Ophthalmic & Physiological Optics ISSN 0275-5408

Associations of systemic diseases, smoking and contact lens

wear with severity of dry eye
Sze-Yee Lee1, Andrea Petznick1 and Louis Tong1,2,3,4
1
Singapore Eye Research Institute, 2Singapore National Eye Centre, 3Duke-NUS Graduate Medical School, and 4Yong Loo Lin School of Medicine,
National University of Singapore, Singapore

Citation information: Lee S-Y, Petznick A & Tong L. Associations of systemic diseases, smoking and contact lens wear with severity of dry eye.
Ophthalmic Physiol Opt 2012, 32, 518526. doi: 10.1111/j.1475-1313.2012.00931.x

Keywords: contact lenses, dry eye, human, Abstract

meibomian gland dysfunction, rheumatoid
arthritis
Correspondence: Louis Tong
E-mail address: louis.tong.h.t@gmail.com
Received: 9 April 2012; Accepted: 13 July
2012
Purpose: Systemic diseases, smoking, ocular surgeries and contact lens wear
have been linked with dry eye but it is not known if these factors are also asso-
ciated with severity of dry eye. A cross-sectional investigation was conducted
on the effect of various systemic and ocular conditions with respect to the
severity of dry eye in Asian patients.
Methods: Prospective recruitment of consecutive new referral patients from a
dry eye clinic was performed. Medical history, dry eye symptoms and clinical
assessment were coded in a standardised form and analysed.
Results: Out of 510 patients (25% men), mean S.D. age 53.0 14.1 years, 25
had previous diagnosis of rheumatoid arthritis, 30 had diabetic mellitus, 41
had thyroid disease, and 33 were current smokers; 23 and 41 patients had pre-
vious LASIK and cataract surgery respectively and 90 were current contact
lenses wearers. A previous diagnosis of rheumatoid arthritis was associated with
more severe superior corneal fluorescein staining (OR = 11.2, 95% CI 4.6
27.4).
Conclusion: Generally, with the exception of rheumatoid arthritis, there were no
associations between dry eye severity and systemic diseases, smoking, previous
ocular surgeries and contact lens wear. Dry eye patients with rheumatoid arthri-
tis tend to have more severe ocular surface damage in the superior cornea.

Many dry eye sufferers are elderly patients with con-

Introduction
Dry eye disease is defined as ocular surface dryness and
discomfort related to abnormal tear film from either
decreased aqueous tear production or excessive tear evap-
oration.1 Significant ocular surface damage and visual dis-
ability associated with dry eye are common.2 Dry eye
disease represents a significant healthcare problem affect-
ing millions of people around the world with prevalence
rates estimated to be as high as 535% of the general
population.36
Meibomian gland dysfunction (MGD) is recognised as
an important condition that is related to dry eye. Since
some of the symptoms and signs of MGD overlap with
that of dry eye, and in particular evaporative dry eye, it is
difficult to distinguish medical risk factors that are
specific to MGD and independent of dry eye disease.
comitant medical conditions.7 Dry eye and MGD may be
an outcome of a systemic medical condition3,8,9 and pre-
vious ocular surgery such as LASIK.3 Systemic risk factors
for dry eye include autoimmune and inflammatory dis-
eases. In Sjogrens syndrome, for example, the lachrymal
gland is attacked by lymphocytes and gradually loses its
function.10 Rheumatoid arthritis (RA), another systemic
autoimmune disease, may cause secondary Sjogrens syn-
drome. However, increased risk of dry eye has been
reported even in RA patients without secondary Sjogrens
syndrome.11 Diabetes mellitus (DM), on the other hand,
affects the corneal nerves which causes a hyposecretory
response from the lachrymal gland.12,13
LASIK-induced dry eye is extremely common with up to
35% of patients having persistent dryness that extends
beyond 6 months after surgery.1416 Another commonly

