Ocular Allergic Diseases Research Articles

Use of Antihistamines in Ocular Therapy

Approximately 20% of the general population have allergic symptoms of various forms. One third of these people have also ocular symptoms. Some forms of ocular allergy can cause severe symptoms and result in significant ocular morbidity. Allergic ocular disease consists of allergic conjunctivitis (including seasonal hay fever and perennial allergic rhinoconjunctivitis and acute anaphylaxis), giant papillary conjunctivitis (including vernalis, atopic keratoconjunctivitis and contact lens induced conjunctivitis), contact dermatokeratoconjunctivitis and microbioallergic disease. Histamine is the most prominent mediator in allergic ocular disease and causes increased vasopermeability, vasodilation, and bronchoconstriction, mediated through histamine receptors. Both H1 and H2 receptors have been identified on the ocular surface. Oral H1-receptor blockers can be given to relieve symptoms in the allergic ocular disease, but side effects such as sedation and systemic anticholinergic reactions are possible. Newer oral antihistamines such as astemizole and terfenadine supposedly have lesser side effects. Topical H1-receptor blocking antihistamine drugs are now available. Levocabastine is an agent with proven efficacy. There are no topical H2-receptor antagonists presently available for ocular use, but such agents have theoretic potential, especially in combination with an H1-receptor blocker Keywords: ocular allergic disease, hay fever, allergic conjunctivitis, seasonal conjunctivitis, vernal conjunctivitis, atopic conjunctivitis, antihistamine, h receptor antagonist

Emerging drugs for ocular allergy

Ocular allergy is a common condition that usually affects the conjunctiva of the eye and is, therefore, often referred to as allergic conjunctivitis. The severity of the disease can range from mild itching and redness, as seen in seasonal allergic conjunctivitis, to the more severe, sight-threatening forms such as vernal and atopic keratoconjunctivitis. The central mechanism in the pathogenesis of these diseases is IgE-mediated mast cell degranulation and activation of T lymphocytes, eosinophils and conjunctival structural cells. The pharmacotherapy of allergic conjunctivitis consists of several classes of drugs: antihistamines, mast cell stabilisers, dual-acting agents and corticosteroids. None of the available drugs completely abolishes the development of ocular allergy. For this reason, new topical antiallergic/anti-inflammatory agents are currently and continually under clinical trials. This review provides a background to ocular allergic diseases, the medical need for therapy and current and potential new treatments.

Methodologies for the Study of Ocular Surface Disease

The ability to obtain reliable results from clinical trials of therapies for ocular allergic disease and dry eye disease is often limited because of inadequate control of variables, such as environment, patient life style, compliance, and individual fluctuations that occur from one assessment visit to another. The controlled allergen challenge (CAC) model of allergic conjunctivitis allows signs and symptoms of the disease to be elicited in a physiologically accurate and reproducible manner. The rigid criteria for subject selection, the controlled allergic reaction, and the standardized and quantified grading systems allow for a reproducible baseline from which statistically and clinically significant differences between formulations can be assessed. Similarly, the controlled adverse environment (CAE) model for dry eye mimics the environmental stimuli that lead to ocular surface drying. Preselected subjects have a reproducible, homogeneous baseline reaction from which the effects of various treatments can be significantly evaluated and compared. CAC and CAE provide accurate means to study highly variable and individual ocular surface disease.

Ocular allergic disease.

