Immunomodulatory Effect of the Topical Ophthalmic Janus Kinase Inhibitor Tofacitinib (CP-690,550) in Patients with Dry Eye Disease

被引:52
作者
Huang, Jing-Feng [1 ]
Yafawi, Rolla [1 ]
Zhang, Min [1 ]
McDowell, Michael [2 ]
Rittenhouse, Kay D. [1 ]
Sace, Frederick [1 ]
Liew, Shiao Hui [3 ]
Cooper, Scott R. [1 ]
Pickering, Eve H. [2 ]
机构
[1] Pfizer Inc, San Diego, CA USA
[2] Pfizer Inc, Groton, CT 06340 USA
[3] Pfizer Inc, Collegeville, PA USA
关键词
FLOW-CYTOMETRIC ANALYSIS; ACTIVE RHEUMATOID-ARTHRITIS; DYSFUNCTIONAL TEAR SYNDROME; INFLAMMATORY MARKERS; IMPRESSION CYTOLOGY; INADEQUATE RESPONSE; EPITHELIAL-CELLS; PLACEBO; TH17; AUTOIMMUNITY;
D O I
10.1016/j.ophtha.2012.03.017
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
Objective: 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). Design: Biomarker substudy of a phase 1/2 prospective, randomized, vehicle- and comparator-controlled clinical trial (NCT00784719). Participants: A total of 82 patients with moderate to severe DED enrolled. Methods: 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. Main Outcome Measures: Reduction in inflammation assessed by change from baseline in conjunctival cell surface level of HLA-DR and tear level of cytokines and inflammation markers. Results: 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)-1 beta 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-1 beta (r = 0.46), IL-12p70 with IL-1 beta (r = 0.90), and IL-17A with MMP-9 (r = 0.82). Conclusions: 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. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012;xx:xxx (C) 2012 by the American Academy of Ophthalmology.
引用
收藏
页码:e43 / e50
页数:8
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