Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

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Atopy refers to hypersensitivities in persons with a hereditary background of allergic diseases, as first described by Cocoa and Cooke (1923). The major, most commonly recognized atopic conditions include eczema (atopic dermatitis), asthma, hay fever, and allergic rhinitis. It has been estimated that atopic conditions affect 20–30% of western populations. Based upon the current United States population estimate of 300 million, some-where between 60 and 90 million people have allergies. Atopic ocular disease includes seasonal allergic conjunctivitis

(PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC). SAC and PAC, with or without nasal involvement, comprise the majority of ocular allergic conditions. The immunopathology of seasonal and perennial allergic conjunctivitis and rhinitis has been characterized as an IgEmediated, mast cell dependent, hypersensitivity response as defined by Coombs and Gell (1962). These conditions are classified as Type I immediate hypersensitivity. There are a number of current therapies available to treat SAC and PAC. They will be discussed

in the following sections. VKC and AKC may cause significant complications and lead to loss of vision. Type I hypersensitivity reactions of the ocular surface are involved in AKC and VKC, but are not considered the only pathophysiologic mechanisms in these similar, yet distinct entities. GPC, VKC, and AKC are discussed separately. AKC and VKC are compared and contrasted.

II. ALLERGIC

CONJUNCTIVITIS – SEASONAL/

PERENNIAL

Allergic conjunctivitis (AC) is a bilateral, self-limiting conjunctival inflammatory process. It occurs in sensitized individuals (no gender difference) and is initiated by allergen binding to the IgE antibody on resident mast cells. The importance of this process is related more to its frequency rather than its severity of symptoms. The two forms of AC are defined by whether the inflammation occurs seasonally (spring, fall) or perennially (year-round). While the inflammatory symptoms are similar for both entities, seasonal allergic conjunctivitis (SAC, “hay fever conjunctivitis”) is more common. It accounts for the majority of cases of AC and is related to atmospheric pollens (e.g. grass, trees, ragweed) that appear during specific seasons. Perennial allergic conjunctivitis (PAC) is often related to animal dander, dust mites, or other allergens that are present in the environment year-round. Both SAC and PAC must be differentiated from the sight-threatening allergic diseases of the eye, namely atopic and vernal keratoconjunctivitis.

A. Clinical Parameters

Prevalence estimates for allergic conjunctivitis are difficult because allergies in general tend to be considerably under-reported. AsurveyconductedbytheAmericanCollege of Allergy, Asthma, and Immunology (ACAAI) found that 35% of families

interviewed experience allergies; of these, at least 50% report associated eye symptoms. Most reports agree that allergic conjunctivitis affects up to 20% of the population (Bielory, 2000). SAC and PAC have been estimated to account for 80 to 98% of all cases of ocular allergy (Katelaris, 2003; Ono and Abelson, 2005; Leonardi, 2005). Often, ocular involvement occurs in patients with respiratory allergies. Approximately 60% of all allergic rhinitis sufferers have associated allergic conjunctivitis, and it has been reported that 90% of patients with allergic rhinitis had ocular symptoms for at least 1 day per week during the pollen season (Ono and Abelson, 2005).

The distribution of SAC depends largely on the climate. For example, in the United States, grass pollen induced SAC generally occurs in the Gulf Coast and southwestern areas of the country from March to October, and from May to August in most of the rest of the country. Conversely, ragweed pollen induced SAC occurs in most of the country during August through October, but in the southern-most states it can begin as early as July and stretch through November. Tree pollens can become a problem as early as January in the south, and March in the north.

The dominant symptom reported in allergic conjunctivitis is ocular itching, which can range from mild to severe. Other symptoms include tearing (watery discharge), redness, swelling, burning, a sensation of fullness in the eyes or eyelids, an urge to rub the eyes, sensitivity to light, and occasionally blurred vision. As stated previously, allergic conjunctivitis is often associated with symptoms of allergic rhinitis. Conjunctival hyperemia and chemosis with palpebral edema are typical. Hyperemia is the result of vascular dilation while edema (chemosis) occurs because of altered permeability of postcapillary venules. “Allergic shiners” (periorbital darkening), due to a transient increase of periorbital pigmentation resulting from the decreased venous return in the skin and subcutaneous tissue, are also common.

B. Pathophysiology

It has been understood for some time that antigen cross-linking of the IgE antibody bound to the high affinity IgE receptor (Fc RI) on mast cells induces release of both pre-formed (granule associated, e.g. histamine and tryptase) and newly synthesized mediators (e.g. arachidonic acid metabolites) that have diverse and overlapping biological effects. Both tissue staining and tear film data have implicated the mast cell and IgE mediated release of its mediators in the pathophysiology of the ocular allergic inflammatory response. Additionally, a number of clinical studies examining topical antihistamine, mast cell stabilizing and dual acting drugs have demonstrated relief of allergic conjunctivitis symptoms (see section II.D).

