Comparison of the efficacy of intense pulsed light, 0.05% cyclosporine A eye drops, and 3% diquafosol sodium eye drops in the treatment of moderate to severe dry A prospective cohort study

Authors: Youlv Lu, Yuhua Tong, Chunyun Feng

Abstract

The study aimed to compare the efficacy of intense pulsed light (IPL), 0.05% cyclosporine A (CsA) eye drops, and 3% diquafosol sodium (DQS) eye drops in treating moderate to severe dry eye. A cohort of 180 patients diagnosed with moderate to severe dry eye was enrolled in the Department of Ophthalmology at Quzhou People’s Hospital between October 2, 2023, and October 2, 2024. The patients were randomly assigned to 3 treatment IPL, 0.05% CsA, and 3% DQS, with each group consisting of 60 patients. Ocular surface parameters were assessed at 4-week and 12-week intervals after the initiation of treatment. The primary outcome measure was the change in the corneal fluorescein staining score (CFSS), used to evaluate the therapeutic efficacy of IPL, 0.05% CsA, and 3% DQS eye drops. The secondary outcomes included the Ocular Surface Disease Index (OSDI), Schirmer Tear Test 1 (STT1), tear meniscus height (TMH), and tear breakup time, used to evaluate treatment efficacy. At week 4 post-treatment, the CsA, DQS, and IPL groups demonstrated statistically significant differences in average NBUT, OSDI score, TMH, and STT1 score (P < .05). The IPL group achieved the most favorable outcomes, showing the highest NBUT, TMH, and STT1 scores, along with the lowest OSDI score. Although CFSS values varied among the groups, the differences were not statistically significant (P > .05). At week 12 post-treatment, significant differences (P < .05) were observed among the CsA, DQS, and IPL groups across multiple parameters. The IPL group continued to show superior results, with the highest tear film breakup time, TMH, and STT1 scores, as well as the lowest OSDI and CFSS values. IPL, 0.05% CsA, and 3% DQS eye drops are effective in treating moderate to severe dry eye. Notably, IPL shows significant advantages over CsA and DQS, owing to its noninvasive nature, effective clearance of meibomian gland obstruction, and marked improvement in tear film quality.

1. Introduction

Dry eye disease (DED) is characterized by insufficient or poor-quality tears, resulting in tear film instability and ocular surface damage. Patients with DED frequently report dryness, foreign body sensation, burning, blurred vision, and ocular fatigue.^[1]^ In severe cases, DED may cause persistent redness, tingling, and marked visual impairment, which can interfere with daily activities and occupational performance. Artificial tears remain the 1st-line treatment, while newer therapeutic options include cyclosporine A (CsA)^[2]^ and diquafosol sodium (DQS).^[3]^ CsA exerts immunomodulatory and anti-inflammatory effects and is widely used to reduce ocular surface inflammation in DED. Because of its poor water solubility, CsA is commonly formulated in oil-based carriers, which may lower drug bioavailability and increase ocular irritation. DQS promotes ocular surface repair and alleviates DED symptoms by stimulating adhesion protein secretion. However, studies^[4–6]^ have reported that DQS may cause ocular pain, conjunctivitis, and, in some cases, keratitis or dizziness. Beyond conventional artificial tears, intense pulsed light (IPL) represents a novel advancement in the management of DED. Owing to its noninvasive nature and high efficacy, IPL has shown promising results, particularly in DED associated with meibomian gland dysfunction (MGD).^[7]^ By targeting the meibomian glands, IPL facilitates obstruction clearance and enhances lipid secretion, thereby improving tear film quality and alleviating DED symptoms. To evaluate the efficacy of IPL, 0.05% CsA, and 3% DQS in treating DED, we conducted a 12-week prospective cohort study to identify the most effective therapeutic option.

2. Subjects and methods

2.1. Subjects and ethical approval

A total of 180 patients diagnosed with dry eye were enrolled at the Department of Ophthalmology, Quzhou People’s Hospital, between October 2, 2023, and October 2, 2024. The study was approved by the Medical Ethics Review Committee of Quzhou People’s Hospital, affiliated with Wenzhou Medical University (approval Quzhou People’s Hospital Ethics Review 2023, No. 058). All examinations and procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from all participants before study initiation.