This review will focus on recent advances in our understanding of the pathogenesis of allergic eye diseases. Common findings in acute allergic conjunctivitis (seasonal and perennial) and chronic allergic conjunctivitis (vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis) include evidence of mast cell activation and eosinophil attraction and activation. Cytokine levels found in tears, conjunctival impression cytology and biopsy specimens, and serum have been evaluated as markers of disease, and as targets of therapeutic intervention. Human conjunctival epithelial cells respond to tumor necrosis factor alpha, interleukin-1 beta, and interferon-gamma individually and in combination. Intracellular adhesion molecule-1 expression is upregulated by interleukin-1 beta and tumor necrosis factor alpha. Conjunctival epithelial cells release interleukin-8 in response to interleukin-1 beta and tumor necrosis factor alpha but not interferon-gamma. Supernatants from activated mast cells cause increased adhesion of eosinophils to conjunctival epithelium. Tear levels of tumor necrosis factor alpha were elevated in vernal keratoconjunctivitis patients compared with normal controls. T cell lines from chronic allergic eye disease patients showed inconsistent production of cytokines in atopic and vernal keratoconjunctivitis and low levels in giant papillary conjunctivitis. Vernal keratoconjunctivitis patients have differing levels of eosinophil cationic protein in their serum if they were serum specific immunoglobulin E positive compared to serum specific immunoglobulin E negative patients. Recent findings continue to expand our basic knowledge of mechanisms and differences between seasonal and perennial allergic conjunctivitis and atopic and vernal keratoconjunctivitis. Understanding the complex interactions and cross talk between cells, cytokines and other mediators is relevant for new therapeutic approaches directed at specific disease entities.

Tear cytokines in acute and chronic ocular allergic inflammation.

Elevated levels of inflammatory cytokines have been reported in tears from ocular allergic disease states. The purpose of this review is to assimilate recent research contrasting tear cytokine concentrations in non-allergic subjects versus subjects with acute (seasonal allergic conjunctivitis) and chronic (giant papillary conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis) ocular allergic inflammation to discover whether the cytokine profiles could provide useful insight into disease mechanisms and therapeutic targets. Recent studies have revealed distinct differences in the cytokine/chemokine concentrations in tears between the various manifestations of ocular allergy. The acute (seasonal allergic conjunctivitis) and iatrogenic (giant papillary conjunctivitis) forms of ocular allergic inflammation are characterized by an overall lack of significant cytokine changes in tears compared with chronic disease (vernal keratoconjunctivitis, atopic keratoconjunctivitis). Chronic ocular allergic inflammation produces increased concentrations of T helper 1 and 2, and proinflammatory cytokines as well as chemokines. However, vernal and atopic keratoconjunctivitis portray distinct differences in the patterns of tear cytokines/chemokines expressed. The plethora of increased cytokines and chemokines in vernal and atopic keratoconjunctivitis compared with non-allergic, seasonal allergic conjunctivitis and giant papillary conjunctivitis provides a new perspective into the complex inflammatory processes occurring on the ocular surface in chronic disease. The ability to measure multiple cytokines in tears, combined with knowledge obtained from in-vitro analysis of the individual and combined effects of these cytokines on various conjunctival cells (i.e. mast cells, epithelial cells, fibroblasts) has facilitated further understanding of specific processes contributing to maintenance of inflammation and progression of vision-threatening disease and paved the way toward new therapeutic targets.

The relation of conjunctival and corneal findings in severe ocular allergies.

Corneal lesions such as ulcers and erosions are major complications observed in patients with severe ocular allergic diseases. We aimed to look into the relationship between specific clinical conjunctival findings and the severity of corneal complications. Thirty eyes of 6 patients with vernal keratoconjunctivitis (VKC) and 13 patients with atopic keratoconjunctivitis (AKC) were evaluated in this study. Slit-lamp photographs of upper tarsal conjunctiva and cornea were used to evaluate the clinical findings objectively. The corneal findings and clinical findings of upper tarsal conjunctiva such as conjunctival injection, edema, the height of papillae, and mucous discharge were evaluated and graded. Statistical correlations between conjunctival findings and the severity of corneal damage were analyzed. Conjunctival injection and edema significantly correlated with the severity of corneal complications. The height of the papillae and the amount of mucous discharge did not correlate with the severity of corneal complications. Direct signs of inflammation such as injection and edema correlated with corneal damage. The height of papillae did not show a significant correlation with the corneal findings. Our results suggest that inflammation of the conjunctiva rather than mechanical factors may play a greater role in the formation of corneal damage in severe ocular allergies.

