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Jul/Aug 2016
Ocular Surface Diseases –
A Perspective of Clinical Practice
Between Present and Future
Saturday 6 February 2016
2016 World Ophthalmology Congress®
of the International Council of Ophthalmology,
Guadalajara, Mexico
Introduction
Concepcion Santacruz Valdes, MD, Mexico
D
ry eye disease (DED) is an important problem for patients
and their eye care providers because it can affect daily
function, quality of life, vision and the outcomes of cataract
and refractive surgery. It is also significant because it is a
common condition in populations around the world.
Dry eye disease seems to be increasing in response to
local alterations already present in the eye, systemic diseases
and external factors like poor air quality, high pollution and,
even, changes in climate. This affects quality of life causing a
disruption of a healthy microenvironment at the ocular surface.
Studies investigating the epidemiology of DED report a
wide range of prevalence rates, which may be explained in
part by the use of different definitions. According to available
data, however, as many as 33% to 40% of adults have dry
eye symptoms. Importantly, findings of studies evaluating
signs of DED (eg., tear film breakup time and tear volume)
suggest there are individuals with dry eye who are not aware
of their condition.
Understanding the risk factors for DED, its possible etiologies,
and the pathophysiologic mechanisms by which it develops and
progresses can help clinicians as they approach the diagnosis
and management of this condition. When evaluating patients
for DED, it is also important to consider that other ocular surface
diseases with overlapping signs and symptoms can mimic DED,
but may coexist with and exacerbate DED. Clearly, unravelling
the root causes of DED is required for successful treatment.
Lately, there have been exciting developments in terms
of understanding the pathophysiology of DED as well as for
improving diagnosis and management. In this program, a
renowned international faculty of DED experts provide an
update on recent and forthcoming advances and share pearls
for clinical practice.
What is the Practical Guidance on Diagnosis and
Treatment Decisions in Dry Eye Disease?
Christophe Baudouin, MD, PhD, France
U
nderstanding that the pathogenesis of dry eye disease
(DED) can be described as a vicious circle in which tear
film instability, tear hyperosmolarity, and inflammation
play central roles provides guidance on diagnosis and
treatment selection, said Christophe Baudouin, MD, PhD, France.
Dr Baudouin described the vicious circle model and how it
supports the idea that a mechanistic approach to treatment
will optimise patient outcomes. In addition, he used the vicious
circle as a framework to explain the benefits of a new advanced
artificial tear formulation that addresses both tear film instability
and the effects of tear hyperosmolarity.
THE VICIOUS CIRCLE
The vicious circle model of DED pathogenesis is consistent with
the modern definition of DED, which states, “Dry eye disease
is a multifactorial disease of the tears and ocular surface that
results in symptoms of discomfort, visual disturbance, and tear
film instability with potential damage to the ocular surface. It
is accompanied by increased osmolarity of the tear film and
inflammation of the ocular surface.”1
The schema of the vicious circle (Figure 1) presents the many
factors that can cause or increase the risk for DED and how
they act as triggers at different points in the pathophysiologic
pathway. The pathophysiologic pathway itself is depicted by
a stepwise series of interacting events. Each step drives the
next, perpetuating the vicious circle in a process that manifests
clinically as DED progression.
“The concept of the vicious circle provides insight into how
acute events, such as ocular surgery or infection, can cause
dry eye and why DED and the patient’s complaints persist
when the inciting cause is removed. Once the vicious circle
is entered and established, it is almost impossible for patients
to exit from it unless the central pathogenic mechanisms are
addressed,” Dr Baudouin said.
Tear film impairment like hyposecretion or abnormalities in
tear composition (eg., lipid changes) appears at the top of the
vicious circle’s pathophysiologic chain.
1
Tear film instability leads to tear hyperosmolarity that in turn
promotes apoptosis of ocular surface epithelial cells, nerve
stimulation, and inflammation. Cytokine release and activation
of matrix metalloproteinases, which occur as part of the
inflammatory cascade, cause loss of mucin-producing goblet
cells. Subsequently, tear film instability worsens, and the vicious
circle continues.
