Preservatives and ocular surface disease: A review

Background Glaucoma is a progressive optic neuropathy that may result in irreversible visual impairment and can diminish quality of life. Lowering intraocular pressure (IOP) through topical eyedrops is usually the primary approach to managing glaucoma. However, long-term treatment poses a risk to ocular surface health, leading to ocular surface disease (OSD). Preservative-containing eyedrops are implicated in OSD development due to their detrimental effects on the tear film and goblet cell density. OSD symptoms may impact patient compliance due to local side effects. This study aims to assess OSD in glaucoma patients receiving topical treatment, quantify symptoms and objective ocular surface parameters, and compare them to a control group not using topical glaucoma medications. Methodology Patients diagnosed with primary open-angle glaucoma receiving topical treatment and a control group were included in this study. To assess OSD, patients completed the Ocular Surface Disease Index (OSDI) questionnaire to evaluate symptoms and underwent objective measurements of ocular surface parameters using a keratograph. These parameters included assessments of bulbar redness and non-invasive keratograph tear break-up time (NIKTBUT). Results A cohort of 92 patients was subjected to examination, comprising 66 individuals diagnosed with glaucoma and 26 controls. Within the glaucoma patient subset, the mean number of IOP-lowering drugs administered was 2.42 ± 0.18, with 22.7% exclusively utilizing preservative-free eye drops. Our investigations unveiled a substantial prevalence of OSD symptoms, manifesting not only within the glaucoma cohort but also among the control group, with 72.7% and 53.8%, respectively (p = 0.224), reporting moderate-to-severe symptoms (OSDI > 23). Remarkably, OSDI scores exhibited higher values among female participants (p = 0.039) and glaucoma patients using prostaglandins (p<0.001) and were negatively correlated to the number of IOP-lowering drugs used (-0.448; p < 0.001). Furthermore, employing keratograph assessment, we discerned heightened bulbar redness (1.86 ± 0.07) in the glaucoma group compared to the control group (1.58 ± 0.07; p = 0.008). Glaucoma subgroup analyses further unveiled higher bulbar redness among glaucoma patients employing carbonic anhydrase inhibitors (p = 0.035) and applying medication preservatives (p = 0.045) but lower among individuals using beta-blockers (p = 0.018). However, the NIKTBUT did not show significant variance between the two groups (glaucoma group: 10.19 ± 0.85 seconds; control group: 10.96 ± 1.37 seconds; p = 0.499). Conclusions Our study revealed a significant prevalence of OSD in our sample, with the OSDI questionnaire showing limited specificity. The notable increase in bulbar redness pointed to an elevated prevalence of OSD among glaucoma patients, emphasizing the considerable impact of preservatives on ocular surface damage. Recognizing the potential damage to the tear film and ocular surface is crucial for glaucoma experts, who must employ comprehensive therapeutic strategies to mitigate symptoms, advocating for the preferential use of preservative-free medications, when possible, for optimizing long-term treatment.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Introduction:Ocular surface disease (OSD) is a major cause of ophthalmological consultation. Within this group, glaucoma patients constitute an important percentage due to the nature of their chronic topical treatment. Advances in the understanding of ocular surface pathology on both a cellular and molecular level, and the interaction to the toxic nature of some topical medication solution compounds, are stimulating the development of better alternatives in topical treatment.Materials and Methods:Extensive review of available literature and current research on topical ophthalmological treatments in both OSD and glaucoma was performed. Emphasis was made on inflammatory modulators of the ocular surface and pathological changes associated with the use of preservatives in solutions, in particular benzalkonium chloride (BAK). Independent research is been also performed by the authors, using a rubbing-induced reflex tears collecting method with capillary tubes. Cytokines in tear samples were subsequently analysed with the multi-Plex System (Luminex® R-200). The 12 cytokines analysed using this method are the interleukins (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, the tumour necrosis factor alpha (TNFα), the vascular endothelial growth factor (VEGF), the granulocyte-macrophage-colony stimulating factor (GM-CSF) and the interferon gamma (IFg).Results:Our unpublished, preliminary results trend to show higher values in IL-5 and IL-6 in glaucoma patients than in normal controls. Also, higher values in IL-2, IL-5 and IL-12 in dry eye syndrome (DES) patients were found versus normal controls.Conclusions:Inflammation is an important element in OSD and strong association seems to exist between this and the use of BAK preservative. New kinds of preservative molecules, as well as single-dose eye drops and sophisticated dispensing bottle mechanisms, are currently available on the market in order to avoid the secondary effects of this topical treatments, increasing patient compliance and adherence to chronic topical glaucoma treatment.

