The Relationship Between Dry Eye Disease and Human Microbiota: A Review of the Science.

A complex relationship exists between human microbiota and the risk for ophthalmic disease. While the homeostatic composition of human microbiota is still being established, including what defines dysbiosis (i.e. changes in diversity and abundance), pilot research has begun to identify the potential influence of demographics, geography, and co-morbidities on the microbiota and describe their impact on ocular health. This review specifically focuses on the scientific relationships of the human oral and gut microbiota to dry eye disease (DED), a set of conditions impacting the tear film and ocular surface. Although data are sparse and often conflict across studies, the literature generally supports associations between microbial imbalance (dysbiosis) and DED and alterations in microbial diversity and abundance to specific aspects of DED. This review examines the relevant science and mechanistic relationships linking gut and oral dysbiosis and DED. Various physiochemical factors and therapeutic approaches that alter microbiota, including medications and fecal transplants are examined in relation to DED.

Living with your biome: how the bacterial microbiome impacts ocular surface health and disease.

Introduction: Microbiome research has grown exponentially but the ocular surface microbiome (OSM) remains an area in need of further study. This review aims to explore its complexity, disease-related microbial changes, and immune interactions, and highlights the potential for its manipulation as a therapeutic for ocular surface diseases. Areas Covered: We introduce the OSM by location and describe what constitutes a normal OSM. Second, we highlight aspects of the ocular immune system and discuss potential immune microbiome interactions in health and disease. Finally, we highlight how microbiome manipulation may have therapeutic potential for ocular surface diseases. Expert Opinion: The ocular surface microbiome varies across its different regions, with a core phyla identified, but with genus variability. A few studies have linked microbiome composition to diseases like dry eye but more research is needed, including examining microbiome interactions with the host. Studies have noted that manipulating the microbiome may impact disease presentation. As such, microbiome manipulation via diet, oral and topical pre and probiotics, and hygienic measures may provide new therapeutic algorithms in ocular surface diseases.

Long-Term Safety and Efficacy of a Water-Free Cyclosporine 0.1% Ophthalmic Solution for Treatment of Dry Eye Disease: ESSENCE-2 OLE.

PURPOSE: The ESSENCE-2 Open-Label Extension study aimed to demonstrate long-term safety, tolerability, and efficacy of a novel water-free, nonpreserved topical cyclosporine 0.1% ophthalmic solution (US brand name VEVYE) for patients with dry eye disease (DED). METHODS: This was a Phase 3, prospective, multicenter, open-label, clinical study. All patients received cyclosporine 0.1% ophthalmic solution and dosed each eye twice a day for 52 weeks. Primary safety end points were ocular and nonocular adverse events (AEs). Secondary safety end points included visual acuity, biomicroscopy, intraocular pressure, and dilated fundoscopy. Efficacy end points, such as total corneal fluorescein staining (tCFS) score (National Eye Institute [NEI] Scale), ocular symptoms (visual analog scale [VAS]), and Schirmer tear test, were also assessed. RESULTS: A total of 202 patients were enrolled from the ESSENCE-2 study. At week 52, 175 patients (86.6%) completed ESSENCE-2 open-label extension. A total of 55 patients (27.5%) reported 74 ocular treatment-emergent adverse events (TEAEs). The most common ocular AE was instillation site pain (6.5%), which was of mild intensity in all cases. Patients showed statistically significant improvements in all prespecified efficacy end points compared with baseline at each visit. Corneal staining improvements were early and stabilized over time while tear production improved continuously. Symptomatology improvement followed these effects with scores reaching a minimum after 1 year of treatment. CONCLUSIONS: The water-free cyclosporine 0.1% ophthalmic solution was safe and well tolerated during long-term use. The results demonstrated sustained 1-year efficacy, in both signs and symptoms of DED, and may help understand short and long-term healing dynamics in a predominant inflammatory DED population.

Associations between Corneal Nerve Structure and Function in a Veteran Population.