A review of the use of olopatadine in allergic conjunctivitis

Ocular allergies are very common and range in intensity from mild, self-resolving, acute conditions to serious, chronic disease that can severely affect vision. The vast majority of sufferers experience relatively mild symptoms, which are often seasonal in nature. Treatments should be simple, comfortable and very safe. They should be able to respond to an ongoing attack but also provide long-term relief from symptoms. Mast cell degranulation is central to all forms of ocular allergic disease and so treatment has concentrated on preventing this process or antagonizing the effects of the primary mediator, histamine. Olopatadine is a relatively new selective H1 antagonist that has mast cell stabilizing properties and has been shown to affect release of TNFalpha and various cytokines from conjunctival epithelial cells. This paper reviews the local ocular use of olopatadine and discusses the place of the drug in the treatment of allergic eye disease.

The promotion of eosinophil degranulation and adhesion to conjunctival epithelial cells by IgE-activated conjunctival mast cells

Allergen-mediated mast cell activation is a key feature of ocular allergic diseases. Evidence of eosinophil-derived mediators in tears and conjunctival biopsy specimens has been associated with chronic ocular allergic inflammation. To examine the role of conjunctival mast cell mediators in eosinophil adhesion to conjunctival epithelial cells and eosinophil degranulation. Conjunctival cells were obtained by enzymatic digestion of cadaveric conjunctival tissues. Eosinophils were obtained from peripheral blood samples using negative magnetic bead selection. The effect of IgE-activated mast cell supernates on eosinophil degranulation and adherence to epithelial cells was compared with supernates obtained from mast cells pretreated with a degranulation inhibitor (olopatadine). Eosinophil adhesion was measured by eosinophil peroxidase assay, and eosinophil degranulation was measured by eosinophil-derived neurotoxin radioimmunoassay. IgE-activated conjunctival mast cell supernates stimulated adhesion of eosinophils to epithelial cells (20.4% +/- 6.3% vs 3.1% +/- 1.0%; P = .048). Degranulation was not required for this process (no effect of olopatadine). IgE-activated mast cell supernates stimulated eosinophil-derived neurotoxin release (108.89 +/- 8.27 ng/10(6) cells vs 79.45 +/- 5.21 ng/10(6) cells for controls, P = .02), which was significantly inhibited by pretreatment of mast cells with a degranulation inhibitor (79.22 +/- 4.33 ng/10(6) cells vs 61.09 +/- 5.39 ng/10(6) cells for olopatadine pretreated and untreated, respectively, P = .02). Mediators released from conjunctival mast cells promote eosinophil adhesion to conjunctival epithelial cells and eosinophil degranulation. Degranulation inhibition studies suggest that different mast cell mediators are involved in regulation of these events.

Animal models of allergic and inflammatory conjunctivitis.

Allergic eye diseases are complex inflammatory conditions of the conjunctiva with an increasing prevalence and incidence. The diseases are often concomitant with other allergic diseases such as allergic rhinitis, atopic dermatitis and allergic asthma. Despite the disabling and prominent symptoms of ocular allergies, they are less well studied and further insights into the molecular basics are still required. To establish new therapeutic approaches and assess immunological mechanisms, animal models of ocular allergies have been developed in the past years. The major forms of allergic ocular diseases, seasonal and perennial allergic conjunctivitis, vernal and atopic keratoconjunctivitis and giant papillary conjunctivitis, each have different pathophysiological and immunological components. In contrast to these distinct entities, the current animal models are based on the sensitization against a small number of allergens such as ovalbumin, ragweed pollen or major cat allergens and consecutive challenge. Different animal species have been used so far. Starting with guinea-pig models of allergic conjunctivitis to assess pharmacological aspects, new models including rats and mice have been developed which mimic major features of ocular allergy. The presently preferred species for the investigation of the immunological basis of the disease is represented by murine models of allergic conjunctivitis. In the future, combined ocular, nasal and aerosolic challenges with allergens may provide a model of allergy that encompasses simultaneously the target organs eye, nose and airways with conjunctivitis, rhinitis and asthma.

Fibrosis in ocular allergic inflammation: recent concepts in the pathogenesis of ocular allergy.