Purpose Ocular Surface Disease (OSD), recognized in 50% of glaucoma patients, can decrease anti‐glaucoma therapy compliance. Benzalkonium chloride (BAK) has been shown to induce OSD. Catioprost® is an unpreserved latanoprost 0.005% cationic emulsion. The design of a study comparing the efficacy and safety of Catioprost® versus a BAK‐free prostaglandin agonist, Travatan Z® (travoprost 0.004%) in patients with glaucoma and OSD is described.Methods Patients with elevated IOP at baseline requiring treatment with ocular anti‐hypertensive therapy were enrolled in this multicenter, phase II, investigator‐masked, randomized study. Following a washout period, patients demonstrating OSD symptoms and signs (corneal fluorescein staining, CFS, score≥1 on the modified Oxford scale and a tear film break up time, TFBUT, ≤10) in at least one eye at the baseline visit were randomized to either Catioprost® or Travatan Z® QD with follow‐up study evaluations at month 1 and 3.Results 105 patients were randomized. Change in diurnal IOP, a change in the global symptoms (ocular discomfort, burning, dryness, grittiness, stinging) and objective signs (CFS, TFBUT, conjunctival hyperemia) of OSD at month 1 and 3 will be presented. Safety outcomes will also be reported.Conclusion Preservative free prostaglandin agonists reduce the risk of ocular toxicity associated with BAK. However, their effect on restoring ocular surface damage is unclear. In this study, the efficacy and safety of an unpreserved latanoprost 0.005% cationic emulsion relative to BAK‐free travoprost 0.004% solution on reducing IOP and improving the signs and symptoms of OSD will be revealed. Commercial interest

To evaluate the effect of air pollution on the ocular surface of patients with Sjögren's syndrome. We investigated the ocular surfaces of thirty patients with Sjögren's syndrome and thirty healthy volunteers (control group) living in the Metropolitan Area of Buenos Aires. We used nitrogen dioxide as an indicator of exposure to air pollution. An ocular symptoms questionnaire was answered by all subjects, who also underwent a complete ocular surface ophthalmic examination-including an Ocular Surface Disease Index questionnaire, biomicroscopy, tear breakup time, Schirmer 1 test, corneal and conjunctival vital staining with fluorescein and lissamine green, tear lysozyme concentration, and impression cytology. In almost all ocular surface test findings, we found a positive and significant correlation between higher levels of exposure to air pollution and higher levels of ocular surface damage in both the control group and Sjögren's syndrome patients. In Sjögren's syndrome patients, the Ocular Surface Disease Index questionnaire, tear breakup time, vital staining and impression cytology showed a significant correlation between high levels of air pollution and ocular surface disease. In the control group, the Ocular Surface Disease Index questionnaire, tear breakup time, and impression cytology showed a significant correlation between high levels of air pollution and ocular surface disease. Here we demonstrated that in patients with dry eye syndrome associated with Sjögren, abnormalities of the ocular surface and eye irritation related to air pollution are more severe than those in the control group. We believe that measuring air quality should be not only an integral part of the evaluation of ocular surface disease but also a therapeutic consideration.

Background: Dry eye disease is a multifactorial disorder of the ocular surface and is a common cause of postoperative discomfort following cataract surgery, especially in the elderly population. Symptoms such as foreign body sensation, grittiness, ocular fatigue, and visual disturbance significantly affect the quality of life and patient satisfaction after surgery. Cataract surgery, being the most frequently performed ophthalmic procedure, particularly for senile cataract, can exacerbate pre-existing or subclinical ocular surface disease due to surgical trauma, corneal nerve damage, and postoperative topical medications. Early identification and management of dry eye are therefore essential to improve postoperative outcomes. Methods: This prospective comparative study included 160 patients undergoing cataract surgery, divided equally into two groups: 80 patients underwent manual Small Incision Cataract Surgery (SICS) and 80 underwent phacoemulsification. Patients were evaluated preoperatively (1 day before surgery) and postoperatively at 7, 30, and 90 days. Dry eye was assessed using the Ocular Surface Disease Index (OSDI) questionnaire, Tear Break-Up Time (TBUT), and Schirmer’s test. The incidence and severity of dry eye and ocular surface damage were compared between the two surgical techniques. Results: A significant increase in dry eye signs and symptoms was observed during the first postoperative week in both groups, evidenced by increased OSDI scores and reduced TBUT and Schirmer’s values. OSDI and TBUT showed better correlation with dry eye severity compared to Schirmer’s test. By 30 and 90 days postoperatively, tear film parameters gradually improved and returned to near-normal levels. Phacoemulsification was associated with a significantly lower incidence and severity of postoperative dry eye compared to manual SICS. Conclusion: Dry eye disease is a common but transient postoperative complication following both manual SICS and phacoemulsification. Symptoms are more pronounced in the early postoperative period, likely due to frequent use of topical medications and ocular surface toxicity and resolve as medications are tapered. OSDI and TBUT are more reliable indicators of postoperative dry eye than Schirmer’s test. Early postoperative ocular surface evaluation and the use of tear substitutes can reduce epithelial damage and improve patient comfort. Phacoemulsification causes less ocular surface disturbance and offers better postoperative patient well-being.

