The Effect of Low-Dose Aspirin on Dry Eye Parameters and Ocular Surface Disease Index Questionnaire

Abstract

Purpose:

To evaluate the effects of acetylsalicylic acid (aspirin) on tear film parameters and dry eye disease.

Methods:

Fifty-seven patients using low-dose aspirin regularly for antiaggregant purposes as well as 49 controls, who required antiaggregant treatment but who had not yet started, were included in the study. Tear osmolarity, tear break-up time (TBUT), Schirmer and Oxford grading of ocular surface staining were performed on all patients and dry eye symptomatology was assessed using the ocular surface disease index questionnaire (OSDI).

Results:

The mean osmolarity was 302.11 ± 16.22 mOsm/L in the aspirin group and 313.88 ± 19.57 mOsm/L in the control group (P < 0.01). The mean Schirmer's score was 24.16 ± 10.52 mm and 21.94 ± 10.11 mm (P = 0.232), TBUT was 13.61 ± 3.31 s and 10.39 ± 4.46 s (P < 0.01), OSDI score was 5.15 ± 5.98 and 16.94 ± 14.17 (P < 0.01), and Oxford score was 0.12 ± 0.33 and 0.12 ± 0.44 in aspirin and control groups, respectively (P = 0.99). Dry eye diagnosis was lower in the aspirin group, but statistical significance was present only in TBUT and osmolarity-based dry eye diagnosis (P ≤ 0.01). In terms of symptom-based dry eye diagnosis with the threshold of OSDI ≥23, none of the aspirin group had dry eye diagnosis, whereas 32.6% of the control group had the diagnosis (P < 0.01).

Conclusions:

The use of low-dose aspirin might be great option for treatment of ocular surface inflammatory disease through increasing TBUT and decreasing tear osmolarity with a resultant symptomatic satisfaction.

Introduction

According to the International Dry Eye Workshop Study, dry eye is now considered to be a multifactorial disease of the tears as well as the ocular surface that results in symptoms of discomfort and visual disturbance.¹ It is accompanied by an increase in osmolarity of the tear film and inflammation of the ocular surface.¹ Tear hyperosmolarity causes expression of inflammatory mediators and the cornea becomes desiccated, which in turn causes ocular surface damage, which in turn triggers the inflammatory response of hyperemia, discomfort, corneal edema, and eventually corneal staining.² Ocular surface damage results in instability of the tear film and hyperosmolarity, then the vicious cycle starts again.

The inflammatory cascade plays different roles in the pathogenesis of dry eye. In aqueous-deficient dry eye, proinflammatory cytokines and inflammatory markers are secreted by the lacrimal gland which further damages the ocular surface. In evaporative dry eye, ocular surface inflammation is attributed to a breakdown of lipids in the meibomian glands. Dry eye is also attributed to a loss of homeostasis of the tear film with corneal desiccation and subsequent inflammation for which the only approved therapeutic medication is topical cyclosporine which is a widely known immunosuppressive agent.³

Acetylsalicylic acid (ASA), commonly known as aspirin, is the archetype of the nonsteroidal anti-inflammatory drug family. Although it was discovered as a painkiller and anti-inflammatory agent, new therapeutic efficacies with different modes of action in different conditions have been discovered.^4–6 Related to ophthalmology practice, Valentic et al.⁷ reported that aspirin, a known inhibitor of cyclooxygenase (COX) and proinflammatory prostaglandins, is secreted into human tears in amounts proportional to its plasma concentration. A recent study reported that subjects receiving aspirin had less dry eye symptoms than controls.⁸ However, this study is a questionnaire-based cross-sectional study and does not include tear parameters especially tear osmolarity, which is the “gold standard” of objective dry eye diagnosis and the single best marker of disease severity.^9,10

In the current study, we hypothesized that aspirin or its metabolites may be secreted into the tears providing a direct anti-inflammatory effect on the ocular surface, it may also be carried through the blood to the conjunctival vessels with subsequent access to the cornea and lacrimal glands, and the drug may accumulate in the lacrimal gland and may prevent the release of inflammatory cytokines with anti-inflammatory as well as analgesic effects. Therefore, aspirin can decrease both dry eye disease and its symptoms.

Accordingly, we evaluated the Schirmer's score, tear break-up time (TBUT), tear osmolarity, and ocular surface vital dye staining scores of low-dose aspirin users (antiaggregant), and compared this with a control group. We also included a questionnaire to reveal the relationship between dry eye symptomatology and aspirin. To our knowledge, our study is the first to evaluate the relationship of aspirin and tear osmolarity.

