Dry eye disease (DED), a disease of the lacrimal functional unit, is a complex autoimmune-based chronic inflammatory condition that can have a significant negative impact on quality of life and the patient’s ability to effectively carry out everyday activities. Further, DED may lead to contact lens intolerance, and may adversely affect refractive surgical outcomes and be associated with post-ocular surgery complications. The ocular surface system is in constant dynamic equilibrium; however, if damage is severe or too prolonged, repair mechanisms can fail, initiating a feedback loop of increasing inflammation known as the ‘vicious cycle’. Stress to the ocular surface triggers the initial inflammatory events that lead to autoimmunity; autoantibodies may contribute to complementdependent ocular surface pathology. With an aging population and with lifestyles becoming increasingly dependent on screen technology, the burden of DED is likely to escalate in the future. There are multiple challenges in the management of DED, not least the lack of medications for chronic use.
Dry eye disease (DED), ocular surface system, immunopathogenesis, anti-inflammatory therapy
Maurizio Rolando has the following potential conflicts of interest to report as consultant, speaker or research grant recipient: Alcon, Allergan, Bausch & Lomb, Eupharma, Farmigea, Horus, Medivis, Novartis, Pfizer, Santen, Sifi, Shire, SOOFT, Thea, TRB Chemedica. Michael E Stern has worked as a consultant for Allergan, Shire, Novaliq and an employee of ImmunEyez, LLC. Over the past 12 months, Margarita Calonge has had research contracts, consultantships, given lectures and been involved in advisory boards for the following: Allergan, Chiesi, Esteve, Ferrer International, Horus Pharma, Santen, Shire and Zealand Pharma. However, Margarita Calonge has no financial interest in any product or technology presented in this symposium. This article covers to proceedings of a symposium
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
July 14, 2017
September 21, 2017
Maurizio Rolando, ISPRE Ophthalmics Genoa Via Antiochia 29 R, 16129 Genoa, Italy. E. firstname.lastname@example.org
The publication of this article was supported an Independent Educational Grant from Shire. The views and opinions expressed in the article are those of the authors and not necessarily those of Shire.
The Changing Landscape of Dry Eye Disease in Europe
ISPRE Ophthalmics, Genoa, Italy
The latest model of dry eye disease (DED) states that: ‘Dry eye is a
multifactorial disease of the ocular surface characterised by a loss of
homeostasis of the tear film, and accompanied by ocular symptoms,
in which tear film instability and hyperosmolarity, ocular surface
inflammation and damage, and neurosensory abnormalities play
etiological roles.’1 The ocular surface system is in a constant dynamic
equilibrium, always adapting to changing environmental and external
insults. However, if the initial damage is severe or too prolonged, repair
mechanisms can fail, ultimately resulting in a feedback loop of escalating
inflammation termed the ‘vicious cycle’.2 Once the cycle is initiated,
the continuous environmental challenge acting on a compromised
ocular surface allows the vicious cycle to perpetuate, even if the
initial cause has been removed or reduced.3–5 The most frequent
results of the vicious cycle are: tear instability, epithelial malfunction/
damage and inflammation.6 Tear film abnormalities are associated
with hyper-evaporation and reduced tear clearance.7 The resulting
increased osmolarity leads to eye irritation, which, if persistent, causes
production of pro-inflammatory cytokines on the ocular surface to be
upregulated. The result is a chronic immuno-inflammatory condition,
with the recruitment, activation and involvement of regulators, helper
and killer lymphocytes. Pathophysiological factors that contribute to
this immune-mediated disorder include: aqueous deficiency, mucin
abnormalities, and evaporation (as occurs in Meibomian gland disease
[MGD] or when the blink rate exceeds the tear film break-up time
[TBUT]).7 There are multiple causes and contributors to an abnormal
tear film, which include ageing, dry environment, hormonal changes,
medications, blepharitis, surgery (laser-assisted in situ keratomileusis
[LASIK]) and autoimmune disease.7
The prevalence estimates of DED in Europe8–11 are consistent with global
data, which indicate a prevalence of between 7% and 30%.12 The exact
prevalence is difficult to accurately determine due to a lack of consensus
on diagnostic methods, a mismatch between signs and symptoms, and
the use of restricted cohorts that have traditionally excluded younger
individuals with multiscreen lifestyles. While the typical patient seen in the
past might have been female and aged over 50 years,4 modern patients
may be younger contact lens wearers.13 With the average UK adult now
spending more time using digital media than sleeping,14 lifestyle-driven
DED is set to increase. This increase is in combination with the rise due
to the ageing population.