Dry Eye Disease is a
Multifactorial Disease of the
Tears and Ocular Surface
“That inflammation is a prominent feature and ubiquitous
mechanism in DED is a key point. Nevertheless, the
importance of inflammation may be overlooked if DED
is thought of only as a disease of the tears and because
eyes with DED may not present with redness, swelling,
and pain, which are the classic signs of inflammation,”
Dr Baudouin said.
“However, there is good scientific support for the role of
inflammation and also emerging evidence that DED is not
only an inflammatory ocular disease but also a systemic
disease with involvement of immune system activation.”
Dr Baudouin supported his comments by reviewing findings
from a number of preclinical and clinical studies investigating
inflammation in DED. The data included his own unpublished
research showing that hyperosmolarity induces the expression
of inflammatory cytokines by human conjunctival cells and
studies using different diagnostic techniques to demonstrate
markers of inflammation in eyes with DED (both related to
Sjogrens syndrome and non-Sjogrens) or reduction of those
signs through anti-inflammatory treatment.2-6
Ocular Surface Diseases – A Perspective of Clinical Practice Between Present and Future
Figure 2. A mechanistic approach to treatment selection for DED considers
where different therapies act in the vicious circle of disease pathogenesis. A
new advanced artificial tear is novel in its ability to both improve tear film stability and protect ocular surface cells from hyperosmotic-associated damage.
CHOOSING TREATMENT FOR DED
Offering practical guidance on therapeutic decisions for
patients with DED, Dr Baudouin said that the severity-based
treatment algorithm proposed by the first Dry Eye WorkShop
seems to offer a simple and convenient tool. Its application
can be challenging, however, in situations where there is
not concordance in the severity of a patient’s DED signs and
symptoms. Consider a patient who reports severe symptoms
and yet has no or minimal corneal or tear signs of DED, Dr
Baudouin said.
He explained, “This example raises the question of how to
grade DED severity in order to select treatment. Should the
grading be based on the signs, the symptoms, or both?”
The mechanistic approach to treatment suggested
by Dr Baudouin recognizes that different interventions
act at different points in the vicious circle of DED
pathogenesis (Figure 2)
He proposed that compared with other artificial tears,
a new product formulated with two lubricant polymers—
carboxymethylcellulose (CMC) and hyaluronic acid (HA)—plus
osmoprotectant excipient ingredients may work better because
it addresses multiple mechanisms of DED pathogenesis. Like
other artificial tears, the novel formulation stabilises the tear
film, but this effect is enhanced by synergism of its dual-polymer
system. In addition, the new artificial tear targets another central
mechanism in DED pathogenesis as it protects ocular surface
epithelial cells from damage precipitated by hyperosmotic stress.
Summarising data from clinical trials, Dr Baudouin reported
that the new artificial tear demonstrated advantages when
compared with other marketed products containing only
CMC or HA. One multicenter clinical trial enrolling 80
patients met its primary endpoint, demonstrating the new
artificial tear was non-inferior to an HA-only product for
improving ocular surface staining after 35 days.7 However,
a significantly greater number of patients considered the
dual-polymer artificial tear with osmoprotectants easier to
use (P=.0002).
In another head-to-head comparison study, both the
dual-polymer osmoprotectant formulation and a CMC-only
artificial tear produced rapid and sustained improvements
in symptom severity and tear film breakup time.8 Results of
subgroup analyses, however, showed the new artificial tear
product was significantly superior to the CMC product for
improving symptoms in patients with severe ocular surface
staining at baseline.
“Symptoms are often what brings patients to seek treatment
for their DED, and so it is important that a product used in
the management of DED provide effective symptom relief,” Dr
Baudouin said.
REFERENCES
1.The definition and classification of dry eye disease: report of the
Definition and Classification Subcommittee of the International Dry
Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92.
2. Goyal S, Chauhan SK, Zhang Q, Dana R. Amelioration of murine
dry eye disease by topical antagonist to chemokine receptor 2.
Arch Ophthalmol. 2009;127(7):882-7.
3.Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell
subpopulations in Sjogren’s and non-Sjogren’s patients with dry
eye. Invest Ophthalmol Vis Sci. 2002;43(8):2609-14.
4.Kunert KS, Tsdale AS, Stern ME, Smith JA, Gipson IK. Analysis
of topical cyclosporine treatment of patients with dry eye
syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol.
