Quintessence of currently approved and upcoming treatments for dry eye disease.

Dry eye disease (DED), also known as dry eye syndrome, is a multifactorial ocular surface disease. The aim of this review is to present the details of currently approved and upcoming treatment options for DED in a nutshell. We conducted a thorough literature search using PubMed and searched US FDA website, clinicaltrials.gov, and data available in public domain for currently approved and upcoming treatment options for DED. Currently, the US Food and Drug Administration (FDA)-approved medical treatments for treatment of DED include cyclosporine formulations (RESTASIS® [cyclosporine 0.05% ophthalmic emulsion], VEVYE® [cyclosporine 0.1% ophthalmic solution], and CEQUA™ [cyclosporine 0.09% ophthalmic solution]), XIIDRA® (lifitegrast), a leukocyte function-associated antigen-1 (LFA-1)/intracellular adhesion molecule-1(ICAM-1) inhibitor, EYSUVIS™ (loteprednol etabonate ophthalmic suspension 0.25%), a corticosteroid, and MIEBO™ (perfluorohexyloctane ophthalmic solution), a semifluorinated alkane. TYRVAYA™ (varenicline solution nasal spray), a cholinergic agonist, is another formulation approved for the treatment of the signs and symptoms of DED. The medical devices approved for treating DED due to meibomian glands dysfunction (MGD) include Lumenis OptiLight™ (intense pulsed light [IPL] device), TearCare® system, and TearScience™ LipiFlow™ thermal pulsation system. Punctal plugs are another treatment option approved for management of DED. There are hundreds of clinical studies evaluating newer treatments for managing the signs and symptoms. Cyclosporine formulations TJO-087 (cyclosporine A nanoemulsion 0.08%), SCAI-001 eye drops (cyclosporine 0.01%, 0.02%) are being evaluated against RESTASIS® and other approved treatments. The potential treatments being assessed include IC 265, OK-101, PL9643, SYL1001 (tivanisiran), SHJ002, OXERVATE® (cenegermin-bkbj ophthalmic solution 0.002%), HBM9036 (tanfanercept ophthalmic solution), OCS-02 (licaminlimab), MIM-D3 (tavilermide ophthalmic solution 5%), AR-15,512, BRM421, reproxalap, and AZR-MD-001 (selenium sulphide ointment 0.5%). The pathophysiology of DED is complex and multifactorial; there is a need to understand it even deeper. The new treatments and different delivery systems seem promising and provide a hope of effective treatment for DED.

Schirmer tear test-1 with open or closed eyelids: An evaluation in brachycephalic and nonbrachycephalic dogs.

PURPOSE: Assess aqueous tear production when measured with the dogs' eyelids open or closed. METHODS: Thirty healthy dogs (15 Shih Tzus, 15 Labrador retrievers) were recruited. With the order of testing randomized for each dog, two sessions (separated by 30 min) of STT-1 testing were performed with the dogs' eyelids closed or open. Schirmer strip wetness (every 10 s for 60 s) and number of time(s) the strip dislodged during testing were recorded in each eye. Preferred STT-1 method was surveyed via a global Listserv of the veterinary ophthalmology community. RESULTS: STT-1 values were significantly higher in closed versus open eyes in Shih Tzus (18.6 ± 2.7 mm/min vs. 16.3 ± 2.5 mm/min; p = .002) and Labrador retrievers (21.6 ± 2.9 mm/min vs. 17.8 ± 3.2 mm/min, p < .001), findings that were also significant at times <60 s for either breed (p ≤ .004). Schirmer strips dislodged from six dogs with open eyelids and no dogs with closed eyelids. Maximal STT-1 difference with closed versus open eyelids was 13 mm/min in Labrador retrievers and 7 mm/min in Shih Tzus. Survey results from 275 veterinarians showed STT-1 performed with "closed eyelids" (38.5%), "open eyelids" (26.9%), or "never paid attention, sometimes closed, sometimes open" (34.6%). CONCLUSIONS: Eyelids status (closed or open) during STT-1 testing had a significant impact on aqueous tear secretion in brachycephalic and nonbrachycephalic dogs, highlighting the importance of consistency when repeating STT-1 in a canine patient. STT-1 differences are likely due to sustained reflex tearing throughout the test duration when the dogs' eyelids are closed.

