Dry Eye Disease May Respond to New Topical Treatment

Lara C. Pullen, PhD

May 31, 2012

May 31, 2012 — Tofacitinib, a topical ophthalmic Janus kinase (JAK) inhibitor, may be effective in patients with dry eye disease (DED), according to a new study. Treatment for 8 weeks resulted in a reduction of cell surface HLA-DR expression, as well as a reduction in tear levels of proinflammatory cytokines and inflammatory markers.

Previous studies have implicated the proinflammatory Th1 and Th17 cells in DED pathogenesis. Jing-Feng Huang, PhD, and colleagues at Pfizer Inc, San Diego, California, published the results of the biomarker substudy of a phase1/2 clinical trial online May 18 in Ophthalmology. This exploratory substudy is the first to demonstrate tofacitinib-mediated JAK inhibition modulating inflammation in patients.

Stephen Pflugfelder, MD, from Baylor College of Medicine in Houston, Texas, and a clinical correspondent with the American Academy of Ophthalmology, reviewed the study for Medscape Medical News and commented via email. "This new class of anti-inflammatory drug...produced significant reductions in tear and conjunctival inflammatory biomarkers in a relatively small pilot clinical trial. [The investigators] suggest that this drug may effectively inhibit dry eye–associated ocular surface inflammation. However, they didn't report how this correlated to changes in clinical signs and symptoms."

The authors measured conjunctival impression cytology (IC) and collected tear fluids from the same eyes before and after 8 weeks of treatment (doses of 0.0003%, 0.001%, 0.003%, or 0.005% tofacitinib twice daily or 0.005% once daily intraocularly). The study included 82 patients (81 completed the study), 65 of whom had IC samples and 64 of whom had tear samples that met the analytic criteria at baseline.

HLA-DR levels were quantified using flow cytometric plots of conjunctival epithelial cells (as determined by gating based on forward and side scatter).

At week 8, the authors observed a decrease in conjunctival cell surface expression of HLA-DR in patients treated with tofacitinib 0.005% once daily (71% of baseline) and 0.003% twice daily (67% of baseline) compared with 133% of baseline in patients treated with vehicle (P = .023 and P = .006 when compared with vehicle). The active comparator (cyclosporine ophthalmic emulsion 0.05%) did not suppress HLA-DR expression.

Tear fluids, collected at baseline and at the end of the 8-week treatment period, were also analyzed for concentrations of cytokines and inflammatory markers. The authors noted promising modulation of tear fluid levels of matrix metalloproteinase (MMP)-9 and MMP-3, as well as the proinflammatory cytokines IL-1β, IL-17, and IL-12 in the tofacitinib 0.005% once-daily group when compared with baseline.

MMP-3 levels in tears were reduced from baseline at week 8 (40% of baseline; P = .035); the vehicle group showed 77% of baseline (P > .20). IL-1β in tears was 36% of baseline (P = .053) in the tofacitinib 0.005% once-daily group and 95% of baseline (P > .20) in the vehicle group.

The authors reported no significant association between clinical signs and symptoms and tear protein markers or expression of HLA-DR as seen by IC. There was, however, a correlation between the changes in HLA-DR and the tear inflammation markers (P < .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).

The authors hypothesize that the result is because of a local effect, as opposed to a systemic effect, of tofacitinib because of the relatively low dosage administered in the eye.

When contacted to comment on the article, Pfizer issued a statement via email: "Tofacitinib, formerly known as CP-690,550, is a novel, oral [JAK] inhibitor that has been explored in a broad clinical development program for a wide variety of conditions, including a topical formulation for dry eye disease. Pfizer believes the findings from our Phase 2 study in patients with dry eye disease are promising and we are currently evaluating the results."

All authors were employees of Pfizer Inc at the time of the study. Dr. Pflugfelder is a consultant for Allergan, GSK, Bausch and Lomb, and Alcon. He also receives research funding from Allergan and GSK.

Ophthalmology. Published online May 18, 2012. Abstract

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