RESUMEN
Purpose: The purpose of this study was to explore the effects of a PGF2α analog, latanoprost, and its preservative, benzalkonium chloride (BAK), on the cell viability and lipidomic expression of immortalized human meibomian gland epithelial cells (HMGECs). Methods: Differentiated HMGECs were exposed to latanoprost (0.05 to 50 µg/ml), BAK (0.2 to 200 µg/ml), or combined latanoprost-BAK (0.05-0.2 to 50-200 µg/ml). EP- and FP-type receptors, the cognate receptors of PGE2 and PGF2α, were inhibited, thereby sparing and isolating the function of each receptor to one condition. Cell viability was assessed by ATP quantitation, and lipid extracts were analyzed by ESI-MSMSALL with a Triple TOF 5600 Mass Spectrometer (SCIEX, Framingham, MA) using SCIEX LipidView 1.3. Results: Latanoprost and BAK were found to be lethal to HMGECs at the highest concentrations (p < 0.001 for both). The cytotoxicity of latanoprost was mediated through FP- and EP-independent mechanisms. Both latanoprost and BAK significantly modulated the lipidomic expression of several cholesteryl esters (8% and 30%, respectively) and triacylglycerols (10% and 12%, respectively). The combined latanoprost-BAK agent appeared to be no more toxic and to only negligibly alter the lipid profile relative to its individual components. Conclusions: The use of latanoprost and BAK in glaucoma may alter the viability of the meibomian glands and their lipid expression in vivo. Sublethal concentrations of BAK appear to modulate meibum lipid expression, particularly in relation to sterol biosynthesis. Non-preserved latanoprost had less cytotoxicity at lower doses and fewer lipidomic effects compared to BAK, further strengthening the argument in favor of BAK-free pharmaceutical preparations.
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Compuestos de Benzalconio , Glándulas Tarsales , Humanos , Supervivencia Celular , Latanoprost , Células EpitelialesRESUMEN
ABSTRACT: Demodex blepharitis is a common disease of the eyelid, affecting approximately 25 million Americans. This article reviews what is known about the mechanisms and impact of Demodex blepharitis, risk factors, signs and symptoms, diagnostic techniques, current management options, and emerging treatments. Demodex mites contribute to blepharitis in several ways: direct mechanical damage, as a vector for bacteria, and by inducing hypersensitivity and inflammation. Risk factors for Demodex blepharitis include increasing age, rosacea, and diabetes. The costs, symptom burden, and psychosocial effects of Demodex blepharitis are considerable. The presence of collarettes is pathognomonic for Demodex blepharitis. Redness, dryness, discomfort, foreign body sensation, lash anomalies, and itching are also hallmarks of the disease. Although a number of oral, topical, eyelid hygiene and device-based options have been used clinically and evaluated in studies for the management of Demodex blepharitis, none have been FDA approved to treat the disease. Recent randomized controlled clinical trials suggest that lotilaner ophthalmic solution, 0.25%, is a topical treatment with the potential to eradicate Demodex mites and eliminate collarettes and eyelid redness for an extended period.
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Blefaritis , Infecciones Parasitarias del Ojo , Pestañas , Infestaciones por Ácaros , Ácaros , Animales , Humanos , Infestaciones por Ácaros/diagnóstico , Blefaritis/diagnóstico , Párpados , Inflamación , Infecciones Parasitarias del Ojo/diagnósticoRESUMEN
SIGNIFICANCE: Acquired ptosis is a condition of the upper eyelid that has negative cosmetic and functional effects but is likely underdiagnosed and undertreated. Given the evolving understanding of the condition and expanding therapeutic options, this review reappraised published evidence and clinical experience regarding diagnosis and treatment of acquired ptosis.The authors met over two structured virtual working sessions to review current evidence and develop timely recommendations for acquired ptosis identification, differential diagnosis, characterization, and treatment selection. Diagnostic algorithms, plus management and referral guidelines, are presented. Eyelid evaluation and, when needed, ptosis diagnostic workup are essential in the comprehensive eye examination. Acquired ptosis can be efficiently identified via patient questionnaire, history, and photograph review combined with assessment of eyelid position and symmetry using established methods. When ptosis is present, it is essential to evaluate onset, symptoms, pupil diameter, and extraocular muscle function to identify or rule out serious underlying conditions. If signs of serious underlying etiology are present, immediate referral/follow-up testing is required. After ruling out serious underlying causes, masquerade conditions, and pseudoptosis, pharmacologic or surgical treatment should be selected based on the clinical evidence. Effectively managing acquired ptosis requires practice-wide commitment to thorough eyelid evaluation, accurate diagnosis, and adoption of new treatment modalities. Aided by evolving pharmacologic therapeutic options, shifting from a "detect and refer" to a "diagnose and manage" approach can support identification and treatment of more patients with acquired ptosis, particularly mild-to-moderate cases.
