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Evaluation of NAAGA efficacy in dry eye syndrome
Abstract
The aim of this study was to assess the efficacy of Naabak((R)) eyedrops in reducing inflammation in dry eye syndrome.
This pilot, multicenter, randomized, double-blind, parallel study was carried out in adult patients suffering from moderate dry eye syndrome. Patients were treated for three months with preservative-free NAAGA (Naabak((R))) or with sodium chloride 0.9% without preservative (Larmabak(R)). They received the treatment four to six times a day during the 1(st) month and three to four times a day during the 2(nd) and 3(rd) months. At each visit (D28 and D84), clinical tests were performed as well as a biological evaluation of HLA-DR and MUC5AC expression on conjunctival imprints using flow cytometry.
After three months of treatment, the ocular surface symptoms and overall discomfort were improved in patients treated with Naabak(R) and in those treated with Larmabak(R) with no significant difference between the groups. Cytological impression showed a significant decrease in the expression of inflammatory markers, notably antigen HLA-DR, in the Naabak(R) group.
This study confirms the anti-inflammatory property of preservative-free NAAGA (Naabak(R)) in the context of dry eye syndrome with a similar clinical efficacy compared to sodium chloride solution (Larmabak(R)). Naabak(R) could present an additional advantage compared to artificial tears and could be indicated in the treatment of moderate inflammatory dry eye syndrome.
... NAAGA is also known to have anti-inflammatory effects and plays a role in mast cell stabilization and complement activation [9]. A previous study applied the NAAGA eye drops for their anti-inflammatory effect in dry eye patients and found that NAAGA eye drops reduced the expression of inflammatory markers, which could present an additional advantage to inflammatory dry eye [10]. ...
... It is known to be related to disease severity [16] and is correlated with symptoms and signs of dry eye [17]. Brignole-Baudouin et al. [10] reported a significant decrease in the expression of inflammatory markers, notably antigen HLA-DR, in patients with dry eye treated with NAAGA eye drops. In this study, patients treated with 4.9% NAAGA eye drops had improvement in dry eye and MGD parameters as well as symptoms. ...
... A published article on NAAGA [10] and the SANSIKA study [18] reported significant improvements in inflammatory markers in the treatment group compared with those in the control group, but there was no significant difference in the OSDI score between the groups. In both studies, all patients had more severe dry eye than the patients in this study. ...
Purpose
We aimed to investigate the difference in the treatment effects of 4.9% N-acetyl-aspartyl glutamic acid (NAAGA) and 0.05% cyclosporine A (CsA) eye drops in dry eye patients.
Methods
We retrospectively reviewed the medical records of 86 patients (86 eyes) who were diagnosed with dry eye and treated with NAAGA or CsA eye drops. Patients treated with NAAGA or CsA eye drops were designated as group A or B, respectively. We also calculated Ocular Surface Disease Index (OSDI), dry eye, and meibomian gland dysfunction (MGD) parameters before treatment and at 1 and 3 months after treatment. Eye drop discomfort was assessed by calculating visual analog scale (VAS) scores at 1 month and 3 months after treatment.
Results
There were no significant differences in patients’ demographics and OSDI, dry eye, and MGD parameters between the two groups. OSDI, dry eye, and MGD parameters at 1 month and 3 months after treatment were found to be improved in both groups. However, at 1 month after treatment, the dry eye and MGD parameters of group A, except for corneal fluorescein staining, showed more improvement than those of group B. Additionally, at 3 months after treatment, the lid margin abnormality score, corneal staining score, tear break-up time, and OSDI of group A were significantly lower than those of group B. VAS scores of group A at 1 and 3 months after treatment were significantly lower than those of group B.
Conclusion
Treatment with NAAGA eye drops was effective in dry eye patients and demonstrated faster treatment response and less discomfort during application than CsA eye drops.
... 65-76 / issn: 1692-8415 duladores (ciclosporina y tacrolimus). Hoy en día se está investigando la propiedad antinflamatorios que tienen los antialérgicos en la mejoría de los signos y la disminución de la respuesta inflamatoria en el tratamiento de ojo seco (Brignole et ál., 2009). La búsqueda de nuevos agentes terapéuticos favorece el desarrollo investigativo en el tratamiento del síndrome en Colombia y mayor entendimiento de la fisiopatología, en especial la participación de la respuesta inflamatoria e inmunológica. ...
... Después de tres meses de tratamiento, hubo una disminución significativa en las manifestaciones clínicas y en la expresión del antígeno hla-dr en el grupo tratado con naaga, confirmando la propiedad antinflamatoria del fármaco, lo cual representa una ventaja adicional sobre las lágrimas artificiales, ya que el fármaco actúa sobre la condición que agrava y perpetúa el síndrome. Los autores concluyen que el ácido nacetil aspartil glutámico podría estar indicado en el tratamiento del síndrome de ojo seco moderado(Brignole et ál., 2009).Otro hallazgo estadístico y clínicamente significativo fue la mejoría en la tinción de la superficie ocular valorada con lisamina verde en los ojos intervenidos con clorhidrato de epinastina al 0,05 %. Al igual que la sintomatología, su efecto fue más marcado en el segundo control a los 45 días, donde el 90 % de los pacientes obtuvieron una tinción correspondiente al grado 1, incluso en los pacientes con síndrome de sjögren (figura 3). ...
Antihistamínicos como el clorhidrato de epinastina tienen actividad antinflamatoria y podrían usarse como tratamiento del síndrome de ojo seco. Objetivo: evaluar los cambios en la sintomatología, película lagrimal y superficie ocular antes y después del tratamiento con clorhidrato de epinastina en pacientes con síndrome de ojo seco. Materiales y métodos: se realizó un estudio piloto doble ciego en 20 pacientes con diagnóstico clínico de ojo seco moderado. Un ojo de cada paciente recibió tratamiento con clorhidrato de epinastina al 0,05 % y el otro recibió hialuronato de sodio al 0,4 %. Los dos ojos recibieron suplemento lagrimal con hialuronato de sodio al 0,4 %. La dosis de tratamiento fue una gota tres veces al día por 45 días. Antes del tratamiento y 30 y 45 días después, se aplicó cuestionario validado para ojo seco (osdi), test de Schirmer 1, but y lisamina verde. Se aplicó la prueba t de Student y rangos de Wilcoxon. Resultados: se encontró un mejoría estadísticamente significativa en sintomatología a los 30 días de intervención con epinastina (p = 0,000) y 45 días (p = 0,0000). En la superficie ocular hubo mejoría clínica y significativa estadísticamente a los 45 días (p = 0,0001). No se encontraron cambios significativos en la calidad ni en la cantidad de la película lagrimal. La reducción en la sintomatología y el grado de tinción con la epinastina a los 45 días fue estadísticamente significativa (p < 0,05) con respecto al grupo control. Conclusión: la combinación clorhidrato de epinastina al 0,05% y hialuronato de sodio al 0,4% mejora la sintomatología y la superficie ocular en los pacientes con ojo seco moderado.
Introduction:
Inflammatory disorders of the anterior surface of the eye consist of a spectrum of disorders that range from ocular allergy, dry eye syndrome (DES), and various infections. They exhibit similar pathological profiles, but have divergent immune mechanisms with some overlap. A number of novel treatments are currently being studied that capitalize on the growing understanding of underlying immunopathophysiology.
Areas covered:
The goal of this review is to examine the emerging pipeline for noninfectious inflammatory disorders of the anterior surface of the eye - primarily allergic conjunctivitis (AC) and DES - in light of the recent basic science discoveries that have fueled their development. Novel molecules for the treatment of AC and DES from clinicaltrials.gov as well as recently filed patents for new molecular entities were reviewed from PUBMED and OVID.
Expert opinion:
Significant progress toward targeted treatments for AC and DES has become increasingly reliant on understanding the immunomodulatory and inflammatory mechanisms of the conjunctiva.
