The Ocular Surface 17 (2019) 9–19

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The Ocular Surface

journal homepage: www.elsevier.com/locate/jtos

Review Article

The impact of dry eye disease treatment on patient satisfaction and quality T
of life: A review
José A.P. Gomesa,∗,1, Ruth M. Santob,∗∗,1
a
Department of Ophthalmology and Visual Sciences, Federal University of Sao Paulo (UNIFESP/EPM), Brazil
b
Department of Ophthalmology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

A R T I C LE I N FO A B S T R A C T

Keywords: Several aspects of the quality of life (QoL) and treatment satisfaction of patients with dry eye disease (DED) may
Dry eye disease be underestimated. Ocular symptoms, which are assessed by validated patient-reported questionnaires and may
Patient satisfaction include stinging, burning, itchiness, grittiness, dryness and discomfort, reduce QoL by affecting daily activities
Quality of life and work productivity. Self-reported symptoms do not always correlate with post-treatment improvements in
Patient-reported
clinical measures such as tear film break-up time, inflammation and osmolarity. Thus, treatments may improve
Artificial tears
clinical ocular features without improving symptoms that affect daily life.
This review explores 1500 abstracts from congress presentations and peer-reviewed journals for QoL and
treatment satisfaction data on the use of active lubricants, osmoprotectants, secretagogues, and im-
munomodulators present in topical formulations for DED treatment, and validated symptom questionnaires.
Patient-reported symptoms of DED are generally improved after treatment with topical formulations for tear
replacement, tear stimulation or anti-inflammatory therapy compared with baseline or a control treatment.
However, more data are required to compare the performance of active ingredients. It is fundamental to diag-
nose patients with DED accurately, recognising the major cause behind their dry eyes. Studies are also necessary
to identify how patient satisfaction and QoL may be improved through long-term use of topical preparations. We
conclude that careful and thorough consideration of patient-reported symptoms should be integrated into DED
management to help tailor treatment to patient needs.

Introduction which, if severe, may lead to permanent loss of vision [5].

Dry eye disease (DED) is a multifactorial disease characterised by
the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop
(DEWS) II as ‘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 abnorm-
alities play etiological roles.’ [1] Patient-reported symptoms include
dryness, grittiness, itching, redness, fluctuating visual disturbances and
ocular fatigue; however, owing to the subjective nature of the symp-
toms and their definitions, clinical identification of these symptoms is
challenging [2]. Dryness and irritation of the patient's eyes can have a
negative impact on the patient's visual function and ability to perform
daily visual tasks [3]. These detrimental effects may result in psycho-
logical comorbidities, leading to a reduction in the patient's quality of
life (QoL) [4], and make the patient susceptible to corneal infection,
DED is prevalent worldwide. Prevalence rates vary widely among
countries as a result of differences in the definition of DED and the
patient inclusion criteria among studies [6]. In Europe, prevalence has
been reported to range from 11.0% in Spain [7] to 29.6% in France [8].
DED is generally more common in Asian than Caucasian populations
[6], with the highest prevalence being reported in China (52.4%) [9].
Despite this trend among Asian populations, one study reported an
unusually low prevalence rate of 6.5% in Singapore [10]. In the US,
Paulsen et al. observed an overall prevalence of 14.5%, with sig-
nificantly more females than males (17.9% vs 10.5%) suffering from
DED [11]. Associated risk factors for DED include female gender, Asian
ethnicity [6], hormonal dysfunction and treatments [5], autoimmune
diseases [4], reduced blinking [12], lifestyle factors (such as alcohol
consumption and cigarette smoking) [13], contact lens wear [3], ageing
[13] and medications [6]. Projections of greater life expectancy and

∗
Corresponding author. Rua Botucatu, 821 - Vila Clementino, Sao Paulo, 04023-062, Brazil.
∗∗
Corresponding author. Avenida Dr. Eneas de Carvalho Aguiar, 255 - ICHC 6º andar sala 6120 – Cerqueira Cesar, Sao Paulo, SP, 05403-000, Brazil.
E-mail addresses: japgomes13@gmail.com (J.A.P. Gomes), ruth.santo@hc.fm.usp.br (R.M. Santo).
1
José A. P. Gomes and Ruth M. Santo contributed equally to this review and should be considered joint first authors.

https://doi.org/10.1016/j.jtos.2018.11.003
Received 1 February 2018; Received in revised form 2 November 2018; Accepted 7 November 2018
1542-0124/ © 2018 Elsevier Inc. All rights reserved.

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 Table 1
Literature search results for dry eye disease treatment lubricants.
Search terms (cut-off date: May Downloaded abstracts, n Publications Level of Study sponsor
2017) reporting in vivo evidence
PubMedb Web of Google ARVO ARVO SOE TFOS TFOS TFOS TFOS studies with patient based on
Scienceb Scholarc congress congress congress congress congress congress congress satisfaction or QoL AAOPP [15]
2016d 2017d 2015d 2007d 2010d 2013d 2016d data
J.A.P. Gomes, R.M. Santo

Active ingredients “carbomer” and “dry eye” and 19 19 983 – 1 – 1 – – – [None] – –

“patient”
“carboxymethylcellulose” or 33 29 996 2 1 2 – 4 – – Cohen et al. 2014 1 Alcon
“CMC” and “dry eye” and [31] Laboratories
“patient”
Kaercher et al. 2009 2 Allergan
[32]
Kiran et al. 2017 2 [None]
[33]
Labetoulle et al. 1 Alcon
2017a [34] Laboratories
Labetoulle et al. 1 Allergan
2017b [35]
Mencucci et al. 2015 1 Allergan
[36]
Simmons et al. 2007 1 Allergan
[37]
Simmons et al. 2015 1 Allergan
[38]
“hyaluronic acid” and “dry eye” 81 39 2030 8 2 1 2 1 3 1 Chiambaretta et al. 1 Laboratories
and “patient” 2017 [39] Théa

