Abstract
Background/Aim: To evaluate the clinical efficacy of combination therapy with diquafosol sodium and sodium hyaluronate in dry eye patients after small incision lenticule extraction (SMILE). Patients and Methods: A prospective randomized controlled study was conducted on consecutive patients who were diagnosed with dry eye disease (DED) and ready to accept SMILE from January 2021 to December 2021. The participants were randomly allocated to either a combination with diquafosol sodium 3% and sodium hyaluronate 0.3% group (DQS group, n=40) or a sodium hyaluronate 0.3% group (HA group, n=41). Dry eye disease parameters included tear film break-up time (TBUT), Shirmer I test (SIT), corneal and conjunctival fluorescein staining score (FS score), and Ocular Surface Disease Index (OSDI); tests were conducted before surgery and at 1 week, 1 month, and 3 months after surgery. Results: At 1 week after surgery, there were no statistically significant overall differences in DED parameters between the 2 groups. At postoperative month 1, the FS score was significantly lower in the DQS group than in the HA group (1.20±1.06 vs. 1.83±1.41 respectively, p=0.026). At 3 months after the surgery, the DQS group was significantly superior to the HA group in OSDI (12.98±7.29 vs. 16.82±8.25, p=0.029), TBUT (5.83±2.02 vs. 4.24±0.94, p=0.0002), and SIT (7.75±3.92 vs. 5.24±3.42, p=0.003). Conclusion: Our study showed that combination therapy with diquafosol and hyaluronate was beneficial for improving both signs and symptoms of dry eye patients after small incision lenticule extraction.
Over the last decade, small incision lenticule extraction (SMILE) has been proven to be the most popular and effective refractive surgery (1). However, dry eye disease (DED) is reported to be a common postoperative complication, and one which may reduce patients’ satisfaction (2). DED may cause ocular surface damage, which not only leads to symptoms of ocular discomfort but also degrades the visual quality. Artificial tears, physical therapy of meibomian gland dysfunction, punctal plugs and other treatments are used to relieve the symptoms caused by DED after SMILE (3). Nevertheless, according to the literature, dry eye symptoms persist for months or even years in a lot of patients (4).
Diquafosol sodium (DQS) is a P2Y2 receptor agonist that stimulates the secretion of fluid and mucin from the conjunctiva into tears (5). Many studies have shown that 3% DQS ophthalmic solution is beneficial for the stability of tear film and for improving dry eye symptoms (5-8). In previous studies, DQS was shown to be superior to sodium hyaluronate in terms of treatment effects for patients with dry eye after cataract surgery or laser in situ keratomileusis (LASIK) (9-13).
However, there has been no report on the application of DQS in dry eye patients after SMILE. The aim of the current study was to evaluate the clinical efficacy of combination therapy with diquafosol sodium and sodium hyaluronate in eyes with DED after SMILE.
Patients and Methods
Patients. This was a prospective randomized controlled study. All study procedures followed the tenets of the Declaration of Helsinki and were approved by the local Institutional Review Board of Shanghai Tenth People’s Hospital. Written informed consent was obtained from all participants.
Consecutive patients who were diagnosed with DED and were ready to accept SMILE from January 2021 to December 2021 at Shanghai Tenth People’s Hospital were enrolled in this study. Patients with mild to moderate dry eye based on the Dry Eye Workshop (DEWS) report were included (14). Exclusion criteria included the following: a history of diabetes, hyperthyroidism, and autoimmune malignant tumours; ocular comorbidities such as glaucoma, uveitis, serious ocular surface disease and lacrimal or eyelid disease; having used contact lens within 2 weeks of the study; having undergone ocular surgery within 3 months of the study; being a pregnant or lactating woman.
Patients were randomly allocated to the sodium hyaluronate group (HA group) and the combination with DQS and sodium hyaluronate group (DQS group). The HA group used 0.3% sodium hyaluronate ophthalmic solution (Hialid; Santen, Osaka, Japan) 4 times a day, while the DQS group used 3% diquafosol sodium ophthalmic solution (Diquas; Santen) 6 times a day as well as 0.3% sodium hyaluronate ophthalmic solution 4 times a day. The eye drops were used until 3 months after surgery in both groups.