Sjögren's syndrome is a chronic inflammatory disease of the lacrimal and salivary gland with subsequent keratoconjunctivitis sicca and xerostomia. Histopathologic findings include damaged acini of the lacrimal and salivary glands with mononuclear cell infiltrates of lymphocytic and plasma cell type. The cause of the damage is cell-mediated cytotoxicity. The pathogenesis of Sjögren's syndrome is still unknown. The role of viral infections failed to show a causative effect. On the other hand, tissue destruction was shown to be mediated by activated T cells of CD4+ type that home into the lacrimal gland. This process is signal-mediated through the T-cell receptor that interacts with class II antigen on the epithelial cells of exocrine glands. This, in turn, induces the expression of Fas/APO-1 and Fas-mediated apoptosis of acinar cells. Granzyme A and perforin are cytolytic enzymes secreted by activated T lymphocytes that seem to participate in acinar cell destruction.
The conventional technique of impression cytology provides a non-invasive method for the evaluation of conjunctival epithelium alterations. Using indirect immunofluorescence procedures two inflammatory markers, class II MHC antigens HLA DR and the receptor to IgE (CD23), were sought in impression cytology specimens obtained from 80 patients. In normal subjects conjunctival epithelial cells did not show any reactivity. Only scattered dendritic cells were found to express class II antigens but not the receptor to IgE. In contrast patients with chronic conjunctivitis of various aetiologies, mainly infectious or allergic, had 40-100% of brightly positive conjunctival cells for one or both antigens. In these cases epithelial cells and goblet cells reacted similarly. Twenty four eyes in 12 patients with idiopathic dry eye syndrome disclosed results similar to those from normal conjunctival specimens. However 18 other specimens from patients suffering from idiopathic tear deficiency but undergoing multiple substitutive treatments for dry eye had moderate to strong positivity for HLA DR and/or the receptor to IgE (20-100% of cells). As these results were independent of the degree of squamous metaplasia the expression of these membrane markers may reflect local inflammation in addition to tear deficiency, possibly due to sensitisation to the eye drops used. These immunocytological techniques thus provide useful methods of investigating conjunctival inflammation and allergy. They may constitute valuable aid in the diagnosis and appropriate treatment of ocular surface disorders.
In primary Sjögren's syndrome (SS), ocular surface changes within the conjunctival epithelium include lymphocytic infiltration, squamous cell metaplasia, and a reduction in goblet cell number. These changes may be the simple result of increased mechanical abrasion secondary to dryness. Alternatively, they may represent a local response to ocular and/or systemic inflammatory processes, perhaps in response to Epstein-Barr viral (EBV) infection, an agent recently implicated in the etiology of SS. To determine whether inflammatory processes or local infection by EBV contribute to the ocular surface pathology of SS, we examined the expression of inflammatory cell surface markers, cytokines, and EBV gene products within the ocular conjunctiva of patients with SS.
Ocular conjunctival tissue was isolated from patients with primary SS and nondry eye control patients by impression cytology or direct biopsy. These specimens were examined by immunofluorescence microscopy and reverse-transcriptase polymerase chain reaction (RT-PCR) for the expression of various markers.
The authors found the frequency of expression of HLA-DR (P < 0.0001), ICAM-1 (P < 0.035), and IL-6 (P < 0.0001) to be significantly elevated in patients with primary SS versus nondry eye control patients. The IL-2 receptor and cytokines IL-1 beta and IL-8 were each found to be expressed with relatively high frequency in both patient populations, whereas mRNAs encoding cytokines IL-2, IFN-gamma, GM-CSF, and TGF-beta were not reproducibly detectable in either population. Messenger RNA encoding a marker for passive-latent EBV infection (EBNA-1) was detected with high frequency in both SS and normal populations. The EBV IL-10 analog BCRF-1 was expressed with low frequency in the SS population; however, these levels were not significantly different from the control population. The expression of two other markers of EBV infection, latent membrane protein (LMP, a lytic and latent marker), and BZLF-1 (putative latent-lytic switch gene) was undetectable in either study population.
Based on the increased expression of the cell surface molecules HLA-DR and ICAM-1, and the inflammatory cytokine IL-6, the authors propose that local inflammatory processes contribute to the ocular surface changes and ocular surface dryness associated with primary SS.
Topical cyclosporine has been used by veterinary ophthalmologists since 1989 for the treatment of ocular surface inflammatory disease and keratoconjunctivitis sicca (KCS). As well as ameliorating clinical signs of ocular surface lymphocyte-driven inflammation in the dog, cat and horse, topical cyclosporine significantly raises tear production in both normal and KCS-affected animals. A licensed ointment preparation of 0.2% cyclosporine, Optimmune (Schering-Plough), is now available for administration to dogs. In this paper we examine the mechanisms by which cyclosporine exerts both its immunomodulatory and its lacrimogenic actions. The pharmacokinetics of topical cyclosporine are examined to determine whether these effects are truly local or are influenced by generalised immunosuppression caused by systemic absorption of topically applied drug. The paper reviews the few side effects of cyclosporine preparations in the experience of veterinary ophthalmologists and the experimental evidence which appears to implicate the vehicle rather than the active agent cyclosporine as causing many of these effects. Given that topical cyclosporine has been so widely accepted as a valuable ophthalmic preparation in the veterinary world and licensed as such, it is surprising that human ophthalmologists have not employed the drug to the same extent for conditions from vernal keratoconjunctivitis to Sjögren's syndrome.
Dry eye syndrome (DES) is believed to be one of the most common ocular problems in the United States (US), particularly among older women. However, there are few studies describing the magnitude of the problem in women and how this may vary with demographic characteristics.
Cross-sectional prevalence survey.
Study population: we surveyed 39,876 US women participating in the Women's Health Study about a history of diagnosed DES and dry eye symptoms. Main outcome measure: we defined DES as the presence of clinically diagnosed DES or severe symptoms (both dryness and irritation constantly or often). We calculated the age-specific prevalence of DES and adjusted the overall prevalence to the age distribution of women in the US population. We used logistic regression to examine associations between DES and other demographic factors.
The prevalence of DES increased with age, from 5.7% among women < 50 years old to 9.8% among women aged > or = 75 years old. The age-adjusted prevalence of DES was 7.8%, or 3.23 million women aged > or = 50 in the US. Compared with Whites, Hispanic (odds ratio [OR] = 1.81, confidence interval [CI] = 1.18-2.80) and Asian (OR = 1.77, CI = 1.17-2.69) women were more likely to report severe symptoms, but not clinically diagnosed DES. There were no significant differences by income (P([trend]) =.78), but more educated women were less likely to have DES (P([trend]) =.03). Women from the South had the highest prevalence of DES, though the magnitude of geographic differences was modest.
Dry eye syndrome leading to a clinical diagnosis or severe symptoms is prevalent, affecting over 3.2 million American women middle-aged and older. Although the condition is more prevalent among older women, it also affects many women in their 40s and 50s. Further research is needed to better understand DES and its impact on public health and quality of life.
Background: Most dry-eye symptoms result from an abnormal, nonlubricative ocular surface that increases shear forces under the eyelids and diminishes the ability of the ocular surface to respond to environmental challenges. This ocular-surface dysfunction may result from immunocompromise due to systemic autoimmune disease or may occur locally from a decrease in systemic androgen support to the lacrimal gland as seen in aging, most frequently in the menopausal female. Hypothesis: Components of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and interconnecting innervation act as a functional unit. When one portion is compromised, normal lacrimal support of the ocular surface is impaired. Resulting immune-based inflammation can lead to lacrimal gland and neural dysfunction. This progression yields the OS symptoms associated with dry eye. Therapy: Restoration of lacrimal function involves resolution of lymphocytic activation and inflammation. This has been demonstrated in the MRL/lpr mouse using systemic androgens or cyclosporine and in the dry-eye dog using topical cyclosporine. The efficacy of cyclosporine may be due to its immunomodulatory and antiinflammatory (phosphatase inhibitory capability) functions on the ocular surface, resulting in a normalization of nerve traffic. Conclusion: Although the etiologies of dry eye are varied, common to all ocular-surface disease is an underlying cytokine/receptor-mediated inflammatory process. By treating this process, it may be possible to normalize the ocular surface/lacrimal neural reflex and facilitate ocular surface healing.
