Definition Of Remodeling In Ocular Allergy

Mechanisms and Management of Allergic Inflammation in the Eye

Sergio Bonini1 and Andrea Leonardi2

1Department of Medicine, Second University of Naples and 2Department of Neurosciences, Eye Clinic, university of Padua. Italy

1.Mechanisms of ocular allergy

2. Classification of ocular allergic diseases: SAC, PAC, AKC, VKC, GPC

3. Differential diagnosis

4. Diagnostic tools

5. How to assess cytokines and growth factors in the human eye

6. Cytokine expression and production in the animal model of ocular allergy and in ocular allergic patients: do they match?

7. Are cytokines relevant and correlated with the clinical phases of the disease?

8. Definition of remodeling in ocular allergy

9. Metalloproteases in ocular allergy

10. Dry Eye

11. Management of ocular allergy

1. Mechanisms of ocular allergy Three major mechanisms have been reported to be involved in causing diseases included under the umbrella term of allergic conjunctivitis (or ocular allergy of the external eye surface):a) the typical Type I hypersensitivity reaction, where the IgE- mediated release of mast cell and basophil mediators is responsible for symptoms (redness, chemosis, excess tearing and mucus, itching and burning), as a result of vasodilation, exudation, stimulation of glands and nerve endings; b) eosinophilic inflammation, both dependent and independent by a late-phase IgE mediated reaction; c) conjunctival hyperreactivity, often related to the eosinophilic inflammation but also possibly due to an abnormal tissue response to non-specific stimuli (cold air, pollutants, excess lighting,etc.). These hallmarks of allergic eye disease, although often related to each other, depend on different genetic and environmental factors and may help to identify different phenotypes of ocular allergy with different clinical presentation, severity and treatment.

2. Classification of ocular allergic diseases: SAC, PAC, AKC, VKC, GPC

Seasonal allergic conjunctivitis (SAC) is the most common form of allergy and is associated with sensitization and exposure to environmental allergens, particularly pollen. The perennial form (PAC) usually involves sensitization to mites or to multiple antigens. Both forms are characterized by an onset in childhood or early adulthood; patients present with ocular itching, conjunctival hyperemia, and at times lid and conjunctival edema of varying severity, mild serous or serous-mucous secretions, and/or slight papillary or follicular hypertrophy of the conjunctiva. This symptomatology is chronic in PAC. The only diagnostic factor is the presence of itching: if the patient does not complain of conjunctival or peri-ocular itching, it is almost surely not allergic conjunctivitis. Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease that occurs predominately in children. VKC is characterized by intense ocular symptomatology: itching, photophobia, foreign body sensation, conjunctival hyperemia, and mucous secretion, typically accompanied by giant papillae on the upper tarsal conjunctiva, or, in the limbal form, by limbal infiltrates or nodules, or both signs in the mixed form. Corneal involvement is common, characterized by punctate keratitis or sterile corneal ulcers, the result of epitheliotoxic proteins and enzymes released by activated eosinophils. VKC is an IgE- and Th2-mediated disease in which only 50% of patients present a clear allergic sensitization. Atopic keratoconjunctivitis (AKC) is typical of adult patients, although it can be observed in children with atopic dermatitis. In addition to the cutaneous involvement, AKC can be associated with rhinitis, seasonal rhinoconjunctivitis and asthma. AKC can be a very severe disease due to its prolonged chronicity and exacerbations during the winter months. Frequently the cornea is involved as diffuse superficial epitheliopathy and/or ulcers that result in scarring, irregular astigmatism, or corneal pannus, all of which can compromise visual function. Giant papillary conjunctivitis (GPC) is a non-IgE-mediated inflammation induced most frequently by the use of contact lenses. All types of contact lenses can trigger GPC, as can the use of ocular prostheses, the presence of corneo-conjunctival sutures or protruding scleral buckling. The upper tarsal conjunctiva is subjected to repetitive or constant micro-trauma generated by a conjunctival 'foreign body'; this phenomenon is then complicated by an immune reaction against a protein or residue deposited on the lens. Table 1. Ocular allergic diseases