Histopathologic and laboratory manifestation of allergic ocular diseases has been evaluated. Synthesis of inflammatory mediators varies according to the phenotype and tissue location of the mast cell. Granuleassociated neutral proteases (tryptase and chymase) unique to mast cells are generally accepted as the most appropriate phenotypic markers to categorize human mast cells into subsets. On this basis, mast cells have been divided into MCT (tryptase) and MCTC (tryptase/chymase) phenotypes. The phenotype of normal human conjunctival mast cells has been well documented using immunostaining of conjunctival biopsy specimens. Mast cells are rarely present in the normal human conjunctival epithelium; but when they are found, they appear to be limited to the MCT phenotype. Mast cells (MCT phenotype) and eosinophils are found to be increased in the conjunctival epithelium of individuals with SAC and PAC. In the substantia propria of the normal human conjunctiva, mast cells are found and 95% are of the MCTC phenotype (Irani et al., 1986; Baddeley et al., 1995; Morgan et al., 1991). The total number of mast cells (MCTC phenotype) is also increased in the substantia propria of individuals with AC (Irani et al., 1986).

Clinical evidence for mast cell activation is found in SAC and PAC. Tear film analysis of patients consistently reveals the presence of IgE antibody, histamine (Abelson et al., 1980; Venza et al., 2004), tryptase (Butrus et al., 1990), eotaxin 1 (Eperon et al., 2004), and eosinophil cationic protein (Muromoto et al., 2006). The contributions of granuleassociated, pre-formed (histamine, tryptase, bradykinin), and arachidonic acid derived, newly formed (leukotrienes, prostaglandins), mediators present in ocular inflammation have been well documented. Pre-formed mediators are released immediately upon allergen exposure, while roughly 8 to 24 hours are required for release of newly formed mediators. These mediators are known to have overlapping biological effects that contribute to the characteristic ocular itching, redness, and watery discharge associated with allergic eye disease. Histamine is involved in the regulation of vascular permeability, smooth muscle contraction, mucus secretion, inflammatory cell migration, cellular activation, and modulation of T-cell function. Arachidonic acid metabolites and tryptase originating from mast cells have also been shown to be specifically involved in the regulation of many of these same processes. Mast cells also synthesize cytokines and chemokines. Less well documented and defined are the effects of these mediators in the ocular allergic inflammatory process. Cytokines stored in mast cells are likely the first signals initiating infiltration of inflammatory white blood cells, such as eosinophils. Once these cells arrive, they gain access to the conjunctival surface by moving through the already dilated capillaries. Recently, the tear film of patients with AC has been found to have a more rapid tear break-up time, and to be thicker than control patients (Suzuki et al., 2006).

Immunohistochemical staining of human conjunctival tissue biopsies shows that the inflammatory cytokines, IL-4, IL-5, IL-6, and TNF α, are localized to mast cells in normal and allergic conjunctivitis (Macleod et al., 1997). These cytokines are consistent

with a T helper 2 (Th2) cytokine profile. Inflammatory cytokines (e.g. TNFα) have also been measured in human tears (Donshik, 1994; Metz et al., 1996; Hogan, 1953; Bonini et al., 2000; Vesaluoma et al., 1999; Uchio et al., 2000; Fujishima et al., 1995; Cook et al., 2001b; Nakamura et al., 1998). While it is difficult in vivo to determine the cellular source of cytokines in tears, recent studies comparing allergic to non-allergic subjects indicate that cytokine levels may be important indicators of ocular allergy. It has been demonstrated that tears from allergic donors (when compared to nonallergic donors) contained significantly less of the anti-inflammatory cytokine IL-10 and a trend toward decreased levels of the Th1 cytokine, interferon gamma (IFN) (Cook et al., 2001b).

Finally, IgE mediated release of histamine and cytokines from mast cells can also initiate secondary effects on conjunctival epithelial cells. The activation and participation of epithelial cells in allergic inflammation is an active field of research. Human conjunctival epithelial cells express H1 receptors coupled to phosphatidylinositol turnover and calcium mobilization (Sharif et al., 1996a). Cytokines released from mast cells upregulate intercellular adhesion molecule 1 (ICAM-1) expression on conjunctival epithelial cells (Bagnasco et al., 1997). This has become a marker of allergic inflammation. ICAM-1 appears to play a critical role in the migration of inflammatory cells, and is rapidly expressed following ocular allergen provocation.