Dry eye is a complex clinicopathological entity involving tear film, lacrimal glands, eyelids, and a wide spectrum of ocular surface cells, including epithelial, inflammatory, immune, and goblet cells. From the tightly regulated lacrimal film functions and structure, a large variety of investigations have been developed, including tear meniscus measurements, fluorophotometry, meibometry, interference pattern analysis, evaporation rate, tear osmolarity, and thermography. Dry eye conditions also interfere with the ocular surface, causing corneal irregularities that may be explored using the techniques of videokeratography and in vivo confocal microscopy, or optical impairment, as confirmed by aberrometry. At the level of ocular surface cells, impression cytology remains a standard for assessing cell alterations. It has greatly benefited from new confocal microscopy, molecular biology, and flow cytometry techniques. Biological assessment of tear proteins or other mediators is also useful. Major limits should be acknowledged, however, such as technical issues in tear film collection, especially in dry eyes, and the lack of standardization of most measurements. Tear osmolarity, electrophoresis, and dosage of normal tear proteins, such as lysozyme or lactoferrin, remain the most useful tests. Finally, some extraocular explorations such as accessory gland biopsy or serum antinuclear antibody dosage may be useful for assessing the diagnosis of Sjögren's syndrome.
Introduction
Les acides gras polyinsaturés (AGPI) sont impliqués dans les réactions inflammatoires via les prostaglandines (PG) dont ils sont les précurseurs. Or, l’inflammation de la conjonctive est une composante importante de la sécheresse oculaire. Nous avons étudié le rôle des AGPI n-6 et n-3 associés à des anti-oxydants donnés par voie orale chez des patients présentant un syndrome sec.
Patients et méthods
Nous avons mené une étude prospective en double insu, randomisée chez 71 patients atteints d’un syndrome sec débutant ou modéré qui ont reçu par voie orale une association d’AGPI n-3 et n-6 (Nutrilarm®) ou un placebo, deux fois par jour pendant 6 mois. Un test de Schirmer, une évaluation du temps de rupture du film lacrymal (BUT), une coloration à la fluorescéine et au vert de lissamine ont été réalisés à l’inclusion des patients dans l’étude et un, trois et six mois après le début de la supplémentation. De plus, un questionnaire évaluant les symptômes et la qualité de vie a été rempli à chaque visite.
Résultats
Le test de Schirmer, le BUT et les colorations à la fluorescéine et au vert de lissamine ont été améliorés dans le groupe traité versus placebo, mais sans atteindre un seuil statistiquement significatif. L’efficacité jugée par le patient et l’investigateur était proche du seuil statistique fixé à p = 0,05 (p = 0,052 et p = 0,054 respectivement). L’amélioration atteignait le seuil de significativité pour certains signes comme le larmoiement réflexe et l’hyperhémie conjonctivale (respectivement p = 0,047 et p = 0,045). La qualité de la peau et la sensation de bien-être étaient également améliorées dans le groupe traité (61 % d’amélioration contre 36 % dans le groupe placebo).
Conclusion
Cette étude pilote en double insu montre que les acides gras polyinsaturés semblent constituer une prise en charge intéressante de la sécheresse oculaire. Ces résultats devront être confirmés sur une cohorte de patients plus importante.
The role of the Diagnostic Methodology Subcommittee of the Dry Eye Workshop was 1) to identify tests used to screen, diagnose and monitor dry eye disease, 2) to establish criteria for test performance, and 3) to consider the utility of tests in a variety of clinical settings. The committee created a database of tests used to diagnose and monitor dry eye, each compiled by an expert in the field (rapporteur) and presented within a standard template. Development of the templates involved an iterative process between the Chairman of the subcommittee, the rapporteurs, and, at times, an additional group of expert reviewers. This process is ongoing. Each rapporteur was instructed on how to the complete a template, using a proforma template and an example of a completed template. Rapporteurs used the literature and other available sources as the basis for constructing their assigned template. The Chairman of the subcommittee modified the template to produce a standardized version and reviewed it with the rapporteur. The completed database will be searchable by an alphabetical list of test names, as well as by functional groupings, for instance, tests of aqueous dynamics, lipid functions, etc. The templates can be accessed on the website of the Tear Film and Ocular Surface Society (www.tearfilm.org). This report provides a general overview of the criteria applied in the development of tests for screening and diagnosis.
The aim of the DEWs Definition and Classification Subcommittee was to provide a contemporary definition of dry eye disease, supported within a comprehensive classification framework. A new definition of dry eye was developed to reflect current understanding of the disease, and the committee recommended a three-part classification system. The first part is etiopathogenic and illustrates the multiple causes of dry eye. The second is mechanistic and shows how each cause of dry eye may act through a common pathway. It is stressed that any form of dry eye can interact with and exacerbate other forms of dry eye, as part of a vicious circle. Finally, a scheme is presented, based on the severity of the dry eye disease, which is expected to provide a rational basis for therapy. these guidelines are not intended to override the clinical assessment and judgment of an expert clinician in individual cases, but they should prove helpful in the conduct of clinical practice and research.
Les classifications et schémas actuels des syndromes secs oculaires ne rendent pas compte de manière satisfaisante des liens physiopathologiques qui existent entre le film lacrymal et la surface oculaire. Ils présentent les syndromes secs oculaires comme provenant de maladies très différentes, souvent disparates, qui peuvent entraîner, de manière séparée ou associée, une hyposécrétion ou une instabilité du film lacrymal protecteur. Mais ils n’expliquent pas pourquoi certaines maladies peuvent déclencher un syndrome sec qui pourra lui-même évoluer de manière autonome, indépendamment de son facteur causal même lorsque celui-ci a disparu. Nous présentons ici une nouvelle approche physiopathologique de cette pathologie complexe dans laquelle les étiologies ne sont plus des maladies indépendantes responsables de syndromes secs autonomes, mais bien des points d’entrée dans un véritable cercle vicieux biologique faisant intervenir tous les acteurs de la surface oculaire, film lacrymal, conjonctive, cornée, mucocytes, cellules inflammatoires et paupières. La flore microbienne peut elle-même jouer un rôle important par le biais de toxines et d’enzymes qui vont altérer la couche lipidique et contribuer à une instabilité supplémentaire du film lacrymal. L’ensemble réalise de véritables cercles auto-entretenus. Lorsque l’œil entre dans un tel cycle biologique, même si la cause initiale a disparu (arrêt du port de lentilles de contact, suppression de conservateurs toxiques ou de médicaments entraînant une hyposécrétion…), le cercle vicieux continue à tourner pour lui-même et enferme les patients dans une souffrance et une inflammation chroniques. Le but de ce type de schéma physiopathologique, dont l’approche mécanistique est tout à fait innovante par rapport aux schémas actuels, est de mieux comprendre pourquoi les patients aux yeux secs sont si souvent enfermés dans une pathologie chronique qui résiste autant à des traitements qui, s’ils ne sont que symptomatiques ou adaptés à un mécanisme isolé, ne pourront être que partiellement efficaces, voire totalement inopérants.The mechanistic view of dry eye disease aims at completing the classic etiological approach that classifies the disease as parallel ocular surface disorders leading to lacrimal film impairment and dry eye. This approach proposes two levels of ocular surface impairment (with standard etiologies, previously validated in the NEI/Industry workshop), which may not be independent diseases but rather risk factors and/or ways to enter a self-stimulated biological process involving the ocular surface. All external disorders proposed in this model, although unlikely to be fully exhaustive, are classical mechanisms considered to be causes of tear film impairment and ocular surface damage, by tear instability and evaporation, tear hyposecretion, or both. These mechanisms, sometimes alone – when severe or becoming chronic or repeatedly present on the ocular surface and when two or more are present – may cause the patient to enter the self-stimulated loop. Tear film instability/imbalance can be considered as the key point of dry eye disease. It will cause local or diffuse hyperosmolarity of the tear film and therefore of superficial epithelial cells of the cornea and/or conjunctiva, stimulating epithelial cells and resident inflammatory cells. Cell damage in the cornea and conjunctiva, by means of apoptosis and direct mechanical and/or osmotic stress, will stimulate the reflex neurosensory arc, in turn stimulating lacrimal gland and neurogenic inflammation, with inflammatory cytokine release, MMP activation, and inflammatory involvement of the conjunctival epithelium. Goblet cell loss is thus directly related to chronic inflammation and surface cell apoptosis subsequent to cell hyperosmolarity and chronic damage, resulting in further tear film instability/imbalance. On the other hand, bacterial changes and an imbalance resulting from specific diseases or from tear film abnormalities may trigger release of endotoxins, lipopolysaccharides, and/or lipase activation, causing eyelid inflammation, meibomian gland dysfunction, and lipidic changes, directly influencing tear film stability and favoring tear evaporation. The lipidic hypothesis therefore participates in the vicious circle as a parallel, independent, or complementary loop. This mechanistic approach proposes a synthetic combination of mechanisms previously validated independently, with two levels of ocular surface impairment, a first level including many possible acute or chronic causes that favor or trigger the imbalance and can be reversible if correctly and specifically managed when possible, and the further involvement of a series of biological cascades centered by tear film imbalance and inflammatory stimulation, finally acting as an independent vicious circle, however the patient entered the loop. Clinically, this approach may explain examples of dry eye syndrome occuring after ocular surgery, contact lens wear, chronic allergy or systemic or topical drugs, and the long-lasting effect even though all causal factors have been removed or have disappeared. This model should be considered as a basis for further reflection on biological mechanisms that could be even more complex but individually constitute potential leads for targeting therapeutic strategies to allow patients to leave the loop even though the triggering factors are still present or can only be attenuated, such as in Sjögren syndrome or ocular rosacea. It also should be considered a complement to more classic etiological and severity classifications aimed at understanding and classifying the large number of diseases that may cause dry eye disease and better assessing the major impairment it causes on the patient's quality of life.