Mast cells and eosinophils are the main effector cells in allergic inflammation, but there is now compelling evidence that fibroblasts are also important players in the inflammatory response. In fact, they respond to different stimuli and release several mediators that modulate mast-cell and eosinophil functionality. In several allergic conditions such as vernal keratoconjunctivitis, asthma and atopic dermatitis the chronic presence of the inflammatory process has been associated with fibrosis and tissue remodeling, which in turn could cause irreversible alterations in the organ anatomy and functions. This review will discuss current advances in mast cell, eosinophil and fibroblast interactions in terms of their importance in the perpetuation of allergic inflammation and in contributing to the fibrosis and/or remodeling process in ocular allergy. As a main example of allergic ocular diseases associated with fibrosis, vernal keratoconjunctivitis is discussed in the light of recent findings. Several studies have recently shown that fibroblasts can modulate the functions of mast cells and eosinophils through the membrane form of stem cell factor and granulocyte-macrophage colony-stimulating factor, respectively. On the other hand, fibroblasts can be affected by inflammatory mediators derived from mast cells and eosinophils, such as transforming growth factor beta and nerve growth factor and by the T helper type 2 cytokines, IL-4 and IL-13, and vernal keratoconjunctivitis-derived fibroblasts display altered functions. Considerable useful information has been gained about the role of mast cells, eosinophils and fibroblasts in the perpetuation of allergic inflammation and tissue fibrosis and/or remodeling in general, and specifically in ocular allergy.

Animal models of ocular allergy and their clinical correlations.

Ocular allergic diseases represent a wide spectrum of disorders, from the acute self-limited, mild form of seasonal allergic conjunctivitis to the chronic, severe, sight-threatening atopic keratoconjunctivitis. The least problematic forms are the most prevalent, and several animal models have contributed to elucidate their etiopathogenetic mechanisms and have served to test numerous anti-allergic compounds. The most severe and chronic, although less prevalent, ocular allergic problems have not benefited from a similar advance, with the subsequent lack of full understanding and a limited therapeutic armamentarium. Research in this field is currently concentrating efforts in developing more protracted models of ocular allergic inflammation involving the cornea and mimicking more closely the human disease caused by chronic ocular allergy. Most recent experimental models are demonstrating that inhibiting Th2 cells and their secreted cytokines might be one important therapeutic target for inhibiting chronic allergic inflammation in the ocular surface.

Ocular Allergic Disease: Mechanisms, Disease Sub-types, Treatment

AbstractOcular allergy refers to a variety of hypersensitivity disorders that affect the lid, conjunctiva, and/or cornea. Its incidence is estimated at over 20% of the general population in the United States. This review will discuss the various forms of ocular allergy, their pathophysiology, clinical presentation, and treatment. New frontiers in mechanisms, therapy, and management in the office are emphasized throughout.

A randomized, double-blind, parallel-group comparison of olopatadine 0.1% ophthalmic solution versus placebo for controlling the signs and symptoms of seasonal allergic conjuctivitis and rhinoconjunctivitis