Condition Prevalence Severity Causes Sign/Symptoms SAC/PAC Most frequent Mild/ Genetic predisposition Itching ocular allergic moderate Associated with rhinitis Redness disease. Seasonal allergens (pollens, Tearing 10-15% of molds, chemicals) Watery population Perennial allergens (dust, discharge animal dander, foods, Chemosis chemicals Lid swelling VKC Rare Severe Genetic predisposition? Extreme Ages 3-20 Associated with atopic itching Under 14 M>F disorders (50%) Ropy mucous In adults M=F Th2 up-regulation discharge Non-specific eosinophil Cobblestone activation papillae Trantas’ dots Keratitis/ulcer Conjunctival eosinophilia

AKC Rare Severe/ Genetic predisposition Itching 2nd to 5th Sight Associated with atopic Burning decade of life threatening dermatis Tearing M>F Environmental allergens: Photophobia food, dust, pollens, animal Chronic dander, chemicals redness Blepharitis Periocular eczema Mucous discharge Keratitis/ulcer Conjunctival and corneal scarring cataract

GPC Iatrogenic Mild Trauma induced by contact Lens 2nd to 5th lens edge, ocular prosthesis, intolerance decade exposed sutures, aggravated Blurred vision by concomitant allergy Foreign body sensation Abnormal thickening of conjunctiva Giant papillae

Contact Not known Moderate Contact delayed type Eyelid eczema blepharitis/ hypersensitivity Eyelid itching dermatitis Exogenous haptens Conjunctival (cosmetics, metals, redness chemicals) Punctate keratitis Topical preparation (drugs, preservatives) 3. Differential diagnosis

At times, pseudoallergic forms, with clinical manifestations similar to allergy but with a non-allergic equivocal pathogenesis, are difficult to distinguish from allergic forms, with their precisely defined pathogenic mechanisms. Several clinical forms may mimic the clinical pictures of ocular allergy (Table2), including tear film dysfunction, subacute and chronic infections, toxic and mechanical conjunctivitis.

Table 2. Differential diagnosis of chronic allergic disease from:

Dry Eye Blepharitis Uncorrected visual defects Chlamydia ‘Medicamentosa’ (drug-induced conjunctivitis) Viral Conjunctivitis Contact lenses intolerance Non-specific hypereactivity Hyperuricemia Toxic conjunctivitis Mechanichal conjunctivitis

4. Diagnostic tools

If ocular allergy is suspected:  Complete an accurate clinical history and ocular examination  Perform skin tests  Identify specific and total serum IgE levels  Analyze Complete blood count (CBC, hemochrome) with the eosinophil count  If all of these systemic tests are negative, perform local tests (cytology, conjunctival provocation, tear IgE) However consider that:  Cytological tests are useful in the active phase of the disease.  Conjunctival allergen provocation proves local hypersensitivity.  Low tear volume limits its potential usefulness in analytical diagnosis.  The measurement of tear specific IgE is not practical.  The measurement of total tear IgE by paper strips is easy, but not highly specific. (Research presently also involves a unit device to measure tear osmolarity and possibly IgE).

5. How to assess cytokines and growth factors in the human eye

Tear samples and cytokine assessment: Tear collection is not painful or traumatic, with only its insurmountable limitation regarding the quantity of sample obtainable. The concentration and distribution of inflammatory mediators or inhibitors in tear fluid have been extensively used in ocular allergy to find either a ‘disease marker’, to better understand the immune mechanisms involved in the ocular surface inflammation, or to identify potential targets for therapeutic interventions.

Initially, cytokines were measured in tissues and fluids individually, and thus there was great limitation in what could be learned from one sample. Advances in techniques have now allowed for multiple cytokine assaying. Indeed, membrane array characterization allows for the identification of up to 80 chemokines, cytokines and growth factors in one tear sample, and consequently, a more global picture of immunoregulation is coming into focus.