10
Labetoulle et al. 1 Allergan
2017b [35]
Mencucci et al. 2015 1 Allergan
[36]
Pinto-Bonilla et al. 1 Laboratories
2015 [40] Théa
Pinto-Fraga et al. 1 Avizor S.A.
2017 [41]
Saeed et al. 2013 2 [None]
[42]
Solomon et al. 1998 2 [None]
[43]
“hydroxypropyl 21 8 1410 1 – 1 – – – – Toda et al. 1996 2 [None]
methylcellulose” or “HPMC” and [44]
“dry eye” and “patient”
Prabhasawat et al. 1 [None]
2007 [45]
48 12 1580 2 1 2 1 1 Davitt et al. 2010 1 Alcon

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“polyethylene glycol” and “dry – –
eye” and “patient” [46] Laboratories
Labetoulle at al. 1 Alcon
2017a [34] Laboratories
“polyvinyl alcohol” and “dry 22 12 1370 2 – – – – – – [None] – –
eye” and “patient”
“propylene glycol” and “dry eye” 15 7 686 1 1 3 – – 1 1 Davitt et al. 2010 1 Alcon
and “patient” [46] Laboratories
Labetoulle at al. 1 Alcon

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2017a [34] Laboratories
“trehalose” and “dry eye” and 7 7 216 1 3 – – – 1 1 Chiambaretta et al. 1 Laboratories
“patient” 2017 [39] Théa
(continued on next page)
The Ocular Surface 17 (2019) 9–19
 Table 1 (continued)

Search terms (cut-off date: May Downloaded abstracts, n Publications Level of Study sponsor
2017) reporting in vivo evidence
b
PubMed Web of Google ARVO ARVO SOE TFOS TFOS TFOS TFOS studies with patient based on
Scienceb Scholarc congress congress congress congress congress congress congress satisfaction or QoL AAOPP [15]
2016d 2017d 2015d 2007d 2010d 2013d 2016d data
J.A.P. Gomes, R.M. Santo

Pinto-Bonilla et al. 1 Laboratories

2015 [40] Théa
Osmoprotectants “L-carnitine” and “dry eye” and 6 6 212 – – – – – – – Baudouin et al. 2012 1 Allergan
“patient” [47]
“erythritol” and “dry eye” and 1 1 65 – – – – – – – Baudouin et al. 2012 1 Allergan
“patient” [47]
Labetoulle et al. 1 Allergan
2017b [35]
“glycerine”a and “dry eye” and 16 6 1730 1 – – – – – – Kaercher et al. 2009 2 Allergan
“patient” [32]
Labetoulle et al. 1 Allergan
2017b [35]
Solomon et al. 1998 2 [None]
[43]
Gelling agent “hydroxypropyl-guar” and “dry 18 14 226 – – – 1 – – 1 Sanchez et al. 2010 1 GR-UCM/
eye” and “patient” [48] Alcon
Baudouin et al. 2016 1 [Unknown]
[49]
Rolando et al. 2009 1 [Unknown]
[50]
Hartstein et al. 2006 1 Alcon
[51] Laboratories

11
ARVO, Association for Research in Vision and Ophthalmology; CMC, carboxymethylcellulose; HPMC, hydroxypropyl methylcellulose; SOE, European Society of Ophthalmology; TFOS, Tear Film & Ocular Surface Society.
a
Includes searches for “glycerin” and “glycerol”.
b
Relevant references were hand searched from these lists.
c
Relevant references were hand searched from the first 40 most cited hits only.
d
Only abstracts reporting patient-assessed symptom scores are noted.

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The Ocular Surface 17 (2019) 9–19
 J.A.P. Gomes, R.M. Santo

Table 2
Literature search results for topical secretagogues and immunomodulators.
Search terms (cut- Downloaded abstracts, n Publications Level of Study
off date: May 2017) reporting in vivo evidence sponsor
PubMeda Web of Google ARVO ARVO SOE TFOS TFOS TFOS TFOS studies with patient based on
Sciencea Scholarb congress congress congress congress congress congress congress satisfaction or QoL AAOPP [15]
2016c 2017c 2015c 2007c 2010c 2013c 2016c data

Topical secretagogues “diquafosol” and 37 47 543 1 1 – 1 – 3 3 Shimazaki et al., 1 Otsuka/

“dry eye” and 2017 [52] Santen
“patient” Pharma.
Takamura et al., 1 Santen
2012 [53]
Yang et al., 2015 2 Chonnam
[54] National
University
“rebamipide” and 22 20 296 3 1 – – – 2 – Igarashi et al., 2015 2 [None]
“dry eye” and [55]
Shimazaki et al., 1 Otsuka/

12
“patient”
2017 [52] Santen
Pharma.
Topical immunomodulators “cyclosporine” and 251d 257d 8340 1 1 1 1 1 2 3 Sall et al., 2000 [56] 1 Allergan
“dry eye” and Stevenson et al., 1 Allergan
“patient” 2000 [57]
“tacrolimus” and 21 25 ∼2000 – – 1 – – 1 – [None] – –
“dry eye” and
“patient”
“lifitegrast” and 4 5 166 – – – – – – 1 Holland et al., 2016 1 Shire
“dry eye” and [58]
“patient” Sheppard et al., 2014 1 Shire
[59]

AAOPP, American Academy of Ophthalmology Preferred Practices; ARVO, Association for Research in Vision and Ophthalmology; SOE, European Society of Ophthalmology; TFOS, Tear Film & Ocular Surface Society.
a
Relevant references were hand searched from these lists.
b
Relevant references were hand searched from the first 40 most cited hits only.
c
Only abstracts reporting patient-assessed symptom scores are noted.

For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
d
Relevant references were hand searched from the first 70 most cited hits only.

