Cyclosporine beneficial for treating patients with dry eye

May 1, 2008

Cyclosporine 0.05% ophthalmic emulsion (Restasis, Allergan) is beneficial for treating patients with dry eye because it increases goblet cell density and production of transforming growth factor ?2, an immunoregulatory factor, compared with artificial tear formulations, which do not.

Key Points

Houston-Cyclosporine 0.05% ophthalmic emulsion (Restasis, Allergan) is beneficial for treating patients with dry eye because it increases goblet cell density and transforming growth factor (TGF)-ß2 production compared with artificial tear formulations, which do not.

Reduced conjunctival goblet cell density is a substantial component of chronic dry eye, and a treatment that reverses that process is an obvious boon for patients. In addition, TGF-ß2, an important immunoregulatory factor, is secreted by goblet cells.

Tear formulations have been the mainstay of treatment for patients with dry eye but do not have an effect on goblet cell density, in contrast to treatment with cyclosporine 0.05%, which was found to be associated with increased goblet cell density. Increased goblet cell density has also been associated with decreases in punctate corneal fluorescein staining, blurred vision, and use of artificial tears in patients concomitantly treated with cyclosporine 0.05%.

Six patients (five women, one man; mean age, 56.6 years) with diagnosed dry eye disease participated in their study. Before the study, patients had used various tear formulations (Refresh Plus, Allergan, n = 2; Systane, Alcon Laboratories, n = 2; TheraTears, Advanced Vision Research, n = 1; Genteal, Novartis, n = 1. Upon entrance into the study, the patients instilled one artificial tears formulation (Refresh Plus), four times daily for 4 weeks and then cyclosporine 0.05% twice daily for 12 weeks. Impression cytology was performed bilaterally on the bulbar conjunctiva at baseline, after treatment with artificial tears, and following 6-and 12-week treatment with cyclosporine, and the goblet cells were counted. The membranes from the fellow eye were stained for TGF-ß2.

"After 4 weeks of use of the study artificial tears, no differences in mean goblet cell density were found in temporal and inferior bulbar specimens compared with baseline. However, after 6 weeks of treatment with topical cyclosporine 0.05% ophthalmic emulsion twice a day, the goblet cell density increased by 4.1-fold and 3.1-fold in the temporal and inferior bulbar conjunctiva, respectively, relative to the levels found after treatment with artificial tears only," the investigators reported.

The difference in goblet cell density from baseline in the inferior bulbar conjunctiva reached statistical significance (p < 0.01).

Twelve weeks after the beginning of treatment with cyclosporine, the goblet cell density in the temporal and inferior bulbar conjunctiva increased by 2.8-fold and 3.1-fold, respectively, compared with artificial tear treatment (p < 0.01).

The number of goblet cells that were positive for TGF-ß2 increased after 6 and 12 weeks of therapy with cyclosporine, the investigators reported.

They said, "The findings indicate that cyclosporine inhibits the pathologic mechanisms leading to reduced conjunctival goblet cell density in chronic dry eye disease. In addition to the observed increase in goblet cell density, there was a change in appearance of the conjunctival epithelial cells from loosely adherent larger cells to more tightly adherent sheets of small cells.''

Dr. Pflugfelder and colleagues also cited another important finding, i.e., "the goblet cells function like the lacrimal glands in secreting growth factors into the tear.''

They explained that in a murine model, goblet cells in the conjunctiva produce and secrete TGF-ß2, the same as in humans in this study, and that TGF-ß2 increased after treatment with cyclosporine.

"The implications of normalizing TGF-ß2 concentrations in the tears as a result of cyclosporine therapy have not been determined; however, TGF-ß has been found to have many immunoregulatory effects, including inhibition of lymphocyte proliferation," the authors said.

"It is increasingly clear that normalization of the ocular surface in dry eye requires regeneration of conjunctival goblet cells. Cyclosporine emulsion is the only therapeutic agent thus far that has been demonstrated to have this effect," Dr. Pflugfelder concluded.