dry eye

The Vagaries of Dry Eye “Treatment”

Look closely at definitions. We may ask, “What, exactly, are we doing?”

Kelly Nichols, O.D., M.P.H., Ph.D.

Merriam-Webster (www.m-w.com) defines the verb “treat” as to act upon with some agent, especially to improve or alter. Medical dictionary definitions of the verb offer greater detail relative to the patient: to care for medicinally or surgically; to manage in the use of remedies or appliances; as, to treat a disease, a wound, or a patient; or to subject to some action; to apply something to; as, to treat with a substance.

Yet, to practitioners, “treatment” often indicates “prescription” and further, that “treatment” addresses the underlying pathophysiology of the condition, and is not considered solely palliative. So what are we doing in dry eye management, where the pathophysiology is not completely understood, few prescription options exist, and practitioners may start management with artificial tears or lubricants that are considered palliative?

Crystal clear, right?

To answer these questions, let's explore the definitions in detail:

To act upon with some agent…

In managing dry eye disease, current algorithms suggest we discuss medications, systemic history, environmental and diet factors (including omega-3 consumption), consider lid hygiene and initiate lubrication in mild cases of disease.

As disease severity increases, immune modulators are added (topical cyclosporine and topical steroid) to the “treatments” for mild disease. Severe dry eye warrants consideration of autologous serum, bandage or large diameter contact lenses, oral immunosuppressive therapies with the possibility of corneal stem cell or other lid-related surgical techniques.

Except for patient education, I believe all these options fall into the category of “some agent,” and thus could be considered a “treatment” in the most general sense of the term.

…especially to improve or alter.

Obviously, any application of an “agent” should improve the disease state. Interestingly, the definition does not answer the critical question—improve or alter what? In dry eye, the “what” could be the ocular surface, the eyelids, the tear film or any component of the tear film (e.g. protein or lipid).

What is less clear is the relative importance of each, as well as the order in which each of these components is affected in dry eye disease. For example, is a change in some component of the tear film the end result of the disease process, or is it the beginning, the “cause”? This differentiation is important for the selection of a “treatment,” as an agent impacting the underlying pathophysiology may be quite different from a therapy used to manage sequelae of the condition.

To care for medicinally or surgically; to manage in the use of remedies or appliances; as, to treat a disease, a wound, or a patient; or to subject to some action; to apply something to; as, to treat with a substance.

Beyond the wordiness of this definition lies the essence of the concept of treatment—the patient. At the end of the day, we treat patients. We merge what we know of a disease and the associated therapies with what we perceive the patient needs and/or will be able to adhere to. Therein is the quality that makes us medical professionals: We diagnose disease, rule out conditions, consider appropriate management approaches and discuss all this with a patient in an effort to help them get better.

The literature says…

To make the less-than-clear murkier, the concept of treating dry eye with just about everything has appeared in the literature during the past year. For example, a combined Medline search on the terms “treat” and “dry eye,” identifies 4,446 papers.

Refining the search to Medical Subject Headings, or MeSH, yields 2,845 papers, and limiting publication within the last year results in a manageable 134 papers. These papers describe the following as treatments for dry eye: artificial tears, cyclosporine, methotrexate, sub-mandibular gland transplantation, acupuncture, hydroxypropyl cellulose ophthalmic inserts, punctal occlusion with plugs, punctal stenosis with argon laser, intraductal meibomian gland probing, calorie restriction, hormone therapy, oral sea buckhorn oil (containing n-3 and n-6 fatty acids and antioxidants), omega fatty acid (n-3) supplementation, tear lipid substitutes, emulsions and liposomal sprays, sodium hyaluronate, and several investigational inflammatory modulators.

Broadening the search beyond the two terms “treat” and “dry eye” would yield even greater numbers of similar manuscripts. This information is valuable, yet the sheer volume of material and opposing views does little to aid us in finding the most appropriate algorithm for diagnosing and managing dry eye. This information overload may be helpful in the abstract, but in reality, it is a bit like the old saying, “everything but the kitchen sink.” Like I said, crystal clear.

“Treat the symptoms”

The impetus behind writing this column dedicated to the vagaries of dry eye “treatment” was a conversation I had recently on the topic of whether an artificial tear, or lubricant eye drop, could (not my words) “treat” anything. Well, can it? On the basis of the definitions above, it is an agent that acts upon the tear film, with the intent of improving or altering the tear film. The use of artificial tears is recommended in nearly every management scheme for dry eye across disease severity.

But while it is recommended, thus in some eyes deemed a “treatment,” does an artificial tear rise to the level of being medicinal? Interestingly, “medicinal” means “tending or used to cure disease or relieve pain” (m-w.com). “Cure” means recovery or relief from disease (also m-w.com). Have artificial tears been shown to alleviate symptoms (dryness, discomfort, pain) in dry eye disease? Yes. Can artificial tears provide relief from dry eye disease? Yes.

The last point worth arguing is that of whether artificial tears, or any other “treatment” for dry eye for that matter, can provide a recovery from dry eye disease.

An eye-opener

In clinical dry eye research, we often design studies that have end-points that are surrogate measures of disease improvement (e.g. an increase in fluorescein tear break-up time is a surrogate measure of improvement in tear film stability, and thus proposed to be a marker of overall “normalization” of the ocular surface).

This exercise of reviewing the terminology related to treatment and improvement in the case of dry eye disease has been very eye opening for me. It is easy to get caught up in the regulatory terminology and rules for “approval” of a therapeutic or over-the-counter agent for dry eye, as well as which “ingredients,” either active or inactive, are driving the changes seen in clinical studies.

The FDA and other regulatory agencies evaluate the clinical data presented and assess whether the data support a cure—recovery or relief from disease. Every now and then, it is worthwhile to step back and take an overview snapshot of the scene. The FDA of late has required statistically significant differences between the treatment and placebo arms in both a clinical sign as well as a symptom for dry eye disease. While challenging, this is very consistent with the definitions of both “medicinal” and “cure.”

It is our job as clinicians to identify what a “cure” means to a patient who has dry eye disease; and it is the job of those who work at pharmaceutical companies to develop products and design studies with the ultimate goal of addressing that need. And yes, this is a difficult and lofty goal, but I do believe we are all moving toward that goal. OM