We report for the first time the clinical experience of using a novel, combined, multipurpose ocular lubricant (carboxymethylcellulose 0.5%, glycerin 0.9% and trehalose 3%) in a retrospective cohort of 67 eyes (67 patients) with aqua-deficient, evaporative and mixed DED. All patients were treated with CTP at a dosing regimen of 4 times a day for one month without using any other topical or systemic treatment, such as steroids or oral anti-inflammatory medications.
After the treatment we found a statistically significant difference in the OSDI score (primary outcome) from 57.64 +/- 19.16 (SD) to 22.22 +/- 12.93 (SD) points. Other evaluated parameters such as tear osmolarity, NIBUT and meniscus height also showed improvement without showing a statistically significant difference (p < 0.05). There was no change in the percentage of meibomian gland loss before and after treatment (Table 2). The standardization of diagnostic ocular surface tests in patients with dry eye disease with new computer-based technology (Cornea550, Essilor Creteil France) has increased the reliability of parameters such as non-invasive tear film break-up time (NIBUT), tear meniscus height and meibomian gland evaluation in clinical settings. With innovative and more accurate testing with anterior surface topographers, we decreased the intra- and inter observer variability to reduce measurement bias in contrast to clinical evaluation at the slit lamp of patients with dry eye disease.
Regarding the stratified analysis performed by disease severity, we observed a reduction in the proportion of eyes with severe disease (from 91–22%) and a significant increase at the end of the study in the mild dry eye group (from 1–31%. At the end of the study, 24% of eyes were normal according to the OSDI score.
DED is a multifactorial disease that affects a large part of the world’s population, with a prevalence of 5–50% (4, 5, 6). It is more frequent in women, older adults, Asians and in some health conditions such as autoimmune diseases, especially Sjogren's syndrome. Some risk factors for DED are modifiable such as reduced time spent using computer screens or cell phones (6) and the time of use of contact lenses but also reduce the degree of severity of endocrine diseases that affect the production of tears such as hypoestrogenism, hypoandrogenism and hypothyroidism. It is recommended to improve the environmental conditions of low humidity with an excess evaporation rate (ventilation systems, air conditioning and screen use time). In addition, the rational use of antihypertensive drugs such as beta-blockers, antiallergics (antihistamines), antidepressants (serotonin reuptake inhibitors, SSRIs), anxiolytics, and anti-acne therapy (isotretinoin) (4).
One of the novel characteristics of CTP is the presence of the 3% trehalose molecule, a disaccharide with bio-and osmoprotection properties used by certain plants and non-vertebrate animals to defend themselves against periods of extreme drought, using their water retention capacity in rainy seasons. This molecule was originally described by Marceline Berthelot in XIX century, which allows cells to survive in adverse environments and anhydrobiosis (13, 14). Trehalose has a high-water retention capacity with bio and osmoprotection properties. Different in vitro and in vivo studies have confirmed that trehalose prevents apoptosis and protects corneal cells against oxidative stress caused by UV radiation, accelerates corneal wounding and decreases the concentration of inflammatory cytokines in the conjunctiva. It also has other properties such as intracellular cleaning (autophagia) and decreased inflammation (lower concentration of IL 6, IL-8, tumor necrosis factor - TNF, and MMP-9) (15, 16).
In 2007, Chiambaretta and the Trehalose Study Group conducted a randomized, controlled, multicenter clinical trial (France and Tunisia) to evaluate the efficacy and safety of a combination of hyaluronic acid (HA) trehalose (TH) (n = 52) and hyaluronic acid (n = 53) in patients with dry eye syndrome. They used ocular lubricants at doses of 3–6 times a day for a period of 84 days, with staining of the corneal surface as the primary outcome, using the Oxford score on day 35 of the study. In addition, they evaluated the results using the validated OSDI questionnaire, Schirmer test, NIBUT and conjunctival hyperemia at the beginning and on days 35 and 84 of the study, respectively. The results of this study demonstrated a reduction in Oxford staining of -2.5 +/- 2 (HA + TH) vs -2.7 +/- 1.7 (HA) (95% CI -1.34 to 0.40) demonstrating a non-inferiority result for the group with a combined treatment of HA + TH compared to the control group (HA). In addition, they reported a reduction in the OSDI score of -20.6 +/-17.2 (HA + TH) vs -17.6 +/-16.2 (HA) points without finding a statistically significant difference (p = 0.060) (17). In our study, the degree of severity of DED observed after treatment decreased in a greater population of patients with severe DED similar to the observed effect found by Chiambaretta et al. (p = 0.04), with the appearance of a proportion of healthy eyes after one month of treatment. In our study (n = 67) we observed an important decrease in the OSDI score with a reduction of 35.4 +/- 4.4 points (p < 0.001, 95% CI 31-39.8) after a month of treatment compared to the initial values. Similarly, we agree that there was an increase in the proportion of eyes with less severe disease after treatment (1m) in all subgroups (especially in mild DED), and the appearance of a new subgroup of patients with normal OSDI scores confirmed the clinical effectiveness of CTP (from 0–23.9%). The percentage of participants with mild DED increased from 1.5–31.3%. Our results also confirmed that the main subtype of DED was the evaporative with a median meniscus height prior treatment of 0.21 mm, within the normal cutoff value, with a small increase in this parameter at one month after treatment (0.23 mm).
