Topical cyclosporine: effective for more than just dry eye

Issue: July 2004

ByMarc D. Myers, OD, FAAO

ByAndrew S. Gurwood, OD, FAAO

Andrew S. Gurwood, OD, FAAO [photo] Andrew S. Gurwood, OD, FAAO, is an associate professor of clinical sciences and an attending optometric physician at The Eye Institute of the Pennsylvania College of Optometry. He is also a member of the clinical staff in the Department of Ophthalmology at Albert Einstein Medical Center in Philadelphia. Dr. Gurwood can be reached at the Pennsylvania College of Optometry, 1200 West Godfrey Ave., Philadelphia, PA 19141; (215) 276-6134; fax: (215) 276-1329; e-mail: Agurwood@pco.edu. Dr. Gurwood has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

When Restasis (cyclosporine 0.05%, Allergan) was approved by the Food and Drug Administration in December 2002, it was touted as being among the first medications to treat the cause of dry eye. Its mechanism allows for increasing lacrimation in patients whose tear production is presumed suppressed secondary to ocular inflammation associated with the condition known as keratoconjunctivitis sicca (KCS).

When compared to topical corticosteroids, which are also immunosuppressants, topical cyclosporine is considered to be safer. It is documented to have decreased/absent association with increasing intraocular pressure, minimal to no association with delayed wound healing and negligible association with cataractogenesis (Jannus and Lesher, 1995; Donnenfeld and Perry, 2003).

Other uses

In addition to its use in cases of dry eye, cyclosporine has been acknowledged as a treatment for contact lens-intolerant patients (Albietz, Napper and Douglas, 2003). These patients are classically peri-menopausal women in their late 40s to early 50s who are unable to tolerate soft contact lens wear. These patients traditionally see the clinician after having attempted to use various topical rewetting drops and gels, both in and out of the presence of punctal occlusion. Topical cyclosporine has been acknowledged as a potential treatment to control surface physiology, re-establish the tear film and create the healthy contact lens environment conducive to successful wear.

Vernal keratoconjunctivitis, eczema, atopic keratoconjunctivitis and allergic conjunctivitis are all common inflammatory anterior segment diseases. Typical management of these sometimes recalcitrant forms of allergic inflammation may involve the use of topical mast-cell stabilizers, topical and oral antihistamines, topical nonsteroidal anti-inflammatory preparations and topical steroidal agents. It is believed that topical cyclosporine may be effective in controlling the disease process in these cases by producing a stabilizing effect on conjunctival mast cells or by enabling an inhibitory effect against the release of interleukins and retarding the expansion of T-helper-induced lymphocytes (Jannus and Lesher, 1995; Donnenfeld and Perry, 2003; Albietz, Napper and Douglas, 2003; Dept. of Medicine, Pediatrics and Ophthalmology, 2001; Friedlaender, 1998).

Researchers presenting at ARVO 2003 reported that topical cyclosporine produced improvement in the signs and symptoms associated with posterior blepharitis (meibomian gland dysfunction). Dosing twice daily for 3 months demonstrated a statistically significant reduction in meibomian gland occlusions, telangiectasia and corneal staining (Perry, Doshi, Donnenfeld, Bisher and Bloom, 2003).

A small sample size of patients with Theodore’s superior limbic keratoconjunctivitis (SLK) were also treated with topical cyclosporine A 0.5% drops, four times daily in both eyes, as primary or adjunctive therapy after treatment failure using prednisolone acetate 1% drops and topical silver nitrate 0.5% application (Perry, Doshi-Carnevale, Donnenfeld and Kornstein, 2003). These patients showed long-term (6 months to 3 years) improvement of irritation and foreign body sensation, as well as improvement of injection and filamentary keratitis. This study suggested that topical cyclosporine 0.5% can serve as a primary or adjunctive therapy for SLK. It further suggests that the agent deserves consideration as a maintenance drug to prevent recurrence.

How it works

Topical cyclosporine is an immunomodulator that possesses clinical efficacy in the presence of an excellent safety profile. It acts as a selective T-cell immunosuppressive agent. T-cells are lymphocytes (white blood cells) that allow the immune system to protect against viral infections. They also assist other cells in the fight against bacterial and fungal infections, aid in antibody production and assist in the response to cancers as well as play a role in coordinating the activities of other cells within the immune system.

The two main types of lymphocytes are B-cells and T-cells. B-cells are created by and mature in the bone marrow (hence the “B” for bone). T-cells are created in bone marrow but mature in the thymus gland (hence the “T” for thymus).