Corneal wound healing is one of the major issues in ocular surface reconstruction and ocular surface diseases. Amniotic membrane (AM) transplantation is an excellent treatment modality to promote corneal wound healing and treat corneal diseases. It is interesting and valuable to search for another synthetic and biocompatible substitute for the study of mechanism of AM and the treatment of ocular surface disorders. Chitosan, the second-most abundant polymer in nature, has many biological advantages such as biocompatibility, biodegradability, hemostatic activity, and wound-healing property to be used as biomedical applications. The purpose of this project is to evaluate the phenotype of cultured corneal epithelial cells in vitro on synthetic chitosan membrane (CM). We cultivated bovine corneal epithelial cells on CM and AM, and then evaluated their phenotypes. The viability of the respective cell cultures was investigated using the 3-[4,5-dimethylrhiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The cytotoxicity of CM and AM to corneal epithelial cells was evaluated by lactate dehydrogenase (LDH) assay. The morphology of cultivated corneal epithelial cells on CM and AM was observed by scanning electron microscopy. Additionally, immunocytochemical stainings were used to confirm the phenotype of corneal epithelial cells. In MTT and LDH assays we found that the CM can support the growth of cultured corneal epithelial cells in good condition with minimal toxicity. The SEM and immunohistocytochemistry showed that the phenotype of corneal epithelial cells is compatible with that of AM. We conclude that the CM has the potential to be a suitable biomaterial for treating ocular surface disorders.

Aim: To evaluate the prevalence and characteristics of ocular surface disease (OSD) in patients with glaucoma treated with topical anti-glaucoma medications. Methods: This prospective observational study was conducted between May 2022 and May 2024 at a tertiary care hospital in coastal Odisha. Newly diagnosed primary open-angle glaucoma patients were enrolled. Baseline evaluation included the OSDI questionnaire, TBUT, Schirmer’s test, fluorescein staining, and conjunctival impression cytology. Follow-up assessments were done at 6 and 12 months. Results: A total of 187 eyes of 95 patients were included. At 12 months, 54.74% developed OSD. Prevalence increased significantly with age (p &lt; 0.001) and was higher in rural populations (65.4%). OSD was more common with multiple drug therapy (75.86%). TBUT and Schirmer’s values significantly declined over time. Preservative-containing medications showed a higher association with OSD (p &lt; 0.05). Conclusion: Long-term use of anti-glaucoma medications significantly contributes to the development of OSD, especially with multiple drugs and preservatives. Recommendation: Routine ocular surface evaluation and use of preservative-free formulations should be encouraged to improve patient compliance and outcomes.

To highlight the clinical benefits of preservative-free topical therapies in the management of glaucoma, with a focus on preservative-free latanoprost, and their role in improving ocular surface health and long-term treatment outcomes. A targeted literature search was conducted through May 30, 2024, to identify studies evaluating the efficacy, safety, and patient outcomes associated with preservative-free latanoprost (Monoprost®/Iyuzeh™, Laboratoires Théa, France). Glaucoma is a chronic, progressive disease and the leading cause of irreversible blindness globally, with prevalence expected to rise as the US population ages. Most patients begin with topical eye drops-primarily prostaglandin analogs-to reduce intraocular pressure, often requiring lifelong treatment. However, chronic use of preserved formulations, especially those containing benzalkonium chloride, is associated with ocular surface disease, discomfort, and reduced adherence. Preservative-free topical therapies offer equivalent intraocular pressure-lowering efficacy to preserved alternatives, while significantly improving tolerability, reducing ocular surface disease symptoms, and minimizing conjunctival inflammation that may complicate future surgical interventions. In Europe, preservative-free therapies are well established in treatment guidelines. In the US, preservative-free latanoprost 0.005% (Iyuzeh) was approved in 2022, providing a new option for patients sensitive to preservatives or with coexisting ocular surface conditions. Advancements in multidose preservative-free packaging and sustained-release delivery systems further enhance the potential for improved adherence and long-term disease control. This review highlights the benefits of preservative-free topical glaucoma therapies and includes a targeted review of preservative-free latanoprost 0.005%. Recent technologic advancements including multidose preservative-free delivery systems and sustained-release drug delivery approaches are also discussed.

