Abstract
Purpose
To compare the effect of single-drop administration of two different ophthalmic solutions on tear meniscus and tear osmolarity in patients with mild to moderate dry eye disease.
Methods
This prospective study comprised of 122 patients with mild to moderate dry eye disease. These patients received a single dose of either unpreserved trehalose 3%, hyaluronic acid 0.15%, carbomer 0.25% (TH HA, Thealoz Duo Gel) (Group 1) or hyaluronic acid 0.3% (HA) (Group 2) gel-based lubricants. Tear meniscus (height and depth) were measured using anterior segment optic coherence tomography (AS−OCT) at baseline and 10, 60, 120, and 240 min. after instillation. Tear osmolarity, Schirmer I test, tear break-up time (TBUT), gel properties, and patient comfort were evaluated 240 min. after instillation.
Results
Tear meniscus height (TMH) and tear meniscus depth (TMD) showed a significant increase with both lubricants compared to the baseline (p < 0.001). This effect remained significant for up to 60 min. and 120 min. for the TH HA and HA 0.3% solutions, respectively (p < 0.05, for both). Mean comfort duration was 115.1 ± 20.1 min. in Group 1 and 148.3 ± 49.0 min in Group 2 (p < 0.001). Tear osmolarity, Schirmer I test, and TBUT were similar between the baseline and 240 min. for each group.
Conclusions
The results of this study demonstrate that 0.3% HA remains on the ocular surface for longer than TH-HA. The longer ocular residency time also seems to correlate with a longer patient comfort duration.
1
Introduction
Dry eye disease (DED) is highly prevalent throughout the world and is associated with tear instability, visual problems, and a reduction in the quality of life [ ]. DED is a multifactorial disorder of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by hyperosmolarity, inflammation, tear film instability, and neurosensory abnormalities, as described in the Tear Film and Ocular Surface Society’s Dry Eye Workshop (TFOS DEWS) II Report [ ]. The presence of any one of three specified signs: a reduced non-invasive tear break-up time; elevated or a large interocular disparity in osmolarity; and ocular surface staining (of the cornea, conjunctiva or lid margin) in either eye, refers to the loss of homeostasis and confirms the diagnosis of DED [ ].
DED directly affects the tear film and ocular surface. For that reason, objective methods are important for defining its severity and management protocol. Recently, a new method for the non-invasive measurement of tear meniscus based on optical coherence tomography has been developed. Anterior segment optical coherence tomography (AS−OCT) provides high resolution images of the cornea and anterior segment [ ]. AS−OCT can also be used for tear meniscus assessment. Previous studies have shown that tear meniscus height correlates well with objective signs, as well as with subjective symptoms of DED [ , ].
DED management is complicated due to the multifactorial etiology of DED, and no single treatment regimen has been found that is suitable for all patients. According to TFOS DEWS II treatment begins with conventional lubricants for early-stage disease, with progression to more advanced therapies for more severe forms of DED [ ]. Artificial tears have some specific properties for relieving the symptoms and signs of the patients: viscosity, lubricity, lipid content, electrolyte composition, and osmoprotective effects [ , ]. Ocular residence time on the ocular surface is a feature of viscosity and describes the duration of effect of the artificial tears. Although artificial tears are a mainstay of DED management, frequent instillation is a common problem. This is due to the short residence time of lubricants on the ocular surface [ , ]. Increased viscosity will increase ocular residence time [ , ].
Hyaluronic acid (HA) is a natural lubricant and has excellent water-retaining properties, which makes it well-suited for use in artificial tears [ ]. HA has unique viscoelastic properties that are also helpful in the repair of corneal epithelial defects. Hyaluronate has been shown to accelerate the proliferation of human corneal epithelial cells and upregulate the expression of repair cytokines, thereby reducing apoptosis and downregulating the expression of inflammatory cytokines; in addition, it promotes the repair of ocular damage [ ]. HA has a relatively longer residence time on the ocular surface, due to its water-entrapping and mucoadhesive properties, which leads it to be widely used in ophthalmic products [ ]. The viscosity of HA is related to its concentration. Thus, with a higher concentration, ocular residence time will be increased, producing a longer period of improved patientcomfort [ ]. Trehalose and carbomer are also used in artificial tears and have additional effects on the comfort of the patients. Trehalose, a natural disaccharide, is able to stabilize bilipid membranes and labile proteins. It has a protective effect against desiccation and oxidative insult [ ]. Carbomer has a longer residence time by binding with mucin to prolong adhesion of the tear substitute [ ], and is mostly found in gel-type formulations.