2.2. Inclusion and exclusion criteria

The inclusion criteria for DED were as participants met the diagnostic criteria for DED established by the Second International Dry Eye Workshop (DEWS II); and participants were adults aged ≥ 29 years with significant ocular discomfort, including persistent dryness, foreign body sensation, burning, pain, photophobia, or blurred vision. The exclusion criteria for DED were as known allergy to ocular surface medications, such as fluorescein sodium; history of ocular surgery within the past 3 months or ocular trauma; lacrimal punctal embolization or other ocular interventions within the past month; active ocular surface infection or infection within the past month; history of endophthalmitis or viral keratitis; use of medications such as doxycycline or glucocorticoids within the past month; and presence of additional ocular diseases (e.g., corneal ulcer, glaucoma) or systemic conditions that could affect the assessment of treatment efficacy.

2.3. Study protocol

In this prospective cohort study, 180 participants were randomly assigned to 1 of 3 treatment IPL, 0.05% CsA, or 3% DQS. The IPL group received IPL combined with local massage, the 0.05% CsA group received CsA eye drops, and the 3% DQS group received DQS eye drops. All groups followed a 12-week treatment regimen. Clinical outcomes, including corneal fluorescein staining score (CFSS), Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), tear breakup time (TBUT), and Schirmer Tear Test 1 (STT1), were evaluated at 4 and 12 weeks after treatment initiation (Fig. 1).

2.4. Treatment modalities

2.4.1. CSA group

Participants were administered 0.05% CsA ophthalmic solution (RESTASIS; Allergan, Irvine) at a dosage of 1 drop in each eye, twice daily, over a period of 12 weeks.

2.4.2. DQS group

Each participant was administered 3% DQS ophthalmic solution (Diquas, Suntian Pharmaceutical Company, Osaka, Japan) bilaterally, at a dosage of 1 drop per eye, 6 times daily over a 12-week period.

2.4.3. IPL group

In the IPL group, treatments were performed by the same ophthalmologists using the M22 OPT device. The device was set to a 3-pulse mode with a wavelength of 590 nm, with each pulse lasting 5 ms and an inter-pulse delay of 50 ms. A medical ultrasonic coupling gel was applied to the skin before treatment. Physicians wore protective goggles and adjusted the energy to 11 to 14 J/cm². A spot test was 1st performed on the patient’s temporal skin, and energy levels were individualized according to skin color. Treatment covered the right temporal periorbital region, including the eyelid and cheek, extended across the nose, and continued to the left periorbital region (Fig. 2). The procedure was performed close to the edge of the treatment area, with patients instructed to keep their eyes closed. If <10% of light spots were covered, the procedure was repeated, with each session involving 22 to 24 spots. After treatment, the coupling gel was gently removed and the eyelid margin was cleaned. Patients were then instructed to apply a local hot compress twice daily for 5 minutes.

2.4.4. Eye safety measures for IPL treatment

After cleansing the ocular surface, 0.5% proparacaine hydrochloride eye drops were instilled into the conjunctival sac. A sterile eye shield was then placed over the corneal surface to protect the cornea and iris from potential damage caused by IPL. The operator wore protective eyewear throughout the procedure.

2.5. Safety assessment IPL treatment

Visual acuity in both eyes was assessed using a standardized logarithmic chart, and intraocular pressure was monitored in real time with a non-contact tonometer. Key ocular parameters were recorded throughout treatment to enable continuous evaluation of therapeutic effects. The anterior segment and fundus of all patients were carefully monitored to provide a comprehensive assessment of ocular health.

2.6. Evaluation of efficacy

2.6.1. OSDI scale

The OSDI was used to evaluate the severity of ocular surface symptoms. It quantifies symptoms by assessing ocular discomfort, visual function, and environmental triggers, with severity determined from the total score. The OSDI consists of 12 questions, each with 5 response options scored from 0 to 4. The scale covers 3 ocular symptoms (3 items), visual function (6 items), and environmental triggers (3 items). Each item is scored as 0 = none, 1 = a small part of the time, 2 = half of the time, 3 = most of the time, and 4 = all of the time. The final score is calculated as (sum of item scores ÷ number of items answered) × 25, yielding a score between 0 and 100. Scores ≤ 20 indicate mild symptoms, 21 to 45 indicate moderate symptoms, and ≥ 46 indicate severe symptoms.

2.6.2. TMH

TMH was measured using a K5M dry eye analyzer. For each evaluation, 3 images were obtained, and the mean value was calculated to represent the TMH before and after treatment. All TMH values were expressed in millimeters (mm).

2.6.3. TBUT

The physician positioned the patient in a quiet, comfortable environment and explained the procedure clearly to reduce anxiety. A dry eye specialist then applied a sterile fluorescein strip to the lower palpebral conjunctiva, ensuring even staining while avoiding contamination or abrasion. The patient was instructed to blink several times to evenly distribute the fluorescein across the tear film.