Methods

The study was approved by the Institutional Ethics Committee and adhered to the tenets of the Declaration of Helsinki. All participants gave informed consent. A power analysis was performed to determine the number of patients that needed to be enrolled in the study; consequently, 57 patients being followed up in the Cardiology Department and who were using aspirin (Coraspin 100 mg; Bayer HealthCare AG, Germany) regularly for antiaggregant purposes, as well as 49 controls, who required antiaggregant treatment but who had not yet started, were included in the study.

Age, gender, systemic disorders, and medications were noted and no significant difference between the groups was found. Participants with any ocular surface disorder, previous ocular surgery, previous dry eye diagnosis, any topical ophthalmic medication, or contact lens use were excluded. For assessment of dry eye symptomatology, the participants, with no involvement by the clinicians, performed the ocular surface disease index questionnaire (OSDI), a 12-item questionnaire developed by Outcomes Research Group at Allergan, Inc. (Irvine, CA) for rapid and reliable assessment of dry eye symptoms¹¹ before the ophthalmologic examinations.

All ophthalmologic examinations, including best corrected visual acuity; intraocular pressure measurement; anterior segment and dilated fundus examinations; and the dry eye parameters performed in the following order osmolarity, TBUT, Schirmer, and Oxford grading of ocular surface staining, were performed in the morning. Measurements were performed from the right eye in all participants.

Tear osmolarity was measured using TearLab™ Osmolarity System (TearLab™ Corp., San Diego, CA) designed to take a 50 nL sample of tears. We ensured that the system was functioning normally once per day with the electronic check cards as per the product manual instruction guide using monodose saline with an osmolarity value of 300 mOsm/L. The test was performed without anesthesia with the patient looking straight ahead and the tip of the cartridge touching the tear meniscus. TBUT was performed after an impregnated fluorescein 1 mg strip (Visimed, Izmir, Turkey) was moistened and placed into lateral one-third of lower eyelid, the interval between the last complete blink and the appearance of the first corneal black spot in the stained tear film was measured three times and the average of the measurements were calculated.

Lisamine Green 1.5 mg strips (Madhu Instruments, New Delhi, India) were used for ocular surface staining. The strips were moistened by tear substitutes and applied to the inferior palpebral conjunctiva. After 15 s, stained areas in the conjunctiva were examined with a red-free filter on slit lamp. Results were evaluated using Oxford grading scheme from 0 to 5 with increased significance of ocular surface staining.¹² The Schirmer's test (Madhu Instruments) was performed without anesthetic with the eye closed for 5 min after the strip was inserted into the lower conjunctival sac at the junction of the lateral and middle thirds and the length of wetting strips in millimeters was recorded after 5 min.

All data were expressed as mean ± standard deviation. Shapiro–Wilk test was used to assess the normality distribution and as data were normally distributed, the t-test was used in comparison of the groups in terms of OSDI, osmolarity, TBUT, Schirmer, and Oxford scores. Chi-square test was used to evaluate gender differences between the groups. Pearson correlation analysis was also performed for the duration of aspirin use and ocular surface parameters in the aspirin group. For statistical analysis P < 0.05 was accepted as significant.

Results

The mean age was 63.68 ± 9.06 years in the aspirin group and 62.80 ± 10.13 years in the control group. The male to female ratio was 36/21 and 24/25, respectively. There was no statistically significant difference between the groups in terms of age and gender (P = 0.64 and P = 0.17, respectively). The mean osmolarity was 302.11 ± 16.22 mOsm/L in the aspirin group and was 313.88 ± 19.57 mOsm/L in the control group (P < 0.01). The mean Schirmer's score was 24.16 ± 10.52 mm and 21.94 ± 10.11 mm (P = 0,232), TBUT was 13.61 ± 3.31 s and 10.39 ± 4.46 s (P < 0.01), OSDI score was 5.15 ± 5.98 and 16.94 ± 14.17 (P < 0.01), and Oxford score was 0.12 ± 0.33 and 0.12 ± 0.44 in aspirin and control groups, respectively (P = 0.99). Table 1 demonstrates the comparison of dry eye parameters between the groups.

Table 1.