DED can have a substantial effect on general quality of life (QoL) and
health-related QoL.4 In fact, a utility assessment of 44 patients in the UK
with DED found that severe DED may impact a patient’s life to a similar
extent as dialysis and severe angina.15 This impact can be on everyday
activities such as reading, working, computer use, watching television
and daytime or night-time driving, and as such is an important public
health problem.16 It can also result in contact lens intolerance and
discontinuation.4 In general, the impact of DED persists over long periods
of time and increases with disease progression and/or severity.17 DED is
often chronic and progressive. In a study of 398 men and 386 women
who reported they had DED and responded to a questionnaire, those who reported severe symptoms of DED in the past were more likely to
report worsening odds ratio (OR) 1.79 (1.07–3.00).18
An analysis of data from 648 patients with DED (82.7% female; mean age
55.8 year, standard deviation: 15.6 years) from the Groningen LOngitudinal
Sicca StudY (GLOSSY), found that greater symptoms versus signs were
highly associated with lower self-perceived health (p<0.001; Figure 1).19
This discrepancy highlights the importance of accounting for both signs
and symptoms in DED. Significant predictors of greater symptoms than
signs were: chronic pain syndrome; atopic diseases; a known allergy, use
of antihistamines; depression; use of antidepressants; and osteoarthritis.
DED can adversely affect refractive surgery outcomes and may
be associated with increased risk of infection/post-ocular surgery
complications.4 Further, cataract surgery in patients with DED can be
associated with ocular morbidity.4 The risk for refractive regression after
LASIK has been shown to increase in patients with chronic dry eye (27%
of patients [12/45] with chronic DED versus 7% of patients [35/520]
without DED [p<0.0001]).20 In a Korean study, 48 eyes of 34 patients
who underwent uncomplicated phacoemulsification were divided into
two groups: those with pre-existing DED before cataract surgery and
those without. Compared with the non-DED group, the DED group had
significantly higher ocular symptom scores, lower TBUT, higher lid margin
abnormalities, meibum quality and expressibility scores after cataract
surgery.21 There were also significant correlations between interleukin
(IL)-6 and parameters of DED. Furthermore, the presence of dry eyerelated
changes in osmolarity is a significant cause of error in the
measurement of the intraocular lens to be implanted.22
The prevalence of DED in Europe is consistent with global estimates:
7–22%. The burden of DED is likely to escalate in the future, with an
ageing population and as lifestyles become increasingly dependent
on multiscreen technologies. DED is often a chronic disease that can
impact everyday activities and could lead to contact lens intolerance.
In addition, DED may adversely affect refractive surgical outcomes and
may be associated with post-ocular surgery complications.
