Ocular Surface Inflammation: A New Era in Therapy

With the addition of dermatologic creams for atopic disease, oral leukotriene blockers for allergic diseases, and a multitude of systemic medicines, ophthalmologists today have at their disposal a variety of therapies to safely and effectively combat ocular inflammation, which has long held a significant position in the realm of ocular pathophysiology. While the role of inflammation in ocular diseases such as mucous membrane pemphigoid and atopic keratoconjunctivitis is not in doubt, it is now believed that dry eye or the broader category of “dysfunctional tear syndrome” involves some degree of inflammation. As the understanding of ocular inflammation has expanded, so too has the availability of treatment options. Indeed, the modern ophthalmologist has an ever growing armamentarium of agents to treat the patient with ocular inflammatory disease, and many conditions that could only be treated with corticosteroids previously can now be controlled with minimal adverse effects.

Current and Emerging Options for Ocular Allergic Diseases

Topical antihistamines and mast-cell stabilizers provide multiple treatment options for common ocular surface disorders such as atopic and allergic conjunctivitis, and many patients experience adequate relief with these agents. No single agent is predictably more effective than the others, so a trial-and-error approach is often required within this class. However, for patients with severe disease who are resistant to standard therapy or dependent on corticosteroids, the ophthalmologist must pursue other interventions.

Dermatologists have reported excellent results with topical tacrolimus (Protopic 0.1%) and pimecrolimus (Elidel) for atopic dermatitis. While ophthalmic application of these skin creams is not as well studied, there are reports of dramatic improvement in patients with atopic dermatitis of the eyelids treated with these agents, with no evidence of elevated intraocular pressure or systemic side effects (Am J Ophthalmol. 2003;135:297-302). Montelukast sodium (Singulair), an oral leukotriene antagonist which has gained increasing use for the treatment of seasonal allergies and asthma, may also be effective in patients with vernal keratoconjunctivitis (Arch Ophthalmol. 2003;121:615-620).

Immunosuppresive and Biologic Drug Treatments

Even though the treating ophthalmologist may feel uncomfortable managing patients on immunosuppresive medications, it is important to know that such drugs offer relatively safe and effective treatment of severe ocular inflammatory disorders. Patients will be better served by treatment with a properly managed immunosuppressive agent than by long-term corticosteroids or inadequate treatment. Given the known toxicity of systemic corticosteroids and the high risk of visual loss with inadequately treated ocular inflammation, ophthalmologists should have a low threshold for recommending the use of steroid-sparing immunosuppressive agents.

In those patients with severe atopic disease, systemic cyclosporine A has been used at doses lower than typically required for transplant rejection prophylaxis. While this is often effective, the potential for adverse effects has prompted many ophthalmologists to limit its use. A newer antimetabolite, mycophenolate mofetil (Cellcept, Roche), has been reported as efficacious in patients with recalcitrant atopic disease. This drug may be particularly attractive in patients with renal disease, in whom cyclosporine is contraindicated, and in patients undergoing high-risk penetrating keratoplasty (Transpl Int. 2005;18:703-708). Cellcept has also been reported as a treatment for other ocular inflammatory diseases; several recent case series have documented its efficacy as a treatment for mucous membrane pemphigoid, scleritis, and uveitis (Ophthalmology. 2005;112:1472-1477).

Although the inflammation of most patients can be controlled with antimetabolites such as methotrexate, azathioprine, or mycophenolate mofetil, multiple options are available to the patient refractory to these medications. Infliximab (Remicade), a humanized antibody that blocks the actions of tumor necrosis factor alpha (TNF-a), has been used with success in scleritis, peripheral ulcerative keratitis, and uveitis. In addition to the risk of infection inherent in all immunosuppressive medicines, infliximab appears to carry a particular risk of reactivating latent tuberculosis; because of this, patients should have a purified protein derivative (PPD) skin test as well as a chest x-ray prior to initiating therapy.

Daclizumab (Zenapax), a humanized anti-IL2 receptor antibody, has also been used in various ocular inflammatory diseases. A possible limitation of daclizumab is that it may prevent tolerance from developing, due to its inhibition of suppressor T cells. Despite this drawback, in the future daclizumab may be an attractive alternative to alkylating agents such as cyclophosphamide and chlorambucil, especially in younger patients of child-bearing age.

The Next Frontier in Dry Eye Therapy

In medicine, it is often said that the more common a disease is, the less is known about it. Until recently, this applied to the dry eye syndrome. However, with a better understanding of the physiology of the ocular surface and the pathophysiology of the dysfunctional tear states, advanced therapies have become available. The most well-known of these is cyclosporine A 0.05% (Restasis, Allergan). While it may not be the “silver bullet” that doctors and patients have been looking for, it is another tool to assist in the care of dry eye patients. Cyclosporine A 0.05% has also been utilized in a small series of patients with steroid-dependent atopic keratoconjunctivitis (Ophthalmology. 2004;111:476-482), corroborating previous reports of success with cyclosporine A 1% or 2% ophthalmic drops.

Given the current feeling that inflammation plays a role in abnormal tear production, it would seem rational that corticosteroids could be of benefit. Many cornea specialists now use less potent steroids such as loteprednol etabonate 0.5 % or fluorometholone 0.1% intermittently for their dry eye patients, and there is some recent data to support the use of these agents (Am J Ophthalmol. 2004;138:444-457). Dietary supplements containing omega-3 fatty acids, including flaxseed and fish oils, have been used for various dysfunctional tear states. These may have a beneficial effect on ocular surface inflammation and tear production. However, like many of the promising therapies on the horizon, conclusive evidence regarding their use awaits larger prospective trials.

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Author Disclosure

The author states that he has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.