Background: We evaluate the relationship between corneal nerve structure and function in a veteran population. Methods: 83 veterans (mean age: 55 ± 5 years) seen at the Miami Veterans Affairs (VA) eye clinic were included in this study. Each individual filled out questionnaires to evaluate ocular symptoms (5-Item Dry Eye Questionnaire, DEQ5; Ocular Surface Disease Index, OSDI) and ocular pain (Numerical Rating Scale, NRS; Neuropathic Pain Symptom Inventory modified for the Eye, NPSI-Eye). The individuals also underwent an ocular surface examination that captured functional nerve tests including corneal sensation, corneal staining, and the Schirmer test for tear production. Corneal sub-basal nerve analysis was conducted using in vivo confocal microscopy (IVCM) images with corneal nerve density, length, area, width, and fractal dimension captured. IVCM and functional corneal metrics from the right eye were examined using correlational and linear regression analysis. Results: Most corneal structural metrics were not related to functional metrics, except for weak correlations between various IVCM metrics and tear production. In addition, corneal nerve fiber area was positively related to corneal sensation (r = 0.3, p = 0.01). On linear regression analyses, only the corneal fractal dimension remained significantly related to tear production (ß = -0.26, p = 0.02) and only the corneal nerve fiber area remained significantly related to corneal sensation (ß = 0.3, p = 0.01). Conclusions: Most corneal nerve structural metrics did not relate to functional metrics in our veteran population, apart from a few weak correlations between structural metrics and tear production. This suggests that using corneal nerve anatomy alone may be insufficient for predicting corneal function.

Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease.

Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual's well-being. This cumulative impact of DED on an individual's activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.

Tear Film Dynamics in Visual Display Terminal Users: A Review of Impact on Goblet Cells, Lacrimal and Meibomian Gland Function.

PURPOSE: The prevalence of dry eye disease (DED) is rising among visual display terminal (VDT) users, a trend that correlates with the growing use of digital devices. The prevalence of VDT-associated DED is reported based on dry eye questionnaires; however, VDT's impact on tear film parameters is less understood. METHODS: A review of published literature on both the alterations in tear film observed in VDT users and the impact of various interventions on their tear film. RESULTS: Most studies show reduction in tear stability as well as reduction in the blink rate. The role of lacrimal gland hypofunction in visual display terminal (VDT) users is a subject of ongoing debate. Schirmer test values typically exceed the 10 mm threshold, suggesting normal tear production, and tear osmolarity remains within normal ranges but VDT users consistently present with lower Schirmer values compared to non-VDT users. The effects on Meibomian glands and mucin levels need more research as the numbers studied are small. Very few studies have analysed mucin levels in VDT users with reports of normal or reduced values. Even asymptomatic users can have tear film instability; hence, the diagnostic criteria need to be formulated and validated. Different interventions such as neurostimulation, blink improving apps, eyelid warming devices, moist goggles, and lubricants have been explored in VDT users but without a control arm and in asymptomatic VDT users in most studies. CONCLUSION: The alterations have been observed on aqueous, lipid and mucin components of the tear film, although the extent of the impact is variable across studies. There is urgent need of well-designed studies for studying the tear film changes and management options for the upcoming lifestyle epidemic in VDT users.

Examining Tear Film Dynamics Using the Novel Tear Film Imager.

PURPOSE: The purpose of this study was to examine Tear Film Imager (TFI, AdOM, Israel) generated parameters across controls and dry eye (DE) subgroups and examine the changes in TFI parameters with contact lens (CL) placement. METHODS: The retrospective study (n = 48) was conducted at the Miami Veterans Hospital. Symptoms were assessed through validated questionnaires and signs of tear function by tear break-up time and Schirmer scores. Participants were grouped as 1) healthy, 2) evaporative, 3) aqueous deficient, and 4) mixed DE based on tear function. Seventeen individuals had a baseline scan and a repeat scan following CL placement. Descriptives were compared across groups and over time. RESULTS: The median age was 27 years, 74% self-identified as White, 45% as male, and 51% as Hispanic. Subjects in the aqueous deficiency category had lower muco-aqueous layer thickness (MALT) (2672 vs. 3084 nm) but higher lipid layer thickness (47.5 vs. 38.3 nm), lipid break-up time (4.4 vs. 2 seconds), and interblink interval (13.9 vs. 5.4 seconds) compared with the evaporative group. Subjects in the evaporative group had the highest MALT values (3084 vs. 2988, 2672, 3053 nm) compared with healthy, aqueous-deficient, and mixed groups. Symptoms were not significantly correlated with TFI parameters. CL placement significantly decreased MALT values (2869 → 2175 nm, P = 0.001). CONCLUSIONS: The TFI provides unique information regarding the dynamic function of the tear film not captured by clinical examination. TFI generated metrics demonstrate a thinner aqueous layer in individuals with aqueous deficiency but highlight a thicker aqueous layer in those with evaporative DE.