Some recent studies have used Anterior Surface Ocular Coherence Tomography (AS−OCT) to characterize the effect of various eye drops on the tear film. Carracedo et al. found that the residence time of HA drops was positively correlated with HAconcentration [ ]. Wozniak et al. showed that a combination of trehalose 3% + HA 0.15% led to a significantly longer increase in tear film thickness than HA 0.2% only [ ]. Schimidl et al. observed that trehalose 3% + HA 0.15% had a longer residence time than HA 0.15% [ ].
Trehalose combined with HA is a new and promising agent for the treatment of long-term DED patients. In clinical practice, HA formulations mostly have an HA 0.15% concentration. For this study, two commercially available artificial tears: trehalose (unpreserved trehalose 3% + hyaluronic acid 0.15%) (TH-HA) and (HA 0.3%) were compared with the aim of evaluating the effect of a single drop instillation on tear film meniscus height and depth, on tear osmolarity, ocular residency time, and on patient comfort, in patients with mild to moderate DED. The osmoprotective effect of both gel-based topical lubricants was also investigated.
2
Materials and methods
This study, which was prospective, randomized, single-masked, and observer-blinded, was performed in adherence to the tenets of the Declaration of Helsinki. The local ethics committee approved the methodology. Written informed consent was obtained from all of the subjects. Subjects were included, who were at least 18 years of age, diagnosed with primary Sjogren’s syndrome (PSS), history of DED for at least 3 months, tear break-up time (TBUT) ≤10 s or Schirmer I test ≤10 mm, OSDI score ≥13 points, and normal ophthalmic findings except DED. The eye with the lower TBUT was selected as the study eye. If TBUT was identical for both eyes, the eye with the lower Schirmer I test was selected. If Schirmer I test results were identical for both eyes, the right eye was chosen for study purposes. Exclusion criteria were: history of smoking, history of any other ocular disease or surgery, conjunctivochalasis, atopy, severe dry eye (totally unresponsive to topical artificial tear treatment), pregnancy, allergic disease, presence of systemic disease except PSS (diabetes, hypertension, renal or hepatic dysfunction), systemic or local use of one of the following medications: glucocorticosteroids, cyclosporine A, antibiotics, NSAIDs.
A pre-study screening was administered to each patient two weeks before starting the test day to screen for inclusion/exclusion. Selected patients were randomized into two test groups: Group 1 (TH HA) (Thealoz Duo Gel®, Laboratoires Théa, Clermont Ferrand, France), and Group 2 (HA 0.3%) (Vismed Gel®, TRB Chemedica, UK). Patients were asked to stop the use of any artificial tears 12 h before the start of the study. All measurements were completed over one day.
On the test day, measurements of tear meniscus height (TMH), tear meniscus depth (TMD), tear osmolarity, Schirmer I test, tear break-up time (TBUT) and ocular surface disease index (OSDI) questionnaire were evaluated as part of a full ophthalmological examination. The results from these measurements provided a baseline for later comparisons. One drop of lubricant (Vismed Gel or Thealoz Duo Gel) were then administered by single ophthalmologist, according to which test group they were assigned to. Measurements of TMH and TMD were repeated 10, 30, 60, 120, and 240 min. after instillation. After 240 min., patient satisfaction (subjective evaluation of ocular comfort with 5 questions), tear osmolarity, Schirmer I, and TBUT were evaluated. Patient satisfaction was evaluated on gel properties on-eye by asking about: sticky (presence/absence), viscosity (presence/absence), blurring effect (presence/absence), burning or stinging (presence/absence) and relief of symptoms (mild/moderate/severe). The comfort duration of the drops was also recorded.
