重程度 [ 15 , 16 , 17 , 18 , 19 , 20 ]。本研究团队在前期研究中也发现，泪液中IL-6和IL-8含量的改变与慢性oGVHD的治疗效果有关 [ 21 ]。因此我们推测，泪液中炎症因子含量的动态改变或有助于揭示影响他克莫司和环孢素滴眼液治疗慢性oGVHD效果的分子机制。本研究拟比较采用1%他克莫司滴眼液和0.05%环孢素滴眼液治疗慢性oGVHD患者干眼相关指标及泪液炎症因子的不同变化，探讨影响oGVHD对不同治疗药物反应的因素，为临床上oGVHD治疗的药物选择及预后评估提供参考依据。
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备注信息
A
洪晶，Email： mocdef.3ab61104691gnijgnoh
B

马骄：设计试验、实施研究、采集数据、分析/解释数据、文章撰写；申展、胡博浩、赵英涵、刘姝婉、吴蓉：实施研究、采集数据；彭荣梅：实施研究、采集数据、指导试验；洪晶：酝酿和设计试验、实施研究、对文章的知识性内容作批判性审阅及定稿

C
所有作者均声明不存在利益冲突
D
国家自然科学基金项目 (81970768)
北京白求恩公益基金项目 (BJ-GY2021003J)
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