2.6.4. STT1

A dry eye specialist gently retracted the patient’s lower eyelid to expose the conjunctival sac. A test strip was inserted with its marked end placed at the junction of the middle and outer thirds of the sac. The strip remained in place for 5 minutes, during which tear absorption was monitored. After removal, the length of absorbed tears was measured in millimeters. No ocular surface anesthetic was used during the procedure.

2.6.5. Corneal fluorescein staining score

The dry eye specialist applied a small amount of 2% sodium fluorescein solution to the patient’s subfornix conjunctiva using a glass rod. Corneal staining was then examined under a slit-lamp microscope with a cobalt blue filter. The severity of staining was graded according to the Oxford grading system.

2.7. Statistical analysis

The study’s sample size was determined according to analysis of variance requirements. Assuming a significance level of 0.05, a power of 0.80, and a moderate effect size (Cohen f = 0.25), calculations using G*Power 3.1 indicated the need for 50 participants per group, totaling 150 across 3 groups. To account for potential confounders and a 15% to 20% risk of missing data, the sample size was increased by 20%, resulting in a final total of 180 participants. This approach followed CONSORT guidelines to ensure methodological rigor and reliability. Statistical analyses were performed using SPSS version 26.0 (IBM Corporation, Armonk). Data with a normal distribution were reported as mean ± standard deviation (SD), while non-normally distributed data were expressed as median with interquartile range. Group comparisons were made using 1-way analysis of variance for normally distributed variables and the Mann–Whitney U test for non-normal variables. Categorical data were summarized as frequencies and percentages, with comparisons conducted using the chi-square test. A P-value < .05 was considered statistically significant.

3. Results

3.1. Comparison of general data among the 3 groups before treatment

There were no significant differences in gender, age, TBUT, OSDI, CFSS, TMH, and STT1 score among the 3 groups before treatment (P > .05; Table 1).

3.2. Comparison of dry eye evaluation indices among the 3 groups after 4 weeks of treatment

The average TBUT was 5.45 seconds for the CsA group, 5.63 seconds for the DQS group, and 6.18 seconds for the IPL group, showing a statistically significant difference (F = 3.23, P < .05; Table 2). The mean OSDI scores were 31.75 for CsA, 29.00 for DQS, and 25.00 for IPL, with significant differences observed (F = 9.43, P < .05; Table 2). In contrast, the average CFSS was similar across 1.33 for CsA, 1.35 for DQS, and 1.27 for IPL, with no significant difference (F = 0.32, P > .05; Table 2). The average TMH was 0.25 mm for the CsA group, 0.24 mm for the DQS group, and 0.32 mm for the IPL group, with significant differences among the groups (F = 27.19, P < .05; Table 2). Similarly, the average STT1 test scores were 4.62 for CsA, 4.10 for DQS, and 6.03 for IPL, showing significant differences (F = 39.48, P < .05; Table 2).

3.3. Comparison of dry eye evaluation indices among the 3 groups after 12 weeks of treatment

The mean TBUT was 5.67 seconds for the CsA group, 6.10 seconds for the DQS group, and 8.21 seconds for the IPL group, with significant differences observed (F = 36.92, P < .05; Table 3). The mean OSDI scores were 28.39 for CsA, 23.80 for DQS, and 22.18 for IPL, showing significant differences as well (F = 10.29, P < .05; Table 3). The average CFSS was 1.31 for CsA, 0.94 for DQS, and 0.94 for IPL, with significant differences (F = 17.10, P < .05; Table 3). The average TMH was 0.25 mm for both the CsA and DQS groups and 0.36 mm for the IPL group, showing significant differences among the groups (F = 42.17, P < .05; Table 3). The average STT1 scores were 4.41 for CsA, 4.59 for DQS, and 9.09 for IPL, demonstrating a significant difference (F = 387.72, P < .05; Table 3).