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Blefaroptosis , Enfermedades de los Párpados , Algoritmos , Blefaroptosis/diagnóstico , Blefaroptosis/etiología , Blefaroptosis/terapia , Párpados , Humanos , Músculos OculomotoresRESUMEN
Preliminary work has shown that select triacylglycerols (TAGs) are upregulated in a preclinical model of MGD, suggesting that TAGs may be an important outcome variable in research involving human meibomian gland epithelial cells (HMGECs). The purpose of this study was to explore the HMGEC TAG lipidome in culture conditions known to influence differentiation. HMGECs were differentiated in DMEM/F12 with 10 ng/ml EGF, FBS (2% or 10%), and rosiglitazone (0, 20, or 50 µM) for two or five days. Following culture, lipids were extracted, processed, and directly infused into a Triple TOF 5600 mass spectrometer (SCIEX, Framingham, MA) with electrospray ionization. MS and MS/MSALL spectra were acquired in the positive ion mode and performed with the SWATH technology. Only the TAGs that were present in all 48 samples were included in the analysis. Multiple regression techniques were utilized to assess the effects of each factor (FBS, rosiglitazone, and culture duration) on each expressed TAG. The HMGEC TAG lipidome consisted of 115 TAGs with 42-62 carbons and zero to 10 double bonds. Fatty acyl chains had 14 to 26 carbons and zero to five double bonds. C18:1 (oleic acid, 25/115, 21.7%) and C16:0 (palmitic acid, 16/115, 13.9%) were the most common fatty acids. FBS, rosiglitazone, and culture duration were significant predictors for 93 TAGs (80.9%) with R2 values ranging from 0.20 to 0.77 (p < 0.05). FBS and rosiglitazone achieved significance (p < 0.05) for 80 (69.6%) and 67 TAGs (58.3%), respectively. Rosiglitazone demonstrated a selective upregulation of TAGs containing 16 or 18 carbons. Culture duration reached significance (p < 0.05) for only 36 TAGs (31.3%). When comparing the 10 most abundant C18:1-containing TAGs in meibum, FBS was a negative predictor for five TAGs (mean standardized coefficient [SC] = -0.58, p < 0.001), rosiglitazone was a positive predictor for six TAGs (mean SC = 0.41, p ≤ 0.03), and culture duration weakly influenced one TAG (SC = 0.27, p = 0.008). FBS and rosiglitazone, unlike culture duration, are powerful modulators of the TAG profile. Rosiglitazone induces changes that could be consistent with fatty acid synthesis, suggesting that quantifying the TAG lipidome could be an indirect measure of lipogenesis. Though both have been described as differentiating agents, FBS and rosiglitazone induce opposing effects on meibum-relevant TAGs. Culturing with rosiglitazone is associated with a TAG profile that is more consistent with the expected outcome of lipogenesis and with the profile observed in normal human meibum.
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Factor de Crecimiento Epidérmico/farmacología , Células Epiteliales/efectos de los fármacos , Hipoglucemiantes/farmacología , Glándulas Tarsales/efectos de los fármacos , Rosiglitazona/farmacología , Triglicéridos/metabolismo , Recuento de Células , Diferenciación Celular , Células Cultivadas , Células Epiteliales/metabolismo , Humanos , Lipidómica , Glándulas Tarsales/metabolismo , Suero/fisiología , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en TándemRESUMEN
OBJECTIVES: As reported previously, tear film surface quality (TFSQ) should be considered in contact lens (CL) fitting. This study followed noninvasive keratograph tear film break-up time (NIKBUT) in CL wearers for 12 months to validate its clinical utility in predicting CL performance. METHODS: Fifty-five subjects (M/F=17/38) aged 26±4 years were prescribed silicone hydrogel or hydrogel CLs. The study included baseline measurements without CLs; 2 visits for CL fitting and control; follow-up after 3, 6, and 12 months of CL wear; and postwear visit without CLs. Ocular Surface Disease Index (OSDI), 8-Item Contact Lens Dry Eye Questionnaire (CLDEQ-8), first and mean NIKBUT (F/M-NIKBUT), fluorescein tear film break-up time (FBUT), and ocular surface staining were evaluated. RESULTS: Post hoc analysis of each pair of visits showed differences between baseline and all CL visits for F-NIKBUT, M-NIKBUT, FBUT, and corneal staining. No difference was reported in symptoms. In addition, differences between baseline and postwear visits were noted in OSDI, M-NIKBUT, FBUT, and corneal staining, with three of the latter parameters showing a downward trend. CONCLUSIONS: No changes in TFSQ and symptoms were reported over 12 months. Introducing NIKBUT as part of routine CL fitting is advised to improve CL fit and predict success.
