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MICHAEL A. LEMP
O
(DED) and the prospects for the development of new VER THE LAST TWO DECADES, SUBSTANTIAL
therapies. progress has been made in understanding the
DESIGN: Analysis and clinical perspective of the liter- structural elements of the tear film, ocular sur-
ature and recent presentations. face, and the associated tissues that form a single inte-
METHODS: Review and interpretation of literature. grated unit termed the lacrimal functional unit.1 This
RESULTS: The tear film and ocular surface form an information has led to revised concepts about the way in
integrated physiologic unit linking the surface epithelia which the tear film is formed and maintained and the
and secretory glands via a neural network. This sensory- pathophysiologic events operative in the development of
driven network regulates secretory activity in quantity dry eye. In addition, it has opened paths for new thera-
and composition, supporting the homeostasis of the peutic interventions.
Traditionally, the tear film has been thought to consist
system. The tear film forms a metastable covering be-
of three discrete layers, with an innermost mucin layer
tween blinks, subserving clear vision, and maintains the
covering the corneal and conjunctival epithelium, an
health and turnover of the ocular surface cells. Distur-
intermediate aqueous layer produced by the lacrimal
bance of intrinsic factors such as increasing age; hor-
glands, and an outermost lipid layer, the product of the
monal balance; systemic or local autoimmune disease, or
meibomian glands of the eyelids2; this concept has been
both; systemic drugs or extrinsic factors including topical
revised substantially. The contemporary concept of the
medications; environmental stress; contact lens wear; or tear ocular surface structure is that of a metastable tear
refractive surgery result in a final common pathway of film consisting of an aqueous gel with a gradient of mucin
events at the tear film and ocular surface, resulting in content decreasing from the ocular surface to the under-
DED. Diagnosis of DED and the design of clinical trials surface of the outermost lipid layer. The latter structure
for new drugs have been hampered by a lack of correla- interacts with the underlying aqueous and mucin compo-
tion between signs and symptoms and flawed endpoints; nents, retarding evaporative loss of aqueous tears and
successful new drug applications likely will require new contributing to the stability of the tear film between
approaches, such as the use of objective biomarkers for blinks.3
disease severity. The tear film is formed by a blink, which distributes the
CONCLUSIONS: Recent advances in our knowledge of tears over the ocular surface; immediately after the blink,
the causation of DED open opportunities for improving the tear film starts to thin in an orderly fashion, maintain-
diagnosis and disease management and for developing ing a complete aqueous cover until the next blink occurs,
new, more effective therapies to manage this widely reestablishing a thicker film, and the process repeats itself.
prevalent and debilitating disease state. (Am J Oph- At least three distinct types of mucin have been identified:
thalmol 2008;146:350 356. 2008 by Elsevier Inc. transmembrane mucins produced by the corneal and con-
All rights reserved.) junctival cells, gel-forming mucins from the conjunctival
goblet cells, and soluble mucins primarily from the lacrimal
glands.4 The transmembrane mucins contribute to the
surface structure of the epithelial cells, interact with the
Accepted for publication May 14, 2008. gel-forming and soluble mucins of the tear film to stabilize
From the Department of Ophthalmology, Georgetown University the film, and provide a cleansing pathway for the ocular
School of Medicine, Washington, DC.
Inquiries to Michael A. Lemp, 4000 Cathedral Avenue NW, No. surface; lipidmucin interactions support a relatively stable
828B, Washington, DC 20016; e-mail: malemp@lempdc.com tear film between blinks.
Discomfort, severity, and Mild and/or episodic; Moderate, episodic, or Severe, frequent, or Severe and/or disabling
frequency occurs under chronic; stress or constant without and constant
environmental stress no stress stress
Visual symptoms None or episodic mild Annoying and/or activity- Annoying, chronic, Constant and/or possibly
fatigue limiting episodic and/or constant disabling
limiting activity
Conjunctival injection None to mild None to mild / /
Conjunctival staining None to mild Variable Moderate to marked Marked
Corneal staining None to mild Variable Marked central Severe punctate erosions
(severity/location)
Corneal tear signs None to mild Mild debris, 2 meniscus Filamentary keratitis, Filamentary keratitis,
mucus clumping, mucus clumping,
1 tear debris 1 tear debris, ulceration
Lid/meibomian glands MGD variably present MGD variably present Frequent Trichiasis, keratinization,
symblepharon
TBUT (seconds) Variable 10 5 Immediate
Schirmer score (mm/5 minutes) Variable 10 5 2
agent will be required to provide optimal management of high indeed. In fact, the basis for approval of Restasis was
patients. not on a primary efficacy endpoint but rather a secondary
one, that is, improvement in the Schirmer test results and
a correlated improvement in a symptom in a subset of
patients. As increasing evidence is appearing in the liter-
CURRENT PROBLEMS AND FUTURE ature about the difficulties of using standard primary
PROSPECTS IN THE DEVELOPMENT endpoints such as vital dye staining, investigators have
OF NEW THERAPIES been looking to other endpoints. This is a rapidly evolving
ADVANCES IN UNDERSTANDING THE MECHANISMS OPERA-
field in which design of clinical trials largely is proprietary
tive in forming and maintaining a normal tear film and the and, therefore, such information is not available for gen-
pathologic breakdowns that occur in DED have led to a eral scrutiny. A number of trends, however, are apparent
variety of novel interventional strategies. These include: and are discussed in the recently published DEWS report.5
secretogogues of aqueous tears, mucins and lipids, anti- A principal problem encountered in all clinical trials is
evaporative compounds, immunomodulating agents that the placebo effect of artificial tears on outcomes.22 This
have anti-inflammatory effects, corticosteroids, cellular refers to the observation that patients receiving a placebo
protective formulations, and tear film stabilizers. Although or drop with no active ingredients display notable im-
most of the results of clinical trials are proprietary, pub- provements in most trials. The suggested reasons for this
lished papers and abstracts presented at meetings suggest include greater compliance in patients participating in
that more than 20 products have undergone clinical clinical trials, the lubrication effects of drops, and a
testing in the United States. As of this writing, only one regression to the mean in subjects recruited on the basis of
drug formulation has received FDA approval for marketing findings that may be variable over time. The DEWS report
as a therapeutic product for DED. It has been difficult for suggests that substituting a no treatment arm for a placebo
sponsors to generate data that will meet the FDAs criteria arm may be indicated.5
of primary efficacy endpoints. These endpoints usually One innovative approach that attempts to harness the
include improvement in at least one sign and one symptom short-term environmental effects on surface staining has
and that these should be both statistically and clinically been the controlled adverse environment.32 In this exper-
significant. Given the information previously discussed imental design, subjects preselected for prior clinical re-
concerning the lack of concordance between signs and sponse, for example, staining in DED, are exposed to
symptoms in DED, the hurdle for obtaining approval is adverse conditions such as wind and dry climate in a
THE AUTHOR INDICATES NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. THE AUTHOR IS AN OFFICER IN
Ocusense Inc, a company that has developed a tear osmometer. The author was involved in the design and conduct of study; data collection; analysis
and interpretation of data; and the preparation and review of the manuscript.