他克莫司点眼治疗单纯疱疹病毒性盘状角膜基质炎的疗效及其对泪膜的影响

Efficacy of tacrolimus eyedrops topical application for herpes simplex disciform stromal keratitis and its influence on tear

背景 单纯疱疹病毒（HSV）盘状角膜基质炎是一种抗原和抗体在角膜基质层内引起的T细胞介导的迟发型超敏反应,以往的疗法是糖皮质激素联合抗病毒药物的局部应用,但不能耐受糖皮质激素的患者治疗效果不佳,且糖皮质激素的局部应用存在严重的不良反应.FK506滴眼液具有糖皮质激素的免疫抑制和抗炎作用,又不存在糖皮质激素的不良反应,但FK506滴眼液对HSV盘状角膜基质炎的疗效研究很少.目的 探讨他克莫司滴眼液治疗HSV盘状角膜基质炎的疗效、安全性及其对泪膜的影响.方法 在中山大学中山眼科中心伦理委员会批准和患者知情同意下,采用系列病例观察研究设计,纳入2011年6月至2012年6月在中山大学中山眼科中心确诊为活动期HSV盘状角膜基质炎的患者18例18眼,采用质量分数0.05％他克莫司滴眼液局部应用联合抗病毒药物局部和全身应用的方案进行治疗,平均用药（56.0±7.9）d,分别于治疗前、治疗后1个月、2个月以及停药时进行裂隙灯显微镜检查、基础泪液分泌试验（SⅠt）、泪膜破裂时间（BUT）测定和角膜荧光素染色检查,动态观察0.05％他克莫司滴眼液对HSV盘状角膜基质炎的疗效、不良反应及其对泪膜稳定性的影响.结果 患者治疗后角膜厚度开始下降的平均时间为（8.3±2.5）d,角膜水肿消失的平均时间为（25.3±11.5）d,水肿消退最慢的2例患者为糖皮质激素治疗无效者.治疗前、治疗后1个月、治疗后2个月及停药时角膜荧光素染色评分分别为4（6,2）、1（2,1）、1（1,0）和0（1,0）,差异有统计学意义（H=39.90,P＜0.001）,患者治疗后各时间点间角膜荧光素染色评分均明显低于治疗前,差异均有统计学意义（均P＜0.01）;患者治疗前后各时间点的SⅠt值分别为（6.78±1.90）、（7.39±3.53）、（8.06±2.92）和（8.11 ±3.05） mm/5 min,不同时间点SⅠt值的差异无统计学意义（F=0.90,P=0.43）;患者治疗前后各时间点BUT值分别为（0.39±0.50）、（1.11±0.90）、（2.00±1.08）和（3.39±0.92）s,各时间点的总体差异有统计学意义（F=34.54,P＜0.01）,治疗后各时间点的BUT值较治疗前均明显增加,差异均有统计学意义（均P＜0.00l）.18例患者中2例于停药后2个月和5个月复发,再次按相同方案治疗后治愈.治疗期间未发生眼压升高或继发感染等并发症.结论 眼局部应用他克莫司滴眼液联合抗病毒治疗可减轻HSV盘状角膜炎患者的角膜水肿并促进泪膜修复,并可用于糖皮质激素局部应用无效者或有糖皮质激素禁忌证患者.

Background Herpes simplex virus （HSV） disciform stromal keratitis is a T cell-mediated delayed-type hypersensitivity of corneal stroma.The treatment of HSV disciform stromal keratitis is the combination of glucocorticoid and antiviral drug before.However,the therapy is limited for intolerantble patients to glucocorticoid.In addition,the adverse reactions following usage of glucocorticoid can not be ignored.FKS06 solution is proved to has the immunosuppressive and antiinflammatory acttions with less side effects than glucocorticoid drug.But the study on the application of FK506 solution in treatment of HSV disciform stromal keratitis is lack.Objective This prospective clinical trail was to evaluate the efficacy of topical tacrolimus for HSV disciform stromal keratitis and its safety.Methods A prospective study was performed on 18 consecutive cases （18 eyes） who were diagnosed as active HSV disciform stromal keratitis from June 2011 to June 2012 in Zhongshan Ophthalmic Center under the approval of the Ethic Committee of Zhongshan Ophthalmic Center and informed consent of the patients,including 3 patients with refractory to prior steroid eyedrops.All patients received a combination topical tacrolimus eyedrops 4 times per day with topical and systemic anti-viral therapy for mean （56.0±7.9） days.Corneal thickness by slit lamp biomicroscope,visual acuity,intraocular pressure,corneal fluorescein staining,Schirmer Ⅰ test （S Ⅰ t） and tear breakup time （BUT） were performed on the patients before and 1 month,2 months after treatment and at the drug withdrawal to assess the treating efficacy of FK506,and the adverse reactions of eyes were recorded.Results Corneal edema was alleviated in （8.3 ± 2.5） days after treatment in all the patients and returned to normality in （25.3±11.5） days.Corneal edema of 2 eyes with refractory to previous steroid eyedrops showed a slower recovery procedure than that of the others.Corneal fluorescence staining scores were 4 （6,2）,1 （2,1）,1 （1,0） and 0 （1,0） before and 1 month,2 months and at drug withdrawal,respectively,with a significant difference among the four time points （H=39.90,P〈0.001）,and the scores were significantly lower after treatment than before （all at P〈0.01）.The S Ⅰ t values were （6.78±1.90）,（7.39±3.53）,（8.06±2.92） and （8.11±3.05） mm/5 min,respectively in the 4 time points,without statistically significant difference among various time points （F =0.94,P =0.43）.The BUT values were （0.39 ± 0.50）,（1.11 ± 0.90）,（2.00 ± 1.08） and （3.39 ± 0.92） seconds,respectively,showing a significant difference among the 4 time points （F=34.54,P〈0.01） and had the increased values after treatment of FK506.Recurrence was seen in 2 eyes in 2 months and 5 months after cessation of tacrolimus.However,the eyes were healed after a second round regimen.No elevation of intraocular pressure and secondary infection were found in the patients during the treatment and follow-up period.Conclusions The combination therapy of tacrolimus with antiviral drug is effective and safe for HSV disciform stromal keratitis by alleviating corneal edema and promoting the rehabilitation of tear film.