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Acta Ophthalmologica 2012, Vol.38(1-2) ISSN 1452-3868 Pregledni rad UDK.617.711-002 ALLERGIC KERATOCONJUNCTIVITIS – CLINICAL, DIAGNOSTIC AND THERAPEUTIC ENTITIES Mirjana Janićijević-Petrović Clinic of Ophthalmology, Clinical Centre Kragujevac, Faculty of Medical Sciences, University of Kragujevac, Serbia Eye allergy is a hypersensitivity reaction of the eye to specific allergens and the atopy is determined by genetic predisposition to allergic reaction of the eye to a number of allergens. Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are the most common forms of ocular allergies (20% of the population). Vernal keratoconjunctivitis is a disease which tends to appear in warm weather months and also in warm climates. Atopic keratoconjunctivitis (AKC) is a bilateral chronic inflammatory disease of ocular surface and eyelid. Contact allergy (contact dermatitis) is not an IgE mediated allergy and can be considered in a different category than aforementioned allergic conditions. The mainstay of management of ocular allergy involves the use of anti-allergic therapeutic agents such as antihistamine, mast cell stabilizers and multiple action anti-allergic agents. Acta Ophthalmologica 2012;38(1-2):36-41. Key words: conjunctiva, inflammation, treatment Introduction Eye allergy is hypersensitivity reaction of the eyes to contact with allergens and the atopy is determined by genetic predisposition to allergic reaction of the eye to a number of allergens. The clinical presentation of various forms of ocular allergy can be classified as: seasonal allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratocongiuntivitis and giant papillary conjunctivitis (1). Vernal keratoconju-nctivitis (VKC) is self limiting, chronic inflamma-tory disease and it mainly affects boys aged 4 -14 years. The patients present the phases characterized by exacerbation of inflammatory symptoms with 36 a consequent decline of the quality of life. The endocrine, genetic, neurogenic, environmental and socioeconomic risk factors have been identified (2). Immunological and clinical profile of patients affected by VKC was defined by family medical history of autoimmune disorders and autoimmunity pattern (Systemic lupus erythematosus, Hashimoto's thyroiditis, psoriasis, rheumatoid arthritis, etc). Positive analyses of antinuclear antibodies and family history of autoimmune disorders of patients with those diseases may help clinicians to understand association between ocular inflammatory disease, systemic autoimmune disorders and atopic condition (3, 4). It represents a bilateral, Acta Ophthalmologica 2012, 38(1-2) recurrent, allergic disease of conjunctiva characterized by limbal gelatinous hypertrophy and known giant conjunctiva papillae (4). Seasonal allergic conjunctivitis Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are the most common forms of ocular allergies (20% of the population). Contact lenses or ocular prosthesis associated with giant papillary conjunctivitis (GPC) are included in the group of ocular allergy. They should not be considered as real allergic diseases, but as chronic ocular microtrauma related disorders, which need to be managed by ophthalmologists (5, 6). Allergic conjunctivitis is caused by an allergen induced inflammatory response in which allergens interact with IgE bound to sensitized mast cells resulting in clinical ocular allergic expression. The pathogenesis of allergic conjunctivitis is predominantly an IgE mediated hypersensitivity reaction. Activation of mast cells induces enhanced tear levels of histamine, tryptase, prostaglandins, leukotriens and others (early response lasts clinically 20–30 min). Mast cell degranulation induces activation of vascular endothelial cells, which in turn expresses chemokines and adhesion molecules such as intercellular adhesion molecule and vascular cell adhesion molecule. Secreted chemokines include regulations upon activation of normal T-cell expressed chemokines, monocyte chemoattractant protein, interleukin8, eotaxin, macrophage inflammatory protein-1-alpha, etc (7, 8). Signs and symptoms usually occur in the spring and summer (airborne pollens), and generally abate during the winter months, but can occur throughout the year with exposure to perennial allergens. Diagnostic features of SAC and PAC consist of itching, redness, swelling of the conjunctiva (chemoses). Conjunctival injection tends to be mild to moderate. Corneal involvement is very rare. Itching is a fairly consistent symptom of SAC and PAC (7, 8). Vernal