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Lentes de Contacto Hidrofílicos , Síndromes de Ojo Seco , Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/etiología , Ojo , Humanos , Lágrimas , Visión OcularRESUMEN
SIGNIFICANCE: There is a dearth of studies investigating the challenges encountered in dry eye practice. Profiling these barriers is crucial to improving dry eye diagnosis and patient care. PURPOSE: This study aimed to examine the diagnostic and treatment perspectives, and challenges in dry eye practice in Ghana. METHODS: An anonymous paper-based or web survey regarding dry eye practice pattern, practice challenges, and access to diagnostic tools was distributed to 280 potential participants. RESULTS: One hundred thirteen respondents completed the survey. Case history (92.5%), fluorescein tear breakup time (87.5%), and corneal fluorescein staining (72.5%) were the topmost procedures used for dry eye diagnosis. A preserved lubricant drop was the most commonly prescribed treatment of mild, moderate, and severe dry eye at the rates of 77.0, 83.2, and 77.0%, respectively. A few respondents prescribed cyclosporine (2.7%) or punctal plugs (5.3%) across all disease severities, and none used scleral lens, autologous serum tears, or thermal pulsation. Graduate professional training influenced the practice pattern of 82.3% of respondents, whereas continuing professional education influenced less than 1%. Approximately 70.1 and 92.8% of optometrists considered referring dry eye in children and cases that are unresponsive to treatment, respectively. Eighty-eight percent of practitioners indicated they experience a challenge in dry eye practice, with limited access to diagnostic tools (77.9%) and limited availability of effective dry eye medication on the Ghanaian market (50.4%) being the most frequent challenges. More than 85% of respondents had access to a fluorescein dye or slit-lamp biomicroscope; however, none had access to a phenol red thread, lissamine green dye, osmolarity technology, or meibography device. CONCLUSIONS: Practitioners' limited access to diagnostic tools/techniques and the limited effective dry eye treatments are major challenges encountered in dry eye practice in Ghana. Addressing these will improve dry eye practice and treatment outcomes in the country.
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Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/terapia , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Ciclosporina/administración & dosificación , Técnicas de Diagnóstico Oftalmológico , Síndromes de Ojo Seco/epidemiología , Síndromes de Ojo Seco/fisiopatología , Femenino , Fluoresceína/administración & dosificación , Colorantes Fluorescentes/administración & dosificación , Ghana/epidemiología , Humanos , Inmunosupresores/administración & dosificación , Gotas Lubricantes para Ojos , Masculino , Persona de Mediana Edad , Optometristas/estadística & datos numéricos , Concentración Osmolar , Tapones Lagrimales , Suero/fisiología , Encuestas y Cuestionarios , Lágrimas/fisiología , Resultado del Tratamiento , Adulto JovenRESUMEN
The lipidomic analysis of immortalized human meibomian gland epithelial cells (HMGECs) has been proposed as a preclinical model to study meibomian gland dysfunction. An in vitro study was conducted to evaluate neutral lipid recovery following three harvesting techniques and to identify candidate lipid biomarkers of HMGECs. HMGECs were cultured in serum-containing media for two days to promote lipid production. Cells were either harvested by 0.25% trypsin-ethylenediaminetetraacetic acid (EDTA), harvested by 10 mM EDTA, or simultaneously harvested and extracted by 2:1 chloroform-methanol (CM). After extraction by a modified Folch technique, the nonpolar phase was processed and infused into a TripleTOF 5600 mass spectrometer (Sciex, Framingham, MA, USA) with electrospray ionization. MS and MS/MSall spectra were acquired. Nonpolar cholesteryl esters (CEs) were consistently detected in all samples, while wax esters were not. Only small differences in two out of twenty CEs were detected between harvesting methods. CM yielded less CE18:1 than the other methods but greater CE20:4 than the trypsin-EDTA method (p < 0.05 for all). Similar to human meibum, very long-chain CEs with carbon number (nc) ≥ 24 were detected in all samples and may serve as HMGEC lipid biomarkers. Further work is needed to address the absence of wax esters. Overall, the three harvesting methods are reasonably equivalent, though CM promotes much better efficiency and is recommended for higher throughput.