Immunopathogenesis of Dry Eye Disease and its Clinical Relevance
Michael E Stern
ImmunEyez, LLC, CA and Baylor College of Medicine, TX, US
DED is a disease of the lacrimal functional unit;23 which, in the normal
individual provides a homeostatic environment to the ocular surface
through its regulation of tear film composition.24 The three main tear
film components are, firstly, the mucins (secreted in soluble form
by the conjunctival goblet cells and expressed as transmembrane
entities across the ocular surface epithelium). This provides viscosity
and stability during blink cycle. Secondly, the aqueous consists of a
complex mixture of proteins, mucins, electrolytes etc., and, thirdly, the
lipid layer (secreted by the Meibomian glands along the lid margin) that
helps to maintain a smooth optical surface and prevent evaporation.24
New research suggests that mixing of the mucin and aqueous layer
occurs, which forms a hydrated gel that is then covered by the lipid
layer.24 In a typical patient with chronic DED, the tear film features both
aqueous deficiency and an altered lipid layers and mucin profile.25
One of the most common mucins in humans, soluble mucin 5AC is greatly
decreased in DED due to a loss of goblet cells and this impacts on viscosity
of the tear film.25 Antimicrobial proteins such as lactoferrin and lysozyme
are lower in concentration while pro-inflammatory cytokines such as
IL-1 and tumour necrosis factor (TNF)-α are increased and proteases are
activated, which in addition to eliciting a pro-inflammatory environment
on the ocular surface, degrade extracellular matrix and epithelial tight
junctions.24 Finally, increased electrolyte concentrations such as sodium
ions elevate tear osmolarity. Patients with DED display an array of
inflammatory markers such as pro-inflammatory cytokine/chemokine
expression, upregulation of human leukocyte antigen (HLA) expression,
elevated expression of adhesion molecules such as intercellular adhesion
molecule 1 (ICAM-1) and infiltration of inflammatory cells.26
In a comparison of cytokine/chemokine levels in 23 patients with DED
versus nine control subjects, levels of the following were significantly
(p<0.05) elevated in the patients with DED: epidermal growth factor (EGF); fractalkine (CX3CL1), IL-1 receptor antagonist (IL-1Ra), interferon (IFN) inducible protein 10 (IP-10); and vascular endothelial growth factor (VEGF).27 This acute inflammation leads to self-antigen-driven
autoimmunity (Figure 2).23,28 Induction of pro-inflammatory factors
may be initiated by stress-induced signal transduction pathways or
aberrant Toll-like receptor (TLR) signalling.28 Antigen-presenting cells
(APCs) internalise autoantigens, process and present immunogenic
epitopes and upregulate expression of costimulatory molecules. C-C
chemokine receptor type 7 (CCR7), which is expressed on APCs, directs
trafficking to the draining cervical lymph node, activating pathogenic
lymphocytes.29 The local cytokine milieu, produced by mature APCs,
influence activation and differentiation of autoreactive T-helper 1
(Th1cells), which mediate immunity against intracellular pathogens and
secrete, among other cytokines, IFN-gamma. Th17 cells, which are
involved in several inflammatory diseases, are also activated; these
secrete IL-17 and promote elevation in proinflammatory cytokine and
chemokine production in a variety of cell types as well as contributing to
the regulatory T cell (Treg) defect in DED.30
Autoreactive lymphocytes potentiate the chronic autoimmune response
and mediate different pathological consequences on the ocular surface.28
IFN-gamma, derived from Th1 cells, alters mucins on corneal epithelial
cells and has devastating effects on the integrity of the ocular surface.31,32
These include epithelial cell apoptosis in both the conjunctiva and
lacrimal glands, reduced goblet cell density and squamous metaplasia.33
IL-17 increases matrix metalloproteinase (MMP) 3/9 expression and
induces corneal epithelial barrier dysfunction.30,32 Th17-related cytokines
have been shown to correlate with disease severity.
DED is a complex autoimmune-based chronic inflammatory disease.28
Stress to the ocular surface triggers the initial inflammatory events that
lead to autoimmunity.28 Cytokines present within ocular surface tissues
affects T cell differentiation into Th1 and Th17 cells.28 Autoantibodies
derived from autoreactive B cells appear to contribute to complementdependent
ocular surface pathology.28
Challenges in the Management of Dry Eye Disease
General therapeutic schemes are laid out by the Dry Eye Syndrome
Preferred Practice Patterns of the American Academy of
Ophthalmology;34 the 2006 International Task Force (ITF) Delphi Panel
Guidelines for Dry Eye35 and the 2007 Report of the International Dry Eye
Workshop (DEWS).4 An update of the Report of the International DEWS
(DEWS II) is expected in July 2017 but was not available at the time
of writing. Disease severity is considered to be the most important