keratoconjunctivitis Vernal keratoconjunctivitis is a disease which tends to appear in warm weather months and also in warm climates. The prevalence of VKC in Europe ranges from 1.2 to 10.6 cases per 10,000 population, although the prevalence of associated corneal complications is 0.3 - 2.3 per 10,000 population. VKC has three clinical forms: palpebral, limbal and mixed (with preponderance in males) (9). It is a chronic allergic inflammation of the ocular surface mediated mainly by Th2 lymphocyte; in a complex pathogenesis have a role of the overexpression of mast cells, eosinophils, neutrophils, Th2 derived cytokines, chemokines, adhesion molecules, growth factors, fibroblast and lymphocytes. IL-4 and IL-13 are involved in the formation of giant papillae by inducing the production of extra-cellular matrix and the proliferation of conjunctival fibroblasts (9, 10). Symptoms include ocular itching, redness, swelling and discharge. Itching may be quite severe, and even incapacitating. The most characteristic sign is giant papillae on the upper tarsal conjunctiva. These ‘‘cobblestone-like‘‘ swellings can measure several millimeters in diameter, and 10–20 of them are found on tarsal conjunctiva and they can be seen easily by ‘‘flipping‘‘ the upper eyelid. The giant papillae are filled with inflammatory cells, edema and mucous. Neutrophils, plasma cells, mononuclear cells and eosinophils are found in abundance. Mast cells may also be found in the conjunctiva epithelium. The tears of VKC patients contain high levels of IgE and mast cell mediators (10). A punctate keratitis, known as keratitis epithelialis vernalis of El Tobgy, may begin in the central cornea. Vernal plaques may interfere with vision and lead to central scarring of the cornea. Plaques can be removed by superficial keratectomy, but they rarely resolve without surgical therapy. Histologically, plaques are consisted of mucin and epithelial cells, which are literally ground into the central cornea. Tranta’s dots consist of clumps of necrotic eosinophils, neutrophils and epithelial cells. The dots represent almost pure collections of eosinophils. Trantas dots tend to appear when VKC is active, and disappear when symptoms abate (10). Shield ulcers can occur in the superior sectors of the cornea; these are noninfectious, ovalshaped circumscribed epithelial ulcers with underlying stromal opacification. Corneal epithelial punctate keratitis may evolve to macroerosion, ulcers and plaques, which are all expressions of epithelial toxicity 37 Acta Ophthalmologica 2011, 37(1-2) extricated by epitheliotoxic factors released by activated eosinophils (11). Atopic keratoconjunctivitis Atopic keratoconjunctivitis (AKC) is a bilateral chronic inflammatory disease of ocular surface and eyelid. Its pathomechanism involves both a chronic degranulation of mast cell mediated by IgE and immune mechanisms mediated by Th1 and Th2 lymphocyte derived cytokines. It is considered to be the ocular counterpart of atopic dermatitis or atopic eczema, etc (12). Over time, AKC can lead to loss of vision due to corneal complications. The classification, histology, ocular examination findings and complications of AKC are described herein, as well as the roles and interactions of inflammatory cells involved (13). Eczematous lesions are itchy, and scratching them makes them itchier. The eyelid skin may be chemotic with fine sandpaper like texture. AKC patients may develop atopic cataracts. Typically, these are anterior, shield like cataracts, but nuclear, cortical and posterior subcapsular cataracts may develop. VKC resolves by age of 20 years, whereas AKC can persist throughout life. Many patients with AKC (45%) have skin test or allergic sorbent test negative to common allergens (13). Contact allergy and giant papillary conjunctivitis Contact allergy (contact dermatitis) is not an IgE mediated allergy and can be considered in a different category than the aforementioned allergic conditions. It is a type-IV delayed hypersensitivity response that occurs through interaction of antigens with Th1 and Th2 cell subsets followed by release of cytokines. It consists of two phases: sensitization (at the first exposition to allergen, with production of memory Tlymphocytes) and elicitation of the inflammatory response (at the re-exposure to antigen, mediated by the activation of memory allergen-specific T- lymphocytes). In the sensitization phase, antigen presenting cells processed antigen - MHC class II complex interacts with T-lymphocytes, resulting in the differentiation of CD4+ T-lymphocyte into memory