518 Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute
S-Y Lee et al.
performed ocular surgery is cataract surgery. The surgical
incisions during cataract surgery may inadvertently damage
corneal nerves,17 and thus reducing corneal sensation.18
It has not been reported whether the presence of these
systemic or ocular conditions are associated with more
pronounced symptoms or more severe clinical signs of
dry eye or MGD in dry eye patients. This is relevant
because there is a wide range of severity in dry eye
patients and the methods of treatment required are very
different in mild and severe dry eye.19
The present study was a cross sectional study that used
prospectively collected clinical data from a group of dry
eye patients treated in a tertiary eye clinic. The aim of
this study was to evaluate symptoms and clinical signs in
patients with dry eye and/or MGD to identify possible
associations between the presence of ocular and systemic
conditions and the severity of dry eye.
Methods
Patients
Prospective recruitment of patients from the dry eye
clinic at the Singapore National Eye Center was per-
formed between August 2006 and October 2010. Consec-
utive 510 patients visiting the clinic for the first time
were enrolled in the study.
The study protocol was part of a routine, on-going arm
of a long term clinical audit and was approved by the
Institutional Review Board of the Singapore Eye Research
Institute. All study procedures complied with the tenets of
the Declaration of Helsinki on human research. As all pro-
cedures performed were essential for standard clinical care
of these patients, written consent was not required, but
consent was taken by assent. Patients were informed of
the hospital privacy policy that required all patient identi-
fiers to be removed for any publication.
Patients with dry eye symptoms and at least one abnor-
mal finding out of the three objective clinical tests (Schir-
mers test without anaesthetic 10 mm at 5 min, tear
break-up time (TBUT) 10 s, or significant corneal fluo-
rescein staining as evaluated by the referring physician)
were referred to the investigators (LT) clinic and
recruited on their first visit.
Data collection
Dry eye symptoms, ocular surface and eyelid assessments
were coded in a standardized form and analyzed. Patients
were asked about the history of factors known to be asso-
ciated with dry eye, such as current smoking,8,9,2022
current contact lens (CL) wear,2329 previous ocular sur-
geries,3,4,8,9,30 and diagnoses of RA,3,31 DM9,12,13,30,32 and
thyroid disease.3,8,9,30 Current smoking was defined as
Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute
Systemic conditions and associations with dry eye
having smoked within the previous 1 year, whereas a
patient was considered to be a current CL user if lenses
have been worn within the previous 1 month.
Clinical assessment
Assessment of dry eye symptoms was administered by a
trained interviewer using three of eight questions
described previously.33 The patients were interviewed with
the following questions: Did you have sensitivity to bright
lights in the last month?, Did you have a feeling of ocu-
lar grittiness in the last month? and Did you have any
blurring of vision last month? The answer was coded into
0 (none at all), 1 (occasionally), 2 (once in the week), 3 (a
few times per week) and 4 (at least once a day).
Clinical examination was conducted by a single oph-
thalmologist (LT) to avoid inter-examiner discrepancies.
Clinical examinations included Schirmers test (without
anaesthesia), TBUT, corneal fluorescein staining, and
evaluation of meibomian gland status. For TBUT and
corneal staining evaluation, fluorescein was instilled with
a fluorescein strip (Fluorets, http://www.Bernell.com)
moistened with non-preserved sodium chloride. TBUT
was measured with a stopwatch and determined as the
time taken (in seconds) for the first dark spot to appear
on the cornea from the moment of eye opening. Corneal
fluorescein staining was graded according to a previously
reported corneal fluorescein staining scheme.34 The cor-
nea was divided into five zones for evaluation superior,
inferior, nasal, temporal and central. The number of fluo-
rescein spots in each zone was recorded; a greater number
of spots were reflected by a higher score (ranging from 0
to 5). One extra point was added to the grade if there
were filaments present in the zone, and another point if
there was confluent fluorescein staining.
Anteriorization of Marxs line (mucocutaneous junc-
tion) relative to the meibomian gland orifices (Yamaguchi
grading)35 in the eyelid margins was assessed as in our
previous report33 in temporal and nasal halves of each
eyelid. A higher score indicated a greater severity of
MGD.
Statistical analysis
Statistical analysis was performed using SPSS version 17
(http://www.ibm.com/SPSS_Statistics). To maintain inde-
pendence of data points, only the data points obtained
from the right eyes were used in the analysis. The age and
gender distribution of the medical and ocular factors were
evaluated using either the Chi square tests (for ordinal
variables) or MannWhitney U-test (for continuous vari-
ables). Where a cell number was < 7, the Fishers exact
probability test was used instead.
519
Systemic conditions and associations with dry eye S-Y Lee et al.