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The Ocular Surface 17 (2019) 9–19
J.A.P. Gomes, R.M. Santo
prolonged visual tasks necessitated by the ever-increasing demands of
modern life will likely result in an even larger burden of DED on vision-
related QoL [14].
Treatments for DED commonly involve the use of artificial tear
substitutes. These are used to replenish the natural tear film and lu-
bricate the eyes, and they are available without prescription in many
countries [15]. Artificial tears do not target the underlying causes of
DED; therefore, other treatment strategies are necessary for some pa-
tients. These treatment strategies, used in addition to tear supple-
mentation, include topical immunomodulators (such as cyclosporine A
[CsA] and lifitegrast), reduction in tear outflow with lacrimal punctal
occlusion, stimulation of tear production with topical secretagogues
and even surgery in the most severe cases [15].
Several aspects of patients' QoL are affected by the symptoms of
DED, although they are not easily quantifiable and are sometimes un-
derestimated [16]. Furthermore, the QoL burden increases with the
severity of disease [17]. Productivity at work is reduced in patients with
all severities of DED, with significantly greater reductions reported in
patients with moderate or severe DED [18,19] – this presenteeism was
estimated to cost USD 799 per worker annually [20]. Accordingly,
measurement of the impact of DED on patients’ daily lives is now re-
cognised as a critical aspect of disease characterisation [16]. Other
important areas where DED has a negative impact on QoL include sleep
[21] and important daily activities such as reading, computer use,
driving and watching television [14,22].
Patient-reported outcomes (PROs) and questionnaires are accepted
as clinical forms of evaluation to identify the severity and frequency of
symptoms and how they affect patients' QoL. Measuring patients'
symptoms and QoL enables healthcare professionals to understand the
impact of the disease on individual patients, and their consequent
needs. High pain sensitivity and low pain tolerance are associated with
symptoms of DED [23]. However, the subjective nature of many
symptoms, in addition to varying pain thresholds among patients, can
result in a lack of correlation between these symptoms and clinical
findings [24–26]. Neurosensory abnormalities could also play a role in
the disparity between symptoms and clinical signs [1]. Currently, there
is no single test that can accurately predict and assess an individual's
response to treatment [27]. Chalmers et al. compared patient-rated
assessment of dry eye severity with clinician-rated severity based on
clinical examination, including dry eye tests [28]. Although agreement
between the two assessments was significant, clinicians underestimated
the severity by ≥ 1 grade in 40.9% of patients. This underestimation
was more pronounced in patients aged ≥65 years and female patients,
and the authors concluded that eye care physicians need better, more
quantitative tools to improve concordance in severity assessment and to
meet the needs of patients by offering appropriate treatments.
Therefore, it is important to understand that relying solely on ob-
jective clinical measures to evaluate DED and its treatment may not be
appropriate, particularly as the TFOS DEWS II revised definition of DED
reports the importance of both signs and symptoms of the disease [1].
The combination of clinical measures with subjective symptoms and
functional lifestyle evaluation by a well-designed and validated ques-
tionnaire may be the best way to determine the impact of this disease
and its treatment in patients’ lives.
DED treatments and patient satisfaction
This review of the current literature focuses on the impact of
treatment of DED on patient satisfaction and QoL. The structure is
based on the treatment types available: lubricants, topical secretago-
gues and topical immunomodulators. Tear supplementation with ocular
lubricants is still the mainstay of therapy in all stages of DED, either
alone (in mild-to-moderate disease) or in combination with other
treatments (in moderate-to-severe disease) [15,29]. Ocular lubricants
are solutions containing electrolytes, surfactants and viscosity agents
[30]. We included eight of the most common active ingredients in
13
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The Ocular Surface 17 (2019) 9–19
artificial tears in a comprehensive literature search, the selection of
which was based on the extensive clinical experience of the authors:
carbomer, carboxymethylcellulose (CMC), hyaluronic acid (HA, also
known as sodium hyaluronate), hydroxypropyl methylcellulose
(HPMC), propylene glycol (PG), polyethylene glycol (PEG), polyvinyl
alcohol and trehalose (Table 1). We also included osmoprotectants
(glycerine, L-carnitine and erythritol) and a common gelling agent,
hydroxypropyl-guar (Table 1). Besides lubricants, we included two
other categories of topical treatment for DED: secretagogues (diquafosol
and rebamipide) and immunomodulators (CsA, tacrolimus and lifite-
grast) (Table 2). The literature search was conducted using PubMed,
Google Scholar and Web of Science as primary sources to investigate
published and relevant data on the relief and treatment of DED, sup-
plemented by the review of abstracts presented at selected congresses
on DED from January 2007 to May 2017. The searching strategy in-
volved using the ingredient name (selected by the authors) as an initial
search term, with “dry eye” and “patient” terms added for refinement.
No specific searches for symptom descriptors other than “dry eye” or
conditions associated with DED were conducted. All abstracts found
with these three search terms based on masked, comparative trials were
downloaded (n = 24,069), with information extracted only from the
publications reporting in vivo studies with patient satisfaction data or
QoL assessments.
Questionnaires for DED and ocular surface diseases and the
assessment of patients’ quality of life
Patient treatment satisfaction is measured by directly asking pa-
tients questions regarding the treatment's ability to relieve symptoms,
the time it takes for the treatment to start working, ease of use and
convenience [60]. A PRO is defined as any report of the status of a
patient's health condition that comes directly from the patient without
interpretation of the patient's response by a clinician or other third
party [61]. Well-developed PRO questionnaires are precision instru-
ments that accurately assess a patient's health status. The use of PRO
questionnaires complements clinical data to provide more compre-
hensive patient information. In general, scores for PRO measures, in-
cluding those directly reporting the impact of DED on daily activities
and work productivity, are worse in patients with more severe disease
[62]; therefore, PRO measures can often complement quantitative
clinical diagnostic methods.
In reviewing the literature, we found a variety of validated ques-
tionnaires that are used to assess patient satisfaction and improvement
after treatment and aspects of QoL (Table 3). Some DED questionnaires
measure patients' QoL, while others assess symptoms that may impact a
patient's QoL. Questionnaires related to general health status are also
useful in determining QoL in patients with DED. Guillemin et al. con-
ducted a comprehensive assessment of PRO instruments evaluating
symptoms and QoL in patients with DED in 2012 [63], which assess-
ment is updated upon here.
Quality of life measures
The Dry Eye-related Quality-of-life Score (DEQS) is a validated 15-
item questionnaire that focuses on all aspects of DED in the patient's
daily life, including impact on daily activities and bothersome ocular
symptoms [26]. The DEQS was validated by Sakane et al., who reported
significantly higher scores on both subscales for patients with DED than
for a control group (P < .001) [26].
The Impact of Dry Eye on Everyday Life (IDEEL) questionnaire is a
broad assessment that considers all relevant domains of DED [64]. The
questionnaire is relevant to issues that are specific to patients with DED:
it provides assessment of the impact of DED on patient DED-related QoL
and impact of treatment on patient outcomes in clinical trials, and may
aid in treatment effectiveness evaluation [64]. Fifty-seven questions are
asked in total, split into three modules: DED symptom bother, the effect
 Table 3
Questionnaires for patient self-assessment of DED symptoms and general status of health.
Questionnaire Description Questionnaire scoring Contact lens wearers Validation
J.A.P. Gomes, R.M. Santo