T-lymphocyte. In the elicitation 38 phase, the interaction between the antigen MHC-II complex and memory T-cells stimulates the proliferation of T-cells. The memory T-lymphocytes during proliferation release cytokines. Th2 derived cytokine, such as IL-4 and IL-5, participates in the activation and chemotaxis of eosinophils. Two novel Th cell subsets, IL-17-producing Th cells (Th17 cells) and regulatory T cells (Treg cells) are also found to be contributors in the pathogenesis of conjunctivitis (14). Contact allergy involves the ocular surface, eyelids and periocular skin. Examples of allergens include poison ivy, poison oak, neomycin, nickel, latex, atropine, etc. The delay in development of the reaction is due to the slow migration of lymphocytes to the antigen depot. Contact allergic reactions are generally associated with itching. Treatment consists of withdrawing and avoiding contact with allergen. Severe reactions can be treated with topical or systemic corticosteroids (14). Giant papillary conjunctivitis (GPC) is an inflammatory disease characterized by papillary hypertrophy of the superior tarsal conjunctiva, but there is no significant corneal involvement. GPC is not an allergic disease; the incidence of systemic allergy in patients is similar to that of general population, and the stimuli for papillary conjunctiva changes are inert substances rather than allergens. GPC may be caused by limbal sutures, contact lenses, ocular prostheses, limbal dermoids, etc (14). The conjunctival tissues may contain mast cells, basophils, or eosinophils, but not to extent of an allergic reaction. There is no increase of IgE or histaimine in the tears of patients. It appears that protein build-up on the surface of contact lenses, and irregular edges were the main reason for close association between contact lenses and GPC, by immune or mechanical mechanisms: in particular protein deposits on the surface of contact lens could become antigenic and stimulate the production of IgE; mechanical trauma and chronic irritation can determine release of some mediators (CXCL8 and TNF-α) from injured conjunctival epithelial cells (14). About diagnoses The diagnosis of ocular allergy is primarily clinical, but there are laboratory Acta Ophthalmologica 2012, 38(1-2) tests that can be useful in supporting the diagnosis. Allergists can perform skin testing for specific allergens by scratch tests or intradermal injections of allergen. In-vitro tests for IgE antibodies to specific allergens are widely used. Allergic tests would help in differentiating intrinsic and extrinsic forms and would, therefore be helpful in the treatments. In the single dose allergen provocation examination, the patients responded with a typical IgE mediated allergic reaction. Signs and symptoms from both eyes were graded at baseline and at 10 min, 8 and 48 h after conjunctiva provocation. Tear fluid was collected from both eyes for cytokine analyses at baseline and at 8 and 48 h. A significant change in clinical symptoms and signs (redness, chemosis) was evident 10 min after provocation compared with baseline and compared with the unprovoked eye in allergic patients. A significant increase for IFN-γ and IL-6 and a near significant increase for IL-10 were noticed in tear fluid of challenged eye at 48 h after provocation vs. baseline and vs. the control eye for IFNγ, IL-6 and IL-10 in allergic patients (15,16). About therapy The mainstay of management of ocular allergy involves the use of anti-allergic therapeutic agents such as antihistamine, mast cell stabilizers and multiple action antiallergic agents. Topical antihistamines competitively and reversibly block histamine receptors and relieve itching and redness but only for a short time. A limited duration of action requires frequent dosing of up to 4 times per day, and topical antihistamines may be irritating to the eye, especially with prolonged use. Combination treatments using decongestants with antihistamines have been shown to be more effective, and are administered to the eye as drops up to 4 times daily. Decongestants act primarily as vasoconstrictors and are effective in reducing erythema, however, adverse effects include burning and stinging on instillation, mydriasis, and rebound hyperemia or conjunctivitis medicamentosa with chronic use (17). Mast cell stabilizers have a mechanism of action that is unclear. They may increase calcium influx into the cell preventing membrane changes and/or they may reduce membrane fluidity prior to mast cell degranulation. Final result is a decrease in degranulation of mast