2000;118(11):1489-96.
5. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial
proliferation in the conjunctiva of patients with dry eye syndrome
treated with cyclosporine. Arch Ophthalmol. 2002;120(3):330-7.
6. Brignole F, Pisella PJ, Gldschild M, et al. Flow cytometric analysis of
inflammatory markers in conjunctival epithelial cells of patients with
dry eyes. Invest Ophthalmol Vis Sci 2000;41(6):1356-63.
7. Data on file, Allergan. Irvine, CA.
8.Simmons PA, Liu H, Carlisle-Wilcox C, Vehige JG. Efficacy and
safety of two new formulations of artificial tears in subjects with dry
eye disease: a 3-month, multicenter, active-controlled, randomized
trial. Clin Ophthalmol. 2015 Apr 15;9:665-75.
Are There Any Differences Amongst Artificial Tears?
Peter A. Simmons, PhD, USA
A
rtificial tears are a mainstay of treatment for dry eye
disease (DED), regardless of the level of severity.
When recommending a product to patients, however,
physicians need to know that the clinical performance
of an artificial tear is affected by all of the formulation’s
ingredients, said Peter A. Simmons, PhD, USA.
“Artificial tear products with similar active ingredients may
be very different because it is not just the lubricant polymers
listed as active ingredients on the product label that are
important,” he said.
Dr Simmons reviewed properties of specific compounds within
three categories of ingredients used in artificial tears—lubricant
polymers, excipients used as tonicity agents, and preservatives—
and explained how by optimising ingredient selection, formulation
researchers created a new artificial tear to provide enhanced
lubrication and ocular surface protection. The advanced product
contains two water-soluble polymers that in combination exhibit
synergistic viscoelastic behavior; excipients that help protect the
ocular surface from the stress associated with a hyperosmolar tear
film; and a proprietary gentle preservative (Figure 1).
Ocular Surface Diseases – A Perspective of Clinical Practice Between Present and Future
2
INGREDIENT CATEGORY
INGREDIENTS
PROPERTIES
Lubricant polymers
Carboxymethylcellulose
+ hyaluronic acid
Enhanced viscosity under low-shear: increased retention, tear film stabilisation
and ocular surface hydration when the eye is open
Reduced viscosity under high-shear: comfortable lubrication and protection
of the ocular surface against friction from the blinking lid
Tonicity agents (excipients)
Compatible solutes
Osmoprotection: accumulation of these solutes in ocular surface cells under
hyperosmotic conditions prevents initiation of a chain of events leading to
cellular apoptosis
Preservative
Stabilized oxychloro
complex
Effective but gentle: an oxidative antimicrobial agent that dissipates into
harmless ingredients on the ocular surface
Figure 1. Ingredients in a novel advanced artificial tear formulation
LUBRICANT POLYMERS
Lubricant polymers in artificial tears enable drop retention
and act to hydrate and lubricate the ocular surface. The new
artificial tear uniquely combines carboxymethylcellulose (CMC)
and hyaluronic acid (HA).
CMC is a well-established lubricant polymer ingredient in
artificial tears, and findings from in vitro and animal studies
also show that CMC binds to corneal epithelial cells and
promotes epithelial wound healing.1,2
HA is a natural component of the tear film and another leading
ophthalmic lubricant polymer that is found in viscoelastic
products used in ophthalmic surgery in addition to artificial
tears. Dr Simmons pointed out that the properties of lubricant
polymers, including HA, can vary depending on their purity,
method of manufacture, and chain length (molecular weight).
“Originally, HA used in ophthalmic products was derived from
animal sources, but the HA in the new artificial tear is a highly
purified form obtained through a bacterial biofermentation
process,” he said.
“In addition, this HA is a very high molecular weight molecule.
Compared with low and medium molecular weight HA, high
molecular weight HA is less likely to be proinflammatory, and
it has higher viscosity, which results in longer residence time on
the ocular surface.”
HA has other benefits that make it attractive as a lubricant
polymer in artificial tears. Like CMC, it binds to epithelial cells
on the ocular surface, although at different sites, and it displays
high shear thinning behavior so that it provides excellent
lubrication between the ocular surface and the blinking lid.