In recent years, learning from imbalanced data has attracted growing attention from both academia and industry due to the explosive growth of applications that use and produce imbalanced data. However, because of the complex characteristics of imbalanced data, many real-world solutions struggle to provide robust efficiency in learning-based applications. In an effort to address this problem, this paper presents Ranked Minority Oversampling in Boosting (RAMOBoost), which is a RAMO technique based on the idea of adaptive synthetic data generation in an ensemble learning system. Briefly, RAMOBoost adaptively ranks minority class instances at each learning iteration according to a sampling probability distribution that is based on the underlying data distribution, and can adaptively shift the decision boundary toward difficult-to-learn minority and majority class instances by using a hypothesis assessment procedure. Simulation analysis on 19 real-world datasets assessed over various metrics-including overall accuracy, precision, recall, F-measure, G-mean, and receiver operation characteristic analysis-is used to illustrate the effectiveness of this method.
The magnesium salt of N acetyl-aspartyl glutamic acid (Naaga), used in ophthalmic allergies, is a synthetic dipeptide analogue of a natural peptide found in mammalian brains. It has been shown in vitro that Naaga inhibits complement activation, mast-cell degranulation and leukotriene anaphylactic release. In order to verify Naaga's action on leukotriene production, we used the macrophage cell line P388D1 activated by calcium ionophore A23187. Leukotriene determination was performed by high-performance liquid chromatography. It was found that Naaga inhibits 15 to 80% macrophage eicosanoid secretion (10(-9) M to 10(-2) M), acting mainly on LTC4-D4-E4 synthesis. Naaga was as potent as the leukotriene inhibitor nordihydroguaiaretic acid and as dexamethasone in this model. This inhibition of leukotriene secretion could partially explain the in-vivo antiallergic effects of Naaga.
Peripheral leukocytes from allergic subjects were treated for 30 min with sodium cromoglycate (SCG) or with N-acetyl-aspartyl glutamic acid (NAAGA) and challenged for leukotriene B4 (LTB4) production with calcium ionophore A 23187. NAAGA significantly inhibits LTB4 release at concentrations of 10(-2) M (-86%), 5 x 10(-3) M (-49%) and 10(-3) M (-34%), while SCG was not able to block LTB4 production within the range of 10(-2)-10(-4) M. In spite of the fact that SCG and NAAGA are chemically unrelated and that both show antiallergic properties, only NAAGA is able in this model to block production of LTB4, a chemical mediator strongly involved in inflammatory and hypersensitivity reactions.
A synthetic dipeptide, magnesium salt of N-acetyl-L-aspartyl-glutamic acid (NAAGA) identical to a natural dipeptide found as traces in cerebral tissues of mammalian brains, was shown to inhibit, in vitro, the hemolytic activity of both classical and alternate pathways complement; the required concentration of NAAGA was 2 to 10 mM. Cross immuno electrophoretic analysis demonstrated an inhibition of C3 cleavage by both classical and alternate pathway C3 convertases with 24 mM NAAGA. As expected, if C3 convertases were really the target of inhibition, the release of highly inflammatory C3a, C5a fragments scored by R.I.A. was impaired when complement was incubated with activators of classical and alternate pathways. Such a low molecular weight dipeptide, quite atoxic and inhibiting the complement dependent cytotoxicity and release of phlogistic by-products could be interesting for pharmacological manipulation of complement activation in inflammatory processes.
Light microscopy, flat preparation of the corneal endothelium, and scanning electron microscopy were used to evaluate the cytotoxic effect of three ophthalmic preservatives -benzalkonium chloride, chlorobutanol, and thimerosal. Only benzalkonium chloride caused significant damage to all the cellular components of the rabbit corneas including the endothelium. The dissimilarities in absorption may explain the cytotoxic effect of benzalkonium chloride and the lack of significant cytotoxicity of chlorobutanol and thimerosal. Whether or not one preservative is superior or preferable to another cannot be completely determined on the basis of this study. However, some of the limitations of chlorobutanol and thimerosal should be reconsidered on the basis of the cytotoxic effect of benzalkonium chloride.
The toxicity and side effects of drugs and their adjuncts are reviewed according to effect on corneal epithelium, stroma, and endothelium, when topically applied to healthy or wounded surfaces, or introduced into the anterior chamber of the eye. Corneal research techniques are reviewed, including scanning and transmission electron microscopy, electrophysiological techniques, and specular microscope observation. Clinical interpretation of these results is discussed. Reviews of specific toxicologic techniques and of medications are cited. Present research makes it increasingly apparent that not only medications but also their preservatives cannot be considered innocuous. Preservatives may be effective yet less damaging to the ocular integument when used at lower concentrations than those presently available commercially. Complete avoidance of preservatives by the use of special dispensing systems is found increasingly desirable.
For the past 12 years, we’ve studied keratoconjunctivitis sicca (KCS) in dogs to develop a therapeutic intervention to benefit both veterinary and human KCS patients. The spectrum of ocular surface pathology in canine KCS can support a battery of assessment criteria for therapeutic evaluation. Although there are multiple causes of canine KCS, the vast majority appear to be immune mediated.
Leukocytes from ten allergic patients (five allergic to dust-mites and five allergic to pollen) were treated with N-acetyl aspartyl glutamic acid (NAAGA) 4.9%, disodium cromoglycate (DSCG) 2%, lodoxamide (LODO) 1%, and levocabastine (LEVO) 0.5% (concentrations representing the pharmaceutical eyedrop preparations) for 20 minutes. Degranulation was then induced with Complement (rHu5Ca). Histamine was measured in the supernatant with ELISA. LODO and LEVO were inactive in blocking histamine released from human cells, and paradoxical unexpected effects were found with these two agents. They both induced significant histamine release in almost 100% of the samples. DSCG was able to block histamine release in seven patients out of nine (ranging between 5 and 34%). NAAGA was the most active agent on human cells and was able to block basophil degranulation in nine patients out of nine (inhibition ranging between 4 and 66% of total histamine pool).
To investigate feasibility and potential uses of flow cytometry in impression cytology as a new procedure to assess and quantify conjunctival inflammation.
Specimens for cytology were collected by impression from 30 patients with various chronic ocular surface disorders and from 10 normal subjects. Two specimens were obtained in each eye: One was transferred onto a glass slide and processed by immunofluorescence with antibodies to human leukocyte antigen (HLA)-DR antigens; cells from the other were suspended in phosphate-buffered saline for flow cytometry. Monoclonal antibodies to HLA-DR antigens and CD23, the low affinity receptor to immunoglobulin E, were used.
