Title

Clinical characteristics of dry eye patients with chronic pain syndromes

Authors
Jelle Vehof1,2,3*; Nicole Sillevis Smitt-Kamminga1; Diana Kozareva2; Simone A. Nibourg1;
Christopher J. Hammond2,4

Affiliations
1
Department of Ophthalmology, University of Groningen, University Medical Center
Groningen, Hanzeplein 1, Postbus 30.001, Groningen, The Netherlands; 2 Department of Twin
Research & Genetic Epidemiology, King’s College London, St Thomas’ Hospital, Lambeth
Palace Road, Waterloo, London, SE1 7EH, United Kingdom; 3 Department of Epidemiology,
University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus
30.001, Groningen, The Netherlands; 4Department of Ophthalmology, King’s College
London, St Thomas’ Hospital, Lambeth Palace Road, Waterloo, London, SE1 7EH, London,
United Kingdom.

*Corresponding author:
Jelle Vehof
Department of Ophthalmology
University Medical Center Groningen
Hanzeplein 1
Postbus 30.001
Groningen, The Netherlands
phone: +31 503612518
fax: +31 503611744
email: j.vehof@umcg.nl

Short title: Dry eye patients with chronic pain syndromes

1
Introduction

Dry eye disease (DED) is a highly prevalent disorder1,2 and causes significant morbidity, with
symptoms of pain, irritation, and interference with normal visual tasks. The poor correlation
between symptoms and objective signs of the ocular surface disease hampers studies of DED
and the management of patients with DED3,4.

In a population-representative twin study, we recently reported that chronic pain syndromes

are associated with DED.2 Consensus definitions are lacking, but chronic pain syndromes are
often described as conditions with chronic pain of one or more body parts without obvious
tissue-level pathology on adequate patient examination and absent abnormalities on routine
investigation. Chronic pain syndromes include irritable bowel syndrome, chronic pelvic pain
and fibromyalgia (also known as chronic widespread pain syndrome). The exact mechanisms
facilitating chronic pain syndromes have yet to be elucidated, but central sensitization and
impaired descending pain modulation are generally believed to be underlying mechanisms
causing widespread hypersensitivity to pain.5 We have not only showed that these disorders
are associated with DED but also that they share underlying genetic factors with DED6.

The purpose of this study is to investigate whether clinic-based DED patients with a chronic
pain syndrome differ in ocular symptoms and signs from those without a chronic pain
syndrome. In addition, we also investigated the differences in a population-based sample of
DED patients.

Methods

Subjects
The GLOSSY (Groningen LOngitudinal Sicca StudY) cohort is a clinic-based cohort of dry
eye patients from the tertiary dry eye clinic at the University Medical Center Groningen in the
Netherlands. General and ophthalmic medical history, dry eye symptoms, dry eye test results
using standardized methods, and dry eye therapies have been recorded longitudinally since
September 2014, resulting in a clinical cohort with data on approximately 2000 patient visits a
year. The University Medical Center Groningen is a national referral center for Sjögren’s
disease, and has a unique multidisciplinary approach to Sjögren’s disease with regular
checkups by rheumatologists, ophthalmologists, and oral surgeons. Consequently,
approximately half of the patients visiting the tertiary dry eye clinic are Sjögren patients. All
patients in the GLOSSY cohort have either dry eye diagnosed by an ophthalmologist and/or
were under the care of the multidisciplinary Sjögren’s disease service. The study was
approved by the Institutional Review Board (IRB) of the University Medical Center
Groningen and Informed Consent approval was not needed in this observational study. The
research followed the tenets of the Declaration of Helsinki.

Assessment of chronic pain syndromes

In the GLOSSY cohort the assignment of chronic pain syndromes was based on self report by
a questionnaire at baseline. Patients were asked the following question: ‘Have you ever been
treated for or diagnosed by a physician as having …?’ Fibromyalgia, chronic pelvic pain, and
irritable bowel syndrome were among the list of many possible conditions patients were able
to check, so the questionnaire did not appear to be specifically collecting chronic pain
information.

2
Assessment of dry eye outcomes
The study sample completed the Ocular Surface Disease Index (OSDI) at the beginning of
their visit. The OSDI, developed by the Outcomes Research Group at Allergan Inc (Irvine,
California), is a 12-item questionnaire designed to provide a rapid assessment of the
symptoms of ocular irritation consistent with dry eye disease and their impact on vision-
related functioning.7 Presence of symptoms during the last week is rated per item on a five-
point scale (0-4) from 'none of the time' to 'all of the time'. The OSDI total score (ranging
from 0-100) can be calculated with a formula using the sum score of all completed questions.