When CMC and HA are combined in the same formulation,
they form a flexible bridged matrix in which CMC is entangled
within the HA. In this structure, CMC and HA each retain the
ability to interact with their specific epithelial cell binding
sites. However, results of laboratory studies indicate that when
the two polymers are combined, they act synergistically for
enhanced viscoelastic behavior.
Under low-shear conditions, which characterize the tear film
between blinks, the viscosity of the combination is about 60%
greater than the sum of the viscosities of the individual polymers”.3
Then, in response to increasing shear that corresponds to the
effect of the blinking lid, the combination exhibits reduced viscosity.
“The viscoelastic properties of the polymer combination
are consistent with enhanced retention, tear film stabilisation,
ocular surface hydration, and lubrication, and indicate that the
new artificial tear should provide comfortable protection of the
ocular surface,” Dr Simmons said.
TONICITY AGENTS
Dr Simmons noted that the choice of excipients used to adjust
the tonicity of artificial tears is important to a product’s
clinical performance because specific ingredients either
3
promote hyperosmotic stress-induced epithelial cell damage
or provide protection against it.
“When formulating the advanced artificial tear product, the
tonicity agents were carefully selected, favouring beneficial
solutes as a means to minimise the addition of sodium that
causes hyperosmotic stress,” he said.
Dr Simmons explained that when exposed to the hyperosmotic
environment of the altered tear film present in dry eye, ocular
surface epithelial cells initially lose water and shrink. As a
defensive mechanism to re-establish osmotic equilibrium and
restore volume, the cells take up whatever solutes are available
in the environment. If this regulatory process results in uptake
of sodium ions, an intracellular electrolyte imbalance occurs
that initiates a pathway of cellular changes ultimately leading
to apoptosis and triggering an inflammatory response. Uptake
from the environment of other electrolytes and non-ionic
compounds allows safe restoration of cell volume.
“These latter “compatible solutes’ that allow cells to retain
water while avoiding damage from hyperosmolar stress are
referred to as osmoprotectants,” Dr Simmons said.
He added, “Osmoprotection is a well-established mechanism
in human physiology as cells in various internal organs
accumulate compatible solutes in order to protect themselves from
the deleterious effects of changing osmolarity. Its application to
formulate an artificial tear that can prevent damage to ocular
surface cells from hyperosmotic stress is a new concept.”
Figure 2. Comparative effects of ophthalmic preservatives on corneal
cell morphology.
PRESERVATIVE PROTECTION
Multi-dose artificial tears must contain a preservative to protect
against microbial contamination, but some preservatives have
known cytotoxic potential.
The preservative contained in the new advanced artificial
tear, stabilized oxychloro complex, is a proprietary mild agent.
It provides antimicrobial efficacy in the bottle through oxidative
activity, but on contact with the ocular surface it quickly breaks
Ocular Surface Diseases – A Perspective of Clinical Practice Between Present and Future
down into harmless components—sodium and chloride ions,
oxygen, and water.
Dr Simmons presented results from animal studies showing
repeated dosing with the proprietary oxidative preservative
did not adversely affect corneal cell morphology or
survival 4 (Figure 2)
“Exposure to other ophthalmic preservatives, however,
resulted in progressive damage and cell death,” he reported.
“Even with exposure to a level 10-fold greater than that found
in the advanced artificial tear, this oxidative preservative is
not toxic to ocular surface cells. Therefore, it is gentle enough
to use frequently.”
PROOF OF PRINCIPLES
Results from preclinical and clinical studies investigating the
advanced artificial tear support its benefits as an option for
managing dry eye disease, Dr Simmons said.
He cited a published study that investigated the efficacy
of different artificial tears for either preventing or treating
environmentally-induced dry eye in mice.5 Animals were
randomised into five groups to receive the new artificial tear
combining CMC and HA, a product containing CMC or HA
alone, saline, or no treatment.5 In both the prevention and
treatment experiments, animals in all three artificial tear groups
had significantly less corneal staining compared with both
control groups. However, the effect of the CMC + HA product
was significantly better than the effect of using CMC or HA alone.
“This is demonstration that putting the two polymers together
in an osmoprotective formulation gives a superior level of
performance for protecting the ocular surface, and the findings
are borne out by clinical trial data presented earlier by Dr
Baudouin,” Dr Simmons said.