4. Discussion

DED is a common ophthalmic condition with increasing global prevalence and an earlier age of onset.^[8]^ It not only impairs visual function but also significantly reduces patients’ quality of life. The etiology of DED is multifactorial, involving environmental factors, lifestyle habits, ocular disorders, and systemic diseases. Pathophysiological mechanisms include reduced tear secretion, instability of the tear film, and chronic ocular surface inflammation.^[9]^ Current treatment strategies for DED can be broadly divided into pharmacological, physical, and surgical approaches. Pharmacological therapy primarily aims to mimic natural tears by providing hydration, protecting the cornea, and restoring tear film stability, thereby alleviating symptoms. Common artificial tear substitutes include sodium hyaluronate,^[10]^ polyvinyl alcohol,^[11]^ and DQS. Tear-promoting medications, such as bromhexine hydrochloride,^[12]^ pilocarpine nitrate,^[13]^ and cevimeline,^[14]^ enhance tear secretion. Anti-inflammatory agents, including antibiotics and CsA, reduce ocular surface inflammation and improve the tear environment. Physical therapies include hot compresses, meibomian gland massage, atomization therapy, and IPL. For severe DED unresponsive to conservative management, surgical options such as lacrimal punctal occlusion,^[15]^ eyelid suturing,^[16]^ and autologous gland transplantation^[17]^ may be considered. Topical 0.05% CsA has been shown to exert potent anti-inflammatory and immunosuppressive effects.^[18]^ Similarly, 3% DQS, a new generation of artificial tears, has demonstrated strong efficacy and safety in clinical studies.^[19–22]^ DQS prolongs TBUT, promotes mucin secretion, alleviates symptoms, and improves patients’ quality of life. IPL therapy represents a noninvasive physical treatment that delivers specific light wavelengths to periocular skin and ocular tissues without requiring incisions or injections. It is generally safe, well tolerated, and widely accepted by patients. Based on these considerations, we conducted a study to evaluate the therapeutic efficacy of IPL compared with 0.05% CsA and 3% DQS eye drops in patients with DED.

The study demonstrated a significant reduction in mean OSDI scores across all 3 groups at both 4 and 12 weeks after treatment, with the IPL group achieving the lowest scores compared to the DQS and CsA groups (Fig. 3). Significant differences in OSDI scores were observed among the groups (F = 9.43, P < .05). Similarly, TBUT (Fig. 4) and STT1 scores improved significantly in all groups after treatment, with notable improvements at both week 4 and week 12 compared with baseline. The IPL group exhibited the highest mean STT1 scores (Fig. 5). A significant decrease in mean CFSS was recorded in all groups at both time points, with the IPL group showing the greatest reduction relative to the DQS and CsA groups (Fig. 6). In addition, TMH values increased significantly across all groups post-treatment, with the IPL group demonstrating the most pronounced improvement (Fig. 7).

CsA, a widely used therapeutic agent for DED, alleviates symptoms through synergistic, multi-pathway mechanisms. CsA selectively inhibits T-lymphocyte activation and the release of inflammatory mediators,^[23]^ thereby reducing ocular surface inflammation^[24]^ and improving dry eye symptoms. Its immunomodulatory properties correct aberrant immune responses,^[25]^ suppress excessive proliferation of immune cells in the lacrimal gland microenvironment,^[26]^ restore lacrimal gland function, and promote tear secretion. In addition, CsA protects ocular surface tissues by inhibiting apoptosis of lacrimal gland acinar cells and conjunctival epithelial cells,^[27]^ while accelerating tissue repair.^[28]^ Further studies indicate that CsA enhances tear production by modulating intracellular signaling pathways in lacrimal gland cells.^[29]^ A randomized controlled trial involving 162 patients demonstrated that CsA significantly increases tear secretion, improves tear film hydration, and stabilizes tear film integrity.^[30]^ Long-term treatment has also been shown to increase TMH, which correlates with enhanced tear synthesis.^[31]^ Regarding corneal protection, CsA reduces epithelial cell damage by suppressing T-cell-mediated inflammation,^[32]^ thereby lowering CFSS. Despite these systemic benefits (including immunomodulation, anti-inflammatory activity, tear stimulation, and corneal protection) CsA may cause local adverse effects such as ocular irritation, which can limit long-term patient tolerance.

DQS alleviates dry eye symptoms through multiple mechanisms. Primarily, it acts as a potent purinergic receptor agonist on conjunctival epithelial cells. Receptor activation elevates intracellular Ca²⁺, triggering the opening of Cl⁻ channels and aquaporins. This process enhances chloride and water secretion, thereby increasing tear production.^[33,34]^ The subsequent intracellular signaling pathways further stimulate lacrimal gland activity, promoting additional tear synthesis and secretion.^[35,36]^ Concurrently, DQS suppresses the expression of pro-inflammatory mediators, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, thereby reducing ocular surface inflammation. It also stimulates mucin secretion from conjunctival goblet cells, which is critical for tear film adhesion and stability.^[37]^ Furthermore, DQS promotes corneal epithelial repair. In a corneal injury model, it induced the proliferation and migration of corneal epithelial cells by activating the epidermal growth factor receptor and extracellular signal-regulated kinase signaling pathway.^[38]^ This activity reduces corneal epithelial cell loss and damage, subsequently lowering the CFSS. These mechanisms are supported by clinical evidence. A study of 86 dry eye patients undergoing cataract surgery showed that DQS treatment significantly lowered OSDI scores and alleviated symptoms of ocular redness, foreign body sensation, and discomfort. In summary, DQS systemically improves dry eye through its anti-inflammatory effects, enhanced tear secretion, tear film stabilization, and promotion of corneal repair.