SMILE surgery. SMILE was performed by an experienced surgeon using a femtosecond laser system (VisuMax, Carl Zeiss Meditec, Jena, Germany). All surgeries were uneventful. After surgery, topical steroids (0.1% fluorometholone; Santen) were initially used every 2 hours and then tapered over 1 month, and topical antibiotics (0.5% levofloxacin ophthalmic solutions; Santen) were used 4 times daily for 2 weeks, with the exception of artificial tears and diquafosol sodium.
Data collection. Demographic data and medical histories were collected for all study participants. Distant uncorrected visual acuity (UCVA), distant best corrected visual acuity (BCVA), spherical equivalent (SE), intraocular pressure (IOP) with non-contact tonometer, tear film break-up time (TBUT, repeat three times and take the average), Shirmer I test (SIT), corneal and conjunctival fluorescein staining score (FS score), and higher-order aberrations (HOAs) of corneal anterior surface (Pentacam AXL; Oculus, Germany) were conducted before surgery and at 1 week, 1 month and 3 months after surgery. Subjective symptoms were graded according to the Ocular Surface Disease Index (OSDI) questionnaire. All tests for DED were performed by an experienced ophthalmologist.
Statistical analysis. A statistical analysis was performed using SPSS version 20.0 (IBM Corp, Armonk, NY, USA). The data are given as the mean±standard deviation. The differences in baseline characteristics between the two groups were analysed by using the independent samples t-test. Repeated measurement two-factor ANOVA was used to compare the overall differences of TBUT, SIT, FS, OSDI score and HOAs between patients of the two groups after receiving different eye drops at different time points. All of the tests were two-tailed, and a p-Value of less than 0.05 was considered statistically significant.
Results
A total of 96 patients were enrolled and randomly assigned to the DQS and HA groups. Among them, 40 patients in the DQS group and 41 patients in the HA group completed the follow-up, and the data of the right eyes were used in the analyses.
There were no significant differences in the baseline data between the two groups (Table I). In addition, no significant differences were shown in clinical DED parameters (OSDI, TBUT, SIT, FS score) and HOAs between the two groups before surgery. UCVA significantly improved following SMILE (Table II). There were significant differences in mean UCVA between the DQS group (1.13±0.09) and the HA group (1.06±0.12) at 1-month follow-up visits (p=0.004). Moreover, there were no differences between the two groups in UCVA, BCVA, SE, and IOP throughout the study.
Demographic and other baseline characteristics for the DQS and HA patient groups before surgery.
Changes of visual acuity, spherical equivalent, and intraocular pressure in the DQS and HA patient groups after surgery.
In both groups, at postoperative week 1, clinical DED parameters tended to be significantly aggravated, returning to baseline levels at postoperative month 1, and then improving significantly at 3 months after SMILE (Figure 1). At 1 week after surgery, there were no statistically significant overall differences in DED parameters between the 2 groups. At postoperative month 1, FS scores were significantly lower in the DQS group (1.20±1.06) than in the HA group (1.83±1.41) (p=0.026). At 3 months after the surgery, the DQS group was significantly superior to the HA group in OSDI (12.98±7.29 vs. 16.82±8.25, p=0.029), TBUT (5.83±2.02 vs. 4.24±0.94, p=0.0002) and SIT (7.75±3.92 vs. 5.24±3.42, p=0.003).
Mean changes in clinical dry eye disease (DED) parameters in dry eye patients after small incision lenticule extraction (SMILE) (A). Ocular Surface Disease Index, OSDI; (B) Tear film break-up time, TBUT; (C) Shirmer I test, SIT; (D) Conjunctival fluorescein staining score, FS score.
Regarding the HOAs, all corneal HOAs significantly increased at 1 week after surgery and remained stable thereafter (Table III). There were no statistically significant differences in all corneal HOAs at postoperative week 1 and month 1. At postoperative month 3, corneal total HOA (0.701±0.109 vs. 0.795±0.274) and vertical coma (0.405±0.234 vs. 0.533±0.269) were significantly lower in the DQS group than in the HA group (p=0.047 and 0.025, respectively).
Changes of corneal higher-order aberrations in the DQS and HA patient groups after surgery.