REFERENCES
1.Garrett Q, Simmons PA, Xu S, et al. Carboxymethylcellulose
binds to human corneal epithelial cells and is a modulator of
corneal epithelial wound healing. Invest Ophthalmol Vis Sci.
2007;48(4):1559-67.
2.Garrett Q, Xu S, Simmons PA, et al. Carboxymethyl cellulose
stimulates rabbit corneal epithelial wound healing. Curr Eye Res.
2008;33(7):567-73.
3. Simmons PA, Beard BJ, Vehige JG. Optimizing viscosity of ophthalmic
solutions with the combination of two polymers. Presented at the
7th International Conference on the Tear Film & Ocular Surface:
Basic Science and Clinical Relevance; September 18-2013, 2013;
Taormina, Italy.
4. Way WA, Matsumoto S, Apel LJ, Wiese A, Tarlo K, Vehige J. PURITE®
as a nondisruptive preservative for lubricating eye drop solutions in
comparison to alternative preservatives. Invest Ophthalmol Vis Sci.
2001;42(4):S39.
5. She Y, Li J, Xiao B, et al. Evaluation of a novel artificial tear in the
prevention and treatment of dry eye in an animal model. J Ocul
Pharmacol Ther. 2015;31(9):525-30.
How to Manage the Real Patient – Case Studies
Maurizio Rolando, MD, Italy
CASE 1
A 54-year-old woman presents complaining about a 4-year
history of foreign body sensation and eye burning that worsens
in the afternoon and evening. She is using artificial tears on
as needed basis, but says her symptoms are limiting her social
activities. She has no ocular or medical comorbidities.
DIAGNOSIS: Discussing this case, Maurizio Rolando, MD,
Italy, emphasised the need for an accurate diagnosis to guide
specific management (Figure 1).
“The assessment requires recognition that dry eye is not just
a disease of the tears or the cornea. Rather it is a disease
of the ocular surface system, and the examination must also
consider the conjunctiva, the lids with the periocular skin, and
the nerves,” he said.
On clinical examination, the patient had increased blink
frequency and seemed to avoid direct gazing. She had “slightly
dirty” film deposits along her eyelashes, indicating meibomian
gland dysfunction (MGD); severe staining of the bulbar
conjunctiva with lissamine green, showing inflammation; and
staining of the limbic region under the superior lid.
“Always stain the conjunctiva, and don’t forget to look under the
upper lid because staining in this area can suggest a diagnosis
of Sjögren syndrome or thyroid eye disease,” Dr Rolando said.
Tear breakup time was shortened and staining of the inferior
tear meniscus persisted 10 minutes after lissamine green
instillation, which Dr Rolando pointed out demonstrated slow
tear turnover. Tear osmolarity was 325 mOsm/L in the worst
eye, indicating hyperosmotic stress.
MANAGEMENT: Dr Rolando said treatment for this patient will
include an artificial tear, but it must be used on a regular basis
rather than as needed in order to promote tear turnover and
clear the ocular surface of pro-inflammatory mediators.
“The selected product should provide epithelial protection,
prevent hyperosmotic stress, and have good viscoelastic
behavior that will provide lubrication during blinking in order
to relieve lid friction,” he said.
The patient was also advised about lid hygiene for
management of MGD.
CASE 2
A 66-year-old man presents with complaints of persistent eye
redness and discomfort. He reports feeling burning and a
foreign body sensation for the past 2 years. His symptoms
are occasionally worse in the evening, and he has some
intermittent blurring that sometimes improves with blinking.
The patient was diagnosed with type 2 diabetes 20 years
earlier. He takes an oral medication for glycaemic control
and antihypertensive medication. His history is negative for
allergy, ocular surgery, and ocular trauma. He is not using
any topical treatments for his symptoms.
Findings of the ophthalmic examination are as follows:
Mild bulbar hyperaemia OU; reduced lower tear meniscus
OU; Schirmer I test 7 mm/5min OD, 8 mm/5 min OS; TBUT
12/11 sec OD/OS; mild staining of lower nasal conjunctiva
and lower corneal epithelium OU; reduced corneal sensitivity
(cotton thread testing); tear surface irregularities on topography
a few seconds after blinking; tear film osmolarity 321/324
mOsm/L OD/OS; normal lid and periocular skin.