Abnormal expression of HLA-DR and CD23 by conjunctival cells was found in 13 of 18 dry eyes and in 20 of 22 eyes with chronic conjunctivitis, whereas specimens remained almost negative (less than 10% of cells were positive) in normal eyes. Percentages of positive cells ranged between 20% and 98% of all conjunctival cells. Correlation between the two methods, immunocytology and flow cytometry, was highly significant (coefficient of correlation 0.77, P = 0.0001). Moreover, HLA-DR positivity, at its strongest intensity, was observed in a minority of cells (1% to 12%), most of which were resident class II-expressing dendritic cells. Percentages of those cells expressing high levels of HLA-DR were 3 +/- 1.2% in normal eyes, 5.8 +/- 4% in dry eyes (P = 0.05), and 5.9 +/- 3.5% in eyes with chronic conjunctivitis (P = 0.02).
Results of this preliminary study confirm that conjunctival epithelial cells may abnormally express inflammatory markers in chronic ocular surface disorders. Development of flow cytometry in analysis of cytologic specimens provides a new, sensitive, and objective tool for exploring conjunctival pathology.
The authors, in a case-control study, analyzed the topical application of nonsteroidal anti-inflammatory drug (flurbiprofene drops) in patients affected by keratoconjunctivitis sicca in Sjögren's syndrome. The variation of break-up-time values, and xerophthalmia grade were analyzed. A mild increase of mean values of break-up-time (two seconds in the treated group), and a mild decrease of xerophthalmia grade were found.
To study the demographics and estimate the prevalence of dry eye among elderly Americans.
A population-based prevalence study was performed in 2,520 residents of Salisbury, Maryland, aged 65 years and older as of September 1993. The population was derived from the Health Care Financing Administration Medicare database. After completing a standardized questionnaire pertaining to dry eye symptoms, 2,420 subjects underwent Schirmer and rose bengal tests and anatomic assessment of the meibomian glands.
In this population, 14.6% (363/2,482) were symptomatic, defined as reporting one or more dry eye symptoms often or all the time; 2.2% (53/2,448) were symptomatic and had a low Schirmer test result (< or = 5 mm), and 2% (48/2,432) were symptomatic and had a high rose bengal test score (> or = 5). Furthermore, 3.5% (84/2,425) were symptomatic and had either a low Schirmer score or a high rose bengal score, and 0.7% (17/2,420) were symptomatic and had both a low Schirmer score and a high rose bengal score. No association of symptoms or signs was seen with age, sex, or race. Although anatomic features of meibomianitis were associated with the presence of symptoms (P = .01), 76% (67/88) of the individuals with these anatomic features were asymptomatic; 10.5% (260/2,480) reported that they currently use artificial tears or lubricants.
Symptoms and signs of dry eye are common among the elderly but were not associated with age, race, or sex in this population-based sample of elderly Americans. Extrapolating to the United States population aged 65 to 84 years, the study yields an estimate of 4.3 million who experience symptoms of ocular irritation often or all the time.
Cytologic evaluation of conjunctival epithelium using Cytobrush-S: value of slide preparation by ThinPrep technique
Recent clinical trials have indicated that an automated smear apparatus (ThinPrep process) of sample preparation has great diagnostic sensitivity. In this study, conjunctival brush cytology prepared using the ThinPrep method was applied in ocular surface disorders especially for dry eye status. To assess its diagnostic value in cellular samples, 17 patients with keratoconjunctivitis sicca (KCS) and 10 normal volunteer patients were examined using this technique. Conjunctival cells from normal controls revealed fine chromatin and polyhedral cytoplasm without having keratinized cytoplasm. On the other hand, the cellular samples from KCS revealed increased keratinized cells with pyknotic nuclei. They also contained extremely elongated cells. In KCS patients, the mean number of keratinized cells was significantly higher (34.1 cells/300 cells) than that of the normal control group (0.2 cells/300 cells). In patients with KCS, inflammatory cell counts were also higher than those of normal controls. Conjunctival cytology by means of the ThinPrep method obviously deserves additional trials as an adjunct in the cytology of dry eye states, especially in quantitative ocular evaluation for various ocular lesions.
The aim of this work was to evaluate ultrastructural alterations of the conjunctiva during the clinical course of keratoconjunctivitis sicca (KCS), and to detect its earliest and most characteristic morphological changes.
The conjunctiva was studied in biopsies from 75 patients and 10 controls. Patients were classified according to the results of the Schirmer I test, break-up time, rose Bengal staining, osmolarity and impression cytology.
The conjunctiva in these KCS patients showed progressive hyperplasia, hypertrophy and cellular flattening, with diminution of goblet cell density and microvilli. In the severe cases, the epithelial cells lost their organelles, and fibrous material increased. From the early phases of KCS, clear nuclear alterations (indentation, binucleation) were found, but pyknotic nuclei or anucleated cells were only observed in the most severe cases. From the earliest stages to the most severe cases of KCS, decreases in cell membrane interdigitations were observed parallel to increases in the number and size of desmosomes. There were also increases in the number of inflammatory cells. Alterations in blood vessels were only observed in the most severe cases.
Morphological studies alone were able even in the earliest phases of KCS, to detect the squamous metaplasia that progresses from the surface of the epithelium to the connective tissue. This degenerative or adaptative cellular process was characterized mainly by marked proliferation of the cytoskeleton and a general loss of organelles, mitochondria being the least affected.
The exact etiology of dry eye is unknown but is believed to be multifactorial. Apoptosis has been implicated in the pathogenesis of autoimmune diseases such as Sjögren's syndrome (SS). This study attempted to gain a better understanding of the role of apoptosis and its regulation in the patho-physiology of dry eye. The therapeutic effect of immunomodulatory agents such as cyclosporin A (CsA) in the treatment of dry eye, particularly its impact on the level of apoptosis in the target tissues, is also investigated.
A colony of dogs with spontaneous chronic idiopathic keratoconjunctivitis sicca (KCS) was maintained. Nictitans lacrimal gland (NLG), an accessory lacrimal gland, and conjunctival biopsies of the KCS and normal dogs were obtained before and after 12 weeks of treatment with 0.2% topical CsA ophthalmic emulsion b.i.d. (Allergan, Inc., Irvine, CA, U.S.A.). Tissues were prepared for the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) apoptosis assay and immunohistochemical analysis for various apoptosis mediators.
The TUNEL assay demonstrated that (i) the normal NLG and conjunctival epithelial cells exhibited a limited level of apoptosis; (ii) in KCS dogs, lacrimal acinar and conjunctival epithelial cells underwent an increased apoptosis, whereas the lymphocytes had a significantly lower level of apoptosis compared to those of the normal dogs; (iii) after topical CsA, apoptosis was induced in the lymphocytes and suppressed in the acinar and conjunctival epithelial cells in KCS dogs. Immunohistochemistry revealed that p53, fas, and fasL, but not bcl-2 were highly expressed in the target tissues of KCS dogs. The immunoreactivity of p53 was significantly decreased, whereas the bcl-2 level was increased after CsA administration.
The induction of epithelial cell apoptosis and the suppression of lymphocytic apoptosis in the NLG and ocular-surface tissues, such as conjunctiva of KCS dogs, indicates the important role of this phenomenon in the etiology of dry eye. Topical CsA appears to facilitate lymphocytic apoptosis and suppress epithelial cell apoptosis in the KCS dog. The differential expression of various apoptotic mediators after topical treatment implicates CsA in facilitating the reestablishment of the normal apoptotic balance, suggesting additional mechanisms by which CsA is therapeutic for dry-eye syndrome.
Most dry-eye symptoms result from an abnormal, nonlubricative ocular surface that increases shear forces under the eyelids and diminishes the ability of the ocular surface to respond to environmental challenges. This ocular-surface dysfunction may result from immunocompromise due to systemic autoimmune disease or may occur locally from a decrease in systemic androgen support to the lacrimal gland as seen in aging, most frequently in the menopausal female.
Components of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and interconnecting innervation act as a functional unit. When one portion is compromised, normal lacrimal support of the ocular surface is impaired. Resulting immune-based inflammation can lead to lacrimal gland and neural dysfunction. This progression yields the OS symptoms associated with dry eye.
Restoration of lacrimal function involves resolution of lymphocytic activation and inflammation. This has been demonstrated in the MRL/lpr mouse using systemic androgens or cyclosporine and in the dry-eye dog using topical cyclosporine. The efficacy of cyclosporine may be due to its immunomodulatory and antiinflammatory (phosphatase inhibitory capability) functions on the ocular surface, resulting in a normalization of nerve traffic.