Sjögren's syndrome.

Sjögren's syndrome (SS) is characterised as keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth) commonly associated with salivary gland enlargement, and is referred to as Primary Sjögren's syndrome. It is known as Secondary Sjögren's syndrome when it occurs in patients, with connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polyarthritis nodosa, polymyositis, and systemic sclerosis. SS has also been associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation, human immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), chronic biliary cirrhosis, neoplastic and myeloplastic syndromes, fibromyalgia, and chronic fatigue syndrome.

Autoimmune Inflammatory Eye Disease: Demystifying Clinical Presentations for the Internist.

PURPOSE OF REVIEW: Provide a framework for recognizing key symptoms and clinical findings in patients with autoimmune inflammatory eye disease. RECENT FINDINGS: The most common manifestations of autoimmune inflammatory eye disease are episcleritis, scleritis, uveitis (anterior, intermediate, posterior, and panuveitis), and keratoconjunctivitis sicca. Etiologies can be idiopathic or in association with a systemic autoimmune condition. Referral of patients who may have scleritis is critical for patients presenting with red eyes. Referral of patients who may have uveitis is critical for patients presenting often with floaters and vision complaints. Attention should also be directed to aspects of the history that might suggest a diagnosis of a systemic autoimmune condition, immunosuppression, drug-induced uveitis, or the possibility of a masquerade condition. Infectious etiologies should be ruled out in all cases. Patients with autoimmune inflammatory eye disease may present with ocular or systemic symptoms alone, or in combination. Collaboration with ophthalmologists and other relevant specialists is vital to optimal long-term medical care.

Real-world treatment patterns of OTX-101 ophthalmic solution, cyclosporine ophthalmic emulsion, and lifitegrast ophthalmic solution in patients with dry eye disease: a retrospective analysis.

BACKGROUND: Dry eye disease (DED) is a disorder characterized by loss of tear film homeostasis that causes ocular surface inflammation and damage. The incidence of DED increases with age. Cyclosporine ophthalmic solution 0.09% (CEQUA®; OTX-101), cyclosporine ophthalmic emulsion 0.05% (Restasis®; CsA), and lifitegrast ophthalmic solution 5% (Xiidra®; LFT) are anti-inflammatory agents indicated for DED. This analysis compared treatment patterns in patients with DED receiving OTX-101, CsA, or LFT. METHODS: This real-world, retrospective, longitudinal cohort study utilized Symphony Health Integrated Dataverse claims from July 2019 to June 2021. The dataset included all patients with OTX-101 claims and patients with CsA or LFT claims randomly selected 2:1 to OTX-101. Patients were sorted into 3 cohorts based on index treatment. Index date was that of first treatment claim, and follow-up period was from index date to end of clinical activity or data availability. Time to treatment discontinuation (TTD), probability of discontinuation, and treatment persistence were assessed for OTX-101 vs. CsA, then OTX-101 vs. LFT. Subgroup analysis was performed based on age and prior DED treatment. Kaplan-Meier analysis and log-rank test were used to examine TTD. A logistic model evaluated association between index treatment and discontinuation. Unadjusted and adjusted odds ratios, 95% confidence intervals, and P-values were reported, with statistically significant associations based on P-values < 0.05. RESULTS: Overall, 7102 patients (OTX-101 n = 1846; CsA n = 2248; LFT n = 3008) were eligible. Median TTD was 354 days for patients receiving OTX-101 vs. 241 days for CsA and 269 days for LFT. Log-rank test indicated TTD was significantly longer for patients on OTX-101 vs. CsA (P = 0.033). Patients on CsA were 35% more likely to discontinue treatment than patients on OTX-101; OTX-101 and LFT groups had similar discontinuation rates. After 360 days, 49.8% of patients receiving OTX-101 remained on treatment vs. 39.4% of patients on CsA (P = 0.036) and 44.0% of patients on LFT (P = 0.854). CONCLUSIONS: Patients receiving OTX-101 remained on treatment significantly longer and were significantly less likely to discontinue treatment than patients on CsA. Older patients remained on OTX-101 significantly longer than CsA. These findings highlight treatment pattern differences in patients with DED receiving these anti-inflammatory agents.