C. Diagnosis

An individual suspected of having allergic conjunctivitis should have a thorough ocular, medical, and medication history. This will help greatly in differentiating AC from other ocular processes. This history should establish whether the process is acute, subacute, chronic, or recurrent. It should further delineate whether the symptoms/signs are unilateral or bilateral, and whether they are

associated with any specific environmental or work-related exposure. Ocular symptoms such as tearing, irritation, stinging, and burning are non-specific. A history of significant ocular itching and a personal or family history of hay fever, allergic rhinitis, asthma, or atopic dermatitis are suggestive of ocular allergy. Viral and bacterial infections of the eye may mimic allergic conjunctivitis. Because AC is secondary to environmental allergens, as opposed to transmission by eye–hand contact (infectious etiology), SAC and PAC usually present with bilateral symptoms. This is in contrast to transmissible infections caused by viruses and bacteria, which, in general, initially present in one eye; with the second eye becoming involved a few days later. Furthermore, viral conjunctivitis may cause subepithelial corneal infiltrates not seen in AC. Palpable pre-auricular nodes would also signify infectious etiology for the ocular symptoms.

The type of ocular discharge (watery, mucoid, mucopurulent, or grossly purulent) can also be helpful in determining the underlying cause of conjunctival inflammation. A watery discharge is most commonly associated with viral or allergic ocular conditions. A mucopurulent or purulent discharge, with morning crusting and difficulty opening the eyelids, would strongly suggest a bacterial infection.

In allergic inflammation, the eye appears red. This color change is most evident in the conjunctiva. Vision, pupil shape, ocular movement, light reactivity, and the red retinal reflex remain normal in allergic conjunctivitis. Dry eye (secondary to a decrease of the aqueous portion of the tear film) gives symptoms suggestive of a foreign body in the eye and may result in conjunctival redness. Similar symptoms are possible from anticholinergic side effects of systemic medications. Typically, itch is not reported with dry eye.

Medication history should include questions concerning the patient’s use of over-the-counter topical ocular medications, cosmetics, contact lenses, and systemic

medications. Any of these can produce acute or chronic conjunctivitis. This inquiry should include direct questions and should not rely on the patient to volunteer information. Many individuals do not appreciate the potential for non-prescription topical ocular medications to cause eye symptoms or partially treat AC. Differentiation of AC from the more chronic and sight threatening forms of allergic eye disease is discussed below in the context of the specific conditions.

D. Treatment of Allergic Conjunctivitis

Allergic conjunctivitis can be debilitating to some degree, and may cause the individuals affected to seek any type of help for relief of symptoms. The itching and tearing may be unbearable and sleepless nights frequent. Ocular allergic conjunctivitis symptoms may be worse than the nasal symptoms in those suffering from rhinoconjunctivitis. Furthermore, treatment of the nasal symptoms with topical nasal steroids may help the rhinitis, but not be effective for relieving ocular symptoms.

Management of allergic conjunctivitis is, therefore, primarily aimed at alleviating symptoms. Establishing the cause is the first step in treating allergic conjunctivitis. The best treatment is avoidance of the specific allergen, which, unfortunately, is sometimes not possible. Avoidance of scratching or rubbing, application of cool compresses, artificial tears, and refrigeration of topical ocular medications are practical interventions to alleviate discomfort. While oral antihistamines may help to relieve eye discomfort, this may also decrease tear production, causing more ocular symptoms.

The treatment of choice for mild to moderate AC is a dual acting topical ocular medication. Currently available compounds include olopatadine, azelastine, ketotifen, and epinastine. The mast cell stabilizing component of these drugs benefits patients most if treatment is started before

the height of symptom onset. Patients usually note rapid onset of relief of itch upon drop instillation, as most dual action medications have high H1 receptor affinity.

In severe disease, combination therapy is recommended. This therapy may include topical medications (antihistamines, mast cell stabilizers, NSAIDs, or combinations), and oral antihistamines. Non-steroidal drugs inhibit cyclooxygenase, resulting in decreased formation of prostaglandins and thromboxanes, but not leukotrienes. Therefore, these compounds are useful in controlling itching and some inflammation, but not the infiltration of inflammatory cells. In extreme cases, use of a topical steroid 4 times a day should be considered. All patients receiving topical steroids should have their intraocular pressure measured frequently. Immunotherapy performed by an allergist may be beneficial in decreasing the severity of future ocular allergy symptoms. Sublingual immunotherapy specifically for perennial allergic conjunctivitis has been demonstrated effective in relieving symptoms (Potter, 2006).

E. Pharmacology

As noted above, SAC and PAC are manifestations of conjunctival mast cell degranulation and effects of pro-inflamma- tory mediators on tissue receptors causing physiological changes. Drugs that successfully prevent mast cell degranulation or block mediator binding to tissue receptors provide clinical benefit. Histamine released from mast cells directly affects nerve endings, vascular tissues, and epithelial cells in the eye, and antagonists of the histamine H1 receptor provide symptomatic relief. The first generation antihistamines used in topical ocular preparations include antazoline and pheniramine. These drugs have been used for years, but are limited by in vivo potency, duration of action, and patient acceptability (Sharif et al., 1997; Lanier et al., 1983). These molecules were also inferior to emedastine and levocabastine, second