Dry eye tests were performed in both eyes in the following order: amount of conjunctival
hyperaemia, tear osmolarity, Schirmer value, visual acuity (Snellen), staining of the cornea
with fluorescein, tear breakup time (TBUT), amount of mucus, staining of the nasal and
temporal conjunctiva with lissamine green. Conjunctival hyperaemia was measured using the
CCLRU grading system on a scale from 0 to 4 interpolated into 0.5 increments.8 Tear
osmolarity was measured from the inferior lateral meniscus with a laboratory-on-a-chip by the
TearLab Osmolarity System (San Diego, Ca) following standard protocols.3 An
unanaesthetized Schirmer-1 value after 5 minutes (mm/5 min) using sterile strips was
measured in both eyes following standard protocols.3 Best corrected visual acuity was
measured in both eyes using a Snellen chart. For the statistical analysis the Snellen visual
acuity was first transformed to a logMar score. Staining of the cornea with fluorescein was
performed using the Oxford Schema grading, ranging from grade 0 to 5, based on the number
of punctate dots for the total exposed inter-palpebral cornea.3 Staining of the conjunctiva with
lissamine green was performed in a similar way using the Oxford Schema grading, scoring
both the temporal and nasal zone and taking the sum of these scores per eye, ranging from 0
to 10.3 TBUT was measured by instilling a drop of fluorescein counting the seconds after a
blink before the tear film was broken up, following standard protocols.3 Each eye was
measured three consecutive times and the average value per eye was used. The amount of
mucus clumping per eye was scored from 0 (none), 1 (mild debris: mucus dots), 2 (moderate
debris: mucus flocks), to 3 (mucus threads and filaments).9 Ophthalmologists that graded the
dry eye were not aware of the study question and were not aware of the participants’
responses to questions about chronic pain syndromes.

Statistical analysis
Data were cross-sectionally analyzed with the SPSS statistical package (version 22.0; SPSS,
Inc). First, the demographics of the study sample was calculated. Second, outcome variables
in patients with and without a chronic pain syndrome were calculated. The mean value of both
eyes was taken for the analyses of all dry eye outcome variables. Since both all symptoms and
signs outcome variables turned out to have non-normal distributions, non-parametric Mann-
Whitney U tests were used to test for a difference between groups. Additional similar analyses
were performed looking at Sjögren and non-Sjögren DED patients separately. P <.05 was
considered statistically significant in all analyses.

Population –based dry eye patients from the TwinsUK cohort

In addition, to see whether results were similar in a population-based sample with less
potential of ascertainment bias than a tertiary eye care clinic, we investigated DED patients
from The TwinsUK Adult Twin Registry10, held at King’s College London, UK. This is a twin
registry that has been ascertained from the general population through national media
campaigns. Twins from this registry have been shown to be comparable to the age-matched
general population singletons for a broad variety of medical and behavioral traits.11 606
female twin subjects that were included in a heritability study on DED12 were asked the

3
following two questions in a questionnaire as proxy for having DED: 'Have you ever been
diagnosed (by a clinician) as having dry eye syndrome?', and 'Do you currently use artificial
tear eye drops or gel?’.6,13 A strict definition of DED was applied to reduce the possibility of
misclassification. If a participant answered 'Yes' to both of these two questions, she was
assigned as having DED and subsequently included in this study. Local ethics committee
(IRB) approval was obtained for the study, and twin volunteers gave informed consent but
were unaware of the precise hypotheses being tested. The research followed the tenets of the
Declaration of Helsinki. In this study sample classification of the different chronic pain
syndromes was based on standard, validated criteria, see Vehof et al.6 Three dry eye tests in
the TwinsUK cohort were performed in both eyes in the following order: tear osmolarity,
Schirmer value, and tear break-up time (TBUT). The tests were all performed using
standardized methods by the same trained research nurse. For more information on how these
tests were performed we refer to Vehof et al.12

Results
The 425 first consecutive DED patients from the GLOSSY cohort were included (85%
female). Mean age (s.d.) of the DED patients was 58.4 (15.7) years. Chronic pain syndromes
were highly prevalent (n=74 (17.4%) having at least one, n=11 (2.6%) having more than one)
with irritable bowel syndrome (n=40, 9.4%) and fibromyalgia (n=38, 8.9%) most prevalent,
and chronic pelvic pain less prevalent (n=7, 1.6%). Patients with a chronic pain syndrome did
not have a different age than patients without a chronic pain syndrome (both groups 58.4 yrs,
P=.98). 96% of patients with a chronic pain syndrome were female, compared to 83% of
patients without a chronic pain syndrome (P=.002, Fisher exact test).