Is Meibomian Gland Dysfunction One Disease? Heterogeneity Among Phenotypes.

PURPOSE: The purpose of this study was to examine ocular surface symptoms, tear metrics, and tear cytokines by Meibomian gland dysfunction (MGD) features. METHODS: Symptom questionnaires and an ocular surface evaluation were performed on 40 individuals with varied MGD signs [Meibomian gland (MG) plugging, eyelid vascularity, meibum quality, and MG dropout]. Tear proteins were extracted off Schirmer strips and analyzed for 23 human inflammation-related proteins. Statistical analysis was performed to examine associations between dry eye metrics inflammatory proteins and MGD features. RESULTS: The study involved 40 South Florida veterans with a mean age of 61 ± 13 years; most individuals were male (95%), White (31%), and non-Hispanic (85%). MGD features differentially related to dry eye signs. Eyelid vascularity, meibum quality, and MG dropout, but not MG plugging, correlated with higher corneal staining and lower tear production. MGD features also differentially related to tear cytokines. Eyelid vascularity most closely related to inflammation with significant correlations for interferon-gamma-γ (r = 0.36, P = 0.02), interleukin-4 (IL-4) (r = 0.43, P = 0.006), IL-17A (r = 0.42, P = 0.007), matrix metalloproteinase-2 (r = 0.39, P = 0.01), C-X-C motif chemokine ligand 5 (Regulated upon Activation, Normal T-Cell Expressed and presumably Secreted [RANTES]) (r = 0.32, P = 0.04), and tumor necrosis factor α (r = 0.36, P = 0.02). The other 3 MGD signs were less related to inflammation. Multivariable models revealed IL-4 to be most closely related to eyelid vascularity (standardized ß = 0.39, P < 0.0001). CONCLUSIONS: Eyelid vascularity was the MGD sign most closely related to inflammatory cytokines, suggesting that different MGD features may be driven by different pathophysiological mechanisms.

Role of Polyunsaturated Fatty Acids (PUFAs) and Eicosanoids on Dry Eye Symptoms and Signs.

Polyunsaturated fatty acids (PUFAs) generate pro- and anti-inflammatory eicosanoids via three different metabolic pathways. This study profiled tear PUFAs and their metabolites and examined the relationships with dry eye (DE) and meibomian gland dysfunction (MGD) symptoms and signs. A total of 40 individuals with normal eyelids and corneal anatomies were prospectively recruited. The symptoms and signs of DE and MGD were assessed, and tear samples (from the right eye) were analyzed by mass spectrometry. Mann-Whitney U tests assessed differences between medians; Spearman tests assessed correlations between continuous variables; and linear regression models assessed the impact of potential confounders. The median age was 63 years; 95% were male; 30% were White; and 85% were non-Hispanic. The symptoms of DE/MGD were not correlated with tear PUFAs and eicosanoids. DE signs (i.e., tear break-up time (TBUT) and Schirmer's) negatively correlated with anti-inflammatory eicosanoids (11,12-dihydroxyeicosatrienoic acid (11,12 DHET) and 14,15-dihydroxyicosatrienoic acid (14,15, DHET)). Corneal staining positively correlated with the anti-inflammatory PUFA, docosahexaenoic acid (DHA). MGD signs significantly associated with the pro-inflammatory eicosanoid 15-hydroxyeicosatetranoic acid (15-HETE) and DHA. Several relationships remained significant when potential confounders were considered. DE/MGD signs relate more to tear PUFAs and eicosanoids than symptoms. Understanding the impact of PUFA-related metabolic pathways in DE/MGD may provide targets for new therapeutic interventions.

Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan.

Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.

Chronic inflammation as a proposed risk factor for ocular surface squamous neoplasia.