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Técnicas de Cultivo de Célula/métodos , Células Epiteliales/citología , Lipidómica/métodos , Glándulas Tarsales/citología , Técnicas de Cultivo de Célula/normas , Fraccionamiento Celular/métodos , Línea Celular , Células Cultivadas , Células Epiteliales/metabolismo , Humanos , Lipidómica/normas , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
The lipid composition of human meibomian gland secretions (meibum) has been analyzed using both targeted and untargeted mass spectrometric approaches, each of which has its advantages and disadvantages. Herein we report the results of shotgun lipidomic profiling of human meibum using a new approach that combines the advantages of targeted and untargeted analyses to yield highly sensitive and comprehensive profiles. Samples containing an estimated 7-13 µg (8-16 nL) of human meibum lipids were analyzed using MS/MSall, an untargeted approach for MS/MS. Using MS/MSall with ESI and successive polarity switching, we obtained tandem mass spectra in both modes at every 1 Da step for all ions in the m/z 200-1,200 range. In approximately 12 min, a total of 2 MS spectra and 2,000 MS/MS spectra were acquired for each sample, from which targeted analysis information was extracted. This approach allowed for the comprehensive and highly sensitive detection of meibum lipids, including species low in abundance. Altogether, more than 600 unique lipid molecular species were identified in meibum, 3 times more than previously reported in untargeted analyses of meibum samples. This untargeted MS and MS/MSall approach may be extended to other biological systems for the detection of lipids with sensitivity comparable to targeted analysis.
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Glándulas Tarsales/metabolismo , Espectrometría de Masas en Tándem/métodos , Ésteres del Colesterol/metabolismo , Ácidos Grasos/metabolismo , Humanos , Fosfolípidos/metabolismo , Triglicéridos/metabolismoRESUMEN
PURPOSE: Lifitegrast is a lymphocyte function-associated antigen-1 antagonist developed to reduce inflammation in dry eye disease (DED). We report the results of OPUS-3 (NCT02284516), a phase III study evaluating the efficacy and safety of lifitegrast versus placebo in participants with DED. DESIGN: Twelve-week, phase III, randomized, double-masked, multicenter, placebo-controlled study. PARTICIPANTS: Adults aged ≥18 years with Schirmer tear test (without anesthesia) ≥1 and ≤10 mm, corneal fluorescein staining score ≥2.0 (0-4 scale), eye dryness score (EDS) ≥40 (0-100 visual analogue scale [VAS]), and history of artificial tear use within 30 days of study entry. METHODS: After a 14-day placebo run-in, participants were randomized 1:1 to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 days. MAIN OUTCOME MEASURES: The primary efficacy end point was change from baseline to day 84 in EDS. Key secondary efficacy end points were change from baseline to days 42 and 14 in EDS. Other secondary efficacy end points included additional VAS items (burning/stinging, itching, foreign body sensation, eye discomfort, photophobia, pain), ocular discomfort score (ODS), and safety/tolerability of lifitegrast versus placebo. RESULTS: In the study, 711 participants were randomized: placebo, 356; lifitegrast, 355 (intention-to-treat [ITT] population). At day 84, lifitegrast-treated participants experienced significantly greater improvement from baseline in EDS versus those receiving placebo (treatment effect [TE], 7.16; 95% confidence interval [CI], 3.04-11.28; P = 0.0007). Mean changes from baseline in EDS also significantly favored lifitegrast on days 42 (TE, 9.32; 95% CI, 5.44-13.20; P < 0.0001) and 14 (TE, 7.85; 95% CI, 4.33-11.37; P < 0.0001). No statistically significant differences were observed in ODS between treatment groups at days 84, 42, or 14. A greater improvement was observed in lifitegrast-treated participants at day 42 in itching (nominal P = 0.0318), foreign body sensation (nominal P = 0.0418), and eye discomfort (P = 0.0048) versus participants receiving placebo. Most treatment-emergent adverse events were mild to moderate in severity; no serious ocular adverse events were reported. CONCLUSIONS: Lifitegrast significantly improved symptoms of eye dryness, as measured by EDS, versus placebo in participants with DED. Improvement in EDS was observed as early as day 14. Lifitegrast appeared well tolerated.