Inflammatory bowel disease and the associated risk of dry eye and ocular surface injury: a nationwide matched cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with lacrimal gland dysfunction and ocular inflammation. The objective of this research was to elucidate the temporal relationships between IBD, dry eye disease (DED), and corneal surface damage. METHODS: In a matched nationwide cohort study, we evaluated the risk of DED and corneal surface damage associated with IBD. Multivariable Cox proportional hazards regression analyses were implemented to estimate the risk of ocular complications. RESULTS: A total of 54,293 matched pairs were included for analyses. The median follow-up time was 8.3 years (interquartile range: 5.5 - 10.5). The period incidence of DED was 8.18 and 5.42 per 1000 person-years in the IBD and non-IBD groups, respectively. After adjusting for confounders, statistically significant associations were found between IBD and DED [adjusted hazard ratio (aHR): 1.43, 95% confidence interval (CI): 1.35 - 1.51, p < 0.0001], Sjögren's syndrome-related (aHR: 1.67, 95% CI:1.46 - 1.90, p < 0.0001) and non-Sjögren's syndrome-related subtypes (aHR: 1.38, 95% CI: 1.30 - 1.46, p < 0.0001). Furthermore, increased risks of corneal surface damage (aHR: 1.13, 95% CI: 1.03 - 1.24, p = 0.0094) among the patients with IBD were observed when compared with the controls. Other independent factors associated with corneal surface damage were age (aHR: 1.003), sex (male vs. female, aHR: 0.85), and monthly insurance premium (501-800 vs. 0-500 U.S. dollars, aHR: 1.45; ≥ 801 vs. 0-500 U.S. dollars, aHR: 1.32). CONCLUSIONS: Our results suggested that IBD was an independent risk factor for DED and ocular surface damage. Clinical strategies are needed to prevent visual impairment or losses in these susceptible patients.

Efficacy and safety of 0.05% micellar nano-particulate (MNP) cyclosporine ophthalmic emulsion in the treatment of moderate-to-severe keratoconjunctivitis sicca: a 12-week, multicenter, randomized, active-controlled trial.

BACKGROUND: Keratoconjunctivitis sicca or dry eye disease (DED) is a multifactorial disorder underpinned by a complex inflammatory cycle. Introduction of topical cyclosporine has been a significant advance in the management of DED. In recent years advancements in formulation technology have led to development of micellar nano-particulate (MNP) cyclosporine formulations that promise better penetration into ocular target tissues and potential for reduced ocular surface irritation. METHODS: We compared two dosing regimes of a proprietary MNP cyclosporine emulsion with the widely marketed topical cyclosporine formulation Restasis™ in a multicenter parallel-group randomised trial in patients with DED. Patients were randomised to one of 3 treatment groups with 90 patients eligible for the per protocol analysis: 30 in the higher dose test arm A; 32 in the lower dose test arm B; and 28 in the Restasis™ control arm C. All scored efficacy endpoints were tested for significance by comparing the mean change in scores from baseline in the test groups with that in the control group at 12 weeks, using the Student's t test. Wilcoxon's rank sum test was used to test individual symptom scores and clinician's global evaluation of treatment grades. RESULTS: Corneal fluorescein staining score, the primary efficacy endpoint, decreased by 6.8 ± 4.0, 5.7 ± 3.9, and 4.6 ± 3.6 points in the 3 groups respectively, indicating superior efficacy in test arm A in comparison to control arm C (p = 0.0026). Schirmer's tear test, conjunctival lissamine staining score, ocular surface disease index, and individual dry eye symptom scores also favoured higher dose MNP cyclosporine over Restasis™. The study failed to differentiate the treatment arms in terms of clinician's global evaluation of treatment, use of tear substitutes, best corrected visual acuity or safety and toleration. CONCLUSION: The results indicate that the dose of 1 drop of a 0.05% w/v ophthalmic emulsion of MNP cyclosporine administered topically twice daily yields better outcomes at 12 weeks than the lower dose tested in the study, and is more efficacious than an equivalent dose of Restasis™, the active control used in the study. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Registry of India on 29/03/2019, and was assigned registration number CTRI/2019/03/018319.