factor for treatment decision-making and has been categorised into
four levels (Table 1).36
Inflammation is always present in DED, regardless of the type
of DED.4 Anti-inflammatory agents used to tackle this are all offlabel
and include topical steroids, topical azithromycin and oral
tetracyclines (doxycycline). Topical steroids most frequently utilised
in the short-term therapy for DED are loteprednol etabonate,37–39
fluorometholone40,41 and glucocorticoid.42,43 In a randomised, vehiclecontrolled
trial, three-week topical 0.1% fluorometholone therapy was
shown to be effective not only in reducing ocular surface signs in
patients with DED but also in preventing exacerbation by exposure to
Immunomodulatory agents used in DED include topical cyclosporin
A, tacrolimus and lifitegrast. Cyclosporin A has restricted availability
worldwide whereas lifitegrast is not approved yet outside the
US.44 Topical cyclosporin A inhibits T-cell-mediated inflammation
and activation and has anti-inflammatory, anti-apoptotic and
immunomodulatory effects.45 Its use also brings about an increase
in lacrimal gland production of tears.45 Topical 0.05% unpreserved
cyclosporin A is not approved in the European Union while 0.1% topical
unpreserved cyclosporin A has recently become available in some
EU countries.46 Clinical trials have shown that topical cyclosporin A
decreased lymphocyte infiltration and activation, and markers of
apoptosis and proinflammatory cytokines.45 In general, improved
symptom scores, decreased ocular staining, and increased Schirmer
scores were observed with cyclosporin A treatment.47 Goblet cell
density, tear meniscus height and volume and corneal sensitivity have
also been shown to improve,47 as well as decreased use of artificial
tears.48 Topical tacrolimus, an immunomodulatory macrolide, has a
similar mechanism of action to cyclosporin A with 10- to 100-times
more potency.49 It inhibits calcium-dependent events such as IL-2 gene
transcription, nitric oxide synthase activation, cell degranulation and
apoptosis.49 Topical tacrolimus suppresses the immune response by
inhibiting the release of other inflammatory cytokines (IL-3, 4, 5 and 8,
IFNα, TNFα).49 Topical lifitegrast targets ICAM-1/ lymphocyte functionassociated
antigen (LFA)-1,50,51 interrupting the inflammatory cycle.52
5% topical lifitegrast solution is currently approved only in the US.53
Clinical trials of the potential benefits of lifitegrast showed reduced
signs of DED as measured by corneal and conjunctival staining, and
reduced symptoms of eye dryness and discomfort.54–58 In addition,
it was generally well tolerated, as evidenced by short-term (84 day)
clinical trials and a longer term (360 day) safety study.54–58
Summary of challenges in the management of dry eye disease
- Lifestyle modifications (e.g. environmental, nutritional, omega 3 supplements).
- Withdraw any non-required topical/systemic medications.
- Treat MGD aggressively.
- Artificial tear substitutes are always indicated.
- Autologous serum and derivatives are very useful when indicated.
- Tear drainage blockade is controversial
- Doxycycline oral/azithromycin topical or oral, for eyelids and cornea.
- Topical steroids short-term are essential, though an improved safety profile is needed.
- Topical cyclosporin: prepare ocular surface for tolerance.
- Topical lifitegrast: limited real-world experience in the US, no experience elsewhere.
- Systemic immunosuppressants: Sjögren’s syndrome, graft-versushost disease.
- The most significant challenge is the scarcity of medications available for chronic use.
Q: Are there any notable trends with respect to prevalence of DED?
We are observing a rise in prevalence owing to MGD. We are now seeing more young people with DED due in part to over-use of screens and the
effect of pollution on the ocular surface.
Q. What are the three top bio markers for DED?
IL-6, which is a precursor of Th 17-mediated inflammation; epidermal growth factor receptor; and MMP9 are the most studied although the biomarker
may vary depending on the drug.
Q. What in general drives patients to your office: signs, symptoms or both?
Most patients present because of their symptoms and the impact they have on their lives, for example, their ability to work and drive.
Q. If inflammation is under control, do we break the vicious cycle and restore ocular surface heath?
Resolution of the disease or at least disease control is possible with long-term suppression of inflammation. For optimal results, we need an anti-inflammatory agent for chronic use (many years).
Q. What antigen plays a key role in the vicious cycle?
There are two hypotheses: destroyed pathogenic bacteria may release antigens; or TLRs may be activated by DNA segments shredded from apoptosis.
Q. When are punctal plugs useful?
These can be harmful in that they can maintain the inflammatory soup present on the ocular surface. They should not be used in the case of MGD or
blepharitis in general and whenever improvement is not observed, the plugs should be removed.