DIAGNOSIS: Dr Rolando commented that the patient’s complaints
of blurred vision could be explained by irregularity and
instability of the tear film. He said the findings of the examination
Ocular Surface Diseases – A Perspective of Clinical Practice Between Present and Future
4
correspond with a diagnosis of non-Sjögren aqueous-deficient
dry eye disease, and the presence of reduced corneal sensitivity
is consistent with the hypothesis that sensory neuropathy is an
underlying mechanism, triggering the vicious circle of dry eye
pathogenesis by disrupting the reflex arc for tear stimulation.
Tear film hyperosmolarity arises from the reduced tear secretion
and drives the vicious circle, he explained.
“Although this patient had no other signs of diabetic
neuropathy, we are learning that neuropathy in the cornea can
occur very early in diabetes. Therefore, it is important to assess
corneal sensitivity when checking for effects of diabetes on
ocular health,” Dr Rolando said.
MANAGEMENT
The approach to management of this patient aimed to provide
symptomatic relief and interrupt the vicious circle of DED
pathogenesis by addressing the tear film instability, epithelial
damage, and inflammation.
“The ocular surface disease in this patient was not very severe,
but it is important to intervene to prevent it from worsening,”
Dr Rolando said.
Treatment for controlling ocular inflammation was initiated,
including oral unsaturated omega-3 fatty acid supplementation,
topical cyclosporine A, and a short-tapering course of a welltolerated topical corticosteroid as induction therapy with the
cyclosporine A. The patient was also given an artificial tear product
with a formula optimised to protect the epithelium from both shear
stress imparted during blinking and a hyperosmotic environment.
“Once the ocular surface inflammatory response has been
controlled, it may be possible to discontinue the cyclosporine
and maintain the patient on a regularly administered tear
substitute that is formulated to provide lubrication and
osmoprotection,” Dr Rolando said.
What are the Future Trends in the Management
of Dry Eye Disease?
José AP Gomes, MD, PhD, Brazil
A
look at ongoing research suggests the future will bring
promising new modalities for the management of dry
eye disease, said José AP Gomes, MD, PhD, Brazil.
“The high and rising prevalence of dry eye has
captured the attention of scientists, ophthalmologists, and
industry,” he said.
“Now we are seeing developments in medical management,
device-based approaches, and surgery.”
MEDICAL MANAGEMENT
Lifitegrast is an investigational pharmacotherapy in late stage
clinical development. This small molecule integrin antagonist acts
by interfering with the immunological synapse, blocking binding of
lymphocyte function-associated antigen-1 to intercellular adhesion
molecule-1 and thereby preventing T-cell activation, inflammatory
cell migration, and release of pro-inflammatory cytokines.
Phase 3 studies comparing lifitegrast 5% with placebo have
been completed. Published results from one of those trials
showed statistically significant improvement in dry eye-related
symptoms, but not in ocular surface staining,1 Dr Gomes said.
Diquafosol, another new molecule for management of
dry eye, has been available in Japan for more than 5 years
and is in Phase 3 development in the United States. Acting
as an agonist of the P2Y2 cell receptor, diquafosol stimulates
secretion of ocular mucins.
Results of a study evaluating diquafosol 3% and sodium
hyaluronate 0.1% used alone or together showed diquafosol
was more effective than sodium hyaluronate for improving signs
and symptoms of DED, and the combination was significantly
more effective than diquafosol monotherapy.2 Rebamipide,
which has been available for decades in Japan as a treatment
for gastric ulcer prevention and treatment of gastrititis, also
increases mucin production and has anti-inflammatory activity.