Determination of tear mediator, cytokine, chemokine levels or expression of adhesion molecules is not yet used for diagnosis, but only for the study of allergic physiopathology or for the evaluation of efficacy of anti-allergic agents. Tear cytokine analysis is currently carried out using ELISA techniques. The “multiplexed bead based flow cytometry” allows the simultaneous measurement of various mediators in one sample of 10-20 microliters of tear fluid. More than just the assaying of a single cytokine, it is possible to identify relationships between cytokines or groups of cytokines with opposing or complementary functions. A significant differences in the ratios of TNF /IFN  , IL-5/IFN  and IL-5/IL-10 between allergic and non-allergic patients has been shown, but not in the single cytokines. In a different study, the type Th2 cytokines, Il-4, IL-5 and IL-13, were significantly increased in all forms of allergic disease, particularly in VKC, compared to normal tears. IFN- , was also increased in the more severe forms of VKC and AKC. IL-8 was exceptionally high in GPC tears. Pro-inflammatory cytokines, IL-1, IL-6 and TNF were increased in lacrimal fluid. Among the chemokines, eotaxin was elevated in VKC and was correlated with IL-5 and IL-4 levels.

Seasonal allergic conjunctivitis, long thought to be a self-limiting disorder resulting only from specific mast cell activation, is now known to have a significant gamut of Th2 cytokines involved in its insurgence: levels of IL-1 , IL-2, IL-4, IL-5, IL-6, IL-12, IL-13, IFN and MCP-1 all increase in comparison with non-allergic controls. The all- inclusive nature of these results strongly indicates that cells other than mast cells are involved not only in VKC and AKC, but also in SAC.

Dozens of cytokines, chemokines, growth factors, angiogenic modulators, enzymes and inhibitors can be identified in small tear samples using proteomic techniques. Membrane assay is a relatively un-expensive technique that can be applied to tear samples.

The conjunctival epithelium is now known to have a pivotal immunomodulatory role in ocular allergic inflammation. Different chemokines and surface receptors are expressed on conjunctival epithelium in acute and chronic ocular disease states. Changes that occur in the epithelium with ocular inflammation appear to be dependent on the chronicity of the reaction/disease state. In acute allergic disease, the conjunctival epithelium expresses ICAM-1, involved in leukocyte adhesion and activation, and releases IL-8, resulting in a cellular infiltrate of predominantly neutrophils and eosinophils. In chronic allergic inflammation such as VKC and AKC, conjunctival epithelial cells express HLA-DR, involved in T-lymphocyte activation, and a cellular infiltrate characterized by increased numbers of activated T lymphocytes is observed in hand with greater expression of IFN , the pro-inflammatory Th1 cytokineknown to be a potent stimulator of surface receptor ICAM-1 and HLA-DR on conjunctival epithelial cells. Conjunctival fibroblasts reveal a strikingly similar cytokine and chemokine profile as that of tears, and are known to constitutively produce IL-6, IL-8, MCP-1 and RANTES. However, other ocular surface cells including epithelial cells, intraepithelial lymphocytes (CD8+), dendritic cells, and resident mast cells are potential sources of these cytokines. The demonstration of eotaxin-1 production by conjunctival fibroblasts in response to IL-4 strongly suggests that these cells produce this chemokine, which is then detected in tears.

6. Cytokine expression and production in the animal model of ocular allergy and in ocular allergic patients: do they match?

In the murine model of experimental allergic conjunctivitis (EC) the activation of mast cells by IgE alone can induce conjunctival eosinophil infiltration. However, IgE- induced mast cell activation only provokes mild conjunctival eosinophil infiltration. In contrast, the transfer of Ag-primed T cells followed by Ag challenge in the conjunctiva induced severe conjunctival eosinophil infiltration. Since the severity of ocular allergy is dependent on the numbers of infiltrating eosinophils, it appears that T cells play more important roles than IgE in the severe more chronic forms of allergic conjunctivitis.

Although CD4+ Th2 cells clearly play an essential role in the development of EC, the functions of CD4+ Th1 and CD8+ T cells remain controversial. CD8+ T cells may play a significant role during the induction phase by aiding IgE production and the generation of Th2 cytokines in the conjunctiva, thus promoting the development of EC. During the effector phase, IFN-gamma acts to promote the severity of EC

An essential role for IL-1 receptor activation was first demonstrated using a mouse model of allergic conjunctivitis, in which treatment with an IL-1 receptor antagonist in allergen-challenged animals significantly reduced allergen-induced responses. It is also well known that IL-1 can stimulate pro-inflammatory conjunctival epithelial cell responses in vitro and that these responses are amplified when TNF is present, as in AKC and VKC.