Discussion
Dry eye disease (DED) is one of the most common complications of corneal refractive surgery. SMILE is a recently developed novel flapless surgery that involves a smaller corneal incision and less transected corneal nerves; it is theoretically less prone to DED (15). Although some studies have shown that SMILE reduces the incidence of DED compared to FS-LASIK, others have shown no significant differences between the two groups (2, 15-18). Dry eye symptoms or changes in tear film stability have been documented in 56% of patients after SMILE (19).
Traditionally, artificial tear supplementation is considered the first-line treatment for DED. Recently, diquafosol sodium has been reported to promote hydration of the ocular surface and tear film stabilization, independent of tear secretion from the lacrimal gland (5). Numerous studies have shown that 3% diquafosol sodium eye drops are effective in relieving the symptoms and signs of dry eye and stabilizing the tear film (5-8). A meta-analysis by Nam et al. showed that 3% diquafosol eye drops significantly improved subjective symptoms, tear production, TBUT, corneal fluorescein staining score, symptom score, and subjective symptoms (7). Its unique mechanism of action appears to be beneficial in the management of the dry eye.
The present study investigated the clinical efficacy of 3% DQS combined with 0.3% HA compared with 0.3% HA in DED patients who underwent SMILE. Our findings showed that post-SMILE dry eye tended to worsen in the first postoperative week and then returned to baseline levels from 1 month after the operation, which is consistent with studies in other postoperative dry eye patients (10, 11). At postoperative month 3, clinical DED parameters in both groups were significantly improved, compared with those before surgery. One week after SMILE, there was no significant difference in the clinical data between the two groups. However, the FS score of the DQS group was significantly lower than that of the HA group at postoperative month 1, which suggests that recovery of the corneal and conjunctival epithelium was enhanced by DQS and HA combination therapy (20, 21). Thus, a better UCVA was found in the DQS group. At 3 months after SMILE, the DQS group showed advantages over the HA group in OSDI, TBUT and SIT. These results indicate the superiority of hyaluronate and diquafosol combination therapy over hyaluronate alone in the treatment of dry eye patients after SMILE.
Although there were no significant differences in UCVA and BCVA between the two groups at 3 months after SMILE, total HOA was statistically significantly lower in the combined treatment group. Irregular astigmatism may be corrected to some extent by improving the uneven or missing mucin distribution on the tear film surface, thus reducing corneal aberration and diffraction (22). Koh et al. showed that in patients with short-TBUT dry eye, the visual function of LogMAR was significantly increased after the use of DQS (23). Further studies on the short- and long-term effects of DQS on the ocular optical quality of dry eye patients with water deficiency showed that HOA was significantly reduced, and corneal epithelial injury was alleviated, while tear film stability was enhanced after 4 weeks (24). These results indicate that DQS can effectively alleviate corneal irregularity, and improve optical quality, which is consistent with the results of this study. However, all corneal HOAs significantly increased after SMILE in both groups. Further study will be required to investigate the changes in HOAs after SMILE.
This study has several limitations. The subjects’ age, dioptre and cutting depth in the operation were not further grouped, which may have led to differences in corneal morphology, irregularities, and refractive regression rates, thus influencing the results. Moreover, the sample size was small and this study was not designed to be double-blinded. Therefore, well-designed studies with larger sample sizes should also be conducted to test the current results.
Conclusion
To our knowledge, this is the first comparative study on the application of diquafosol sodium in dry eye patients after SMILE. The results showed that combination therapy with diquafosol and hyaluronate was better than hyaluronate alone in improving both symptoms and signs in eyes with DED after SMILE. Diquafosol sodium may be used as an effective therapeutic agent for dry eye patients after SMILE.
Acknowledgements
This work was supported by the Project of Shanghai Science and Technology (20ZR1443600), the Multi-Center Clinical Research Project of Shanghai Shenkang Hospital Development Center (SHDC2020CR1043B-009), and the Clinical Science and Technology Innovation Project of Shanghai Shen Kang Hospital Development Center (SHDC12018103).
Footnotes
Authors’ Contributions
All Authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Y. L., Y. Q., L. L., M. L., H. Y., and J. Z. The first draft of the manuscript was written by Y. L. and Y. Q., and all authors commented on previous versions of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest.
- Received July 12, 2023.
- Revision received August 20, 2023.
- Accepted August 25, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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