cells, which prevents release of histamine and other chemotactic factors that are present in the preformed and newly formed state. Mast cell stabilizers do not relieve existing symptoms and they can be used on a prophylactic basis to prevent mast cell degranulation with subsequent exposure to allergen. Mast-cell stabilizing medications can also be applied topically to the eye, and may be suitable for more severe forms of conjunctivitis. They require a loading period during which they must be applied before the antigen exposure. Therefore, poor compliance should be taken into account as a possible drawback (18). In recent years several multimodal anti-allergic agents have been introduced, such as olopatadine, ketotifen, azelastine and epinastine that exert multiple pharmacological effects such as histamine receptor antagonist action, stabilize mast-cell degranulation and suppress activation and infiltration of eosinophils (19). Non-steroidal anti-inflammatory drugs (NSAIDs) can be used as additive drugs, in order to reduce the conjunctiva hyperemia and the pruritus, related in particular to prostaglandin D2 and prostaglandin E2 (20). Corticosteroids used in the more severe variants of ocular allergy are also effective in the treatment of acute and chronic clinic forms. Corticosteroids possess immunosuppressive and anti-proliferative properties since they can hinder transcription factor that regulates the transcription of Th2derived cytokine genes and differentiation of activated T-lymphocytes into Th2-lymphocytes. But, these agents are appropriate for short courses (2 weeks); if needed for longer durations, an eye examination should be carried out, including baseline assessment of cataracts and intraocular pressure measurement (21). The efficacy of immunotherapy against ocular symptoms precipitated by conjunctiva antigen challenges was originally demonstrated at the beginning of the 20th century and this well-established method may be considered for the long-term control of ocular allergy (22). Traditionally, immunotherapy is delivered via subcutaneous injections. Sublingual (oral) immunotherapy (SLIT) is gaining momentum among allergists. SLIT requires 39 Acta Ophthalmologica 2011, 37(1-2) further evaluation for ocular allergy relief. It has been shown to control ocular signs and symptoms, although ocular symptoms may respond less well than nasal symptoms. Oral antihistamines are commonly used for the therapy of nasal and ocular allergy symptoms. Second-generation antihistamines can, however, induce ocular drying, which may impair the protective barrier provided by the ocular tear film and thus actually worsen allergic symptoms. Intranasal corticosteroids are highly effective for treating nasal symptoms of allergic rhinitis, but there is no consistent evidence that they may also be effective for the treatment of ocular symptoms (22). Current evidence supports the use of cyclosporin A, topically or systemically, as well tolerated and effective steroid sparing agent. Seasonal atopic conjunctivitis is treated with antihistamines, cromoglycate and short courses of corticosteroids, in severe cases with subcutaneous or sublingual immunotherapy. Chronic conjunctivitis requires yearround treatment with mast cell stabilizers, antihistamines or topical corticosteroids. For atopic keratoconjunctivitis corticosteroid and, if necessary, cyclosporine eye drops are needed. First-line therapy of vernal conjunctivitis involves mast cell stabilizers and, if necessary, corticosteroid eye drops. Treatment of non-allergic eosinophilic conjunctivitis involves mast cell stabilizers, corticosteroid and cyclosporine eye drops (21). Other modes of treatment include acetylcysteine (mucus, plaque), surface excimer laser - keratectomy, tarsal steroid injections (dexa, triamcinolon), cryotherapy, excision of giant papillae, amniotic membrane transplantation, etc. Treatment is symptomatic and causal, with the use of artificial tears, cold compresses, dark glasses, treatment of associated blepharitis, etc (22). Understanding the immunepathogenesis of atopic disease has already influenced therapy and is essential to the development of future immune-modulating treatments. The current challenge is to find more specific topical and systemic immunemodulating therapies with a better side effect profile. Ocular allergy represents one of the most common ocular conditions encountered in clinical work, diagnoses and therapy, and represents the common conditions encountered by ophthalmologists, allergists and other causal specialists. Literature 1. Hodges MG, Keane-Myers AM. Classification of ocular allergy. Curr Opin Allergy Clin Immunol 2007;7(5):424-8. 