PURPOSE: Chronic inflammation is a predisposing factor for metaplastic changes and ultimately dysplasia. We describe cases of OSSN occurring in the setting of chronic ocular surface inflammation. METHODS: Sixteen eyes from 14 individuals were included from one ocular oncology clinic between 2010 and 2023. Patients presented with ocular surface squamous neoplasia (OSSN) in the setting of chronic inflammation. The diagnosis of OSSN was made using anterior segment high-resolution optical coherence tomography (HR-OCT) and confirmed by histopathological analysis in all cases. RESULTS: Median age on presentation was 61 [IQR 47.5-69.2] years. Eleven (86%) individuals were male and five (36%) identified as White Hispanic. Ten eyes were referred with ocular surface diagnoses including pannus (n = 4), scarring (n = 3), pterygium (n = 2), and herpetic keratitis (n = 1). Only six eyes were referred as possible neoplasia. All individuals had a history of ocular surface inflammation. The most common inflammatory conditions were ocular rosacea (seven individuals) and atopic keratoconjunctivitis (AKC) (five individuals). Two individuals were found to have bilateral OSSN, one in the setting of ocular rosacea and the other in the setting of AKC. All 16 eyes from 14 individuals were suspected to have OSSN based on HR-OCT findings which guided the location of the incisional biopsies that subsequently confirmed histopathological diagnosis in all cases. CONCLUSION: OSSN may arise in the setting of chronic inflammation on the ocular surface. Identification of the tumor can be challenging in these cases, and HR-OCT can be a key diagnostic tool in detecting OSSN.

Punctal and Canalicular Stenosis Following Topical 1% 5-Fluorouracil Eye Drop Therapy for Ocular Surface Squamous Neoplasia.

PURPOSE: To present the first known cases of punctal and canalicular stenosis following topical 5-fluorouracil (5-FU) eye drops for ocular surface squamous neoplasia (OSSN). METHODS: A retrospective chart review of patients with OSSN receiving topical 1% 5-FU eye drops as a primary or adjuvant treatment between 2013 and 2021 was performed. Individuals diagnosed with punctal or canalicular stenosis during or after topical 5-FU use were included in this study. Four individuals met these criteria; we report clinical findings and treatment course for each patient. RESULTS: We reviewed 303 patients (316 eyes) with OSSN. All patients were treated with topical 1% 5-FU eye drops in cycles, given 4 times daily for 1 week with 3 weeks off. Four patients (5 eyes) developed punctal stenosis, for a frequency of 1.3%. The mean age at 5-FU initiation in the 4 individuals was 61 years (range 53-69). Most individuals were male (75%), White (75%), and non-Hispanic (100%). The most common presenting symptom of stenosis was epiphora, noted 4.6 ± 3 months after initiating topical 5-FU (after 4.9 ± 2.0 cycles). This occurred in 4 eyes while on therapy (3, 2, 4, and 4 months since 5-FU initiation) and in 1 eye after stopping therapy (10.3 months since 5-FU initiation). In 1 eye, punctal stenosis and epiphora resolved spontaneously after stopping 5-FU. Punctal dilation led to symptom resolution in 2 eyes. Surgical intervention (punctoplasty and external dacryocystorhinostomy) was needed in 2 eyes for punctal and canalicular stenosis, respectively. CONCLUSIONS: Punctal or canalicular stenosis is a rare and previously unreported adverse effect of topical 5-FU that may require surgical treatment.

Therapeutic Response to Treatment of a Papillomatous Ocular Surface Squamous Neoplasia With Intramuscular Human Papillomavirus Vaccine.

PURPOSE: The purpose of this study was to describe the response of a papillomatous ocular surface squamous neoplasia (OSSN) to the intramuscular (IM) 9-valent human papillomavirus (HPV) vaccine after failed medical and surgical interventions. METHODS: A 79-year-old White man with a conjunctival lesion underwent a biopsy which revealed OSSN and positivity for high-risk HPV. Initially treated with medical therapy and surgical excisions, the patient developed a recurrence and refused further surgery. He was given 4 doses of IM HPV vaccine at the 6-week interval. RESULTS: A dramatic reduction in lesion size and reduced epithelial thickening and hyperreflectivity was noted on slitlamp examination and high-resolution anterior segment optical coherence tomography after receiving the IM HPV vaccine. Although lesion size was markedly reduced, the therapy did not achieve total resolution, resulting in further treatment with topical 1% 5-fluorouracil (5-FU) eye drops and later 0.04% mitomycin C eye drops. The patient then elected to discontinue further treatment and solely observe. CONCLUSIONS: This case report adds to the growing literature demonstrating the potential therapeutic use of vaccines in cancer treatment. Although HPV vaccination is currently approved for prophylaxis, the use of HPV vaccines as a therapeutic option for various HPV-mediated diseases, including OSSN, should be further explored. The HPV vaccine yielded significant initial improvement in this patient who refused further surgical interventions. The use of IM HPV vaccine as an adjunctive treatment of papillomatous OSSN may represent a potential therapeutic option in cases refractory to standard treatment modalities.

Rethinking Sjögren Beyond Inflammation: Considering the Role of Nerves in Driving Disease Manifestations.