Although the etiologies of dry eye are varied, common to all ocular-surface disease is an underlying cytokine/receptor-mediated inflammatory process. By treating this process, it may be possible to normalize the ocular surface/lacrimal neural reflex and facilitate ocular surface healing.
Fas antigen (CD95) is a membrane receptor that plays a major role in induction of apoptosis. In surface conjunctival epithelial cells the expressions of Fas, Fas ligand, the apoptotic marker APO2.7 and of HLA DR class II antigen, a membrane marker known to be expressed in inflammatory conditions were investigated. Impression cytology specimens were collected in 65 patients: 20 normal ones, 15 contact lens wearers, 20 receiving chronic topical antiglaucoma treatment and 10 with nonspecific chronic conjunctivitis. Cells were processed for flow cytometry, using monoclonal antibodies to Fas, Fas ligand, APO2.7, HLA DR antigens and a negative isotypic control. Percentages of positive cells were recorded and levels of fluorescence quantified using fluorescent beads at standardized fluorescence intensities. In addition, a human conjunctival cell line was incubated with anti-Fas stimulating antibodies in order to test Fas-induced apoptosis in vitro. Fas was found in all specimens in most of the conjunctival cells, but quantitation of levels of fluorescence showed a significantly higher expression in pathologic eyes than in normal ones. Fas ligand and APO2.7 were variably expressed by conjunctival cells, but in a significantly higher percentage of cells in pathological eyes than in normal ones. In these eyes a strong expression of HLA DR was also observed, whereas normal eyes showed lowest levels. Highly significant correlations were found between Fas, Fas ligand, APO2.7 and HLA DR levels. Anti-Fas antibodies in vitro induced strong apoptosis in epithelial cells as confirmed by APO2.7 expression and DAPI staining. This study confirms that conjunctival epithelial cells normally express Fas antigen, and more inconstantly its ligand, as do corneal ones or keratinocytes. Fluorescence quantitation by flow cytometry showed much higher expression in inflammatory eyes than in normal ones, and demonstrated a strong correlation between apoptotic and inflammatory pathways in the ocular surface.
To review the efficacy and side effects of topical nonpreserved corticosteroid therapy for treatment of severe keratoconjunctivitis associated with Sjögren syndrome.
Retrospective, noncomparative case series.
Twenty-one patients with Sjögren syndrome-associated keratoconjunctivitis sicca and annoying ocular irritation.
Treatment with topical nonpreserved methylprednisolone sodium succinate.
Symptom severity, frequency of instillation of artificial tears, corneal fluorescein staining scores, resolution of filamentary keratitis, steroid-related side effects.
Before starting methylprednisolone therapy, all patients were experiencing moderate-to-severe eye irritation despite prior punctal occlusion in most cases and frequent use of nonpreserved artificial tears by all. After 2 weeks of topical application, three to four times per day, moderate (43%) or complete (57%) relief of irritation symptoms was experienced by all patients and no complications were observed. An average decrease in corneal fluorescein scores of 2.6 +/- 0.5 points (on a 12-point scale) was observed, and filamentary keratitis resolved in all ten eyes with this condition. Therapy was stopped after 2 weeks in eight patients, and six of these patients reported that their symptoms remained at a tolerable level for weeks to months. Lower dose steroid therapy was continued in the remaining patients, whose symptoms worsened after attempted weaning. Complications of corticosteroid therapy in patients receiving prolonged therapy included increased intraocular pressure in one patient at 3 months, worsening of pre-existing posterior subcapsular cataracts in one patient at 6 months, and formation of posterior subcapsular cataracts in another patient at 6 months.
These findings indicate that topical nonpreserved methylprednisolone is an effective treatment option for patients suffering from severe keratoconjunctivitis sicca who continue to experience bothersome eye irritation despite maximum aqueous enhancement therapies. They also suggest that inflammation is a key pathogenic factor in this condition. Careful monitoring is essential in dry eye patients treated with corticosteroids for more than 2 weeks because steroid-related complications (increased intraocular pressure and cataract formation) were observed after several months of therapy in this series. Because of the chronic nature of this disease and the likelihood of patients developing steroid-related complications with their long-term use, topical nonpreserved methylprednisolone therapy appears to be most appropriate for short-term "pulse" treatment of exacerbations of keratoconjunctivitis sicca.
Sjögren's syndrome is a chronic inflammatory disease of the lacrimal and salivary gland with subsequent keratoconjunctivitis sicca and xerostomia. Histopathologic findings include damaged acini of the lacrimal and salivary glands with mononuclear cell infiltrates of lymphocytic and plasma cell type. The cause of the damage is cell-mediated cytotoxicity. The pathogenesis of Sjögren's syndrome is still unknown. The role of viral infections failed to show a causative effect. On the other hand, tissue destruction was shown to be mediated by activated T cells of CD4+ type that home into the lacrimal gland. This process is signal-mediated through the T-cell receptor that interacts with class II antigen on the epithelial cells of exocrine glands. This, in turn, induces the expression of Fas/APO-1 and Fas-mediated apoptosis of acinar cells. Granzyme A and perforin are cytolytic enzymes secreted by activated T lymphocytes that seem to participate in acinar cell destruction.
Keratoconjunctivitis sicca is a common ocular surface disease that develops in patients with aqueous tear deficiency. Recent advances have been made in diagnosis, pathogenesis, and therapy of this condition. Advances in diagnosis include improved understanding of the specificity of the tests used for diagnosis, elucidation of the mechanism of the ocular surface rose bengal and fluorescein staining that occurs in this condition, and the expanded use of impression cytology. Advances in pathogenesis include the concept that keratoconjunctivitis sicca is a condition of abnormal growth and differentiation and immune activation of the ocular surface epithelium. These findings indicate that keratoconjunctivitis sicca may represent a chronic wound-healing response to a poorly lubricated and inflamed ocular surface. Advances in therapy include improved nonpreserved artificial tears and therapies targeted at decreasing ocular surface inflammation.
To compare epidermal growth factor (EGF) concentration in tear fluid and levels of inflammatory cytokines in the conjunctival epithelium of patients with Sjögren's syndrome keratoconjunctivitis sicca with those of normal controls.
Schirmer 1 tear testing, corneal fluorescein staining and conjunctival impression cytology for quantitation of goblet cell density were performed in ten patients with Sjögren's syndrome-associated keratoconjunctivitis sicca and ten asymptomatic normal controls. ELISA was used to detect the concentration of EGF in tear fluid and interleukin 6 in lysates of conjunctival cytology specimens obtained from all subjects. The levels of RNA transcripts encoding inflammatory cytokines [interleukin 1alpha_(IL-1alpha), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha_(TNF-alpha), and transforming growth factor beta1 (TGF-beta1)] as well as a housekeeping gene (G3PDH) were evaluated in conjunctival cytology specimens taken from all subjects by semiquantitative competitive reverse transcriptase polymerase chain reaction (RT-PCR).
Decreased tear fluid EGF concentration was noted in Sjögren's syndrome patients (mean 0.68 +/- 0.59 ng/ml) compared to controls (mean 1.66 +/- 0.45 ng/ml, P = 0.004). Significantly increased levels of IL-1alpha, IL-6, IL-8, TNF-alpha and TGF-beta1 RNA transcripts were found in the conjunctival epithelium of Sjögren's syndrome patients compared to controls (P < 0.05), while the level of G3PDH was similar in both groups. The concentration of IL-6 protein was significantly higher in Sjögren's syndrome conjunctiva samples (P = 0.012). Tear EGF concentration correlated with Schirmer 1 scores (rho 0.767, P < 0.001), corneal fluorescein staining scores (rho -0.562, P = 0.01), conjunctival goblet cell density (rho 0.661, P = 0.001) and the levels of IL-1alpha_and IL-8 RNA in the conjunctival epithelium (rho -0.677 and -0.747, respectively, P = 0.001). Both IL-1alpha_and IL-8 RNA in the conjunctival epithelium increased as Schirmer 1 scores decreased (P </= 0.001). IL-8 RNA level correlated with corneal fluorescein staining (rho 0.690, P = 0.001) and conjunctival goblet cell density (rho -0.767, P < 0.001). A significant decrease in IL-8 RNA level, corresponding to improvement in irritation symptoms and ocular surface disease, was observed in six eyes after two weeks of topical corticosteroid therapy.