Dry Eye Parameters in the Aspirin Versus Control Group

	Aspirin group	Control group	P
Tear osmolarity	302.11 ± 16.22	313.88 ± 19.57	<0.01
Schirmer's score	24.16 ± 10.52	21.94 ± 10.11	0.232
Oxford score	0.12 ± 0.33	0.12 ± 0.44	0.99
TBUT	13.61 ± 3.31	10.39 ± 4.46	<0.01

Characters in bold mark statistically significant P values.

TBUT, tear break-up time.

The mean aspirin use was 7.96 ± 4.91 years in the aspirin use group and it was not correlated to any of the dry eye parameters or OSDI (Table 2). If cutoff values for dry eye diagnosis were set as Schirmer's test <10 mm^12–14 TBUT <10 s,¹¹ osmolarity >316 mOsm/L,⁹ dry eye frequency in the aspirin and control groups were 17.5% and 18.3%, 17.5% and 46.9%, and 17.5% and 40.8%, respectively. Dry eye diagnosis was lower in the aspirin group, but statistical significance was present only in TBUT and osmolarity-based dry eye diagnosis (P ≤ 0.01). In terms of symptom-based dry eye diagnosis with the threshold of OSDI ≥23,¹¹ none of the aspirin group had dry eye diagnosis, whereas 32.6% of the control group had the diagnosis (P < 0.01).

Table 2.

Demographic Factors and Ocular Surface Disease Index Scores in the Aspirin Versus Control Group

	Aspirin group	Control group	P
Age	63.68 ± 9.06	62.80 ± 10.13	0.64
Male/female	36/21	24/25	0.17
OSDI	5.15 ± 5.98	16.94 ± 14.17	<0.01

OSDI, ocular surface disease index.

Discussion

Aspirin is a nonselective COX inhibitor, which reduces the production of inflammatory prostaglandin synthesis and achieves an anti-inflammatory, antiaggregant, antioxidant, as well as an analgesic action. The second mechanism of action for which aspirin is most widely used is its antiaggregant action in low doses.¹⁵ Aspirin has also been reported to have antioxidant, anticancer, and antidementia actions through C5X-dependent or independent pathways.^2–4 Therefore, it is a widely used drug in the elderly population, who are at an increased risk of dry eye disease.

In a study by Valentic et al.,⁷ aspirin is excreted in the tears at levels proportional to the plasma levels. In another animal model, selective and nonselective COX inhibitors were demonstrated to improve both dry eye findings and ocular surface inflammation, histopathologically.¹⁶ Finally, Tong and Wong⁸ found that subjects using aspirin had less dry eye compared with nonaspirin users (2.4% and 6.7%, respectively). The studies mentioned above were either animal studies or human studies performed with respect to symptom-based dry eye questionnaires. For this reason, we designed this study to demonstrate not only subjective, but also objective dry eye diagnostic parameters in the elderly population through comparing aspirin users and subjects who needed aspirin treatment, but who had not yet started.

The participants were elderly patients and we know that aging is related with pathologic changes that lead to dry eye such as decreased tear volume and stability, increased osmolarity, and alterations in meibomian lipid compositions.^17,18 In accordance with this knowledge, our control group mean tear osmolarity corresponds to mild-to-moderate dry eye diagnosis interval (308–316 mOsmol/L), which is compatible with their aging process.¹⁹ As an important finding, the aspirin group had a statistically lower mean osmolarity value (302.11 ± 16.22 mOsm/L) when compared with controls. The percentage of subjects having severe dry eye¹⁰ (>316 mOsmol/L) in the control group was 40.8%, which was nearly 2.5 times more frequent than the aspirin group (17.5%). These results conclude that the antiaggregant dose aspirin had a role in decreasing the tear osmolarity that is the indicator of ocular surface inflammatory status.

We now know that tear film hyperosmolarity is a central cause of ocular surface inflammation, damage, and symptoms of dry eye.^11,10 Therefore, the reduction of tear osmolarity should have ameliorative outcomes in other potential dry eye diagnostic tools, such as TBUT, OSDI, Schirmer, and vital dye staining. According to our results, the TBUT was close to the threshold level in the control group and aspirin significantly improved the mean TBUT value (10.39 ± 4.46 and 13.61 ± 3.31 s, respectively). Similarly, the percentage of TBUT-based dry eye diagnosis was also significantly lower in the aspirin group (17.5% vs. 46.9%).