T reg cells play a suppressive role in the development of experimental allergic conjunctivitis in splenocyte transfer experiments suggesting that modulation of T reg cells may be a possible therapy for ocular allergy. However, in the EC model IL10 and TGF beta did not have immunosuppressive effects in the development of experimentally induced allergic conjunctivitis. Rather, they augment the infiltration of eosinophils into the conjunctiva during the effector phase of experimentally induced allergic conjunctivitis.

7. Are cytokines relevant and correlated with the clinical phases of the disease?

Several cytokines have been found increased in the active phase of ocular allergy. A clinical role of TNFa have been proven since many of its biological effects can be found in ocular allergic patients. After conjunctival mast cell degranulation TNF can be found in tears.

IL-5, IL-6 and IL-8 are highly expressed in VKC. However none of the studied cytokine in tears is strongly correlated with a clinical picture.

A defect in microbial defense has been implicated in the pathogenesis of atopic dermatitis and AKC, in which colonies of s. aureus are increased. In a recent study by Cook et al, IFN and S aureus up-regulates TLR-2 expression and augments responses to TLR-2 agonists in conjunctival epithelial cells in vitro. S aureus stimulation alone up-regulates ICAM-1, HLA and CD14 expression and increases TNF and IL-8 release. This infectious component to the immune offensive in AKC might be what distinguishes it from other ocular allergic diseases, explaining why Th1 cytokines are called up together with Th2 cytokines to combat this unique disorder.

The role of Th17-cells is still unknown.

8. Definition of remodeling in ocular allergy

Remodeling can be considered a wound healing process gone awry, thus, mechanisms of wound healing give insight into how remodeling and fibrosis occur as a dysregulation of post-inflammatory healing. One of the most spectacular events in chronic ocular allergies, VKC AKC and GPC, is the overgrowth of the conjunctival connective tissue, with the formation of large and sessile papillae from which overflow an abundance of collagen fibers. The term 'tissue remodeling' defines a gamut of alterations involving structural cells and tissues such as conjunctival thickening, subepithelial fibrosis, mucus metaplasia, neovascularization and scarring. Many elements contribute to this dramatic response, including epithelial changes, connective tissue deposition, edema, inflammatory cell infiltration, and glandular hypertrophy.

Remodeling involves both production and deposition of extracellular matrix components (EMC) as well as degradation and clearance of newly synthesized products. Immunohistochemical studies have shown the increased deposition of collagens in giant papillae of VKC patients, possibly as a result of increased expression of growth factors, which may stimulate resident fibroblasts to produce extracellular matrix proteins. The predominant collagens present in giant papillae are types I and III. Both IL-4 and IL-13 have been reported to activate conjunctival fibroblasts to produce collagens I and III, while INF- may have an inhibitory activity on fibroblasts.

Growth factors are known to regulate the expression of integrins, collagens and ECM components. Expression of NGF, VEGF, TGFb, FGF, PDGF and EGF is upregulated in the conjunctiva of VKC patients. 9. Metalloproteases in ocular allergy

MMPs are a family of zinc- and calcium-dependent enzymes involved in many physiological and pathological processes, including tumor progression and metastasis, inflammatory diseases, and wound healing. MMPs help support the extravasation and infiltration of leukocytes through limited proteolysis of basement membranes and matrix material. Their increased production and activation, or imbalance between MMPs and their natural tissue inhibitors, TIMP, are all probably involved in the pathogenesis of conjunctival inflammation, remodeling and corneal changes in VKC. Inflammatory cells, particularly eosinophils, and structural cells are the probable cellular source of these enzymes.

Both proforms and active forms of MMP-1, MMP-2 and MMP-9 are present in tear fluids of patients with VKC, while only the inactive proforms are present in normal non-allergic tears.