The impact of dry eye disease on corneal nerve parameters: A systematic review and meta-analysis.

PURPOSE: Dry eye disease (DED) is a growing global health problem with a significant impact on the quality of life of patients. While neurosensory abnormalities have been recognised as a contributor to DED pathophysiology, the potential role of in vivo corneal confocal microscopy in detecting nerve loss or damage remains unclear. This systematic review with meta-analysis (PROSPERO registered CRD42022381861) investigated whether DED has an impact on sub-basal corneal nerve parameters. METHODS: PubMed, Embase and Web of Science Core Collection databases were searched from inception to 9 December 2022. Studies using laser scanning confocal microscopy to compare corneal nerve parameters of DED with healthy eyes were included. Study selection process and data extraction were performed by two independent members of the review team. RESULTS: Twenty-two studies with 916 participants with DED and 491 healthy controls were included, with 21 of these studies included in subsequent meta-analyses. There was a decrease in total corneal nerve length (-3.85 mm/mm2 ; 95% CI -5.16, -2.55), corneal main nerve trunk density (-4.81 number/mm2 ; 95% CI -7.94, -1.68) and corneal nerve branch density (-15.52 number/mm2 ; 95% CI -27.20, -3.84) in DED eyes compared with healthy eyes, with subgroup analysis demonstrating that these differences were more evident in studies using NeuronJ software, a semi-automated procedure. While this review found evidence of loss of corneal nerve parameters in eyes with DED compared with healthy controls, particularly with the use of a semi-automated image analysis method, it is evident that there is substantial heterogeneity between studies in terms of corneal nerve imaging methodology. CONCLUSIONS: Standardisation is required in terms of terminology and analysis, with more research needed to potentially improve the clinical applicability and practicality of corneal nerve imaging. Further investigation is also required to confirm the diagnostic accuracy of this imaging modality and its potential for monitoring DED treatment efficacy.

Precorneal retention time of ocular lubricants measured with fluorophotometry in healthy dogs.

OBJECTIVE: Determine the precorneal retention time of five different ocular lubricants commonly used in dogs. ANIMALS STUDIED: Six healthy Beagle dogs (n = 12 eyes). PROCEDURES: Five ocular lubricants were studied: Artificial Tears Solution® (1.4% polyvinyl alcohol), I-Drop® Vet Plus (0.25% hyaluronate), Optixcare® Eye Lube Plus (0.25% hyaluronate), Systane® Ultra (0.4% polyethylene glycol 400 and 0.3% propylene glycol), and Artificial Tears Ointment® (mineral oil/white petrolatum). Each lubricant was mixed with 10% sodium fluorescein to achieve 1% fluorescein formulations. Following topical administration of 35 mg in each eye, tear fluid was collected with capillary tubes at selected times (0, 1, 5, 10, 20, 30, 40, 50, 60, 90, 120, 180 min) and fluorescein concentrations were measured with a computerized scanning ocular fluorophotometer. RESULTS: Tear fluorescence was significantly greater with Artificial Tears Ointment® compared with other lubricant formulations from 1 to 20 min post-administration. Median (range) precorneal retention times were significantly different among the 5 lubricants, ranging from 40 minutes (20-90 min) for Artificial Tears Ointment®, 35 min (20-90 min) for Systane® Ultra, 30 min (10-60 min) for I-Drop® Vet Plus, 25 min (10-60 min) for Optixcare® Eye Lube Plus, and 10 min (10-20 min) for Artificial Tears Solution®. Precorneal retention time was significantly lower for Artificial Tears Solution® compared with the other 4 formulations. CONCLUSIONS: This study established normative data for the retention time of common lubricants on the ocular surface of dogs, which may be used to guide clinicians with their choice of lubricant and frequency of administration.

A review of diagnostic tests for qualitative and quantitative tear film deficiency in dogs.