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Síndromes de Ojo Seco/tratamiento farmacológico , Soluciones Oftálmicas/uso terapéutico , Fenilalanina/análogos & derivados , Sulfonas/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Dolor Ocular , Femenino , Humanos , Antígeno-1 Asociado a Función de Linfocito/efectos de los fármacos , Masculino , Persona de Mediana Edad , Fenilalanina/uso terapéutico , Agudeza VisualRESUMEN
PURPOSE: Inflammatory mediators have been shown to modulate dry eye (DE) disease and may correlate with disease severity, yet the methods used and the associated findings vary significantly in the literature. The goal of this research was to compare two methods, the quantitative microarray and the magnetic bead assay, for detecting cytokine levels in extracted tear samples across three subject groups. METHODS: Tears were collected from Schirmer strips of the right and left eyes of 20 soft contact lens wearers (CL), 20 normal non-contact lens wearers (NOR), and 20 DE subjects and stored at -80 °C. Tear proteins were eluted and precipitated using ammonium bicarbonate and acetone. The right and left eye samples were combined for each subject. Following the Bradford protein quantitation method, 10 µg of total protein was used for each of the two analyses, Quantibody® Human Inflammation Array 3 (RayBiotech) and High Sensitivity Human Cytokine Magnetic Bead Kit (Millipore). The assays were run using the GenePix® 4000B Scanner (Molecular Devices) or the Luminex MagPix® plate reader (Luminex), respectively. The data were then compared between the two instruments and the three subject groups. RESULTS: Of the 40 proteins on the Quantibody® microarray, seven had average expression levels above the lower limit of detection: ICAM-1, MCP-1, MIG, MCSF, TIMP-1, TIMP-2, and TNF-RI. Significant differences in expression levels (p<0.05) were detected between the CL and DE groups for MCSF, TIMP-1, and TNF R1, between the NOR and DE groups for ICAM-1, and between the CL and NOR groups for ICAM-1, MCP-1, MCSF, TIMP-1, TIMP-2, and TNF-R1 when using the Student t test. Of the 13 proteins tested with Luminex, IL-1ß, IL-4, IL-6, IL-7, and IL-8 had expression levels above the minimum detectable level, and these were most often detected using the Luminex assay compared to the Quantibody® microarray. Contrarily, IL-2, IL-12, IL-13, INF-g, and GM-CSF were detected more frequently using the Quantibody® microarray than the Luminex assay. Significant differences in expression levels (p<0.05) were only detected between the CL and DE groups for IL-7 and IL-8 and between the CL and NOR subjects for IL-8. CONCLUSIONS: In addition to detecting more significant differences between the subject groups, the Quantibody® microarray detected more inflammatory cytokines in total within the range of detection than the Luminex assay. Differences were also noted in the types of cytokines each assay could detect from the limited protein samples. Both methods offer advantages and disadvantages; therefore, these factors should be considered when determining the appropriate assay for analyzing tear protein samples.
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Citocinas/metabolismo , Síndromes de Ojo Seco/metabolismo , Proteínas del Ojo/metabolismo , Mediadores de Inflamación/metabolismo , Lágrimas/metabolismo , Lentes de Contacto Hidrofílicos/efectos adversos , Síndromes de Ojo Seco/etiología , Humanos , Inmunoensayo/métodos , Análisis por Matrices de Proteínas/métodos , Errores de Refracción/terapiaRESUMEN
PURPOSE: To determine the repeatability and agreement between the noninvasive Keratograph tear break-up time (NIK-BUT) as measured by the Oculus Keratograph 4 and fluorescein tear break-up time (FBUT). METHODS: Sixty subjects were recruited for two study visits separated by 7 (± 2) days. At each visit, three NIK-BUT measures and FBUT measures were obtained. Each NIK-BUT measure from the Keratograph included a first and an average NIK-BUT. The means of the measures obtained, first NIK-BUT, and average NIK-BUT and FBUT were calculated for each visit. Between- and within-visit agreement was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman 95% limits of agreement (LoA) analyses of log-transformed data. RESULTS: Between-visit ICCs were 0.53 [95% confidence interval (CI), 0.32 to 0.69] for first NIK-BUT, 0.59 (95% CI, 0.40 to 0.73) for average NIK-BUT, and 0.66 (95% CI, 0.49 to 0.78) for FBUT, whereas 95% LoA were -0.65 to 0.67, -0.44 to 0.48, and -1.14 to 1.10 [back transformed: (visit 1 + 0.01)/(visit 2 + 0.01) = 0.22 to 4.68, 0.36 to 3.02, and 0.07 to 12.59] for the aforementioned methods, respectively. The visit 1 within-visit ICC between first NIK-BUT and FBUT was 0.44 (95% CI, 0.21 to 0.62), whereas the 95% LoA was -0.84 to 1.18 [back transformed: (first NIK-BUT + 0.01)/(FBUT + 0.01) = 0.14 to 15.14]. Likewise, the visit 1 within-visit ICC between average NIK-BUT and FBUT was 0.41 (95% CI, 0.18 to 0.60), whereas the 95% LoA was -0.58 to 1.44 [back transformed: (average NIK-BUT + 0.01)/(FBUT + 0.01) = 0.26 to 27.54]. CONCLUSIONS: The 95% LoA suggest that the average NIK-BUT has better between-visit agreement compared with the first NIK-BUT or FBUT. The first NIK-BUT showed better within-visit agreement with the FBUT than the average NIK-BUT. In addition, there is better between- and within-visit agreement for all measures at lower values.