In 2022, Barabino et al. updated the classification of ocular lubricants into three categories based on their interaction with the ocular surface: wetting agents, multiple-action tear substitutes and ocular surface modulators. Wetting agents lubricate the ocular surface for a limited time, whereas multi-action tear substitutes can improve quality and quantity without interacting with it. Rather, ocular surface modulators interact with and influence the ocular surface to decrease signs of DED. Among the main ingredients that make eye lubricants are agents that increase the viscosity of the tear film, electrolytes, osmotic protectors, lipid agents, antioxidants and preservatives. Viscosity-increasing agents (VEA) are the most frequently used and are also known as demulcents or lubricants, including cellulose derivatives, dextran, gelatins, liquid polyols, polyvinyl alcohol and povidone (FDA). It has been demonstrated that these molecules increase the thickness of the tear film and its retention; in addition, their ability to retain water prevents evaporation (18). Carboxymethylcellulose, a component of CTP at 0.5% concentration, is a vegetable derivative that has shown benefits in patients with mild and moderate SOS by improving surface moisture and maintaining tear film integrity. Additionally, the properties of reconstitution and maintenance of the mucin layer have been recognized, depending on the concentration used. In addition, it can change its properties upon contact with the ocular surface, gelling and increasing the maintenance time on the ocular surface to partially compensate for the lack of mucin in the tear film (18).
The presence of lipids in the tear film plays an important role in the control of surface tension and therefore in the wetting of the ocular surface. The tear evaporation rate is increased in patients with deficiency of the lipid component; therefore, lipids have been incorporated into ocular lubricants in the form of liposomes (phospholipids in spherical vesicles) or nanoparticles. We also found them in the form of emulsions, which can be non-ionic, anionic or cationic, the latter being the ones that best interact with the mucinous layer (negative charge) giving greater stability to the tear film and increasing the BUT. The presence of glycerin 0.9% in CTP improves tear film stability in patients with evaporative or mixed DED and meibomian gland dysfunction (MGD). Trehalose is a molecule that protects the ocular surface from oxidative stress and prevents apoptosis of the corneal and conjunctival epithelial cells. In addition, its ability to reduce the concentration of inflammatory factors such as interleukin 6, interleukin 8, and tissue necrosis factor (TNF) and the activation of corneal metalloproteinases (MMP-9) has been confirmed (19). This unique ability of this molecule reduces the inflammatory component of the ocular surface in patients with DED.
This study has some limitations such as being a retrospective cohort with a short-term follow-up (1 month). However, the parameters evaluated with the validated OSDI questionnaire and quantitative variables measured in a standardized way, with an anterior surface topographer, allowed us to reduce measurement biases and intra- and inter-observer variability compared to clinical measurements at the slit lamp evaluation. Future studies should be performed to confirm our results with the current standard of care in a randomized, blinded and controlled clinical trial study design with a longer follow-up time.
In conclusion, we report for the first time, the clinical effectiveness of a new multipurpose-combined ocular lubricant (0.5% carboxymethylcellulose, 0.9% glycerin and 3% trehalose, CTP) in subjects with dry eye disease diagnosed using a validated dry eye questionnaire (OSDI), lacrimal osmolarity and ocular surface parameters (NIBUT, meniscus height and Meibomian gland population) through a computerized anterior surface topographer (Cornea550, Essilor, Creteil France) to decrease measurement bias and intra/interobserver variability.