Dry eye disease (DED) is a complex multifactorial condition caused by loss of ocular surface homeostasis from quantitative and/or qualitative tear film deficiency. Schirmer tear test (STT) is often the only diagnostic test used to assess for DED in veterinary practice. STT is invaluable in the diagnosis and monitoring of quantitative tear film deficiency (i.e., keratoconjunctivitis sicca); however, it is not sufficient to optimize therapy and fully recognize other contributing factors for the disturbance in ocular surface homeostasis. The present work reviews diagnostic tests for assessing aqueous tear production in veterinary medicine, as well as the quality of tears, corneal epithelial barrier integrity, and the lacrimal functional unit.

Ocular surface physiology and aqueous tear secretion in cats of diverse cephalic conformations.

OBJECTIVE: To describe normative ocular surface and aqueous tear testing data for cats of various cephalic conformation. ANIMALS STUDIED: Fifty-three healthy adult cats (11 British Shorthair, 11 Burmese, 10 Devon Rex, 10 Scottish Fold, and 11 Sphynx). PROCEDURES: Blink rate, corneal tactile sensation (CTS), and Schirmer tear test with or without topical anesthesia (STT-1, STT-2) and with nasolacrimal stimulation (NL-STT1, NL-STT2) were assessed. Palpebral fissure length (PFL) and skull morphology were measured, and cephalic index (CI) and craniofacial ratio (CFR) calculated. RESULTS: Mean ± SD test results were as follows: blink rate (5.0 ± 2.3 blinks/min), CTS (3.2 ± 0.7 cm), STT-1 (11.2 ± 4.3 mm/min), STT-2 (6.7 ± 3.6 mm/min), NL-STT1 (13.4 ± 5.7 mm/min), NL-STT2 (13.5 ± 5.2 mm/min), and PFL (2.0 ± 0.2 cm). Corneal sensitivity did not differ significantly among breeds (p = .152) but was negatively correlated with body weight (r = -.32, p = .019). STT-1 significantly differed among breeds (p < .001) and was lowest in Sphynx cats (8.7 ± 4.3 mm/min). A positive correlation was detected between STT-1 values at 30 and 60 s (r = .98; p < .001). The nasolacrimal reflex significantly increased STT in anesthetized and unanesthetized eyes (approximately +100% and +20%, respectively; p ≤ .002). STT-1 tended to be higher in intact versus neutered cats (p = .062). Age did not impact any test result (p ≥ .085). CONCLUSIONS: Normative data described here serve as a baseline for future studies assessing ocular surface disease in multiple feline breeds. Unlike dogs, brachycephalic cats did not have lower CTS or STT-1 than non-brachycephalic cats.

Transregional autologous serum eye drop provision by a large German Red Cross Blood Donation Service.

BACKGROUND: The Blood Donation Service West serves North Rhine-Westphalia (NRW), Rhineland-Palatinate (RP), and Saarland, an area of 56,500 km2. In addition to routine red blood cell concentrates, plasma, and platelets, special products are provided. Since 2014, this has included autologous serum eye drops (ASED) for topical use in patients suffering from different illnesses accompanied by dry eye disease. METHODS: A volume of 250-525 mL of patient blood was collected into an anticoagulant-free blood bag. Laboratory testing included Hepatitis B/C-, HIV 1/2-, and Lues-serology. Coagulation and centrifugation were followed by leukoreduction. Single-use vials were obtained by filling mini-bag systems using a sterile tube welder. Storage at ≤-20 °C enabled a shelf-life of up to 6 months and 30 days at 4 °C after thawing for shipment. RESULTS: Contracts were closed with 15 ophthalmology clinics and medical practices in NRW and RP to supply patients with ASED. The patient pool increased from 19 in 2014 to 46 in 2020, with an average age of 43-55 years. Overall, blood collections almost tripled from 31 to 100 per year, increasing the stock of deliverable single-use vials from 3328 to 13,358. Delivery in a liquid state allowed engagement of 44 pharmacies located in the patient neighborhoods for continuous supply. CONCLUSION: Manufacturing in a closed bag system allowed integration into blood bank operations. However, cost-coverage by health insurance remained a case-by-case decision. Allogeneic application as 'just-another-blood-product' could be an aspiration. Yet, conclusive data from large clinical trials are needed for licensed provision in Germany.