The balance of cytokines in the tear fluid and conjunctival epithelium is altered in Sjögren's syndrome. The severity of keratoconjunctivitis sicca in this condition increases as tear fluid EGF concentration decreases and levels of inflammatory cytokines in the conjunctival epithelium increase. These findings provide new insight into the pathogenesis of keratoconjunctivitis and provide potential targets for therapy.
Conjunctivitis, episcleritis and scleritis are inflammation of external part of the eye ball. All these disease induce "red eyes". Some of these inflammation are potentially severe. Visual function can be involved. Conjunctivitis, episcleritis and scleritis can also be the first location of a severe systemic disease.
To investigate in impression cytology (IC) specimens the expression of inflammatory and apoptosis-related markers by conjunctival epithelial cells from patients with dry eye as a rationale for treatment with topical cyclosporine.
Immunologic anomalies were identified at baseline, before treatment with the masked medication, in a homogeneous series of patients with dry eye syndrome, who were enrolled in a large European multicenter clinical trial (Cyclosporin A Dry Eye Study; Allergan, Irvine, CA). IC specimens were collected in 243 patients with moderate to severe keratoconjunctivitis sicca (KCS), with or without Sjogren's syndrome (SS). Fifty normal subjects were separately examined to provide normal control values. Specimens were analyzed in a masked manner by flow cytometry, using antibodies directed to markers of the immune system and/or apoptotic pathway: HLA DR, CD40, CD40 ligand, Fas, and APO2.7. Levels of expression were quantified, and results were compared with those obtained in the 50 normal patients.
One hundred sixty-nine specimens were successfully interpreted at baseline, including 41% from patients with SS. A highly significant increase of HLA DR expression by conjunctival cells was found in KCS-affected eyes compared with normal eyes, which did not express this marker or did so very weakly. HLA DR expression in eyes with SS was significantly higher than in KCS-affected eyes without SS. Fas and APO2.7 were found at low levels in all normal and KCS-affected eyes. CD40 and CD40 ligand expressions were significantly increased in eyes with KCS compared with normal eyes. HLA DR, CD40 and Fas were found at significantly higher levels in the SS group than in the non-SS group. CONCLUSIONS. Conjunctival cells from patients with dry eye with moderate to severe KCS, with or without SS, overexpress inflammatory and apoptosis-related markers. Whether inflammation is a primary phenomenon in KCS or is the consequence of repetitive abrasion of the ocular surface after tear film deficiency remains to be determined. These data, nevertheless, support the use of immunomodulatory and/or anti-inflammatory drugs in the treatment of patients with KCS.
Homeostasis of the tear film involves delicate hormonal and neuronal regulatory mechanisms. The eye appears to be a target organ for sex hormones, particularly the androgens, as they modulate the immune system and trophic functions of the lacrimal glands and the functioning of the meibomian glands. The cornea, lacrimal glands, mucous cells, and meibomian glands are all richly innervated, indicating the importance of nervous regulation in their function. Parasympathetic, sympathetic, and sensory innervation play complex stimulatory or inhibitory roles, and neuronal pathways interact via complex surface results cascades. Abnormalities at any point in these pathways can cause overall dysregulation of lacrimal function. Whatever the initial causes of dry eye, chronic dryness of the ocular surface results in inflammatory reactions and gradual destruction of the lacrimal glands and conjunctival epithelium. Once dry eye disease has developed, inflammation is the key mechanism of ocular surface injury, as both the cause and consequence of cell damage. In practice, dry eye can be associated with Sjögren's syndrome, allergies, infection, blepharitis, and preservative-containing eye drops.
To examine the expression of HLA-DR, a marker of inflammation, in the early stages of dry eye disease and to locate the appearance of this marker on specific areas of the bulbar conjunctiva.
Dry eye patients were identified and their condition classified as mild (n = 16) or moderate (n = 16) based on Schirmer testing, vital staining, tear break-up time, and symptom questionnaire scores. Brush cytology was used to collect epithelial cells from the nasal, temporal, and superior conjunctivae of patients and age-matched controls. HLA-DR positive cells were detected by immunohistochemical staining and quantified.
Patients with moderate dry eye had the highest rate of conjunctival HLA-DR-positive cells, with significantly higher rates than controls regardless of which region of the conjunctiva was sampled (P < 0.01). The mild dry eye group had similar rates of HLA-DR-positive cells in the superior conjunctival region compared with controls. However, in the nasal and temporal regions, they displayed a significantly higher rate of HLA-DR-positive cells than controls (P < 0.01) and the nasal region showed a significant difference (P < 0.01) when compared with the temporal one. Some of these mild dry eyes had no vital staining.
The HLA-DR expression pattern in mild and moderate dry eyes appears to reflect disease progression. Overexpression of HLA-DR in mild dry eyes showing no vital staining suggests that inflammation may be a primary cause of ocular surface damage. These data support the use of immunomodulatory drugs in the treatment of dry eye disease.
As tear secretion and tear clearance decrease in the dry eye, an inflammatory response is initiated on the ocular surface that appears to involve both soluble and cellular mediators. Although the traditional approach to treating dry eye is to hydrate and lubricate the ocular surface with artificial tears, symptoms and/or sight-threatening corneal disease may persist in some patients on such aqueous enhancement therapies. In these patients, treatment with anti-inflammatory agents, such as cyclosporin A, corticosteroids, tetracyclines, or autologous serum, may be considered. Results of studies investigating the use of these agents are discussed. During treatment, patients should be conscientiously monitored for adverse effects.
Polyunsaturated fatty acids (PUFAs) are involved in inflammatory pathways via prostaglandins. Conjunctival inflammation is a hallmark of all dry eye syndromes. We investigated the role of dietary n-6 and n-3 fatty acids in patients suffering from ocular dryness.
Seventy-one patients presenting with mild to moderate dry eye syndromes were randomly assigned to Nutrilarm or placebo capsules, twice a day for 6 months. The Schirmer test, BUT, fluorescein staining, and lissamin green stainings were performed at inclusion and after 1, 3, and 6 months. Furthermore, a questionnaire related to the dry eye symptoms and global discomfort was provided at every visit.
The Schirmer test, BUT, fluorescein staining, and lissamin green stainings were improved with treatment when compared to placebo but the difference was not statistically significant. The efficacy evaluated by the patients and the investigator were nearly significant (p=0.052 and p=0.054, respectively). For some signs, such as reflex tearing and conjunctival hyperemia, the improvement reached the threshold of significance (p=0.047 and p=0.045, respectively). The same results were found with skin quality and emotional condition, which were improved (61% with treatment versus 36% with placebo).
This double-masked pilot study shows that PUFAs seem to be an interesting tool to alleviate the symptoms related to dry eye syndrome. These results should be confirmed using a larger study population.
Dry eye is a condition of altered tear composition that results from a diseased or dysfunctional lacrimal functional unit. Evidence suggests that inflammation causes structural alterations and/or functional paralysis of the tear-secreting glands. Changes in tear composition resulting from lacrimal dysfunction, increased evaporation and/or poor clearance have pro-inflammatory effects on the ocular surface. This inflammation is responsible in part for the irritation symptoms, ocular surface epithelial disease, and altered corneal epithelial barrier function in dry eye. Anti-inflammatory therapies for dry eye target one or more of the inflammatory mediators/pathways that have been identified in dry eye.
Dry eye is a complex clinicopathological entity involving tear film, lacrimal glands, eyelids, and a wide spectrum of ocular surface cells, including epithelial, inflammatory, immune, and goblet cells. From the tightly regulated lacrimal film functions and structure, a large variety of investigations have been developed, including tear meniscus measurements, fluorophotometry, meibometry, interference pattern analysis, evaporation rate, tear osmolarity, and thermography. Dry eye conditions also interfere with the ocular surface, causing corneal irregularities that may be explored using the techniques of videokeratography and in vivo confocal microscopy, or optical impairment, as confirmed by aberrometry. At the level of ocular surface cells, impression cytology remains a standard for assessing cell alterations. It has greatly benefited from new confocal microscopy, molecular biology, and flow cytometry techniques. Biological assessment of tear proteins or other mediators is also useful. Major limits should be acknowledged, however, such as technical issues in tear film collection, especially in dry eyes, and the lack of standardization of most measurements. Tear osmolarity, electrophoresis, and dosage of normal tear proteins, such as lysozyme or lactoferrin, remain the most useful tests. Finally, some extraocular explorations such as accessory gland biopsy or serum antinuclear antibody dosage may be useful for assessing the diagnosis of Sjögren's syndrome.