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Técnicas de Diagnóstico Oftalmológico , Lágrimas/química , Adulto , Femenino , Fluoresceína/química , Colorantes Fluorescentes/química , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Purpose: This study was intended to characterize the impact of meibomian gland dysfunction (MGD) on patients' quality of life. Methods: In this prospective, multicenter, noninterventional clinical study (NCT01979887), eligible individuals (age ≥40 years; absence of uncontrolled ocular/systemic disease) were categorized, based on composite grading of ocular symptoms, Schirmer score, and meibum quality, into (1) non-MGD, (2) mild/moderate MGD, or (3) severe MGD cohorts. The MGD Impact Questionnaire (MGD IQ), a 10-item patient-reported outcome measure, was self-administered at clinic visit on day 1, and readministered on day 22 to assess intervisit agreement regarding MGD IQ responses. Results: In total, 75 subjects were assigned to the study cohorts (25 per cohort). Across cohorts, MGD IQ item scores rose incrementally with increasing MGD severity. The severe MGD cohort experienced greater difficulty with reading and performance of leisure activities, greater time on eye care, and greater bother with eye care and eye appearance than the mild/moderate MGD cohort (all P < 0.05). Compared with the non-MGD cohort, the mild/moderate MGD cohort had greater difficulty working on computer, whereas the severe MGD cohort had greater difficulty reading, driving, and performing leisure activities, more frequent difficulty with outdoor activities, more time on eye care, and greater bother with eye care (all P < 0.05). Intervisit agreement between MGD IQ responses was fair to moderate (weighted kappa statistic 0.33â0.58). Conclusions: Vision-related activities are negatively impacted by increasing severity of MGD. The MGD IQ instrument can help characterize disease severity and amplify the patient's voice in patient-centric clinical research. ClinicalTrials.gov NCT01979887.
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Síndromes de Ojo Seco , Disfunción de la Glándula de Meibomio , Adulto , Humanos , Síndromes de Ojo Seco/diagnóstico , Disfunción de la Glándula de Meibomio/diagnóstico , Disfunción de la Glándula de Meibomio/terapia , Glándulas Tarsales , Estudios Prospectivos , Calidad de Vida , LágrimasRESUMEN
Dry eye is a common ocular surface disease of multifactorial etiology characterized by elevated tear osmolality and inflammation leading to a disrupted ocular surface. The latter is a risk factor for ocular surface infection, yet overt infection is not commonly seen clinically in the typical dry eye patient. This suggests that important innate mechanisms operate to protect the dry eye from invading pathogens. This article reviews the current literature on epidemiology of ocular surface infection in dry eye patients and laboratory-based studies on innate immune mechanisms operating at the ocular surface and their alterations in human dry eye and animal models. The review highlights current understanding of innate immunity in dry eye and identifies gaps in our knowledge to help direct future studies to further unravel the complexities of dry eye disease and its sequelae.
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Conjuntiva/metabolismo , Síndromes de Ojo Seco/etiología , Queratitis/complicaciones , Aparato Lagrimal/metabolismo , Lágrimas/metabolismo , Síndromes de Ojo Seco/metabolismo , Humanos , Queratitis/metabolismo , Concentración OsmolarRESUMEN
Allergic conjunctivitis has been reported to be increasing in prevalence in the United States. It significantly impacts patient quality of life and reduces their productivity. It has been noted that nasal and ocular symptoms are equally bothersome in the majority of patients. Despite the development of new therapeutic interventions, ocular allergy is often underdiagnosed and undertreated. This article outlines current best practices regarding diagnosis and treatment of allergic conjunctivitis; suggests criteria for referral to a colleague with different expertise; and provides an algorithm for step recommendations including treatment with antihistamines, mast cell stabilizers, corticosteroids, nonsteroidal anti-inflammatory drugs, and immunotherapy.