QoL measures
The Dry Eye-related Quality-of-life
Score (DEQS)
Impact of Dry Eye on Everyday Life
(IDEEL)
Symptom measures
McMonnies dry eye Questionnaire (MQ)
Ocular Surface Disease Index (OSDI)
Symptom Assessment iN Dry Eye
(SANDE)
QoL-specific questionnaire with two subscales: impact 15 items using two subscales: impact on daily life and bothersome ocular Not specified Sakane et al., 2013 [26]
on daily life and bothersome ocular symptoms symptoms
A Likert scale ranging from 0 to 4 measures the frequency of symptoms, where 0
indicates no symptoms and 4 indicates high frequency of symptoms
Extensive questionnaire examining how DED symptoms 57 items, three modules: Not specified Rajagopalan et al., 2005 [66],
affect QoL and patient satisfaction with current DED 1. Symptom bother Abetz et al., 2011 [64]
treatments 2. Daily activities (including activity limitations, work limitations and
emotional impact)
3. Treatment satisfaction
Questions are marked on a scale of 0–100
Screening questionnaire on the history of DED 12 items Yes McMonnies 1986 [68], Nichols
symptoms et al., 2004 [69]
Evaluates the severity and frequency of DED symptoms 12 items, each scored from 0 (always) to 4 (never) Yes but not specific to Schiffman et al., 2000 [70]
and how these are affected by environmental factors Overall scores range from 0 (no DED) to 100 (severe DED); 0–12 = no DED, contact lens wearers
13–22 = mild DED, 23–32 = moderate DED, ≥ 33 = severe DED
DED symptoms only, based on a visual analogue scale Two questions: Not specified Schaumberg et al., 2007 [72]
1. How often do your eyes feel dry and/or irritated?
2. How severe do you feel your symptoms of dryness and/or irritation are?
0–100 mm scale from ‘rarely’ to ‘all the time’ and ‘very mild’ to ‘severe’,

14
Ocular Comfort Index (OCI)
Five-Item Dry Eye Questionnaire (DEQ-
5)
Standard Patient Evaluation of Eye
Dryness (SPEED)
Dry Eye/Contact Lens Dry Eye
Questionnaire (DEQ/CLDEQ)
General health measures
National Eye Institute Visual Function
Questionnaire (NEI VFQ)
Medical Outcome Study Short Form-36
(SF-36)
respectively
Assesses the impact of ocular surface irritation on 12 items, evaluating both frequency and intensity of ocular pain, sting, Not specified Johnson & Murphy 2007 [73]
patient well-being and improvements in symptoms grittiness, itching, dryness and tiredness
before and after treatment A higher score indicates greater frequency and intensity
Evaluates the severity and frequency of three common Five items Not specified Chalmers el al. 2010 [74]
DED symptoms Patients are required to self-assess either the severity or frequency of these
symptoms from five questions on a scale of 0–5, with 5 being the most severe or
frequent
DEQ-5 scores in excess of 12 are considered to be indicative of SS
Evaluates the severity and frequency of DED symptoms, Eight items on a 5-point scale, split into frequency and severity of ocular Not specified Ngo et al., 2013 [76]
monitoring change over a period of time dryness symptoms
Screening questionnaire for contact lens wearers 23 items Yes Nichols et al., 2002 [78]
assessing frequency and severity of symptoms
General ocular health, but reliable across several 25 items, two ocular pain subscale questions Not specified Mangione et al., 1998 [80]
common eye diseases, including DED
a
Measure of general health status related to QoL 36 items across nine dimensions: 5. Mental health (five questions) Not specified Brazier et al., 1992 [81]
1. Physical functioning (10 questions) 6. Vitality (four questions)

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2. Social functioning (two questions)
3. Role limitations – physical problems
(four questions)
4. Role limitations – emotional problems
(three questions)
7. Pain (two questions)
8. General health perception (five
questions)
9. Health change (one question)

DED, dry eye disease; QoL, quality of life; SS, Sjögren's syndrome.
a
Validation was not specific to DED.