ABSTRACT: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease characterized by destruction of mucosal glands resulting in dry eye and dry mouth. Ocular presentations can be heterogenous in SS with corneal nerves abnormalities that are structural, functional, or both. Some individuals present with corneal hyposensitivity, with a phenotype of decreased tear production and epithelial disruption. Others present with corneal hypersensitivity, with a phenotype of neuropathic pain including light sensitivity and pain out of proportion to signs of tear dysfunction. A similar correlate can be found outside the eye, with dry mouth predominating in some individuals while pain conditions predominate in others. Understanding how nerve status affects SS phenotype is an important first step to improving disease management by targeting nerve abnormalities, as well as inflammation.

Pharmacogenomic Analysis of Response to Topical Tumor Necrosis Factor α Antagonist Licaminlimab (OCS-02) in Dry Eye Disease.

PURPOSE: The purpose of this study was to evaluate the pharmacogenomics of response to topical ocular tumor necrosis factor α (TNFα) inhibitor licaminlimab in patients with DED. METHODS: Three single-nucleotide polymorphisms (SNPs) associated with Sjögren syndrome, 3 in the TNFα gene and 1 in the TNF receptor 1 (TNFR1) gene, were assessed for association with response to licaminlimab in participants from a randomized, vehicle-controlled, Phase 2 study in which adults with DED and severe ocular discomfort persisting despite treatment with artificial tears received licaminlimab or vehicle for 6 weeks. Response was assessed for change from baseline in Global Ocular Discomfort score at Day 29 of treatment. The pharmacogenomic analysis was a prospectively specified exploratory objective of the study. mRNA expression for TNFα, interleukin (IL) 1ß, and IL8 in conjunctival epithelium cells was determined. The relationship between SNPs and response to licaminlimab was assessed using a mixed model repeated measures analysis. RESULTS: SNP rs1800693 in the TNFR1 gene showed a significant effect on response to licaminlimab (P < 0.0001, initial association test); no effect was seen for any of the other SNPs tested. The CC genotype of rs1800693 was associated with much greater response to licaminlimab than the CT or TT genotypes: LS mean changes from baseline to Day 29 in Global Ocular Discomfort score were -29.5, -0.09, and -3.90, in patients with the CC, CT, and TT genotypes, respectively (P < 0.0001). No significant effect was observed in vehicle-treated patients. Improvements from baseline were seen in 3/4 licaminlimab-treated participants with the CC genotype. Conjunctival epithelium cell levels of mRNA for TNFα, IL1ß, and IL8 decreased from baseline in participants with the CC genotype, but not with the CT or TT genotypes. Between-genotype differences in mRNA levels were not observed in participants receiving vehicle. CONCLUSIONS: The CC genotype of rs1800693, relatively common in patients with DED, was strongly associated with response to licaminlimab and decreased inflammatory cytokine gene expression in ocular surface cells during treatment. This study is one of the first to our knowledge to investigate pharmacogenomics in the treatment of DED.

Role of Topical 5-Fluorouracil in Demodex -Associated Blepharitis.

PURPOSE: The aim of this study was to report clinical observations suggesting the efficacy of topical 1% 5-fluorouracil (5-FU) in treating Demodex -associated blepharitis. METHODS: An observational retrospective review of 13 eyes from 13 individuals with conjunctival neoplastic lesions and concomitant Demodex lash infestation that received topical 1% 5-FU eye drops. Patients underwent slit-lamp examination at each follow-up visit. Clinical photographs of the lash line were obtained after treatment initiation. In a subset of patients, lashes were epilated bilaterally and microscopically analyzed for presence of Demodex mites before and after treatment initiation. RESULTS: The mean age of the population was 68 ± 14 years (range: 30-84 years) and 92% were male. In all 13 patients, a marked reduction in cylindrical dandruff was noted in the treated eye by slit-lamp examination after 2 cycles of 5-FU. There was complete resolution of cylindrical dandruff in 10 of 13 treated eyes compared with 0 resolution of cylindrical dandruff in untreated eyes ( P = 0.0001). In the 6 patients who received epilation, the lashes from the treated eye showed no Demodex , whereas lashes from the fellow untreated eye revealed persistent Demodex . CONCLUSIONS: Topical 1% 5-FU shows efficacy in treating Demodex -associated blepharitis. Further studies are indicated to reproduce our findings and evaluate the potential use of 5-FU as a treatment ingredient.