The presence of systemic disease, smoking, ocular sur-
gery and CL wear were analysed as independent variables
against the outcome measures (dry eye tests) as depen-
dent variables. Outcome variables such as TBUT were
compared between dichotomous groups (such as smokers
vs non-smokers) using the MannWhitney U-test since
the data were not normally distributed.
Spearman correlation analysis was first performed to
determine any correlation between severity of clinical
signs and symptoms with age. In logistic regression

Table 1. Frequency of medical and ocular conditions in the study population

Age group Total (%) Male (%) Female (%) p-value

Demographics
N 510 130 (25) 380 (75)
Age (mean S.D.) in years 53 14 51 16 54 13
40 95 35 (36.8) 63 (66.3) < 0.001*
4160 244 53 (21.7) 191 (8.3)
61 171 42 (24.6) 129 (75.4)
p-value < 0.001*
Medical history
Rheumatoid arthritis Total 25 (4.9) 1 (0.8) 24 (6.3) 0.008
40 2 (2.1) 1 (2.9) 1 (1.6)
4160 15 (6.1) 0 (0.0) 15 (7.9)
61 8 (4.7) 0 (0.0) 8 (6.2)
p-value 0.28
Diabetes mellitus Total 30 (5.9) 11 (8.5) 19 (5.0) 0.19
40 0 (0.0) 0 (0.0) 0 (0.0)
4160 9 (3.7) 3 (5.7) 6 (3.1)
61 21 (12.3) 7 (16.7) 14 (10.9)
p-value < 0.001*
Thyroid disease Total 41 (8.0) 3 (2.3) 38 (10) 0.004#
40 1 (1.1) 0 (9.0) 1 (1.6)
4160 24 (9.8) 0 (0.0) 24 (12.6)
61 16 (9.4) 3 (7.1) 13 (10.1)
p-value 0.032
Current smoking Total 33 (6.5) 26 (20) 7 (1.8) < 0.001*
40 7 (7.4) 5 (14.3) 2 (3.2)
4160 10 (4.1) 8 (15.1) 2 (1.0)
61 12 (7.0) 10 (23.8) 2 (1.6)
p-value 0.33
Ocular history
LASIK Total 23 (4.5) 5 (6.4) 17 (5.8) 0.81
40 7 (7.4) 0 (0.0) 7 (11.1)
4160 13 (5.3) 3 (5.7) 10 (5.2)
61 4 (2.3) 2 (4.8) 2 (1.6)
p-value 0.17
Cataract surgery Total 41 (8.0) 12 (9.2) 29 (7.6) 0.58
40 0 (0.0) 0 (0.0) 0 (0.0)
4160 9 (3.7) 2 (3.8) 7 (3.7)
61 32 (18.7) 10 (23.8) 22 (17.1)
p-value < 0.001*
CL wear Total 90 (17.6) 12 (9.2) 78 (20.5) 0.005#
1030 41 (43.2) 8 (22.9) 33 (52.4)
4150 33 (13.5) 4 (7.5) 39 (20.4)
6170 7 (4.1) 2 (4.8) 7 (5.4)
p-value^ < 0.001*

RA, rheumatoid arthritis; DM, diabetes mellitus; TD, thyroid disease; CL, contact lens.
*p < 0.001.
#
p < 0.005.
p-value for significant inclination towards a gender.
^p-value for significant association of condition with age.