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The Ocular Surface 17 (2019) 9–19
J.A.P. Gomes, R.M. Santo
of DED on daily life, and treatment satisfaction. A higher score in the
DED symptom bother module indicates more bothersome DED symp-
toms, with the average scores of patients with mild and severe DED
being 40.0 and 64.3, respectively [65]. Higher scores for daily life
impact and treatment satisfaction questions correspond to better QoL
and better treatment satisfaction. The disease-specific IDEEL scales are
better able to discriminate between severity levels than the majority of
the generic QoL scales [66]. With the exception of the treatment sa-
tisfaction module, the IDEEL questionnaire can significantly dis-
criminate between levels of severity in DED (P < .0001) [66]. Fur-
thermore, treatment efficacy can be assessed using the symptom bother
module; Fairchild et al. found that a 12-point shift in the IDEEL-
symptom bother module after treatment was a clinically important
difference in symptoms [67].
Symptom measures
One of the pioneering questionnaires for the self-assessment of
symptoms is the McMonnies dry eye Questionnaire (MQ), which was
primarily used as a screening tool for patients with a history of DED
symptoms [68]. Patients are asked questions regarding their DED
symptoms, including soreness, dryness and grittiness, in addition to
their treatment strategies and other health problems. In 2004, Nichols
et al. used the MQ to investigate its psychometric properties for DED,
concluding it to be only fairly valid for use as a patient-reported in-
strument in clinical studies owing to its lack of consistency between
patient visits (test-retest reliability 95% confidence interval [CI] −8.6
to +9.6) [69].
The Ocular Surface Disease Index (OSDI) questionnaire is used to
evaluate visual symptoms, including pain or light sensitivity, and en-
vironmental factors that may enhance symptoms, such as dry en-
vironmental conditions over the past 7 days [70]. The OSDI comprises
12 questions, which are divided into three subsections (vision-related
function, ocular symptoms and environmental triggers). The OSDI is
considered to be a reliable and valid measurement for the severity of
DED [70,71] despite some limitations in only discussing certain visual-
related effects of DED [65]. Patient symptoms can be categorised as
normal (0–12), mild DED (13–22), moderate DED (23–32), or severe
DED (33–100) [71]. A high OSDI score has been correlated with low
work productivity and reduced satisfaction with over-the-counter DED
treatments [62].
The Symptom Assessment in Dry Eye (SANDE) questionnaire is used
to quantify the severity and frequency of DED symptoms based on a
visual analogue scale [71]. The SANDE questionnaire was validated in
2007 by Schaumberg et al., who found reproducibility in SANDE scores
taken at baseline, within a few days of starting treatment and again at a
2-month follow-up [72]. Amparo et al. reported that the SANDE ques-
tionnaire showed significant correlation with the OSDI questionnaire
[71].
The Ocular Comfort Index (OCI) is a psychometric, patient-assessed
measure of ocular surface irritation that was validated for use in clinical
trials in 2007. Johnson and Murphy found that the OCI had a positive
correlation with OSDI score (P < .0001) and a negative correlation
with tear film break-up time (TBUT, P < .0001), and it was able to
detect improvements in symptoms before and after treatment
(P < .0001) [73].
Validated by Chalmers et al. in 2010, the five-item Dry Eye
Questionnaire (DEQ-5) [74] focuses on three common symptoms of
DED: watery eyes, eye discomfort and eye dryness. This questionnaire's
aim is to diagnose patients with DED, but it may additionally be used to
identify the need for further clinical testing for Sjögren's syndrome, an
autoimmune disease that induces hyposecretion of tears [75]. DEQ-5
scores ≥5 indicate DED, and ≥12 are considered to be indicative of
Sjögren's syndrome [74,75].
Long-term symptom changes over 3 months may be assessed using
the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire,
15
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The Ocular Surface 17 (2019) 9–19
which was validated with respect to existing DED questionnaires in
2013. The SPEED questionnaire consists of eight questions on a 5-point
scale, split into frequency and severity of ocular dryness symptoms. The
SPEED questionnaire was able to distinguish between symptomatic
(OSDI score ≥ 13) and asymptomatic (OSDI score < 13) groups of
participants (P > .05), but correlations between clinical measurements
were inconsistent [76].
Most of the questionnaires designed to assess DED symptoms were
not designed with contact lens wearers in mind [77]. However, the
Contact Lens Dry Eye Questionnaire (CLDEQ), which was piloted by
Begley et al. in 2000 [77] and validated by Nichols et al. in 2002 [78],
is an assessment of symptoms associated with DED among contact lens
wearers. Frequency and severity of ocular discomfort, dryness, blurry
vision, eye closing frequency, and removing contact lenses for relief are
all included in the CLDEQ-8 [79]. Visual analogue scales are used to
measure the presence, frequency, severity and intrusiveness of common
symptoms that may be related to the use of contact lenses and DED,
such as dryness, discomfort, irritation and blurry, and changeable vi-
sion. Begley et al. reported a significant difference (P < .00001) be-
tween the severity of dryness with and without contact lenses in pa-
tients using the CLDEQ [77]. A shortened version of the CLDEQ, the
eight-item CLDEQ-8, was later developed to be used alongside the DEQ-
5. Questions in the CLDEQ-8 aim to reflect the satisfaction with and
overall opinion of soft contact lenses in patients with significant soft
contact lens–related DED complaints.
General health status measures
Although they do not always correlate with clinical measures for
evaluating DED, the DED questionnaires mentioned above tend to
correlate, albeit weakly, with each other [65]. The DED-specific QoL
questionnaire results also appear to correlate with general health-re-
lated QoL questionnaire results, such as the 51-item National Eye In-
stitute Visual Function Questionnaire (NEI VFQ) or the Medical Out-
comes 36-item Short Form Health Survey (SF-36), and these
correlations are used to validate the reliability of the questionnaires and
collect further information about each patient [26].
The NEI VFQ was validated in 1998 by Mangione et al. who tested
its reliability and validity in 598 participants with common eye con-
ditions, including those with DED symptoms. Subscales in the NEI VFQ
include general health, vision, ocular pain, difficulties with driving,
reading, and vision-specific mental health [80].
The SF-36 is a 36-item questionnaire on physical functioning, bodily
pain, general health perceptions, social functioning, and limitations
caused by emotional and physical problems [81,82]. The performance
and validity of the SF-36 questionnaire have not been formally assessed
in patients specifically with DED. However, Mertzanis et al. used the SF-
36 to assess the burden on health status and QoL of patients with DED.