The mechanistic view of dry eye disease aims at completing the classic etiological approach that classifies the disease as parallel ocular surface disorders leading to lacrimal film impairment and dry eye. This approach proposes two levels of ocular surface impairment (with standard etiologies, previously validated in the NEI/Industry workshop), which may not be independent diseases but rather risk factors and/or ways to enter a self-stimulated biological process involving the ocular surface. All external disorders proposed in this model, although unlikely to be fully exhaustive, are classical mechanisms considered to be causes of tear film impairment and ocular surface damage, by tear instability and evaporation, tear hyposecretion, or both. These mechanisms, sometimes alone--when severe or becoming chronic or repeatedly present on the ocular surface and when two or more are present--may cause the patient to enter the self-stimulated loop. Tear film instability/imbalance can be considered as the key point of dry eye disease. It will cause local or diffuse hyperosmolarity of the tear film and therefore of superficial epithelial cells of the cornea and/or conjunctiva, stimulating epithelial cells and resident inflammatory cells. Cell damage in the cornea and conjunctiva, by means of apoptosis and direct mechanical and/or osmotic stress, will stimulate the reflex neurosensory arc, in turn stimulating lacrimal gland and neurogenic inflammation, with inflammatory cytokine release, MMP activation, and inflammatory involvement of the conjunctival epithelium. Goblet cell loss is thus directly related to chronic inflammation and surface cell apoptosis subsequent to cell hyperosmolarity and chronic damage, resulting in further tear film instability/imbalance. On the other hand, bacterial changes and an imbalance resulting from specific diseases or from tear film abnormalities may trigger release of endotoxins, lipopolysaccharides, and/or lipase activation, causing eyelid inflammation, meibomian gland dysfunction, and lipidic changes, directly influencing tear film stability and favoring tear evaporation. The lipidic hypothesis therefore participates in the vicious circle as a parallel, independent, or complementary loop. This mechanistic approach proposes a synthetic combination of mechanisms previously validated independently, with two levels of ocular surface impairment, a first level including many possible acute or chronic causes that favor or trigger the imbalance and can be reversible if correctly and specifically managed when possible, and the further involvement of a series of biological cascades centered by tear film imbalance and inflammatory stimulation, finally acting as an independent vicious circle, however the patient entered the loop. Clinically, this approach may explain examples of dry eye syndrome occurring after ocular surgery, contact lens wear, chronic allergy or systemic or topical drugs, and the long-lasting effect even though all causal factors have been removed or have disappeared. This model should be considered as a basis for further reflection on biological mechanisms that could be even more complex but individually constitute potential leads for targeting therapeutic strategies to allow patients to leave the loop even though the triggering factors are still present or can only be attenuated, such as in Sjögren syndrome or ocular rosacea. It also should be considered a complement to more classic etiological and severity classifications aimed at understanding and classifying the large number of diseases that may cause dry eye disease and better assessing the major impairment it causes on the patient's quality of life.
To investigate the expression of CCR5 and CCR4, two chemokine receptors, as markers of the T helper (Th) 1 and Th2 pathways, respectively, and class II antigen HLA-DR as a hallmark of inflammation on conjunctival cells obtained from patients receiving long-term glaucoma treatment.
Case-control study.
A total of 18 normal subjects and 70 glaucoma patients treated with topical antiglaucoma drugs for more than 1 year: 14 receiving a beta-blocker as monotherapy, 38 treated with a prostaglandin analog alone (19 with latanoprost, 6 with travoprost, 13 with bimatoprost), and 18 receiving multiple treatments.
Impression cytologic specimens (ICSs) were obtained from 1 eye of the patients and processed for flow cytometry. Conjunctival cells were extracted and incubated with monoclonal antibodies against CCR4, CCR5, HLA-DR, or their specific controls to measure, in a masked manner, the percentages of conjunctival cells positive for the 3 markers.
HLA-DR and chemokine receptors (CCR4 and CCR5) in ICSs.
Compared with all other groups, HLA-DR expression was raised significantly in the multitreatment group, whereas all monotherapies showed slight and nonsignificant increases. Both CCR4 and CCR5 were increased significantly in all 5 glaucoma groups compared with normal subjects, with no between-group differences.
This study demonstrates the overexpression of 2 chemokine receptors in the conjunctival epithelium of glaucoma patients treated over the long term. These results show the simultaneous overexpression of CCR4 and CCR5, suggesting that the chronic use of topical treatments may stimulate both the Th1 and Th2 systems simultaneously. These results also suggest that inflammatory mechanisms combining allergy with toxicity are at work and illustrate the complexity of inflammatory reactions occurring in the ocular surface of glaucoma patients.
To investigate whether conjunctival inflammation represents a primary event in the pathogenesis of keratoconjunctivitis sicca or whether it is a secondary inflammatory reaction caused by enhanced mechanical irritation as a result of surface dryness and whether anti-inflammatory drops (corticosteroids and nonsteroidal anti-inflammatory) have therapeutic effects and are similar.
Single-masked, randomized, prospective clinical trial.
Thirty-two keratoconjuctivitis patients with or without Sjögren syndrome were included in the study. The patients were randomized to three groups. Group 1 patients received a topical artificial tear substitute (ATS); group 2 received ATS plus nonsteroidal anti-inflammatory drops (NSAID); and group 3 received ATS plus topical corticosteroidal drops. The eye symptom severity scores, Schirmer test values, rose bengal and fluorescein staining scores were evaluated before treatment and 15 and 30 days after start of treatment. Impression cytology specimens were stained using immunohistochemical methods to detect the percentages of human leukocyte antigen II (HLA-DR) positive, Apo 2.7 positive, and periodic acid-Schiff positive cells. Statistical analyses were performed within and between groups. Group 3 patients had significantly lower symptom severity scores, fluorescein and rose bengal staining, and HLA-DR positive cells on days 15 and 30 compared with patients in other groups. They also had a significantly higher number of periodic acid-Schiff positive (goblet) cells in their impression cytology specimens on days 15 and 30 compared with the other patients. On day 30, group 3 patients had significant differences compared with their baseline measurements in terms of above-mentioned parameters. However, we did not detect a significant effect of any treatment schedule on the Shirmer test value and the numbers of Apo 2.7 cells in impression cytology specimens.
Topical corticosteroids had a clearly beneficial effect both on the subjective and objective clinical parameters of moderate-to-severe dry eye patients. These effects were associated with the reduction of inflammation markers of conjunctival epithelial cells.
To present evidence establishing the relationship between inflammation and dry eye and supporting the use of antiinflammatory therapy for dry eye.
Analysis of literature.
Research studies that evaluated inflammation in dry eye pathogenesis and clinical trials of antiinflammatory therapies for dry eye were reviewed.
There is increasing evidence that decreased tear secretion, decreased tear turnover, and desiccation promote inflammation on the ocular surface. An increase in soluble mediators (cytokines and proteases) in the tear fluid, adhesion molecule expression by the conjunctival epithelium, and T-cell infiltration of the conjunctiva have been observed in dry eye patients. This inflammation appears to have a role in the pathogenesis of the ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS), that develops in dry eye. Clinical improvement of KCS has been observed after therapy with antiinflammatory agents including corticosteroids, cyclosporin and doxycycline. Cyclosporin A emulsion was approved by the Food and Drug Administration as therapy for dry eye. Randomized placebo-controlled FDA clinical trials showed that cyclosporine A was superior to vehicle in stimulating aqueous tear production, decreasing corneal punctuate fluorescein staining, reducing symptoms of blurred vision, and decreasing artificial tear use in patients with KCS. No ocular or systemic toxicity was observed from this medication.
Ocular surface and lacrimal gland inflammation has been identified in dry eye that plays a role in the pathogenesis of KCS. Antiinflammatory therapy has efficacy for treating KCS. Cyclosporin A is the first FDA approved therapy for this indication. It improved signs and symptoms of KCS, and it is safe for long-term use.
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