Topical applications of allogeneic adipose-derived mesenchymal stem cells ameliorate the canine keratoconjunctivitis sicca.

BACKGROUND: Canine keratoconjunctivitis sicca (KCS) is predominantly an immune-mediated disease. Current therapy of canine KCS is mainly by immunosuppressant, but the effectiveness was limited in some patients. In the past few years, some studies showed the results of the use of mesenchymal stem cells in treating canine KCS via periocular injections. However, the periocular injection procedure requires sedation or general anesthesia, and may lead to iatrogenic or incidental injury during the injection process. The aim of this study was to investigate the efficacy of topical allogenic canine adipose-derived mesenchymal stem cells (cAD-MSCs) in clinical patients of canine KCS. RESULTS: The cAD-MSCs used in this study were characterized for their capability of tri-lineage differentiation and immunomodulatory properties. In addition, preparation methods for eye drops of cAD-MSCs was developed and its optimal preservation was tested. The canine KCS patients were recruited for clinical trial and divided into two groups based on their history of previous treatment. All patients received topical cAD-MSCs treatment once per week for 6 consecutive weeks and complete ophthalmic examinations were performed 1 week before treatment (week 0) and at 3rd, 6th, 9th weeks, respectively. The results showed that the quantity and quality of tears have improved significantly following topical cAD-MSCs treatment based on Schirmers tear test-1 and tear break-up time. More than half of all patients were found improved in the tear quantity. In particular, 56.5% of the patients that were unresponsive to prior immunosuppressant therapy had an effective increase in tear volume. The severity of clinical signs was also ameliorated according to the numeric rating scale score from both patient owners and the clinician. CONCLUSION: To sum up, topical cAD-MSCs may be beneficial especially in KCS patients with poor owner compliance for frequent daily use of eye drops or those who are unresponsive to immunosuppressant therapy.

Neurogenic keratoconjunctivitis sicca in 34 dogs: A case series.

OBJECTIVE: To describe the clinical findings, imaging features, underlying conditions, treatment, and progression of dogs presented between 2010 and 2019 with neurogenic keratoconjunctivitis sicca (NKCS). METHODS: Dogs diagnosed with NKCS were searched in the clinical database. Inclusion criteria were STT-1 readings <15 mm/min, clinical signs of KCS with concurrent ipsilateral xeromycteria. RESULTS: Thirty-four cases were identified. Mean age at presentation was 8.2 years, median 8.9 years (0.3-14.7). Twenty dogs were male, and 14 dogs were female. Concurrent neurological deficits included facial neuropathy (n = 13, 38%), peripheral vestibular syndrome (n = 10, 29%), and Horner's syndrome (n = 5, 15%). Advanced imaging was acquired in 53% of cases (n = 18). Etiologies included idiopathic (n = 18, 53%), endocrinopathy (n = 6, 18%), otitis interna (n = 4, 12%), head trauma (n = 3, 9%), iatrogenic (post-TECA-LBO, n = 1, 3%), brainstem mass (n = 1, 3%), and an area of inflammation in the pterygopalatine fossa (n = 1, 3%). Treatment for NKCS was initiated in most cases (n = 30, 88%) including: oral pilocarpine 2% and lacrimostimulant (n = 19), oral pilocarpine 2% only (n = 3), or lacrimostimulant only (n = 8). A mean time follow-up of 3.7 months, median 3 months (1-14) was available in 23 cases (68%). Eleven cases with follow-up were responsive (48%) with resolution of the clinical signs in a median time 4 months (1-10), and all of them were treated with oral pilocarpine (±lacrimostimulant). CONCLUSIONS: Most cases presented as idiopathic NKCS; in others, an underlying cause of facial neuropathy was identified. All responsive cases were treated with oral pilocarpine 2%.

Bilateral Microvascular Submandibular Gland Transfer with Implantation of Wharton's Duct in Superior Conjunctival Fornix: A Vision-Saving Procedure for Severe Dry Eye Disease.