Patients with DED scored lower on all SF-36 scales compared with a
control group, and the more severe the disease among the DED groups,
the lower the SF-36 score [83]. Furthermore, as DED symptoms in-
crease in severity, more aspects of life are affected on a clinically
meaningful level, including perceptions of health, physical functioning,
social functioning, and role-emotional limitations [83]. The results in-
dicate that DED has a negative impact on daily activities and emphasise
the need for disease-specific measures for DED examination. The study
published by Santo et al. also reinforces the concept that DED has an
impact on health-related QoL. In their study, patients with DED an-
swered the OSDI, 25-item Visual Function Questionnaire (VFQ-25) and
SF-36. The scores were compared using Spearman's correlation test, and
a negative association was found between OSDI and VFQ-25 total score
and between the OSDI and five SF-36 domains [84].
Critical review of DED treatments and quality of life
Using the comprehensive searching method as previously described,
J.A.P. Gomes, R.M. Santo
relevant publications with abstracts that reported the investigation of
DED treatments with qualitative symptom measures were hand-picked.
The patient-reported satisfaction and QoL data for each treatment in-
gredient, collected by patient-assessed questionnaires, are discussed in
this section. It should be noted that differences in study design make
comparisons between phase VI post-marketing studies and controlled,
randomised clinical trials challenging; therefore, conclusions on the
effects of different treatments on patient satisfaction and QoL should be
considered with caution.
Active ingredients
HPMC is a modified polymer and an active ingredient found in ar-
tificial tears or ophthalmic inserts to prolong drug retention on the
ocular surface. Other hydrophilic polymers, such as polyvinyl alcohol,
are also often added to artificial tears for the same reason [44,85].
HPMC treatments have been associated with improvements in sub-
jective symptom scores, OSDI scores and overall enhancement of pa-
tients' QoL. Subjective symptoms, such as ocular fatigue, pain and
itching, were assessed by patients before and after treatment with ar-
tificial tears containing HPMC 0.5%. These symptoms, measured on a
scale from 0 to 5, significantly improved (P < .01) after treatment with
HPMC in patients with non-Sjögren's DED (n = 9) and in patients with
Sjögren's syndrome (n = 11) [44]. Prabhasawat et al. investigated the
effect of HPMC 0.3%/dextran 0.1% eye drops in 10 patients with DED
by using the MQ. After a single instillation, there were significant im-
provements from baseline in MQ score (P < .05) [45].
CMC is the most common polymeric ingredient included in artificial
tears for the treatment of DED symptoms, and it is available in a range
of concentrations from 0.25% to 1.5% [37]. Mencucci et al. established
that a CMC 0.5%-containing lubricant had higher clinical efficacy, in
terms of TBUT (P = .0003), in patients with DED than a topical ster-
oidal formulation [36]. The addition of CMC to an artificial tear for-
mulation has also been shown to result in significant increases in pa-
tient-reported symptom tolerability compared with an artificial tear
formulation without CMC as the primary lubricant (P < .04, for all
items) [38]. In over 250 patients with DED symptoms, OSDI scores were
lower with CMC compared with a lipid-based tear formulation without
CMC [38]. Furthermore, after using CMC-containing eye drops for 6
weeks, 147 patients with clinical signs of DED were significantly more
satisfied (P = .0310) than a control group using PEG-containing arti-
ficial tears for the ‘I was bothered by blurriness shortly after using my
eye drops’ statement in the IDEEL questionnaire; however, all other
items were similar for both groups [31]. Artificial tears containing CMC
0.5% were also associated with improved QoL from baseline, with
85.4% of patients reporting improved local comfort and 90.9% of 5277
patients with DED reporting satisfaction with the treatment after 2–4
weeks [32]. When a CMC solution was compared with an HPMC solu-
tion, CMC was shown to have a significantly slower rate of clearance
from the eye, increasing its duration of action on the ocular surface
[33].
HA is a lubricant polymer with distinctive viscoelastic and hygro-
scopic properties that have therapeutic effects in patients with DED
[42]. HA occurs naturally in humans and is found in the synovial fluid
of the joints and eyes, acting as an anti-inflammatory agent. Saeed et al.
assessed the effectiveness, safety and tolerability of an HA 0.4%-based
ophthalmic solution in 240 patients with DED. After 8 weeks of treat-
ment, ocular signs and symptoms had decreased from baseline, with a
5.3% decrease in foreign body sensation and itching [42]. Pinto-Fraga
et al. reported a significant difference in patient satisfaction between
HA 0.2%-containing artificial tears and a saline 0.9% solution in a 1-
month crossover study of 16 patients with mild DED. Patient satisfac-
tion increased by 26.8% using the HA 0.2% solution, compared with a
13.3% decrease for the saline solution (P ≤ .04) [41]. Other polymeric
ingredients, such as carbomer gel, are added to artificial tears to
maintain the tear film for an extended period [86]. The severity of
16
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The Ocular Surface 17 (2019) 9–19
common symptoms of DED, including ocular dryness and discomfort,
was reported to significantly decrease (P < .05) with the addition of a
carbomer to an ophthalmic solution compared with placebo [86]. There
are no reports of the effects of carbomer on patient satisfaction to date.
A combination of HA 0.1% and CMC 0.5% has been shown to be ef-
fective in reducing symptoms of DED in patients recovering from cat-
aract surgery; mean OSDI scores were significantly reduced from
baseline (P < .0001) after 5 weeks of treatment with a CMC 0.5%/HA
0.1% solution [36].
Trehalose is a natural bioprotectant that promotes bioprotection of
ocular epithelial cells against inflammation and apoptosis triggered by
osmotic stress. In turn, this helps manage tear hyperosmolarity, which
may be caused by factors such as insufficient tear production in patients
with DED [39]. Artificial tears containing HA and trehalose as the ac-
tive ingredients have previously been shown to increase patient sa-
tisfaction ( ± standard deviation [SD]) by 25.7% ( ± 25.0) and de-
crease OSDI scores ( ± SD) by 15.2 ( ± 10.9) from baseline after a 7-
day course of treatment in 17 patients with moderate-to-severe DED
[40]. OSDI score was a secondary efficacy endpoint in a phase III,
randomised, multicentre study comparing HA eye drops with trehalose-
containing HA eye drops in patients with DED. At Day 84, both the
change from baseline in OSDI score and the number of patients with an
OSDI class of none or mild were significantly greater in patients re-
ceiving HA/trehalose than in patients treated with HA alone (P < .06)
[39].
Lubricants such as PEG and PG aid the restructuring of the tear film
by forming a gel matrix [87]. The PEG/PG combination has been shown
to significantly decrease OSDI scores (P = .0013) and significantly re-