520 Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute
S-Y Lee et al. Systemic conditions and associations with dry eye

models the significant medical\ocular factors were evalu- Table 2. Dry eye symptom grading stratified by the presence of the
ated as independent variables and the associated clinical various systemic conditions and history of ocular surgery
features of dry eye as the dependent variable. The regres- Light Burning
sion results were presented as crude and adjusted odds Condition sensitivity Grittiness sensation
ratios (OR). The measurements for the dependent vari-
Overall median 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.02.0)
able were dichotomised into values above or below the
(interquartile
mean of the variable values into 1 and 0 respectively in range)
logistic regression analyses. RA 2.0 (0.04.0) 2.0 (0.04.0) 2.0 (0.03.0)
Since multiple statistical tests have been performed in No RA 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.02.0)
this study, the level of statistical significance (p < 0.05) p-value 0.020 0.081 0.052
for the crude analysis was adjusted using the Bonferroni DM 0.0 (0.02.0) 1.0 (0.02.5) 0.0 (0.02.0)
correction. For the analysis for associations between No DM 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.02.0)
p-value 0.45 0.44 0.39
symptoms and various conditions a significant p-value
TD 0.0 (0.03.0) 2.0 (0.04.0) 1.0 (0.02.0)
0.002 was used. For the analysis for associations between No TD 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.02.0)
clinical signs and various conditions, a Bonferroni adjust- p-value 0.93 0.26 0.53
ment would provide a p-value of 0.0006, but as SPSS can Smoking 1.0 (0.03.3) 2.0 (0.04.0) 0.0 (0.01.0)
only provide a level of significance up to three decimal No smoking 0.0 (0.03.0) 1.0 (0.030) 0.0 (0.02.0)
places, this value was rounded up to p < 0.001. p-value 0.39 0.12 0.19
LASIK 0.0 (0.03.5) 2.0 (0.04.0) 1.0 (0.04.0)
No LASIK 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.02.0)
Results p-value 0.93 0.68 0.14
Cataract 0.0 (0.04.0) 2.0 (0.04.0) 1.0 (0.02.5)
Patient demographics surgery
The mean S.D. age of the patients was 53.0 No cataract 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.02.0)
14.1 years, with 130 men (25%) (Table 1). 87.8% of the surgery
study population was Chinese, 1.8% Malay, 3.9% Indian p-value 0.67 0.81 0.87
and 6.5% were of other races. We recognise that this was CL wear 0.0 (0.03.0) 0.0 (0.02.0) 0.0 (0.02.0)
No CL wear 0.0 (0.03.0) 0.0 (0.04.0) 0.0 (0.02.0)
primarily a Chinese population and therefore we reanaly-
p-value 0.86 0.002* 0.92
sed the data using Chinese participants only. This reanal-
ysis however essentially produced the same conclusions RA, rheumatoid arthritis; DM, diabetes mellitus; TD, thyroid disease;
(data not shown). CL, contact lens.
In this study, 4.9%, 5.9% and 8.0% of the patients had MannWhitney U-test.
*p 0.002.
a previous diagnosis of RA, DM, and thyroid disease
respectively, and 6.5% were current smokers. 17.6% of
the patients wore CLs, 4.5% and 8.0% had previously had
LASIK and cataract surgery respectively. only two significant findings remained which were RA
The mean Schirmers test value, TBUT, corneal fluores- and superior corneal staining (p < 0.001), and CL wear
cein staining grades, Yamaguchi scores and symptom and ocular grittiness (p = 0.002).
scores in the factors of interest are shown in Tables 2 On further adjustments for age, sex and other ocular/
and 3. systemic factors using crude analysis, we found that a
Severity of most dry eye clinical signs increased with previous diagnosis of RA was associated with greater fluo-
age, including TBUT (p = 0.03), Schirmers test values (p rescein staining in the superior zone of the cornea com-
< 0.001), corneal fluorescein staining (p < 0.05) and pared to dry eye patients without RA (OR = 11.2, 95%
Yamaguchi scores (p < 0.001) (Table 4). On the other CI 4.6, 27.4) (Table 5).
hand, the severity of symptoms was not associated with Additionally, dry eye patients who wore CLs experi-
age. enced less ocular grittiness than other dry eye patients,
Using crude analysis, significant associations were using crude analysis (p = 0.002) (Table 2) and multivari-
found between RA and corneal fluorescein staining (supe- ate analysis (adjusted OR = 0.48, 95% CI 0.26, 0.88)
rior and inferior zones), previous cataract surgery and (Table 5).
Yamaguchi scores (in 3 out of 4 sectors), CL wear and
Schirmers test, and lastly, CL wear and frequency of ocu-
Discussion
lar grittiness (Tables 2 and 3). To exclude findings that
are confounded by age, we repeated the analyses for these This study investigated associations between the presence
associations and adjusted for age. After these analyses, of ocular and systemic conditions and the severity of dry

Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute 521
Systemic conditions and associations with dry eye S-Y Lee et al.

Table 3. (a) Dry eye clinical signs, (b) Yamaguchi score and MG plaques in the presence of the various systemic conditions and history of ocular surgery

Corneal fluorescein staining grade

Condition TBUT (secs) Schirmers (mm) Superior Inferior Temporal Nasal Central

(a)
Overall median 3.0 (2.03.3) 9.0 (5.015.0) 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.03.0) 1.0 (0.02.0) 0.0 (0.02.0)
(interquartile range)
RA 2.0 (2.03.0) 9.0 (3.016.0) 2.0 (0.02.0) 3.0 (2.04.0) 0.0 (0.03.0) 2.0 (0.03.0) 0.0 (0.01.0)
No RA 3.0 (2.04.0) 9.0 (5.015.0) 0.0 (0.00.0) 1.0 (0.03.0) 0.0 (0.01.0) 1.0 (0.02.0) 0.0 (0.02.0)
p-value 0.37 0.89 < 0.001* 0.001* 0.19 0.16 0.65
DM 3.0 (2.04.0) 7.0 (4.812.3) 0.0 (0.01.0) 3.0 (1.04.0) 0.0 (0.03.0) 1.0 (0.03.0) 0.0 (0.01.5)
No DM 3.0 (2.03.0) 9.0 (5.015.0) 0.0 (0.01.0) 1.0 (0.03.0) 0.0 (0.01.0) 1.0 (0.02.0) 0.0 (0.02.0)
p-value 0.37 0.95 0.71 0.015 0.59 0.82 0.66
TD 3.0 (2.03) 7.0 (4.013.0) 0.0 (0.01.0) 2.0 (0.03.0) 1.0 (0.02.0) 1.0 (0.02.0) 1.0 (0.02.0)
No TD 3.0 (2.04.0) 9.0 (5.015.0) 0.0 (0.01.0) 1.0 (0.03.0) 0.0 (0.01.0) 1.0 (0.0520) 0.0 (0.02.0)
p-value 0.56 0.16 0.82 0.29 0.078 0.23 0.26
Smoking 3.0 (2.04.0) 15.0 (5.817.8) 0.0 (0.02.0) 1.0 (0.03.0) 0.0 (0.03.0) 1.0 (0.03.0) 1.0 (0.03.0)
No smoking 3.0 (2.03.0) 9.0 (5.015.0) 0.0 (0.01.0) 1.0 (0.03.0) 0.0 (0.01.0) 0.0 (0.02.0) 1.0 (0.02.0)
p-value 0.49 0.18 0.028 0.72 0.20 0.23 0.20
LASIK 3.0 (2.54.0) 11.0 (0.035.0) 0.0 (0.00.5) 1.5 (1.03.0) 0.5 (0.01.0) 1.0 (0.02.0) 1.0 (0.02.5)
No LASIK 3.0 (2.03.0) 9.0 (0.035.0) 0.0 (0.01.0) 1.0 (0.03.0) 0.0 (0.01.3) 1.0 (0.02.0) 0.0 (0.02.0)
p-value 0.036 0. 056 0.89 0.69 0.52 0.86 0.22
Cataract surgery 3.0 (2.03.5) 7.0 (3.010.0) 0.0 (0.00.0) 2.0 (0.03.0) 1.0 (0.02.0) 0.0 (0.02.5) 0.0 (0.02.0)
No cataract surgery 3.0 (2.03.0) 9.0 (5.016.0) 0.0 (0.01.0) 1.0 (0.03.0) 0.0 (0.01.0) 1.0 (0.02.0) 1.0 (0.02.0)
p-value 0.78 0.015 0.11 0.57 0.041 0.81 0.054
CL wear 3.0 (2.04.0) 13.5 (6.020.0) 0.0 (0.01.0) 1.0 (0.03.0) 0.0 (0.02.0) 1.0 (0.03.0) 0.0 (0.01.0)
No CL wear 3.0 (2.03.0) 9.0 (5.014.0) 0.0 (0.00.0) 1.0 (0.03.0) 0.0 (0.01.0) 1.0 (0.02.0) 0.0 (0.02.0)
p-value 0.035 < 0.001* 0.16 0.74 0.86 0.87 0.19