Tear osmolarity was measured with the Tear Lab Osmolarity system (TearLab, San Diego, CA, USA). The Tear Lab system consists of a test microchip reader unit, a microchip holder, and an osmolarity test microchip, which is clipped onto the top of the holder. The tip of the test microchip is placed next to the inferior, lateral tear film meniscus, along the lower eyelid, where it can absorb the correct amount of fluid (50 nanolitres). Once the holder is docked with the reader unit, the system reader calculates and displays the osmolarity measurement in mOsm/litre on an LCD screen.
The Schirmer I test was applied to the lower a third of the lateral bulbar conjunctiva without topical anesthesia. The patient was asked to look away from the paper strip and to blink normally. The results were evaluated by measuring the length of wetting of the paper strip after 5 min. Results were recorded in millimeters (mm).
The TBUT test was recorded using sodium fluorescein strip gently touched in upper conjunctiva to stain the tear film and observed under cobalt blue light using a slit-lamp biomicroscope. The patient was asked to look straight-ahead and to blink once, and then to refrain from blinking for as long as possible. The TBUT was recorded as the time in seconds from the final blink until the appearance of the first break in the fluorescein under cobalt blue illumination. The test was repeated 3 times and the average recorded.
OSDI is a questionnaire of 12 items that evaluates the symptoms of eye-related irritation and the effect on visual acuity. The OSDI questionnaire validated in Turkish was used [ ]. The total OSDI score of each patient was calculated as: OSDI score = (Total score of all answered questions x100) / (Total number of questions answered x4). Mild to moderate DED was evaluated according to OSDI score. An OSDI score between 13 and 22 points was evaluated as mild, the one between 23 and 32 points as moderate. OSDI score above 32 points were excluded from the study.
2.1
Tear Meniscus measurement with OCT
OCT measurements were performed using Swept Source OCT (SS−OCT, DRI OCT Triton, Topcon, Tokyo, Japan). The lower tear meniscus height and depth measurements were provided using the SS-anterior segment OCT single vertical scan mode. In follow-up measurements, the scan was applied to the same region of the eyelid just below the corneal vertex, centered on the inferior cornea and the lower eyelid. The patient was asked to blink normally during the imaging procedure while looking at a fixed target within the device. Images were obtained within the first second immediately after a blink. A built-in caliper was used for measuring the tear meniscus height and depth in micrometers. The line at which the meniscus intersected with the cornea (superiorly) and the eyelid (inferiorly) was the tear meniscus height (TMH). The line from TMH to inferior fornix was tear meniscus depth (TMD). ( Fig. 1 )
2.2
Statistical analyses
SPSS 20.0 was used for statistical analysis. The Shapiro-Wilk test was used to test for normality of the data. Descriptive statistics included mean ± SD or median (min–max) for the continuous variables, whereas the number of cases and percentages were calculated for the categorical variables. For non-normally distributed data, the significance of the difference between groups was calculated using the Mann–Whitney U test. The difference within dependent samples was assessed using the Wilcoxon sign test. The Spearman correlation coefficient was used to analyze the statistical significance between quantitative tear meniscus parameters and patient satisfaction values. A P value of less than 0.05 was considered as statistically significant.
3
Results
Fifty-six patients using TH–HA (Group 1) and 66 patients using HA 0.3% (Group 2) were included in the study. No age or gender-related significant difference was detected between study groups (p > 0.05). Demographic data and baseline clinical characteristics are presented in Table 1 . No significant differences were detected between the groups at baseline.
| Group 1 (n = 56) | Group 2 (n = 66) | P-Value | |
|---|---|---|---|
| Age, yrs | 52.5 ± 13.2 | 53.4 ± 11.4 | 0.40 |
| Gender (M/F) | 10/46 | 8/58 | 0.37 |
| OSDI score | 21.4 ± 6.2 | 20.8 ± 5.9 | 0.82 |
| TBUT, s | 3.0 ± 2.5 | 3.4 ± 2.5 | 0.31 |
| Schirmer I test, mm/ 5 mins | 3.3 ± 2.5 | 4.7 ± 3.4 | 0.17 |
| Tear Osmolarity, mOsm/L | 309.3 ± 12.5 | 307.6 ± 8.5 | 0.59 |
| Tear Meniscus Height, μm | 237.4 ± 85.6 | 242.8 ± 75.3 | 0.65 |
| Tear Meniscus Depth, μm | 164.4 ± 55.5 | 159.3 ± 55.1 | 0.49 |
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