duce ocular symptoms, including dryness and burning (P ≤ .0021),
from baseline after 42 days of treatment use [46]. PEG/PG lubricating
eye drops exhibit non-inferiority to osmoprotective CMC-containing
treatment in terms of treatment satisfaction. Using the IDEEL ques-
tionnaire, Labetoulle et al. reported similar differences in scores be-
tween PEG/PG and CMC treatments at Days 35 and 90 [34].
Some artificial tears available as over-the-counter treatments in-
clude the gelling agent hydroxypropyl-guar. Hydroxypropyl-guar acts
by self-developing into a gel-like substance over the eye, protecting the
ocular surface cells and allowing them to recover in a microenviron-
ment [88]. Hydroxypropyl-guar-containing formulations significantly
improve overall OSDI scores compared with a control treatment
(P = .0002) [48]. Furthermore, treatment with formulations of this
type has produced statistically significant improvements in DED
symptoms compared with baseline (P < .0001) after 7, 14 and 28 days,
thus likely contributing to improvements in patients' QoL [50,51]. In a
6-week, prospective, non-inferiority study, patients with DED were
randomised to receive either a hydroxypropyl-guar/HA eye drop or an
over-the-counter HA eye drop that did not contain hydroxypropyl-guar.
At Day 42, IDEEL scores of the hydroxypropyl-guar/HA eye drop group
were improved from baseline in the ‘inconvenience’ category (LSM
change −10.32), and were significantly improved compared with the
over-the-counter HA control group (P = .0001). There was no sig-
nificant difference in the ‘effectiveness’ category between treatments
(P = .4817); the authors thus concluded that a hydroxypropyl-guar-
containing HA solution is non-inferior to a current over-the-counter HA
eye drop [49].
Osmoprotectants
Osmoprotectants are included in artificial tears to protect ocular
surface cells from the effects of hyperosmotic stress due to tear eva-
poration (and consequent inflammation) and to promote the growth of
epithelial cells [89,90]. L-carnitine, erythritol and betaine are examples
of osmoprotectants in nature [91]. Osmoprotective agents are often
included in artificial tear formulations. In an observational study dis-
cussed previously, 90.9% (n = 4797) of patients were somewhat to very
satisfied with an artificial tear treatment containing glycerol 0.9% as an
J.A.P. Gomes, R.M. Santo
osmoprotectant added to a CMC 0.5% formulation [32]. In a phase III
study that compared artificial tears containing CMC and three osmo-
protectants (glycerine, erythritol and L-carnitine) with an HA 0.18%
solution, change in OSDI score suggested that the osmoprotective for-
mulation was non-inferior to HA (P = .578). In the same study, how-
ever, patient satisfaction was greater using the osmoprotective for-
mulation, and patients reported greater ease of use and a requirement
for less frequent use with the osmoprotective formulation compared
with the control tears [47]. Patient satisfaction scores were also sig-
nificantly higher with the use of an HA-based artificial tear formulation
with added glycerine compared with the patients’ current tear sub-
stitute over a 2-week period (P = .0003 after 1 week, P = .0232 after 2
weeks) [43].
Adding an osmoprotectant to the CMC/HA combination has also
been associated with improvements in symptom frequency in patients
with DED. An artificial tear solution containing CMC 0.5%, HA 0.1%,
glycerine and erythritol provided reductions in OSDI score from base-
line at treatment Day 35 and Month 3. Compared with an HA 0.18%
solution, the osmoprotectant combination solution was non-inferior in
improving both objective and subjective signs and symptoms of DED,
offering potential advantages in patient acceptance [35].
Topical secretagogues
Topical pharmacological agents, such as diquafosol, have tear se-
cretion–promoting effects. Diquafosol is a P2Y2 purinergic receptor
agonist that aids the stimulation of aqueous and mucin secretion from
the conjunctival tissue, thus improving the quality and surface activity
of tear fluid [53]. This effect relates to the QoL of a patient with DED
symptoms, as reported by Takamura et al.: diquafosol was significantly
more effective at reducing subjective, patient-assessed symptoms than
treatment with HA (P = .033) [53]. Using a DED treatment containing
diquafosol 3%, patients with moderate-to-severe DED (n = 60) reported
significant improvements in OSDI scores from 43.45 at baseline to
28.01 at Month 1 (P < .001) and to 26.40 at Month 3 (P < .001) [54].
In addition, diquafosol produced significant improvements in OSDI
scores when compared with the T-cell modulator CsA, which has pre-
viously been shown to enhance tear production [54,57]. After 1 month
of treatment, patients with moderate-to-severe DED had significant
improvements (P = .014) in OSDI score with the diquafosol solution
[54]. Similar to diquafosol, rebamipide is an ingredient used in oph-
thalmic solutions that can induce mucin production [55]. Rebamipide
has exhibited good efficacy in clinical measures and has been associated
with significant improvements in subjective patient-assessed symptom
scores. Mean OSDI results were significantly improved in patients with
both ‘definite’ and ‘probable’ DED (P < .01), from 39.0 at baseline to
26.0 after 4 weeks of rebamipide treatment [55]. Rebamipide and di-
quafosol were both tested in a randomised clinical trial for the treat-
ment of DED in office workers. Using the DEQS, patients reported a
significant improvement in overall subjective symptom scores after 4
weeks of either treatment (P < .001). Patients treated with diquafosol
reported significantly better comfort scores than the rebamipide group
(P = .024), although no overall differences between the rebamipide
and diquafosol treatment groups were observed [52].
Topical immunomodulators
Biological treatments that interrupt the inflammation pathway are
also well established for DED [92]. Anti-inflammatory therapy, or im-
munomodulators, directly targets the inflammatory cascade and, as a
result, is considered to be the first causative therapeutic approach. CsA,
a fungal-derived peptide, inhibits T-cell activation and the production
of inflammatory cytokines to reduce inflammation at the ocular surface
[93]. In 877 patients with DED, a CsA 0.05%–containing ophthalmic
solution and a CsA 0.1%–containing ophthalmic solution gave sig-
nificantly greater improvements (P < .05) over 6 months than an
17
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The Ocular Surface 17 (2019) 9–19
artificial tear vehicle in subjective symptom measures of DED, including
blurred vision and need for additional usage [56]. Lifitegrast is a small
molecule that also inhibits T-cell activation, by blocking the binding of
intercellular adhesion molecule 1 to the integrin lymphocyte functio-
n–associated antigen on the T-cell surface, thus reducing T-cell-medi-
ated ocular inflammation [58]. Lifitegrast was recently approved in the
US by the Food and Drug Administration for the treatment of DED;
phase II and III studies have shown that treatment with a lifitegrast
5.0% ophthalmic solution significantly improves visual-related function
vs a placebo treatment for both mild-to-moderate DED (P = .0394) and