The possible explanation for this therapeutic effect in TBUT values might be associated with an osmolarity decrease and thus control of the ocular surface inflammation. The decrease in tear osmolarity could be due to the anti-inflammatory effect of ASA. As a result, the limitation of the damage and apoptosis of the meibomian glands and goblet cells might have yielded better stabilization of the tear film. However, the vital dye staining to show ocular surface damage was not significantly different between groups. Therefore, we can conclude that although the control group had worse tear osmolarity and TBUT values, which might be accepted as ocular surface inflammation indicators, these had not yet resulted in ocular surface damage.

Another explanation for the lack of difference in ocular surface damage might be the subjectivity of the grading system, which might be affected by observer bias although our observer was qualified and blinded to the patients' diagnosis. The Schirmer's score was also lower in the control group, but the difference was statistically insignificant. This result is also compatible with the incidence of dry eye, which was quite similar (17.5% and 18.3%). Both mean and frequency values showed that aspirin did not change tear secretion.

The only human study pertaining to aspirin and dry eye was performed by Tong and Wong⁸ according to a symptom-based diagnosis of dry eye. They asked the participants for the presence of six cardinal symptoms (feeling of dryness, grittiness, burning sensation, redness, crusting of lashes, and eyelids getting stuck) and defined symptomatic dry eye as the presence of at least one symptom often or all the time than found the prevalence rates of dry eye in groups. They reported that participants who used aspirin had significantly lower prevalence of symptomatic dry eye (2.4%) than those who did not use aspirin (6.7%).

To investigate symptom-based dry eye diagnosis we used the OSDI questionnaire, which has been accepted as valid and reliable for measuring the severity of dry eye disease, and possesses psychometric properties to show disease-related quality of life.¹¹ The rate of dry eye in our study was 32.6% in the control group, whereas none of the aspirin users had symptomatic dry eye. The difference was also evident in mean OSDI values, which were 16.94 ± 14.17 and 5.15 ± 5.98 in control and aspirin groups, respectively. Although, signs and symptoms has poor correlation in terms of dry eye disease,²⁰ in our study, it was compatible with the results of TBUT and osmolarity.

The relatively lower rate of symptoms might be a result of the antioxidative and anti-inflammatory action of aspirin leading to better tear stability and the lower osmolarity levels leading to a decrease in the nociceptive stimulus discharge from the ocular surface. Its pain killer effect although below the analgesic dose of the drug may also contribute directly to the decrease in symptoms. It might also be related to pain killer effect, although the dosage is far below the analgesic dose of the drug.

As no previous studies with these parameters were performed to investigate the aspirin dry eye relationship, we have no studies to compare our results with. We only theorized that topical application of COX inhibitors might improve these parameters in a topically applied atropine sulfate-induced animal dry eye model,⁵ as decrease in tears due to parasympathetic blockage could lead to an increase in osmolarity and inflammation, and thus the vicious cycle of dry eye disease and symptoms.

It is widely accepted that, tear osmolarity is the gold standard of dry eye diagnosis and the single best marker in the diagnosis of dry eye^9,10,20 it perfectly reflects the inflammatory status of the ocular surface. It was previously shown that the low-dose aspirin treatment also has anti-inflammatory action.²¹ The anti-inflammatory action might be related to COX inhibition and consequent reduction of inflammatory prostaglandins, tumor necrosis factor, proteinase, histamine, bradykinin, and cytokine-induced hyperalgesia.¹⁶ In an experimental study, low-dose aspirin was reported to have antioxidative action through prostaglandin-independent pathways, such as decreased activation of nuclear factor-κ B (NF-κB), which is a ubiquitous effector of inflammatory response.⁴

Interestingly, Lan et al.²² have declared that NF-κB has a central regulatory role in ocular surface inflammation and diseases. Therefore, systemic use of low-dose aspirin might possibly have a preventive role in inflammatory ocular surface disorders, COX dependent or independent pathways. When viewed from this perspective, it might possess a similar role to tetracycline derivatives that are used in ocular surface disorders, such as dry eye, ocular rosacea, recurrent corneal erosions, or alkaline injuries.^23,24,25 Additionally, its low side effect profile and therapeutic effect in a wide range of systemic diseases might make it a superior medication for use in ocular surface inflammation.

As a conclusion, our results indicate that the use of low-dose aspirin might be a great option for the treatment of ocular surface inflammatory disease through increasing TBUT and decreasing tear osmolarity with a resultant symptomatic satisfaction. Further studies are needed to evaluate the possible mechanism of action thriugh biochemical analyses of human tears.

Footnotes

Author Disclosure Statement

The authors report no declarations of interest.

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