Different patterns of MMP expression seem to characterize different tissues undergoing similar processes of chronic allergic inflammation: Compared to normal tissues, increased immunostaining of MMP-1, MMP-3, MMP-9 and MMP-13 were found in VKC and increased MMP-1 and MMP-9 in nasal polyps. Conversely in asthmatic tissues, a significant increased staining of MMP-13 was observed only in the epithelium, along with a modest increase of MMP-3 and MMP-9 in the stroma. These finding were associated with a higher presence of inflammatory cells (EG-2+ and CD4+ cells) in the stroma of VKC patients compared with that of nasal polyps and asthmatic patients.

Both MMP-9 and MMP-3 are effective proteoglycanases, cleaving the core protein of proteoglycans. The cleavage of bound latent growth factors, such as FGF or TGF- , from proteoglycan storage sites would potentially contribute to fibroblast proliferation and the development of subepithelial fibrosis.

10. Dry Eye

Dry eye is one of the leading causes of patient visits to the eye clinic and one of the most frequent pathological conditions in ophthalmology. The prevalence of dry eye revolves around 14 to 33% of individuals after the 6th decade of age. The incidence rate at which the diagnosis is made is influenced by the criteria used.

The 2007 Report of the Dry Eye Workshop (Ocul Surf 2007;5[2]:65-204) proposed the following definition: “Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface”. Dry eye is not only associated with events occurring locally in the eye. It can be also the reflection of a systemic disease. The composition of tear fluid may be altered and the tear volume may or may not be reduced. A variety of causes are responsible for the clinical features and symptoms associated with the condition of dry eye. To reflect the above diversity, the term tear dysfunction syndrome (TDS) was proposed for these complex conditions. Symptoms: The symptoms can range from mild irritation to severe ocular discomfort and pain that affects the patients’ life style. Often there may be a great discrepancy between symptoms, which may be very severe and the clinical signs, which may be very mild. The reported symptoms may include part or all of the following: discomfort, irritation, foreign-body sensation, burning, stinging, grittiness, transient visual blurring, stickiness with stringy discharge, light sensitivity, itching, redness and heaviness of the lids. Severe pain is not a typical feature of dry eye. Symptoms of dry eye can be aggravated by a number of environmental factors (air conditioner, air travel), low humidity and the blowing of hot air as from heaters or in cars or beside a live fire. Some patients complain of “stuck lids with difficulty to get their eyes open in the morning”.

Signs: Typical signs of dry eye include a narrow or absent tear meniscus along the lid margin at the slit lamp, superficial fine and/or coarse punctate erosions affecting the inferior third of the cornea and bulbar conjunctiva, filamentary keratitis, mucus plaques and conjunctival hyperemia. Evidence of anterior or posterior blepharitis in the form of lid margin hyperemia, pouting or clogged meibomian gland orifices, scales, crusts, telangiectasia and madarosis of lashes may be visible. Blink abnormalities such as infrequent blinking, incomplete blinking and flick blinking should be looked for and detected. Other abnormalities that result in inadequate tear distribution (conjunctival chalasis, pingeucula, neoplasia) may be observed. Today, more patients with dry eye condition have a history of past or recent refractive surgery. It is expected that the number of these patients will grow steadily in the years to come.

Treatment of dry eye: The use of tear substitutes is the first option for the management of patients with mild TDS. The choice of tear substitute is determined by patient tolerance, drug effect and the subjective feeling of the patient. Any underlying ocular or systemic condition including the use of any offending systemic medication should be investigated early. In patients with moderate symptoms (intermediate severity) tear substitutes without preservatives are to be recommended. When patients complain of increased intensity of symptoms on waking, the use of gels or ointments during sleep hours may help. In patients with severe dry eye symptoms and signs, punctal occlusion is to be considered apart from the above measures. In the presence of associated blepharitis, regardless of severity, treatment consists mainly of permanent lid toilet, warm compresses and oral tetracyclines are essential measures to be implemented along with the other modalities. Since the pathology of dry eye/TDS is also associated with inflammatory reactions, anti-inflammatory strategies can possibly benefit treatment outcomes. To this purpose, cyclosporin A (CsA) (0.05%) eye drops have been found beneficial and have been approved for the treatment of dry eye/TDS in the USA. Topical steroids may also be used in the presence of acute inflammatory exacerbations. Their use however, remains controversial due to their far reaching potential for inducing secondary complications. Table 3: Treatment principles of dry eye