Background: The most common form of allergic ocular disease is seasonal allergic conjunctivities, coinciding with the pollen season and generally associated with rhinitis. Symptoms of allergic conjunctivitis include ocular itching, hyperemia, tearing, mucus production, foreign body sensation, chemosis, and lid edema. Similarly, the primary symptoms of allergic rhinoconjunctivitis are nasal itching, irritation, sneezing, watery rhinorrhea, and congestion combined with ocular itching, tearing, and swelling. Objective: This study compared olopatadine 0.1% ophthalmic solution with placebo eyedrops (over-the-counter artificial tear product), instilled in the eye, with regard to the prevention and relief of the ocular and nasal symptoms of seasonal allergic conjunctivitis and rhinoconjunctivitis. Methods: This was a randomized, double-blind, parallel-group study, conducted at 7 US centers, to instill either olopatadine 0.1% ophthalmic solution or placebo eyedrops (artificial tears) in both eyes twice daily for 10 weeks. Patients were evaluated for efficacy (intent-to-treat) and safety. Only patients with proven grass pollen allergy (dermal and conjunctival allergen challenge tests) were selected; all patients were studied during the same period, historically shown to be grass season; and grass pollen counts were obtained. Results: A total of 131 patients (64 olopatadine; 67 placebo) were assessed for efficacy (intent-to-treat); 132 patients were assessed for safety. The mean (SD) age of participants was 38.53 (11.61) years (range, 18 to 87 years), and 58.0% were women ( 76 131 ), with no significant differences between groups for age or sex. In the olopatadine group, 1.6% of patients were black ( 1 64 ), compared with 14.9% of the placebo group ( 10 67 ) ( P = 0.005). Mean scores of ocular itching and hyperemia were lower at all assessment times with olopatadine than placebo. The difference was statistically significant ( P < 0.05) for itching on days 7, 14, 35, 63, and 70, and for hyperemia on days 14, 28, 42, and 63, after correction for multiplicity. Linear regression slopes predicting ocular itching and hyperemia from the pollen count were significantly lower ( P < 0.003 and P < 0.035, respectively) with olopatadine than with placebo. Similar results were obtained for rhinorrhea, sneezing, and nasal itching ( P < 0.006, P < 0.012, and P < 0.034, respectively). With placebo, the proportion of patients with frequent ocular itching and hyperemia increased as a function of pollen level; however, with olopatadine, the proportions remained low and virtually constant. Conclusion: In the population studied, olopatadine 0.1% ophthalmic solution controlled ocular and nasal symptoms of allergic conjunctivitis and rhinoconjunctivitis and was well tolerated when administered twice daily for 10 weeks.

IL-4-induced cell proliferation and production of extracellular matrix proteins in human conjunctival fibroblasts

Giant papillae, characteristic lesions of vernal keratoconjunctivitis, are formed as a result of the proliferation of conjunctival fibroblasts, the deposition of extracellular matrix, and the infiltration of inflammatory cells. The concentration of interleukin (IL)-4 is also increased in the tear fluid of individuals with ocular allergic diseases. The possible role of IL-4 in the development of giant papillae was investigated by examining the effects of this cytokine on cultured human conjunctival fibroblasts. Reverse transcription and polymerase chain reaction analysis revealed the presence of transcripts encoding the IL-4 receptor α chain in these cells, and flow cytometry demonstrated the expression of this protein on the cell surface. IL-4 induced the proliferation of conjunctival fibroblasts in a concentration-dependent manner, and this effect was inhibited by neutralizing antibodies to the IL-4 receptor. Enzyme immunoassays revealed that IL-4 also increased in a concentration-dependent manner the amounts of procollagen type I C-peptide and fibronectin released into the culture supernatant by conjunctival fibroblasts. A whole-cell enzyme-linked immunosorbent assay showed that IL-4 increased the deposition of collagen type III by conjunctival fibroblasts. Furthermore, reverse transcription combined with real-time polymerase chain reaction analysis revealed that IL-4 increased the abundance of collagen type III mRNA in these cells. These results demonstrate that human conjunctival fibroblasts express receptors for IL-4, and that IL-4 stimulates both the proliferation of and the production of extracellular matrix proteins by these cells. These effects of IL-4 might contribute to the formation of giant papillae in individuals with vernal keratoconjunctivitis.

The central role of conjunctival mast cells in the pathogenesis of ocular allergy

Ocular allergic diseases are characterized by specific activation of conjunctival mast cells with subsequent release of preformed and newly formed mediators. Mast-cell numbers on the ocular surface are increased in all forms of allergic conjunctivitis. Mast-cell activation plays a central role in the development of the ocular allergic reaction, which can be divided into an early and a late inflammatory phase. Mast-cell mediators have been measured in tears of patients suffering from various forms of allergic conjunctivitis, and in sensitized patients after specific ocular allergen challenge. Histamine and tryptase are the most studied mediators in tears of allergic patients. Several cytokines, such as IL-4 and TNF-a, are also produced and released by conjunctival mast cells, and probably play a role in the immunoregulation on the ocular surface. In vitro studies of the characteristics and biologic functions of conjunctival mast cells highlight their central role in the pathogenesis of ocular allergy, and have led to new opportunities to evaluate anti-allergic compounds. This review discusses the role of conjunctival mast cells in the development of ocular allergic diseases.

Vernal keratoconjunctivitis: pathogenesis and treatment.