Compared to DQS and CsA, IPL improves DED through unique, multi-target mechanisms. IPL exerts immunomodulatory effects by suppressing T-cell activation, thereby reducing ocular tissue inflammation.^[39]^ A study involving 132 patients with MGD-related DED demonstrated that next-generation IPL not only influences neurotransmitter release but also modulates sympathetic nervous system activity. By regulating neurotransmitter levels, IPL adjusts lacrimal gland secretion, alleviating dry eye symptoms and reducing the OSDI score.^[29]^

The primary mechanism of IPL lies in its photothermal effects. Light at specific wavelengths is selectively absorbed by melanin in the eyelid skin, hemoglobin in blood vessels, and water in the dermis.^[40]^ This absorbed energy is converted to heat, liquefying obstructed meibomian gland secretions and promoting their discharge.^[41–43]^ This restores normal gland function and increases meibum secretion. Meibum is essential for the lipid layer of the tear film, helping maintain stability and reduce evaporation.^[44–47]^ Additionally, IPL’s thermal effects target and eradicate Demodex mites while reducing bacterial load on the eyelid margin,^[48]^ both of which contribute to ocular surface inflammation and corneal damage. Studies confirm that IPL treatment alleviates inflammation, improves meibomian gland function, and reduces CFSS by eliminating these pathogens.^[49,50]^ Notably, IPL does not directly act on the lacrimal gland. Instead, it indirectly enhances tear secretion by stimulating conjunctival epithelial and goblet cells, promoting tear and mucin secretion, and prolonging TBUT.^[51]^ Moreover, IPL improves meibomian gland function, stabilizing the tear film lipid layer, reducing evaporation, and increasing TMH. In contrast to DQS and CsA, which stimulate tear secretion via complex physiological and immune pathways, IPL selectively targets pathological tissues through photothermal action. The heat generated by IPL destroys abnormal blood vessels, sealing their walls^[52]^ and further reducing the release of inflammatory mediators. Multiple studies^[53–55]^ highlight IPL’s pronounced efficacy in MGD-related DED, as its thermal effects not only unclog glands but also improve ocular surface health by modulating the local microenvironment. In this study, we observed that IPL demonstrated superior therapeutic efficacy compared to DQS and CsA in patients with moderate to severe DED. Previous research has compared CsA and DQS and evaluated IPL against a single artificial tear treatment. While these studies provide valuable insights into dry eye management, they lack comprehensiveness. Therefore, this study represents a significant advancement by comparing IPL with 2 advanced dry eye treatments. This direct comparison offers a broader range of therapeutic options and clarifies the advantages and limitations of each treatment modality.

A limitation of this study is its relatively small sample size and the short duration of the follow-up period. The research primarily focused on the short-term efficacy of IPL in treating DED, with no long-term follow-up data. Additionally, patient variability requires individualized adjustments to IPL treatment parameters, such as light intensity and treatment frequency. Future studies should aim to increase sample size, optimize treatment protocols, and include extended follow-up periods to better assess the long-term efficacy and safety of IPL for dry eye management.

5. Conclusions

This study systematically compared the therapeutic effects of IPL, 0.05% CsA, and 3% DQS in patients with moderate to severe dry eye, using a prospective cohort design. The results demonstrated that all 3 treatments effectively alleviated dry eye symptoms, though the degree of efficacy varied. IPL showed particular advantages, primarily due to its noninvasive nature, including enhanced tear secretion, reduced ocular inflammation, and promotion of ocular surface repair. In contrast, 0.05% CsA and 3% DQS exert their therapeutic effects mainly through anti-inflammatory mechanisms and improved tear production. Future studies should incorporate additional outcome measures and extend the follow-up period to provide a more comprehensive evaluation of these treatments’ long-term efficacy in managing DED.

Author contributions

Conceptualization: Youlv Lu.

Data curation: Yuhua Tong.

Supervision: Chunyun Feng.

Writing – original draft: Youlv Lu.

Writing – review & editing: Chunyun Feng.