Dry eye can initially cause mild symptoms of irritation and may rapidly progress to corneal scarring and blindness. Tear substitutes can only help for mild cases. With the advancement in microsurgical techniques, an option of transferring vascularized salivary glands has shown positive results. We present a case of a 5-year-old boy with congenital alacrimia with ocular surface damage. Vascularized autologous submandibular gland transfer was considered as a viable option for this patient. We performed the gland transfer in two separate stages for the two eyes (1 year 5 months apart). The patient was evaluated for up to 2 years for the right eye and for 7 months for the left eye. Dry eye workup showed drastic improvement (right > left). Biochemical analysis showed gradual transition to resemble that of natural tears. This procedure can result in significant symptomatic improvement and can be a promising treatment option for cases of severe dry eye.

Involvement of ocular surface in graft-versus-host disease: An update from immunopathogenesis to treatment.

Graft-versus-host disease is a common complication of hematopoietic stem cell transplantation and the ocular surface is a main target of inflammatory reaction.

Utility of lymphocyte phenotype profile to differentiate primary Sjögren's syndrome from sicca syndrome.

OBJECTIVE: To assess the potential diagnostic utility of advanced lymphocyte profiling to differentiate between primary Sjögren's Syndrome (pSS) and non-Sjögren Sicca syndrome. METHODS: Distribution of peripheral lymphocyte subpopulations was analysed by flow cytometry in 68 patients with pSS, 26 patients with sicca syndrome and 23 healthy controls. The ability to discriminate between pSS and sicca syndrome was analysed using the area under the curve (AUC) of the receiver operating characteristic curve of the different lymphocyte subsets. RESULTS: The ratio between naïve/memory B cell proportions showed an AUC of 0.742 to differentiate pSS and sicca syndrome, with a sensitivity of 76.6% and a specificity of 72% for a cut-off value of 3.4. The ratio of non-switched memory B cells to activated CD4+ T cells percentage (BNSM/CD4ACT) presented the highest AUC (0.840) with a sensitivity of 83.3% and specificity of 81.7% for a cut-off value <4.1. To differentiate seronegative pSS patients from sicca patients, the BNSM/CD4ACT ratio exhibited an AUC of 0.742 (sensitivity 75%, specificity 66.7%, cut-off value <4.4), and the number of naïve CD4 T cells had an AUC of 0.821 (sensitivity 76.9%, specificity 88.9%, cut-off value <312/mm3). CONCLUSION: Patients with pSS show a profound imbalance in the distribution of circulating T and B lymphocyte subsets. The ratio BNSM/CD4ACT is useful to discriminate between pSS and sicca syndrome.

Systemic Conditions Associated with Severity of Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management Study.

PURPOSE: Certain systemic conditions are reported to be risk factors for dry eye disease (DED), but their associations with DED severity are not well studied. We evaluated whether systemic conditions reported to be DED risk factors are associated with severity of DED signs and symptoms. DESIGN: Secondary analysis of data from the Dry Eye Assessment and Management Study, a large-scale multicenter randomized clinical trial of patients with moderate to severe DED. PARTICIPANTS: Five hundred thirty-five adult patients with moderate to severe DED from 27 United States centers. METHODS: Patients reported their medical history at baseline. They underwent ocular surface examinations and symptom evaluation using standardized protocols at baseline, 6 months, and 12 months. We analyzed the associations of systemic conditions (a systemic disease or smoking history) reported as potential DED risk factors with the severity of DED signs and symptoms using generalized linear regression models adjusted by age, gender, race, and visit. MAIN OUTCOME MEASURES: Dry eye disease symptoms assessed using the Ocular Surface Disease Index (OSDI), 6 DED signs (tear film break-up time, anesthetized Schirmer testing, corneal fluorescein staining, conjunctival lissamine green staining, tear osmolarity, and meibomian gland dysfunction), and a composite signs severity score from 0 to 1 (1 = most severe). RESULTS: The mean age was 58 years; 81% were women. More severe DED signs were associated significantly with Sjögren syndrome (mean composite signs severity score 0.52 with disease vs. 0.43 without disease; P < 0.001), facial rosacea (0.47 vs. 0.43; P = 0.002), rheumatoid arthritis (0.47 vs. 0.42; P = 0.002), peripheral artery disease (0.50 vs. 0.43; P < 0.001), and daily smoking history (0.45 vs. 0.43; P = 0.047). Thyroid dysfunction, osteoarthritis, diabetes, irritable bowel syndrome, hypercholesterolemia, hypertension, and hypertriglyceridemia were not associated significantly with DED signs. No conditions were associated significantly with OSDI. CONCLUSIONS: In this large, well-characterized cohort of patients with DED assessed under standardized procedures, patients with certain systemic diseases and smoking history showed more severe DED signs compared with patients without the conditions. The profile of significant DED signs varied by systemic condition, reflecting different DED causes. Understanding the systemic conditions and underlying causes that predispose some patients to severe DED can improve management.