Mucin secretive conjunctival goblet cells (CGCs) in the eye are important for tear film stability and ocular surface health. Because CGC dysfunction is associated with various ocular surface diseases, non-invasive CGC examination will be of great help in the diagnosis and treatment. In this study, we developed a high-speed moxifloxacin-based extended depth-of-field microscopy for real-time CGC examination. The performance was demonstrated by high-speed CGC imaging of both mouse and rabbit models, in vivo. The imaging was insensitive to breathing motion, and the image resolution was sufficient to resolve individual CGCs in rabbit models.

Only a short time ago, patients with severe ocular surface disease (OSD) from limbal stem cell deficiency had a dismal prognosis. The development of limbal stem cell transplantation procedures has dramatically improved our ability to rehabilitate the ocular surface of these patients. Despite these recent advances, there is a significant failure rate both in ocular surface transplantation and subsequent keratoplasty. This chapter will delineate the various causes of limbal stem cell transplantation failure and will discuss potential strategies to improve the success rate. When evaluating whether a patient has had a successful result, it is imperative to consider the length of follow-up. Evaluation of short-term results (i.e., less than one year) reveals a high success rate with most techniques studied. It must be remembered that penetrating or lamellar keratoplasty in a patient with a total absence of stem cells will do well for the short term. An example of this is the practice of penetrating keratoplasty for patients with aniridia.1 The aniridic patient with conjunctivalization of the cornea and stromal scarring achieves dramatic improvement in visual acuity immediately after penetrating keratoplasty. However, because aniridic patients have a limbal stem cell deficiency, when the inevitable sloughing of the donor epithelium occurs, it will be replaced by conjunctiva-like tissue. As a result, the ocular surface will fail. We know from studies of epithelial rejection following keratoplasty that the donor epithelium can survive up to 13 months.2 Therefore, when stem cell transplantation studies have follow-up of less than a year, it may very well be that the surface appears healthy because of the survival of donor corneal epithelium, rather than from repopulation by the transplanted stem cells. Other factors important in evaluating success or failure of a particular stem cell transplantation technique is the preoperative diagnosis and severity of disease of the patients enrolled in the study. Patients with total limbal stem cell deficiency will be more difficult to rehabilitate than those with partial limbal stem cell deficiency, and patients with active conjunctival inflammation will have a higher failure rate than those with normal conjunctiva. This concept is discussed in detail in Chapter 13. Also important are the various factors that one can evaluate in determining success versus failure. Stability of the ocular surface is the fundamental anatomic criterion with which to evaluate stem cell transplantation success. A stable ocular surface has the clinical features of a healthy transparent epithelium and is devoid of neovascularization and inflammation. A stable ocular surface results not only in improvement in visual acuity, but also in resolution of the pain that typically occurs in these patients because of conjunctivalization or persistent epithelial defects. Another important factor in evaluating success of a limbal stem cell transplantation procedure is visual acuity. This factor is, of course, most important to the patient, and must not be forgotten by the clinician. Unfortunately, many patients with severe OSD have decreased visual acuity secondary to other ocular pathology, such as the aniridic patient with foveal hypoplasia. For this reason, visual acuity cannot be the only measure to evaluate the success of a particular technique. In the authors’ experience, approximately 50% of patients with OSD will require a subsequent penetrating or lamellar keratoplasty for visual rehabilitation. Many of these patients will develop with chronic endothelial rejection with a healthy ocular surface, and therefore graft clarity serves as another determinant of overall success. The success of ocular surface transplantation has been reported to be between 0–75%.1,3–5 Rao and coworkers in 1999 reported on their results with livingrelated conjunctival limbal allograft (lr-CLAL).3 Donors were HLA-matched, and patients were not given systemic immunosuppression. In all patients, ocular surface went on to fail.

Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response, and to learn more about the effect of dupilumab on conjunctival goblet cells (GC). This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed. Ocular surface disease (OSD) was present in 91.3% (n=63/69) patients at baseline. DAOSD was observed in 28.9% (n=20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n=10/69) patients. Of the 85.5% (n=59/69) patients without DAOSD or with controlled DAOSD at week 28, 40.7% (n=24/59) patients received anti-inflammatory ophthalmic drugs. OSD is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment.

Improvement of chronic corneal opacity in ocular surface disease with prosthetic replacement of the ocular surface ecosystem (PROSE) treatment

Scleral Lenses in the Management of Ocular Surface Disease

PSS4 The Cost-Effectiveness of Travoprost Preserved With Polyquad® in Newly Treated Open-Angle Glaucoma Patients in 7 Asian Countries