As a 2% preparation, it was shown in a Phase 3 study to be
significantly superior to 0.1% sodium hyaluronate for improving
ocular surface staining and patient symptoms.3
Tavilermide (formerly MIM-D3 is a tyrosine kinase A
receptor agonist that mimics nerve growth factor (NGF),
which is a naturally occurring protein that maintains corneal
nerves, promotes epithelial proliferation, and stimulates mucin
secretion. In a Phase 2 trial, patients treated with topical
5
tavilermide had significant improvements in both signs and
symptoms of dry eye compared with placebo-treated controls,
and the NGF mimetic had favorable safety, comfort, and
tolerability profiles.4
In a Phase 3 study, topical tavilermide significantly improved
fluorescein corneal staining compared with control, and it was
associated with improvements in patient symptoms.5 (Figure 1)
AGENT
PHARMACOLOGICAL ACTIONS
Lifitegrast
Anti-inflammatory
Diquafosol
Stimulates mucin secretion
Rebamipide
Stimulates mucin secretion, anti-inflammatory
Tavilermide
Stimulates mucin secretion, protects neuronal
cells, promotes epithelial cell proliferation
Figure 1. Pharmacotherapy pipeline for DED: novel agents in late
stage clinical development
NON-PHARMACOLOGICAL APPROACHES
Hemoderivative alternatives to autologous serum, including
platelet-rich plasma and an albumin precursor, are also
being investigated as treatments for dry eye with the aim of
maintaining the benefits of autologous serum while avoiding
the logistical difficulties associated with its use.
A novel non-invasive intranasal lacrimal neurostimulator is also
showing promise. So far, there are positive safety and efficacy
results from four clinical studies including more than 200 patients,
and two pivotal trials are planned, Dr. Gomes said.
In the surgical realm, Dr Gomes and colleagues have been
developing a modification of salivary gland transplantation for
the management of extremely severe DED with symblepharon.
He reported positive results in a series of 19 patients with more
than 10 years of follow-up.6
Finally, cell therapy is also being developed for severe DED
with promising results so far.
Ocular Surface Diseases – A Perspective of Clinical Practice Between Present and Future
REFERENCES
1.Tauber J, Karpecki P, Latkany R, et al.; OPUS-2 Investigators.
Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of
dry eye disease: results of the randomized phase III OPUS-2 Study.
Ophthalmology. 2015;122(12):2423-31.
2. Hwang HS, Suny YM, Lee WS, Kim EC. Additive effect of preservativefree sodium hyaluronate 0.1% in treatment of dry eye syndrome with
diquafosol 3% eye drops. Cornea. 2014;33(9):935-41.
3. Kinoshita S, Oshiden K, Awamura S, et al. A randomized, multicenter
phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1%
sodium hyaluronate in the treatment of dry eye. Ophthalmology.
2013;120(6):1158-65.
4.Meerovitch K, et al. Safety and efficacy of MIM-D3 ophthalmic
solutions in a randomized, placebo-controlled Phase 2 clinical trial
in patients with dry eye. Clin Ophthalmol. 2013;7:1275-85.
5. Meerovitch K, Brazzell K, Ousler G, Cumberlidge G. Improvements
in signs and symptoms of dry eye with MIM-D3 1% ophthalmic
solution compared to placebo in different patient populations.
Presented at the 2015 annual meeting of the Association for
Research in Vision and Ophthalmology. May 6, 2015 Denver, CO.
Abstract 4460.
6. Sant’ Anna HE, Hazarbassanov RM, de Freitas D, Gomes JÁ. Minor
salivary glands and labial mucous membrane graft in the treatment
of severe symblepharon and dry eye in patients with StevensJohnson syndrome. Br J Ophthalmol. 2012;96(2):234-9.
Anti-Infective Therapy Guidance and Post-Surgery
Care: What are the Practical Approaches
to Everyday Problems?
Fernando Pellegrino, MD, Argentina
P
atients undergoing cataract surgery are often
prescribed topical treatment with a nonsteroidal antiinflammatory drug (NSAID), a corticosteroid, and an
antibiotic to reduce postoperative pain, inflammation,
and the risk of endophthalmitis. Considering evidence in the
published literature, a regimen comprised of gatifloxacin,
ketorolac tromethamine, and prednisolone acetate is
particularly well-suited to achieve those goals, said Fernando
Pellegrino, MD, Argentina.