The OSDI total symptom score was significantly higher in chronic pain syndrome patients
than in patients without a chronic pain syndrome (45.8 vs 33.8, P<.0005). Figure 1 shows the
mean OSDI subscale scores separated in dry eye patients with and without a chronic pain
syndrome. Interestingly, patients with a chronic pain syndrome scored higher on every single
item of the 12 item OSDI symptom score, with 10 items being statistically significant. The
higher symptom scores in DED patients with a chronic pain syndrome than in DED patients
without a chronic pain syndrome were present in both Sjögren (n=191, 12.0% having a
chronic pain syndrome, OSDI total score 45.9 vs 34.2, P=.03) and non-Sjögren patients
(n=138, 13.8% having a chronic pain syndrome, OSDI total score 44.1. vs 33.9, P=.08).

Table 1 shows the measurements from the dry eye tests, again separated in DED patients with
and without a chronic pain syndrome. Patients with a chronic pain syndrome scored as less
severe on every dry eye test, although only corneal staining score and Schirmer score were
statistically significantly different. In addition, there was a trend of less severe conjunctival
staining and amount of mucus (P<.10).

Based on the two dry eye questions, 64 subjects (10.6%) of the TwinsUK cohort were
assigned as having DED and were included in the additional analysis. Mean age (s.d.) of the
DED patients in this sample was 59.7 (8.5) years and all participants were female. Chronic
pain syndromes were highly prevalent (n=24 (38%) having at least one, and n=4 (6.3%)
having more than one) with chronic pelvic pain (n=17, 27%) most prevalent, followed by
irritable bowel syndrome (n=8, 13%) and fibromyalgia (n=4, 6%). In this population-based
cohort, the OSDI total symptom score was also significantly higher in chronic pain syndrome
patients, with an even bigger difference than in the GLOSSY cohort (34.1 vs 14.1, p=0.001).
Figure 3 shows the mean OSDI subscale scores separated in dry eye patients with and without
a chronic pain syndrome. Again, patients with a chronic pain syndrome scored higher on

4
every single item of the 12 item OSDI symptom score, although not all differences were
statistically significant in this smaller sample. We could find no significant differences in dry
eye disease grading scores between patients with and without chronic pain syndrome in this
cohort: tear osmolarity (297.8 vs 299.0, P=.52), TBUT (3.3 vs 2.8, P=.26), Schirmer (6.1 vs
6.1, P=.87).

Discussion
This cross-sectional study has demonstrated that dry eye patients with a self reported chronic
pain syndrome report worse dry eye symptoms, despite having the same or less severe clinical
grading of their ocular surface disease than dry eye patients without a chronic pain syndrome.
Dry eye symptom scores were higher across all domains of the OSDI (ocular irritation, visual
function and impairment in daily activities). The finding appears to be true not only in clinic-
based patients, but also in patients ascertained systematically from a population-based cohort.
This result is consistent despite differing ascertainment and phenotyping.

We found a prevalence of pelvic pain of 14.0%, of irritable bowel syndrome of 8.6%, and of
fibromyalgia of 7.6% in the overall TwinsUK cohort, which is representative of the general
UK female population, using the same criteria6. So, pelvic pain and irritable bowel syndrome
appear to be more prevalent in our dry eye subjects. Given the high prevalence of chronic pain
syndromes in the general population, and especially in the dry eye population, our results are
an important finding that may help ophthalmologists and family doctors understand the
discrepancy between signs and symptoms in subgroups of patients with dry eye disease.

Our finding of increased symptoms in DED patients with chronic pain syndromes adds further
evidence to the theory that dry eye symptoms are, in part, a consequence of neuropathic
ocular pain, instead of thinking of dry eye as a tear dysfunction syndrome only. Indeed, many
studies have shown dysfunction in the corneal pain system in dry eye settings including the
presence of spontaneous dysesthesias, allodynia, hyperalgesia, and corneal nerve morphologic
and functional abnormalities.14 Peripheral and central sensitization seem to influence DED
and it has been suggested that DED is a heterogeneous group of different disease subtypes
with various levels of dysfunction in the corneal pain system.14 In a previous study we have
shown increased pain sensitivity to a forearm thermal stimulus in participants with dry eye
symptoms, consistent with a role of central nociceptive systems in dry eye.15 Together with
our finding that there are shared underlying genetic factors between DED and chronic pain
syndrome, we hypothesize DED to be a chronic pain syndrome in a subgroup of patients.6