Yamaguchi score

Condition Upper-temporal Upper-nasal Lower-temporal Lower-nasal MG plaques % (95% CI)

(b)
Overall median 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 18.0% (15.0, 21.6)
(interquartile range)
RA 2.0 (1.03.0) 2.0 (1.02.0) 2.0 (2.0230) 2.0 (1.02.0) 24.0% (11.5, 43.4)
No RA 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 17.7% (14.6, 21.4)
p-value 0.52 0.17 0.82 0.70 0.43
DM 2.0 (2.03.0) 2.0 (2.02.0) 2.0 (2.03.0) 2.0 (2.02.0) 16.7% (7.3, 33.6)
No DM 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (1.02.0) 18.1% (14.9, 21.8)
p-value 0.003 0.08 0.08 0.053 0.84
TD 2.0 (1.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (1.03.0) 17.1% (8.5, 31.3)
No TD 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 18.2% (14.9, 21.9)
p-value 0.20 0.54 0.99 0.67 0.86
Smoking 2.0 (2.03.0) 2.0 (2.03.0) 2.0 (2.02.3) 2.0 (2.02.0) 24.2% (12.8, 41.0)
No smoking 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (1.02.0) 17.6% (14.5, 21.3)
p-value 0.037 0.006 0.65 0.085 0.34
LASIK 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 8.7% (2.4, 26.8)
No LASIK 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (1.02.0) 18.4% (15.2, 22.1)
p-value 0.73 0.47 0.78 0.44 0.68
Cataract surgery 2.0 (2.03.0) 2.0 (2.02.0) 2.0 (2.03.0) 2.0 (2.02.0) 23.4% (13.6, 37.2)
No cataract surgery 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (1.02.0) 17.4% (4.2, 21.1)
p-value < 0.001* 0.006 < 0.001* 0.001* 0.75
CL wear 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 21.1% (14.0, 30.6)
No CL wear 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (2.02.0) 2.0 (1.02.0) 17.4% (14.1, 21.4)
p-value 0.02 0.008 0.50 0.89 0.40

RA, rheumatoid arthritis; DM, diabetes mellitus; TD, thyroid disease; CL, contact lens.
MannWhitney U-test.
*p < 0.001.

Expressed as percentage of patients with MG plaques in each group (95%CI of proportion).

522 Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute
S-Y Lee et al. Systemic conditions and associations with dry eye

plaques
eye in Asian patients. Since dry eye patients may present

0.689
with more than one predisposing factor for dry eye, we

MG
performed multivariate analysis adjusted for age, sex, and
other predisposing factors. After adjustments, we found

<0.001*
Lower-

0.297
that RA was associated with more severe signs of dry eye

nasal
which had not been reported previously. This current
temporal study did not include normal control subjects as the focus

<0.001*
of this study was to assess the relationship between sever-
Lower-

0.369 ity of dry eye and selected systemic and ocular condi-
tions.
<0.001*
We first analysed the severity of each clinical feature
Upper-