Even though fourth-generation fluoroquinolones are the latest
topical antibiotics introduced into ophthalmology, these agents
are not new and bacterial resistance is a potential issue.1
Results of a study measuring antimicrobial susceptibility of
ophthalmic isolates, however, showed there was less resistance
to gatifloxacin than to moxifloxacin among both Gram-positive
and Gram-negative organisms.1
Another advantage of gatifloxacin is that its commercially
available formulation is preserved with benzalkonium
chloride (BAK). This is an important feature considering
findings of an in vitro study showing that the addition of BAK
to fourth-generation fluoroquinolones enhances their activity
against leading postoperative endophthalmitis pathogens
and reduces their propensity to select for fluoroquinoloneresistant organisms.2
“In this in vitro study, the MIC90 for gatifloxacin plus BAK
against coagulase-negative staphylococci and both methicillinsensitive and methicillin-resistant Staphylococcus aureus was
≤0.008 μg/mL,” Dr. Pellegrino said.
He added that BAK cytotoxicity is not a relevant safety
concern when choosing an antimicrobial agent for
endophthalmitis prophylaxis because these medications are
used for only a short duration.
Dr. Pellegrino pointed out that bacteria production of biofilm is
another issue to consider when selecting medications for cataract
surgery patients and a reason for choosing ketorolac. He
explained that production of biofilm confers increased bacterial
virulence and antimicrobial resistance, and one study reported
that 75% of Staphylococcus epidermidis strains from eyes with
post-cataract surgery endophthalmitis were biofilm producers.3
“S. epidermidis is the most common case of endophthalmitis
after cataract surgery. Ketorolac 0.5% not only controls pain
and inflammation after cataract surgery, but it has been shown
shown in vitro to reduce S. epidermidis biofilm formation by
almost 50%4,” Dr. Pellegrino said.
Discussing topical corticosteroid use for controlling
postoperative inflammation, Dr. Pellegrino outlined reasons
for using prednisolone acetate 1%. He said it is a potent
corticosteroid, has excellent penetration into the anterior
chamber,5 and is available in some countries as a fixed
combination with gatifloxacin 0.3%.
“In a randomized, double-blind study,6 the fixed combination
was as effective as gatifloxacin plus prednisolone used
separately for controlling inflammation and preventing infection
after cataract surgery,” said Dr. Pellegrino.
“However, the fixed combination is easier for patients to use
and may improve treatment compliance, reduce administration
mistakes, and avoid drug washout that occurs if the two
medications are instilled concomitantly.”
REFERENCES
1. Wong CA, Galvis V, Tello A, Villareal D, Rey JJ. In vitro antibiotic
susceptibility to fluoroquinolones. Arch Soc Esp Oftalmol.
2012;87(3):72-8.
2.Hesje CK, Borsos SD, Blondeau JM. Benzalkonium chloride
enhances antibacterial activity of gatifloxacin and reduces its
propensity to select for fluoroquinolone-resistant strains. J Ocul
Pharmacol Ther. 2009;25(4): 329-33.
3.D’Alessandro L, Rossetti S. Genotypic markers of Staphylococcus
epidermidis virulence among strains isolated from postoperative
endophthalmitis. Invest Ophthalmol Vis Sci. 2002;43(12):4433.
4.Rossetti S, D’Alessandro, Pellegrino F, Carrasco MA. The effect of
ketorolac on biofilm of Staphylococcus epidermidis isolated from postcataract endophthalmitis. J Ophthal Inflamm Infect. 2012;2:89-93.
5.Awan MA, Agarwal PK, Watson DG, McGee CN, Dutton GN.
Penetration of topical and subconjunctival corticosteroids into human
aqueous humour and its therapeutic significance. Br J Ophthalmol
2009;93(6):708-13],
6. Cunha PA, Shinzato FA, Tecchio GT, et al. Efficacy and tolerability
of a gatifloxacin/prednisolone acetate fixed combination for topical
prophylaxis and control of inflammation in phacoemulsification:
a 20-day-double-blind comparison to its individual components.
Clinics (Sao Paulo). 2013;68(6):834-9.
Ocular Surface Diseases – A Perspective of Clinical Practice Between Present and Future
6
This supplement is a write up of a promotional meeting organised and funded by
Allergan. The speakers were paid honoraria towards this meeting. Allergan checked
the content for factual accuracy, to ensure it is fair and balanced, and that it complies
with the ABPI Code of Practice. The views and opinions of the speakers are not
necessarily those of Allergan, or the publisher. No part of this publication may be
reproduced in any form without the permission of the publisher.
Supplement
Jul/Aug 2016