Interestingly, our DED clinical grading data suggest that ocular signs may be less severe in
patients with a chronic pain syndrome than in those without. However, DED signs of the
ocular surface were still present in chronic pain syndrome patients. Three other studies have
investigated dry eye in patients with fibromyalgia. Gallar et al investigated corneal sensitivity
in 20 patients with fibromyalgia and found reduced sensitivity compared to controls
attributable to a moderate decrease in corneal polymodal and cold nociceptor sensitivity. They
also found a decreased Schirmer test value compared to controls.16 Turkyilmaz et al
investigated 53 fibromyalgia patients using OSDI, tear breakup time and Schirmer tests, and
reported increased disease activity of fibromyalgia was associated with dry eye severity, as
well as the fibromyalgia patients having worse scores than age-matched controls.17 These
studies add to the evidence that the ocular surface is also affected in patients with
fibromyalgia. Günaydin et al investigated a sample of 285 fibromyalgia patients and found 40
of them to have dry eye symptoms. These 40 were further analyzed for objective dry eye and
the authors concluded they could not find evidence of objective ocular findings that confirmed

5
dry eye disease in these fibromyalgia patients.18 However, the uncontrolled setting of this
study makes it hard to interpret the results. Further controlled studies are needed to determine
whether fibromyalgia really affects objective dry eye parameters as well. Barton et al are the
only to date to investigate dry eye in irritable bowel syndrome patients and found an increased
prevalence of objective dry eye in 45 irritable bowel syndrome patients compared to a control
group (33% vs 5%).19 To date, no studies have investigated dry eye disease in chronic pelvic
pain.

So, our current results indicate that dry eye patients with a chronic pain syndrome both in the
general population and the dry eye clinic might have dysfunctional pain perception, and this
should be considered, particularly when symptoms appear more severe than the ocular signs
suggest. This subgroup represents a challenge to health care providers, as they may be more
likely to be resistant to standard therapies of dry eye aimed at the ocular surface. We strongly
encourage future treatment studies focusing on dry eye patients with chronic pain syndromes.

The present study has a few limitations. First, a clinic based dry eye sample is vulnerable for
possible ascertainment bias. Therefore, we also investigated a population-based dry eye
sample to see whether the effects were similar. However, DED phenotyping in the TwinsUK
was limited and different methods were used to assess the chronic pain syndromes in our
study samples. We used symptom-based case definitions for the chronic pain syndromes
based on standard questionnaires in the TwinsUK cohort, and the less sensitive method of
self-report of physician diagnosis in the GLOSSY cohort.20 This may be the reason that the
prevalence of chronic pain syndromes is lower in the GLOSSY cohort than in the TwinsUK
cohort. Chronic pelvic pain is highly prevalent in the population but is underdiagnosed by
physicians.21 Despite this limitation the findings in both patients groups are similar and strong,
and the potential underestimation of chronic pain syndromes by self report in the GLOSSY
cohort could only mean an even bigger true effect size of our findings. Second, chronic pain
syndromes are not limited to fibromyalgia, irritable bowel syndrome, and chronic pelvic pain.
We focused on those three chronic pain syndrome since we believe they have been shown
most consistently to be a chronic pain syndrome, and because of the fact that we found shared
genetic factors of these three chronic pain syndromes with DED. The inclusion of other
possible chronic pain syndromes, such as chronic fatigue syndrome or temporomandibular
joint dysfunction, could lead to a more precise and complete definition of chronic pain
syndrome cases and therefore to more reliable results. Third, as several outcome variables
were assessed, there is the possibility that some of the statistically significant associations are
by chance alone, but the fact that they were all in the same direction, in two separate cohorts
with differing ascertainment, suggests they are true.

In conclusion, in DED patients, chronic pain syndromes are common and associated with
increased severity of all dry eye symptoms across the OSDI, while ocular surface findings are
similar or less severe in subjects with chronic pain syndromes compared to those without. In
clinical practice, more awareness of chronic pain syndromes might help in understanding the
discrepancy between signs and symptoms in DED and future studies focusing on non-ocular
therapies might be of benefit to this specific dry eye patient group.

Acknowledgments

a. Funding/Support: none.
b. Financial Disclosures: none for any of the authors.
c. Other Acknowledgments: none.

6
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8
Figure captions

Figure 1. Mean dry eye symptom scores from the Ocular Surface Disease Index subscales in
tertiary clinic dry eye patients (n=425) with and without a chronic pain syndrome

*Significant difference between groups (P<.05)

SE = standard error

Figure 2. Mean dry eye symptom scores from the Ocular Surface Disease Index subscales in
dry eye patients (n=64) with and without a chronic pain syndrome from the population-based
TwinsUK cohort

*Significant difference between groups (P<.05)

SE = standard error