0.327
Yamaguchi Score

nasal

with age and found that most clinical signs were more
Mean age of patients who presented with MG plaques was 53.7 15.1 years and mean age of patients without MG plaques was 53.8 13.9 years. pronounced with increasing age, although such correla-
temporal

tions were not observed between dry eye symptoms and

<0.001*
Upper-

0.377

age (Table 3). Age is a well-known risk factor for dry

eye.6,9,30 However, we noticed that despite the increased
severity of clinical signs in older patients, their symptom
<0.001*
Central

0.159

scores did not differ greatly from younger patients who

presented with fewer, or less severe, clinical signs. This
observation agrees with that of earlier studies which sug-
Nasal

0.069

0.120

gest that clinical signs and symptoms of dry eye show

weak association.36,37 Diminished corneal sensitivity asso-
ciated with age38,39 may explain the absence of symptom
Temporal
Corneal fluorescein staining

increment with age.

0.096

0.030

Rheumatoid arthritis
Inferior

0.091

0.040

Rheumatoid arthritis is a devastating chronic autoim-

mune systemic disease that affects the joints and the sur-
Superior

rounding tissues. Other organs are also commonly

)0.036

0.414

affected by the relentless inflammation including the

eye.40 Although RA is a known risk factor for dry eye,
Table 4. Correlation between severity of symptoms and clinical signs with age

Schirmers

this is not well reported. One previous study has evalu-

<0.001*
)0.179

ated dry eye signs in RA patients and age/gender-matched

controls.41 In that study, they found Schirmers test scores
and TBUTs to be lower in patients with RA but the
)0.021

0.638

authors did not report on the association with corneal

TBUT

staining. In addition, the odds ratios for increased clinical

sign severity in RA patients were not described. As far as
sensation
Burning

the authors of this paper are aware, there is no literature

)0.045

0.314

*p < 0.003 (Bonferroni correction: p = 0.05/15).

that has previously described odds ratios for RA and dry

eye in a controlled epidemiological setting. In one clinic
Grittiness

based study, 22% of female dry eye patients and 32% of

male patients had RA42 but it was not known if RA
0.045

0.315

aggravated the signs of dry eye.

In the current study, corneal staining appeared to be
Symptoms

sensitivity

worse in dry eye patients with RA, significantly in the

)0.040

0.369

superior zone as compared to non-RA dry eye patients.