2. De Smedt S, Wildner G, Kestelyn P. Vernal keratoconjunctivitis: an update. Br J Ophthalmol 2013;97(1):9-14. 3. Zicari AM, Nebbioso M, Lollobrigida V, Bardanzellu F, Celani C, Occasi F, Cesoni Marcelli A, Duse M. Vernal keratoconjunctivitis: atopy and autoimmunity. Eur Rev Med Pharmacol Sci 2013;17(10):1419-23. 4. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy: a schematic approach to different clinical entities. Curr Opin Allergy Clin Immunol 2007;7(5):429-35. 5. Bogacka E. Epidemiology of allergic eye diseases. Pol Merkur Lekarski 2003; 14(84):714-5. 6. Marback PM, de Freitas D, Paranhos Junior A, Belfort Junior R. Epidemiological and clinical features of allergic conjunctivitis in a reference center. Arq Bras Oftalmol 2007; 70(2):312-6. 40 7. Offiah I, Calder VL. Immune mechanisms in allergic eye diseases: what is new? Curr Opin Allergy Clin Immunol 2009;9(5):477-81. 8. Manzouri B, Ohbayashi M, Leonardi A, Fattah D, Larkin DF, Ono SJ. Characterisation of the phenotype and function of monocytederived dendritic cells in allergic conjunctiva. Br J Ophthalmol 2010;94(12):1662-7. 9. Kari O, Saari KM. Review Diagnostics and new developments in the treatment of ocular allergies. Curr Allergy Asthma Rep 2012; 12(3):232-9. 10. Messmer EM. Review Therapeutic options in vernal keratoconjunctivitis. Ophthalmologe 2009;106(6):557-61. 11. Pucci N, Caputo R, Mori F, De Libero C, Di Grande L, Massai C, Bernardini R, Novembre E. Long-term safety and efficacy of topical cyclosporine in 156 children with vernal keratoconjunctivitis. Int J Immunopathol Pharmacol 2010; 23(3):865-71. 12. Sy H, Bielory L. Atopic keratoconjunctivitis. Allergy Asthma Proc 2013;34(1):33-41. Acta Ophthalmologica 2012, 38(1-2) 13. Guglielmetti S, Dart JK, Calder V. Atopic keratoconjunctivitis and atopic dermatitis. Curr Opin Allergy Clin Immunol 2010; 10(5): 478-85. 14. Siddique M, Manzouri B, Flynn TH, Ono SJ. Allergy and contact lenses. Chem Immunol Allergy 2007;92:166-75. 15. Nivenius E, Van der Ploeg I, Gafvelin G, Van Hage M, Montan PG. Conjunctival provocation with airborne allergen in patients with atopic keratoconjunctivitis. Clin Exp Allerg 2012;42(1):58-65. 16. Bonini S, Bonini S, Berruto A, Tomassini M, Carlesimo S, Bucci MG, Balsano F. Review Conjunctival provocation test as a model for the study of allergy and inflammation in humans. Int Arch Allergy Appl Immunol 1989;88(1-2):144-8. 17. Kari O, Saari KM. Treatment of eye allergies. Duodecim 2012;128(3):291-7. 18. Cornish KS, Gregory ME, Ramaesh K. Systemic cyclosporin A in severe atopic 19. 20. 21. 22. keratoconjunctivitis. Eur J Ophthalmol 2010; 20(5):844-51. Anzaar F, Gallagher MJ, Bhat P, Arif M, Farooqui S, Foster CS. Use of systemic Tlymphocyte signal transduction inhibitors in the treatment of atopic keratoconjunctivitis. Cornea 2008;27(8):884-8. Williams PB, Sheppard JD Jr. Review Omalizumab: a future innovation for treatment of severe ocular allergy? Expert Opin Biol Ther 2005;5(12):1603-9. Vitaliti G, Leonardi S, del Giudice Miraglia M, Salpietro A, Artusio L, Caimmi D, Arrigo T, Salpietro C, Ciprandi G, La Rosa M. Mucosal immunity and sublingual immunotherapy in respiratory disorders. J Biol Regul Homeost Agents 2012;39:85–94. Mishra GP, Tamboli V, Jawla J, Mitra AK. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2011;39:26–36.. ALERGIJSKI KERATOKONJUNKTIVITIS- KLINIČKI, DIJAGNOSTIČKI I TERAPIJSKI ENTITETI Mirjana A Janićijević-Petrović Oftalmološka klinika KC Kragujevac Medicinski fakultet, Univerziteta u Kragujevcu, Srbija Alergija oka je reakcija hipersenzitiviteta na alergen i može biti determinisana predispozicijom na alergijsku reakciju oka na mnogobrojne antigene. U radu se govori o najčešćim alergijskim reakcijama konjunktive i njihovim kliničkim manifestacaijama. Sezonski alegijski konjunktivitis je najčešća forma okularne alergije. Vernalni keratokonjunktivitis je bolest koja se najčešće javlja u toplim mesecima i toplim klimatskim uslovima. Atopijski keratokonjunktivitis se opisuje kao hronična alergijska bolest površine oka i kapaka, a kontaktna alergija može nastati u različitim kategorijama aregijskih stanja oka. U terapiji ovih alergijskih stanja koriste se antialergijski terapeutski agensi, kao što su antihistaminici, stabilizatori mastocita , kortikosteroidi i dr. Acta Ophthalmologica 2012;38(1-2):36-41. Key words: conjunctiva, inflammation, treatment Kontakt: Mirjana A Janićijević-Petrović Medicinski fakultet, Univerziteta u Kragujevcu, Srbija 41