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Corticoesteroides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica/métodos , Ojo/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/uso terapéutico , Mastocitos/efectos de los fármacos , Algoritmos , Degranulación de la Célula/efectos de los fármacos , Conjuntivitis Alérgica/diagnóstico , Ojo/inmunología , Ojo/patología , Humanos , Mastocitos/inmunología , Guías de Práctica Clínica como Asunto , Derivación y ConsultaRESUMEN
Meibomian gland dysfunction (MGD) is highly prevalent and is the leading cause of evaporative dry eye disease (DED). MGD is characterized by a reduction in meibum secretion and/or a change in meibum composition that results in the disruption of the tear film lipid layer and an increase in the tear film evaporation rate. Excessive evaporation causes tear film instability, desiccation, tear hyperosmolarity, inflammation, and apoptosis of ocular surface cells, resulting in a continuous cycle of DED. The primary treatment goal for DED associated with MGD is to restore the tear film lipid layer and decrease evaporation, thereby reducing ocular signs and symptoms. The management of MGD includes home care options (eyelid hygiene, warming eye masks, ocular lubricants) and office-based treatments (manual expression, microblepharoexfoliation, thermal pulsation, intense pulsed light, intraductal probing). Topical ophthalmic prescription medications attempt to alter various factors that may contribute to DED (e.g., inflammation, bacterial growth, inadequate tear production). In this review, clinical evidence regarding available treatments and emerging therapies from randomized studies in patients with DED associated with MGD is summarized. Although some treatment modalities have been evaluated specifically for DED patients with MGD, large-scale randomized controlled trials are needed to confirm efficacy and safety in this patient population. Currently, there are no approved prescription pharmacologic treatments specifically indicated for DED associated with MGD, and those medications approved for the treatment of DED do not target the key driver of the disease (i.e., excessive evaporation). NOV03 (perfluorohexyloctane; under review with the US Food and Drug Administration) is the most advanced emerging therapy for DED associated with MGD and has demonstrated statistically significant improvements in both signs and symptoms in randomized controlled trials. Development of novel pharmacotherapies will improve therapeutic options and allow for a more individualized approach for patients with DED associated with MGD.
RESUMEN
Dry eye disease (DED) is a common condition in which tear film abnormalities result in a damaging cycle of tear hyperosmolarity, desiccating stress, inflammation, and ocular surface injury. In a healthy tear film, meibum produced by the meibomian glands forms a lipid layer that stabilizes the tear film and protects against aqueous tear evaporation. Excessive tear evaporation due to a deficient lipid layer is believed to be the most common cause of DED, and most evaporative DED is associated with meibomian gland dysfunction (MGD); this highlights the pathophysiologic importance of the dysfunctional tear lipid layer. Current treatments for DED may be used to supplement hyperosmolar aqueous tears, lubricate the ocular surface, increase meibum flow, decrease inflammation, promote tear production, or otherwise decrease clinical signs of ocular surface damage and/or improve symptoms. Until now, no prescription eye drop has directly addressed the excessive evaporation that occurs in most patients with DED. Perfluorohexyloctane (PFHO) ophthalmic solution (MIEBO™; Bausch + Lomb) is a preservative-free eye drop that has demonstrated the ability to form a long-lasting barrier that inhibits evaporation in preclinical studies. FDA approval of PFHO was based on results from 2 pivotal clinical trials (GOBI [NCT04139798] and MOJAVE [NCT04567329]) in patients with DED and clinical signs of MGD which demonstrated consistent improvements in both signs and symptoms of disease, with a safety profile similar to that of saline eye drops. PFHO is the first and only FDA-approved eye drop that directly targets tear evaporation in patients with DED, thereby promoting ocular surface healing and providing symptomatic relief.
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Síndromes de Ojo Seco , Humanos , Síndromes de Ojo Seco/tratamiento farmacológico , Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/etiología , Inflamación , Lípidos , Glándulas Tarsales/fisiología , Soluciones Oftálmicas/uso terapéutico , Ensayos Clínicos como AsuntoRESUMEN
Purpose: Dry eye disease is attributed to impaired tear production and/or evaporative dry eye. Evaporative dry eye is frequently associated with meibomian gland dysfunction (MGD). The objective of this study was to identify clinical study endpoints related to MGD. Methods: This 22-day, noninterventional, case-control clinical study involved three cohorts with increasing MGD severity: no MGD, mild/moderate MGD, and severe MGD. Symptoms were assessed with an ocular symptom questionnaire grading blurred vision, eye burning, eye dryness, eye pain, light sensitivity, eye itching, eye foreign body sensation, and overall ocular discomfort. Sign assessments included the maximum meibum quality score (MMQS), tear breakup time, Schirmer tear tests, biomicroscopy, and corneal staining. Signs and symptoms were compared between cohorts and study visits. Results: Seventy-five study participants were assigned to the cohorts (25 per cohort). MMQS scores increased with increasing MGD severity, reflecting the selection criteria for the cohorts. Between-visit scores showed a weighted kappa statistic of 0.72 indicating substantial agreement. Mean scores of all assessed symptoms increased with increasing MGD severity. Scores for symptoms showed moderate (κ = 0.41-0.60) to substantial (κ = 0.61-0.80) agreement between visits. Overall ocular discomfort demonstrated the strongest correlation with the MMQS. Conclusion: The MMQS was a reproducible sign of MGD showing good agreement with ocular symptoms. Overall ocular discomfort was well correlated with typical dry eye symptoms and could potentially be used as a single measure of MGD symptoms. The findings from this observational study may inform endpoints for future clinical trials. ClinicalTrials.gov NCT01979887.