Light

This may be due to over expression of pro-inflammatory

cytokines in the tears.43 The presence of the cytokines
correlation
Spearman

may be more damaging to the epithelial cells than the

feature
Clinical

p-value

deficiency of the aqueous. Kang et al.44 previously

reported that tear cytokine interleukin-17 levels was

Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute 523
Systemic conditions and associations with dry eye
Crude analysis Analysis A
Condition Clinical feature p-value Odds ratio (95% CI)
RA Superior corneal 9.1 (3.921.4) 10.5 (4.425.1)
staining
CL Ocular grittiness 0.48 (0.270.83) 0.49 (0.270.90)
RA, rheumatoid arthritis; CL, contact lens.
Crude analysis Logistics regression without adjustments; analysis A Logistics regression
adjusted for age and gender; analysis B logistics regression adjusted for age, gender and mul-
tiple conditions (RA, diabetes mellitus, thyroid disease, Smoking, LASIK surgery, cataract surgery
and CL wear).
correlated with the severity of corneal fluorescein staining,
but did not specify any particular zones. Although specific
tear cytokines in RA have not been documented, they
have been reported in Sjogrens syndrome; another sys-
temic autoimmune condition that affects the eye.45 The
greater severity of corneal staining in dry eye patients
with RA may imply a more severe or even a different
mechanistic type of dry eye in such patients. We postulate
that because the superior cornea is closer to, and proba-
bly constantly in contact with, the upper palpebral
conjunctiva, it may be more exposed to the pro-inflam-
matory cytokines expressed from the palpebral vascula-
ture. The increase in cytokines specifically in that area
may have made it more susceptible to inflammatory dam-
age. However, regional variations in tear cytokine have
not been reported and further studies may be required to
test our hypothesis.
Contact lens wear
Interestingly in the current study, CL wearers experienced
less grittiness. This relationship remained even after
adjustment for the other variables. We suspect this may
be due to the avoidance of CL wear in cases with more
symptomatic dry eye. CL wearers have higher Schirmers
tests (Table 3) suggesting that non-wearers have milder
dry eye. Unlike systemic diseases, CL wear is to some
extent a lifestyle or behavioural choice and can be
avoided.
Published reports have shown that patients wearing
CLs with higher water content have a higher incidence of
dry eye compared to those wearing low water content
CLs.46 Furthermore, there were no significant differences
between gas-permeable CL wearers and hydrogel CL
wearers.47 Different modes and duration of CL wear were
not evaluated in this current study because of the rela-
tively small number of CL-wearing patients. Additional
studies are required to determine associations between CL
wear duration or CL type with dry eye severity.
524 Ophthalmic & Physiological Optics 32 (2012) 518526 2012 Singapore Eye Research Institute
S-Y Lee et al.
Table 5. Adjusted odds ratios
Analysis B
11.2 (4.627.4)
0.48 (0.260.88)
Study strengths and limitations
The strengths of the study were the uniformity of the
clinical methods and the prospective recruitment of a
considerable number of dry eye patients. The clinical
parameters were assessed by a single observer in a stan-
dardised way, such as the measurement of TBUT with a
stopwatch. Most patients had systemic diseases diagnosed
by a large multidisciplinary general hospital adjacent to
the eye centre with departments such as rheumatology
and endocrinology, therefore providing reliable diagnoses
of systemic conditions.
One limitation of this study was that we did not
include other conditions that are commonly linked to dry
eye. This includes Sjogrens syndrome, which was not
present in sufficient numbers to be evaluated. In addition,
we were unable to confirm a cause-effect relationship
between the medical conditions and the ocular features
since this was a cross sectional analysis. Severity of risk
factors, i.e. amount of smoking, duration and type of CL
wear, were not evaluated. Further investigations may be
needed to determine the effect of these factors on dry eye
clinical features.
In our study, we did not examine possible effects of
dry eye treatment, which are often not dichotomous vari-
able and can be complex. This will be the subject of
future studies. Another drawback was the single measure-
ment of TBUT. The average of several readings would
produce more accurate data. Also, an objective measure
of lipid layer thickness or spreading was not used. This
will be added in future studies.
A population-based estimate of the odds of RA
patients having dry eye would be useful. Further studies
in the pathophysiology of RA may shed light on the
increased severity of ocular surface damage in dry eye.
For example, different or increased cytokines in RA com-
pared to other dry eye patients. Further investigations
are warranted to evaluate how RA affects particular zones
of the cornea.
S-Y Lee et al.
Clinical relevance
The current study revealed findings that affect the man-
agement of dry eye patients. The severity of corneal fluo-
rescein staining in patients with RA implied that these
patients would usually require more intense anti-inflam-
matory therapy. Clinicians managing cases of dry eye
should be familiar with signs and symptoms of diseases
such as RA in order to detect these undiagnosed systemic
conditions and facilitate appropriate treatment. Since the
study population is predominantly Chinese, results may
not be applicable to populations consisting of other
races.
Conclusion
The study found that patients with RA were not only pre-
disposed to having dry eye, but also tended to have more
severe dry eye. In the management of dry eye, the sys-
temic diseases should always be assessed, and discussions
with non-ophthalmic physicians on the diagnosis of the
systemic illness should be one component of the manage-
ment plan.
Acknowledgements
Grant support was provided by NMRC/1206/2009,
NMRC/CSA/013/2009, NMRC/TCR/002-SERI/2008 and
NMRC/CG/SERI/2010 from National Medical Research
Council (NMRC), Singapore, and BMRC 10/1/35/19/670
from Biomedical Research Council (BMRC), Singapore.
Competing interest
None to declare.
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