moderate-to-severe DED (P < .0001), as assessed using a patient-re-
ported symptom scale [58]. Patients treated with the lifitegrast 5.0%
ophthalmic solution recorded significant improvements (P < .05) vs
placebo over 12 weeks in OSDI score in the two most commonly re-
ported symptoms at baseline: ‘ocular discomfort’ and ‘eye dryness’ [59].
An alternative topical immunomodulator is the immunosuppressive
drug tacrolimus. DED specialists have indicated that more data on ta-
crolimus are required [94]. Single-arm and placebo-controlled clinical
trials using 0.03% tacrolimus eye drops for the treatment of Sjögren's
syndrome DED demonstrated efficacy in improvement of DED signs;
however, patients complained of moderate burning sensation for a short
time after instillation of the eye drops [95,96].
Discussion and conclusion
Patients with DED suffer from an array of ocular symptoms that can
have detrimental effects on QoL. Driving, reading [22], work pro-
ductivity [19], and sleep [21] are all affected by ocular pain, dryness,
grittiness, and general discomfort. The pain associated with DED may
be comparable with that of moderate-to-severe angina in cases of severe
DED [6]. The key results from the literature search show a variety of
validated, reliable questionnaires available for use to gather informa-
tion on patient-reported symptomology, QoL and satisfaction. DED
symptoms and general health assessments, including the OSDI, IDEEL,
SANDE and SF-36 questionnaires, are widely used in screening patients
for participation in clinical trials and validating clinical data; they are
important measures for determining the extent of patient satisfaction
and QoL with the use of different DED treatments [34,54,83]. However,
given the fact that there is no universally accepted single DED PRO
measure, cross comparison is difficult.
The formulations currently available as over-the-counter treatments
for DED, including HA and CMC, are clinically beneficial in terms of
improving TBUT and lubrication of the ocular surface [36], with levels
of patient-reported satisfaction with these treatments at 64.2% [62].
Higher disease severity levels were associated with lower satisfaction
with treatment, with satisfaction levels of 75.1% and 65.8% for patients
with mild and severe symptoms, respectively [62].
One limitation of the present review is the fact that differences in
study design make comparisons between phase VI post-marketing stu-
dies and controlled, randomised clinical trials challenging; therefore,
conclusions on the effects of different treatments on patient satisfaction
and QoL should be considered with caution. For direct comparison,
drop formulation would need to be the only element altered, which
opens up interesting possibilities for future studies. Furthermore, it
should be acknowledged that given the nature of eye drops (i.e. mul-
tiple active and inactive ingredients), the results of the studies may not
be directly attributable to the identified ingredients. Whilst bearing
these caveats in mind, the results of our literature search showed that
notable improvements in patient satisfaction and QoL are produced by
a CMC 0.5% and glycerol 0.9% ophthalmic solution treatment: 90.9%
of patients using this treatment reported satisfaction with the product,
and 85.4% of patients experienced an improvement in symptoms of
discomfort [32,97]. Osmoprotectants also contribute to increased pa-
tient satisfaction, as demonstrated by Solomon and Merin, who re-
ported a significant increase in patient satisfaction for artificial tears
with added glycerine compared with a control formulation [43].
J.A.P. Gomes, R.M. Santo
Labetoulle et al. observed that a formulation containing CMC, HA and
osmoprotectants was associated with less severe stinging/burning,
sandiness/grittiness and sore eyes compared with a HA-only formula-
tion [35]. In addition, Simmons el al. found that in patients with more
pronounced ocular surface damage, a combination of osmoprotectants,
CMC and HA may be a superior therapeutic option than a standard
CMC-containing formulation [38]. HA as an active ingredient in arti-
ficial tears has also been associated with improving patient QoL and
levels of satisfaction (44.5%–70.2%) after just 7 days of treatment [40].
Overall, treatments with added lubricants, osmoprotectants and gelling
agents all contribute to higher levels of patient satisfaction over a short-
term period (up to 3 months) than those without [46–48]. It should be
noted, however, that some treatments may not be discussed in this
review owing to a lack of published studies reporting QoL or survey
measures in therapeutics with FDA/other regulatory agency approval.
Patient satisfaction and QoL scores generally increase after treat-
ment with many of the ingredients discussed compared with before or
after use of a control treatment, typically a commercially available HA-
only formulation, but there are gaps in the literature on patient sa-
tisfaction and QoL that should be addressed. More data are required to
identify trends and distinguish differences between active ingredients.
In addition, most of these patient-assessment methods are not widely
used in the diagnosis and management of DED over a long period of
time [62]. At present, the studies evidence that tear supplementation
with ocular lubricants results in high satisfaction, especially in patients
with mild-to-moderate DED. More severe cases may require additional
combined therapy.
PROs do not always correlate with clinical data [24], but, owing to
the subjective nature of DED assessments, they are useful and con-
sidered an important measure given the impact DED can have on pa-
tients' daily lives [6,65].Therefore, QoL measures might provide clin-
icians with a more valuable tool for assessing the burden of DED and
response to treatment [97]. Tests of a range of ophthalmic formulations
containing differing active ingredients have shown positive outcomes
for patient satisfaction and QoL enhancement. These data highlight the
need to assess the relative burden of DED sufficiently to reduce the
impact of DED symptoms on patients' daily life, by continuing to
evaluate PRO's as part of effective DED management. The importance of
improving these qualitative aspects should be considered similar to that
of improving clinical aspects, keeping patient well-being at the fore-
front of clinical trials and study design.
Disclosures
José A. P. Gomes, MD, PhD: Consultant for Allergan, MSD, Bausch &
Lomb/Valeant, Mundipharma, EMS/Legrand, Shire; Lecture board for
Alcon, Allergan, Genom, Bausch & Lomb/Valeant, Pfizer,
Mundipharma, Grin, Ofta Vision Health; Grants from FAPESP, Capes,
Cnpq.
Ruth M. Santo, MD, PhD: Consultant for Allergan, Alcon/Novartis,
Bausch & Lomb/Valeant, Shire, EMS/Legrand; Lecture board for
Allergan, Pfizer, Alcon/Novartis, Genom, Mantecorp/Farmasa, Ofta
Vision Health; Grants from FAPESP.
Acknowledgements
The authors thank Newton Healthcare Communications for writing
and editing support, and Dr Sameena Haque at Allergan, UK, for her
valuable insights and contributions. The authors also thank Allergan,
UK, for funding.
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