Labial and buccal minor salivary glands of the dog - location, three-dimensional arrangement and histology.

OBJECTIVE: Transplantation of minor salivary glands (MSGs) to the conjunctiva is a treatment option for patients suffering from dry eye disease. As there is not enough information about labial and buccal MSGs in dogs, the aim of this study was to provide evidence of the presence of these glands and to investigate their spatial arrangement and excretory ducts. METHODS: The oral mucosa of the lower lip of 4 dogs and the whole lower jaw of 1 dog were used for histological and microCT analysis. Presence, number, volumes and the tissue depth of MSGs were assessed. RESULTS: Histological analysis showed that compact tubulo-acinar glands were located in the submucosal connective tissue. MicroCT images revealed that 9 to 21 MSGs were arranged in a single row at the level of the dental alveolae. The volume of the MSGs increased from rostral to caudal and the total volume of glandular tissue per animal ranged from 35.01 mm3 to 549.43 mm3 . The mean tissue depth of MSGs ranged from 0.57 mm to 1.37 mm (upper surface of glands) and between 1.43 mm and 3.09 mm (lower surface of the glands). Excretory ducts left the dorsal part of the glands and ran in dorso-rostral direction. CONCLUSIONS: The location, number and volume of the labial and buccal MSGs in the dog could be detected and described using microCT scans and histology. The present results can provide valuable information for future transplantation of labial MSGs as therapeutic measure against keratoconjunctivitis sicca.

Influence of Schirmer strip wetness on volume absorbed, volume recovered, and total protein content in canine tears.

OBJECTIVE: Determine the protein content and volume of tears sampled by Schirmer strips wetness ranging from 20 to 35 mm. ANIMALS STUDIED: Ten healthy beagle dogs. PROCEDURES: Each dog underwent 20 tear collections per day (10 sessions in each eye, spaced by ≥1 h) for 4 separate days, providing 200 tear samples for each length of wetness evaluated: 20, 25, 30, and 35 mm. A Schirmer strip was placed in each eye until the selected mm-mark was reached, calculating the volume absorbed (VA) as the difference between the post- and pre-collection weight (assuming 1 mg~1 µL for tear fluid), and the volume recovered (VR) as the amount pipetted from the tube following centrifugation. Total protein content (TPC) was measured with infrared spectroscopy. Outcome measures were compared with the Kruskal-Wallis test. RESULTS: Median values for VA (µL), VR (µL) and TPC (mg/mL) were as follows: 20 mm (18, 10, 5.94), 25 mm (22, 12.5, 5.97), 30 mm (25.5, 16, 5.89), and 35 mm (31, 22.5, 7.13). Both VA and VR were significantly greater (p < .001) for Schirmer strips wetness of 35¼30¼25¼20 mm. TPC was significantly greater (p < .001) for 35 > 20-30 mm, but not among other groups (p = 1.000). CONCLUSIONS: The study established normative data to consider when canine studies use Schirmer strips to collect tears for bioanalytical purposes (eg, proteomics, pharmacokinetics). Although 35 mm yielded higher VA and VR, the higher TPC could be explained by greater disruption of ocular surface homeostasis. Absorption to 20-30 mm is the suggested length of strip wetness for bioanalytical tear collection in dogs.