1. Treatment of underlying and associated conditions when possible 2. Elimination or control of environmental or aggravating factors 3. Tear substitution 4. Suppression of inflammation 5. Decreasing tears evacuation. 6. Surgical intervention as applicable

11. Management of ocular allergy

The most common diseases, SAC and PAC, are classic IgE-mediated disorders, in which the therapeutic focus is mostly confined to the suppression of mast cells, their degranulation and the effects of histamine and other mast cell derived mediators. Conversely, severe chronic disorders such as VKC and AKC are both IgE- and T cell- mediated, leading to a chronic inflammation where eosinophil, lymphocyte and structural cell activation characterizes the conjunctival allergic reaction. In these cases, stabilization of mast cells and histamine or other mediator receptor antagonists are frequently insufficient for control of conjunctival inflammation.

Currently available topical drugs for allergic conjunctivitis belong to different pharmacological classes (Table 3): vasoconstrictors, antihistamines, mast cell stabilizers, ‘dual-acting’ agents (with antihistaminic and mast cell stabilizing properties), non-steroidal anti-inflammatory agents. Corticosteroids are usually not needed in SAC and PAC, and may have potential important side effects if used for periods longer than occasional short cycles to control severe recurrences, if any. In SAC and PAC associated with allergic rhinitis –which represent the majority of cases- topical nasal steroids (and particularly new molecules with low systemic bioavailability, such as mometasone furoate and fluticasone furoate) have been shown to control the nasal-ocular reflex component of eye symptoms without increasing the risk of cataracts or of an increased ocular pressure.

Avoidance of the offending allergens, when practically feasible, should always be the primary therapeutic measure. Non-pharmacologic treatments include tear substitutes and lid hygiene to wash out allergens and mediators from the ocular surface combined with cold compresses for decongestion. Olopatadine, ketotifen, epinastine and azelastine, which have antihistamine, mast cell stabilizing and additional anti- inflammatory properties (called “double or multiple action”) are presently available and show evident benefits. Mast cell stabilizers (cromoglycate derivatives) or antihistamines may be used in mild forms of the disease.

Decongestant/vasoconstrictors have little place in the pharmacological treatment of SAC and PAC except for the immediate removal of injection for cosmetic reasons, but do have an adverse effect profile locally (glaucoma) and systemically (hypertension).

Corticosteroid formulations (including the so called “soft steroids”) should be reserved for and carefully used only in the most severe cases which are refractive to other types of medications. The use of non steroidal anti inflammatory drugs (NSAIDS) can be considered, in some cases, for a short period of time, but have had limited effect on ocular pruritus.

Systemic antihistamines should be used only in patients with concomitant major non-ocular allergic manifestations.