Vernal keratoconjunctivitis (VKC) is a recurrent or chronic ocular allergic disease that affects mostly children and young adults living in warm climates worldwide. Understanding and treating VKC has been a challenge for ophthalmologists since the pathogenesis is unclear and anti-allergic therapy often unsuccessful. In this paper, the culmination of 11 years of research into the immunological characteristics of this disease in a group of 221 VKC patients will be presented. Cytological, biohumoral, immunohistological and molecular biological studies indicate that VKC is a Th2 lymphocyte-mediated disease. Mast cells, eosinophils and their mediators play major roles in the clinical manifestation of VKC. In addition to typical Th2-derived cytokines, IL-4, IL-5 and IL-13, other cytokines, chemokines, growth factors and enzymes are over-expressed in the conjunctiva of VKC patients. Furthermore, structural cells, such as epithelial cells and fibroblasts, are involved both in the inflammatory process and in the tissue remodeling phase, ultimately resulting in the formation of giant papillae. Interactions between specific (IgE- and Th2-mediated) and non-specific triggers and mechanisms may account for treatment failure. New insights into the pathogenesis of VKC should generate the means to better design the strategies for this complex disease.

Advances in ocular allergy: basic mechanisms, clinical patterns and new therapies.

Ocular allergy presents unsolved mysteries in molecular and cellular mechanisms, and at the same time continues to challenge ophthalmologists daily in a wide array of disease forms. The recent understanding of the key role of the T helper type 2 cytokines, adhesion molecules and chemokines may provide future avenues for pharmacological targeting of releasable inflammatory mediators. More potent topical mast cell stabilizers and H1 receptor antagonists have become commercially available for the management of the prevalent and benign forms of allergic conjunctivitis. Immunostimulatory DNA sequences present an innovative and promising route for the treatment of ocular allergy, but clinical studies are needed to demonstrate their efficacy in humans. Surgical methods are suggested to reconstruct the ocular surface in the sight-threatening diseases vernal keratoconjunctivitis and atopic keratoconjunctivitis. This review presents an update of the major advances in both the basic mechanisms and clinical and therapeutic aspects of ocular allergic diseases that were reported during the past year.

Ocular allergies.

Ocular allergic disease affects not only the conjunctivae but also surrounding structures including the eyelids. Allergic diseases of the eyelid include atopic dermatitis, contact dermatitis, and urticaria/angioedema. They must be differentiated from nonallergic eyelid diseases. Allergic diseases of the conjunctivae comprise a spectrum of disorders from common, non-sight-threatening conditions such as seasonal allergic conjunctivitis, perennial allergic conjunctivitis, and giant papillary conjunctivitis to less common and potentially sight-threatening diseases such as vernal keratoconjunctivitis and atopic keratoconjunctivitis. Each of these conditions is mediated primarily by type I hypersensitivity reactions. The clinical manifestations, differential diagnosis, and treatment of these conditions are reviewed in this article.

Conjunctival mast cells in ocular allergic disease.

Allergic eye disease is a common clinical problem adversely affecting the quality of life for millions of sufferers. This ocular process is associated with IgE-mediated conjunctival inflammation leading to signs of immediate hypersensitivity including redness, itching, and tearing. Pathologic studies have shown that the conjunctiva contains mast cells that when sensitized with IgE antibody and exposed to environmental allergens can release mediators of allergic inflammation. The type, release kinetics, and concentration of these mediators in the conjunctiva have not been completely characterized. The ability to isolate and purify mast cells and epithelial cells from human conjunctival tissue has permitted the study of mediator release and cell-to-cell signaling in this tissue. Our laboratory has developed in vitro and in vivo models to better understand how inflammatory cells are recruited to and infiltrate conjunctival tissues. These models demonstrate that mast cell activation may supply sufficient cytokine signaling to initiate and direct the well-orchestrated trafficking of eosinophils to the ocular surface, facilitate their adhesion, and cause release of potent mediators of ocular inflammation.

Allergic ocular disease. A review of pathophysiology and clinical presentations.

Allergic ocular disease. A review of pathophysiology and clinical presentations.