T-cells are divided into three groups: helper T-cells (also called T4 or CD4+ cells) that help other cells destroy infectious organisms, suppressor T-cells (also called T8 or CD8+ cells) that help suppress the activity of other lymphocytes so they don’t destroy normal tissue and killer T-cells (also called cytotoxic T lymphocytes or CTLs) that recognize and destroy abnormal or infected cells.

Some cases of dry eye are thought to be the result of errant autoimmune signals that cause T-cells to attack lacrimal gland tissues. These tissues secrete inflammatory mediators that bathe and damage the ocular surface. Cyclosporine, a powerful T-cell modulator, inhibits the T-lymphocytes from producing the toxic mediators. By preventing the activation of the T-cells, cyclosporine eliminates the source of the cyclic tear gland tissue destruction and release of chemical mediators that lead to the patient’s signs and symptoms.

First in IV form

Before the inception of Restasis, ophthalmic practitioners desiring to pursue this modality of treatment, for any number of anterior segment diseases, had to use generic intravenous cyclosporine in an off-label fashion (Kann and Ozden, 1993; Jannus and Lesher, 1995; Donnenfeld and Perry, 2003). The medication had to be ordered from pharmacies familiar with preparing a fortified ophthalmic cyclosporine 2% solution. An additional obstacle was that, frequently, insurers would not pay for the non-formulary preparation, placing the burden of cost on the patient. Further, because these pharmacologically fabricated fortified cyclosporine preparations were non-preserved, they had short shelf lives and were uncomfortable when topically instilled in the eye.

Veterinary uses of topical preparation

Veterinary medicine was among the first to discover the advantages of using the topical preparation, putting cyclosporine in service to manage numerous canine and feline eye disorders. The agent generated interest in the veterinary community when it was discovered to have adjunct properties for relieving the signs and symptoms associated with dry eye in dogs.

KCS is a common problem in small breed dogs because tear production becomes sacrificed during the development of the animal’s immune-mediated inflammation cascade within the tear glands. A commercial cyclosporine 0.2% ointment (Optimmune, Schering-Plough) was introduced and was found to be effective in approximately 85% of KCS-suffering canines. Topical cyclosporine has also been used in the treatment of animal atopic dermatitis (Whitley and Gilger, 1999).

Cyclosporine use in people

In people, the management of dry eye brings many clinical challenges. Most topical interventions take aim at reducing symptoms. Oral supplements and punctal occlusion represent a second level of increasingly complex solutions. Restasis represents a prepackaged, ready-made, properly and sterilely prepared, non-preserved alternative for interrupting the cycle of T-lymphocyte activity. This limits the local cell damage associated with the cascade of events involved with KCS that lead to the root cause of many cases of dry eye.

Interestingly, because lymphocytes live in the body for approximately 110 days, it takes 3 to 6 months to see maximal effects, although many patients begin to experience results within the first month of therapy. Activated lymphocytes must be removed from the lacrimal gland tissues for optimal response and recovery of normal function. Cyclosporine does not turn off the function of the lymphocytes once they have already been activated. Instead, it prevents additional lymphocytes from joining the fray.

While many patients report early relief from Restasis, some of the immediate quelling of symptoms is secondary to the active element of the delivery vehicle (Refresh Endura Emulsion — glycerin, castor oil and polysorbate). It should be noted that in clinical trials Restasis demonstrated improvement in Schirmer’s score and some signs and symptoms of dry eye beyond the vehicle as early as 1 month, according to Allergan. Proper treatment requires continued use to achieve the full therapeutic effect. Patients should be appropriately educated. In the event of severe disease and discomfort, patients may be instructed to supplement their regimen with traditional artificial tears, excluding Refresh Endura.

Contraindications and warnings

Along with being contraindicated in patients with known hypersensitivity, topical cyclosporine should be avoided in patients with active ocular infections. Specific warnings allude to a lack of evidence of effect, pro or con, in cases of or in those with a history of herpes simplex virus keratitis.

As topical cyclosporine gains greater acceptance in the treatment of dry eye syndrome, clinicians and patients may benefit from an expanded role. Further trials in areas of common inflammatory processes involving the anterior segment may result in additional indications for this prepared formulation whose therapeutic value has been long recognized.

For Your Information:
Marc D. Myers, OD, FAAO, is a staff optometrist in the southern New Jersey area in an ocular disease and refractive surgery practice. He completed a primary care residency at the Eye Institute of the Pennsylvania College of Optometry. He can be reached at (856) 691-8188. Dr. Myers has no direct financial interest in the products mentioned in the article, nor is he a paid consultant for any companies mentioned.

Restasis is available from Allergan, PO Box 19534, Irvine, CA 92623; (714) 246-4500; fax: (714) 246-4971; Web site: www.allergan.com.

Contact Editor@PCONSuperSite.com for references.