Treatment of VKC requires a multiple approach attitude that includes conservative measures and the use of drugs. Patients and parents should be made aware of the long duration of disease, the chronic evolution and its possible complications. The potential benefits of frequent hand and face washing along with avoiding eye rubbing have to be emphasized. Exposure to non-specific triggering factors such as sun, wind and salt water should be avoided. The use of sunglasses, hats with visors and swimming goggles are recommended. The use of drugs should be well planned in patients with a history of VKC. Mast cell stabilizers including disodium cromoglycate, nedocromil, spaglumic acid, lodoxamide and topical antihistamines can be initially used and continued at a decreased frequency if effective. Newer topical formulations with combined mast cell stabilizing properties and histamine receptor antagonist, as olopatadine and ketotifen, may be more efficient. Non-steroidal anti-inflammatory drugs such as ketorolac, diclofenac and pranoprofen may be considered for steroid-sparing. These drugs however, should be used for a limited period of time only. Oral aspirin at doses of 0.5-1 gram/day may be beneficial. Moderate to severe VKC may require repeated topical steroid treatment to down- regulate conjunctival inflammation. “Soft corticosteroids” such as clobetasone, desonide, fluorometholone, loteprednol and rimexolone may be considered as first corticosteroid preparations and used carefully. Doses are chosen based on the inflammatory state. Instillation frequency of 4 times/day for 10-15 days is recommended. The “harder” corticosteroids formulations of Prednisolone, Dexamethasone or Betamethasone have to be used as a second line and as a last resort for the management of the most severe cases. Cyclosporine A (CsA) 1% or 2% emulsion in castor or olive oil is the first choice for treating severe VKC and can serve as a good alternative to steroids. Systemic treatment with oral antihistamines or anti-leukotrienes can reduce the severity of ocular flare-up of disease manifestations in patients with additional non ocular allergies. Severe cases not responding to topical therapy may require treatment with systemic corticosteroids (prednisone 1mg/kg a day) for a short period of time. Corneal complications have to be carefully monitored and anti-inflammatory therapy adjusted accordingly. Secondary microbial infection can be prevented by prescription of antibiotics for a period of one week. Surgical removal of corneal plaques is recommended to alleviate severe symptoms and to allow for corneal re-epithelization. Giant papillae excision with or without combined cryotherapy may be indicated in cases of mechanical pseudoptosis or the presence of coarse giant papillae and continuous active disease. More invasive procedures such as oral mucosal grafting should be avoided. Amniotic membrane transplantation, on the other hand, may be considered to promote healing. If a systemic hypersensitivity to identified allergens exists, specific immunotherapy may be considered.

The overall management of AKC involves a multidisciplinary approach. Identification of allergens by skin or blood testing is important for preventive measures. Cold compresses and regular lubrication may provide symptomatic relief. Tear substitutes help remove and reduce the effects of allergens and the release of mediators reducing the potential for corneal involvement. Lid hygiene is essential. It prevents infectious blepharitis, improves meibomian gland function and tear-film quality. Prolonged use of topical anti-allergic drugs and mast cell stabilizers may be required. Topical antihistamines may be useful for the relief of itching, redness and mucous discharge. Topical corticosteroids are effective, but should be used only when other topical treatments are not providing sufficient benefits. Brief periods of intensive topical corticosteroid therapy are often necessary to control the local inflammation in severe cases. Topical cyclosporine may improve the signs and symptoms in steroid- dependent patients, thus reducing the need for corticosteroids to control the ocular surface inflammation. Systemic antihistamines are often used to reduce itching and control widespread inflammation in patients with active skin involvement. Systemic corticosteroids may be necessary in severe cases. Systemic cyclosporine may be an alternative to systemic corticosteroids for the relief of severe AKC.

Prevention is the most important management step in GPC. In patients with contact lenses GPC, discontinuation of lens wear may be necessary. Restarting lens wear with a different type or design may be tried. Mild GPC symptoms may be alleviated by mast cell stabilizers or antihistamine agents. Tear substitutes can be used to minimize conjunctival trauma.

Table 4. Topical Ocular Allergy Medications

Class Drug Indication Comments Vasoconstrictor/ Naphazoline/ - Short duration of action Antihistamine Pheniramine - Rapid onset of action - Tachyphylaxis Combinations - Mydriasis - Ocular irritation - Hypersensitivity - Hypertension - Potential for inappropriate patient use Antihistamines Levocabastine - Rapid onset of action Emedastine - Relief of itching - Short duration of action - Relief of signs and symptoms of SAC Mast cell Cromolyn - Relief of signs and - Long-term usage stabilizers Nedocromil symptoms - Slow onset of action Lodoxamide - Prophylactic dosing NAAGA Pemirolast

Antihistamine/ Azelastine - Treatment of signs and - Bitter taste (azelastine) mast cell Epinastine symptoms of SAC - Non reported serious stabilizers Ketotifen - Rapid onset of action side effects (dual-acting) Olopatadine - Long duration of action - Excellent comfort Corticosteroids Loteprednol - Treatment of allergic - Risk for long-term side Fluormetho- inflammation effects lone - Use in severe forms of - No mast cell Desonide allergies stabilization Rimexolon - Potential for inappropriate patient use - Requires close monitoring References and recommended reading

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