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Síndromes de Ojo Seco , Enfermedades de los Párpados , Disfunción de la Glándula de Meibomio , Humanos , Disfunción de la Glándula de Meibomio/diagnóstico , Glándulas Tarsales , Enfermedades de los Párpados/diagnóstico , LágrimasRESUMEN
Purpose: There is an unmet need for new treatments for allergic conjunctivitis. Objective: To assess the activity of reproxalap, a novel reactive aldehyde species modulator, in a real-world model of seasonal allergen exposure. Methods: The INVIGORATE Trial, a prospective, quadruple-masked, vehicle-controlled, crossover, sequence-randomized Phase 3 trial, tested the efficacy of reproxalap in adults with a history of moderate to severe allergic conjunctivitis, ragweed pollen allergy, and allergen chamber-induced ocular itching and redness. Patients were randomly assigned (1:1) to receive 0.25% reproxalap ophthalmic solution or vehicle, followed by a 2-week washout period before crossing over to the other test article. The primary endpoint was ocular itching from 110 to 210 minutes after chamber entry; the key secondary endpoint was ocular redness over the chamber duration (0-4 scales for both endpoints). Results: Of the 95 randomly assigned patients, 89 completed all visits (reproxalap to vehicle: n = 46; vehicle to reproxalap: n = 43). Primary and key secondary endpoints were met: reproxalap significantly reduced ocular itching (mean [SE]: -0.50 [0.03], p < 0.001) and redness (-0.14 [0.01], p < 0.001) relative to vehicle. Responder analyses confirmed the clinical relevance of both end points. Reproxalap was safe and well tolerated. No clinically significant changes in safety assessments were observed. No serious or severe treatment-emergent adverse events (TEAEs) were reported. The most commonly reported TEAE was mild and transient installation site irritation after reproxalap versus vehicle administration. Conclusion: In this well-controlled allergen chamber trial, reproxalap was statistically superior to vehicle across typical symptoms and signs of allergic conjunctivitis. Trial Registration: NCT04207736.
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Purpose: Information on the relationship between meibum lipid composition and severity of meibomian gland dysfunction (MGD) is limited. The purpose of this study was to analyze the molecular components of meibum collected from individuals with no MGD, mild-to-moderate MGD, and severe MGD. Methods: Adults with and without MGD were enrolled in a prospective, multicenter, exploratory clinical trial (ClinicalTrials.gov Identifier: NCT01979887). Molar ratios of cholesteryl ester to wax ester (RCE/WE) and aldehyde to wax ester (Rald/WE) in meibum samples were measured with 1H-NMR spectroscopy. Results were evaluated for participants grouped by MGD disease status and severity (non-MGD, mild-to-moderate MGD, and severe MGD), as defined by maximum meibum quality scores, Schirmer test results, and Subject Ocular Symptom Questionnaire responses. Results: Sixty-nine meibum samples from 69 individuals were included in the analysis: 24 non-MGD, 24 mild-to-moderate MGD, and 21 severe MGD. Mean RCE/WE was 0.29 in non-MGD, 0.14 in mild-to-moderate MGD (P = 0.038 vs. non-MGD, 51% lower), and 0.07 in severe MGD (P = 0.16 vs. mild-to-moderate MGD, 52% lower; P = 0.002 vs. non-MGD, 76% lower). Mean Rald/WE was 0.00022 in non-MGD, 0.00083 in mild-to-moderate MGD (P = 0.07 vs. non-MGD, 277% higher), and 0.0024 in severe MGD (P = 0.003 vs. mild-to-moderate MGD, 190% higher; P < 0.001 vs. non-MGD, 992% higher). Conclusions: RCE/WE was lowest and Rald/WE was highest in the severe MGD cohort, suggesting that these meibum constituent molar ratios may result from the pathophysiology associated with MGD and can impact ocular surface lipid and tear film homeostasis. These findings may potentially help identify targets for MGD treatment.