Pfizer Inc, San Diego, California, USA.
Ophthalmology. 2012 Jul;119(7):e43-50. doi: 10.1016/j.ophtha.2012.03.017. Epub 2012 May 18.
To evaluate the immunomodulatory effect of topical ophthalmic tofacitinib (CP-690,550) after an 8-week treatment period in patients with dry eye disease (DED).
Biomarker substudy of a phase 1/2 prospective, randomized, vehicle- and comparator-controlled clinical trial (NCT00784719).
A total of 82 patients with moderate to severe DED enrolled.
Patients received 1 of 5 doses of tofacitinib (0.0003%, 0.001%, 0.003%, or 0.005% twice daily [BID] or 0.005% once daily [QD]), active comparator (cyclosporine ophthalmic emulsion, 0.05% [Restasis, Allergan Inc., Irvine, CA]), or vehicle control BID for 8 weeks. Conjunctival impression cytology and tear fluid samples were collected at baseline and after an 8-week treatment period. Conjunctival cells were analyzed by flow cytometry for human leukocyte antigen DR-1 (HLA-DR). Tear fluids were analyzed by microsphere-based immunoassays for tear levels of cytokines and inflammation markers.
Reduction in inflammation assessed by change from baseline in conjunctival cell surface level of HLA-DR and tear level of cytokines and inflammation markers.
At week 8, a decrease in conjunctival cell surface expression of HLA-DR was observed in patients treated with tofacitinib 0.005% QD and 0.003% BID: 71% and 67% of baseline, respectively, compared with 133% of baseline in patients treated with vehicle (P=0.023 and P=0.006, compared with vehicle, respectively). Matrix metalloproteinase (MMP)-3 in tears was reduced from baseline at week 8 (40% of baseline, P=0.035) in the tofacitinib 0.005% QD group, whereas the vehicle group showed 77% of baseline (P>0.20). Interleukin (IL)-1β in tears was 36% of baseline (P=0.053) in the tofacitinib 0.005% QD group and 95% of baseline (P > 0.20) in the vehicle group. Several other cytokines and inflammation markers in tears, including MMP-9, IL-15, IL-17A, and IL-12p70, were markedly reduced in the tofacitinib 0.005% QD group but not the vehicle group. There was an association between the changes in HLA-DR and the tear inflammation markers (P<0.05): HLA-DR with IL-12p70 (r=0.49) and IL-1β (r=0.46), IL-12p70 with IL-1β (r=0.90), and IL-17A with MMP-9 (r=0.82).
Topical ophthalmic tofacitinib may act as an immunomodulator in patients with DED. Treatment for 8 weeks showed a promising reduction of conjunctival cell surface HLA-DR expression and tear levels of proinflammatory cytokines and inflammation markers.
评估 8 周治疗期后局部眼用托法替尼（CP-690,550）对干眼症（DED）患者的免疫调节作用。
一项为期 1/2 期、前瞻性、随机、载体和对照临床试验（NCT00784719）的生物标志物子研究。
共纳入 82 例中重度 DED 患者。
患者接受 1 种剂量的托法替尼（0.0003%、0.001%、0.003%或 0.005%，每日 2 次[BID]或 0.005%，每日 1 次[QD]）、阳性对照（环孢素眼用乳液，0.05%[Restasis，Allergan Inc.，Irvine，CA]）或载体对照 BID，共 8 周。基线和 8 周治疗后采集结膜印迹细胞学和泪液样本。通过流式细胞术分析结膜细胞表面 HLA-DR 的水平。通过基于微球的免疫分析测定泪液中细胞因子和炎症标志物的水平。
通过比较基线时 HLA-DR 水平和泪液中细胞因子和炎症标志物水平的变化，评估炎症的减少。
在第 8 周，与接受载体治疗的患者相比，接受托法替尼 0.005%QD 和 0.003%BID 治疗的患者的结膜细胞表面 HLA-DR 表达下降：分别为 71%和 67%，基线水平为 133%（与载体相比，P=0.023 和 P=0.006）。托法替尼 0.005%QD 组第 8 周 MMP-3 水平较基线降低（基线的 40%，P=0.035），而载体组为 77%（P>0.20）。托法替尼 0.005%QD 组第 8 周泪液中 IL-1β水平为基线的 36%（P=0.053），而载体组为 95%（P>0.20）。托法替尼 0.005%QD 组还显著降低了泪液中的几种其他细胞因子和炎症标志物，包括 MMP-9、IL-15、IL-17A 和 IL-12p70，但载体组没有。HLA-DR 与 IL-12p70（r=0.49）和 IL-1β（r=0.46）、IL-12p70 与 IL-1β（r=0.90）、IL-17A 与 MMP-9（r=0.82）之间存在相关性（P<0.05）。
局部眼用托法替尼可能对 DED 患者具有免疫调节作用。8 周的治疗可显著降低结膜细胞表面 HLA-DR 表达和泪液中促炎细胞因子和炎症标志物的水平。
