title: Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease.
abstract: 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).
  
  
  METHODS
  Biomarker substudy of a phase 1/2 prospective, randomized, vehicle- and comparator-controlled clinical trial (NCT00784719).
  
  
  METHODS
  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.
  
  
  METHODS
  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)-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).
  
  
  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.
authors.affiliation: Pfizer Inc, San Diego, California, USA. jingfenghuang@yahoo.com
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Huang
authors.forename: Rolla
authors.initials: R
authors.lastname: Yafawi
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: McDowell
authors.forename: Kay D
authors.initials: KD
authors.lastname: Rittenhouse
authors.forename: Frederick
authors.initials: F
authors.lastname: Sace
authors.forename: Shiao Hui Melissa
authors.initials: SH
authors.lastname: Liew
authors.forename: Scott R
authors.initials: SR
authors.lastname: Cooper
authors.forename: Eve H
authors.initials: EH
authors.lastname: Pickering
mesh_terms: D000287:Administration, Topical; D003228:Conjunctiva / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015798:HLA-DR1 Antigen / Q000378:metabolism; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D010880:Piperidines; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D013666:Tears / Q000378:metabolism
chemical_list: D016207:Cytokines; D015798:HLA-DR1 Antigen; D009883:Ophthalmic Solutions; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D016572:Cyclosporine; C479163:tofacitinib; D053616:Janus Kinase 3