of Ocular Surface Disease Dry Eye and Molecular Mechanism of Ocular Surface Disease 여의도성모병원 김 현 승

외래 환자들 중 건성안 환자가 차지하는 비율은? 40% 이상 10% 미만 10.2% (20명) 9.2% (18명) 30~40% 외래 환자들 중 건성안 환자가 차지하는 비율은? 40% 이상 10.2% (20명) 10% 미만 9.2% (18명) 30~40% 15.8% (31명) 10~20% 27.0% (53명) 20~30% 37.8% (74명) 조사대상 ; 197명 안과 전문의 2006년 한국외안부연구회 건성안 심포지움

CONTENTS 01 Concepts and Definition 02 Classification 03 Treatment Guideline 04 Molecular Mechanism 05 Related Experiment

Instability of Tear film Definition of Dry Eye National Eye Institute (1994) Tear Deficiency or Excessive Evaporation Instability of Tear film Damage to the Ocular surface Symptoms of Ocular discomfort

Lacrimal Gland Functional Unit Ocular Surface and Lacrimal Gland Functional Unit Emotion  Neurogenic Inflammation Immune Activation Role of Androgens Maintain Anti-inflammatory State of the Functional Unit Normalization of Meibomian Lipid Composition Restoration of Ocular Surface CNS CN VII Efferent Parasympathetic     CN V1 Afferent  “Tears on Demand” Tear Support & Maintain Ocular Surface Pflugfelder at al. 1998, Cornea

Pathology in Dry Eye Patients Langerhans cells in conjunctiva Abnormal expression of class II HLA DR Ag Abnormal expression ICAM-1 protein Abnormal increase of dendritic cells Baudouin C. The Pathology of Dry Eye. Surv Ophthalmol 45(Suppl 2);2001:S211–20. Gao J, Morgan G, Tieu D, Schwalb TA, Luo JY, Wheeler LA, Stern ME. ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjögrens syndrome-like MRL/lpr mice. Exper Eye Res 2004;78:823–835.

Interrupted Secretomotor Tears Inflame Ocular Surface Dry Eye Disease; “An Immune-Mediated Inflammatory Disorder” Interrupted Secretomotor Nerve Impulses Lacrimal Glands: Neurogenic inflammation T- cell activation Cytokine secretion into tears Tears Inflame Ocular Surface Cytokines Disrupt Neural Arc Pflugfelder SC, Cornea, 2000

- 17 international specialists on dry eye in Delphi Panel Dysfunctional Tear Syndrome A Delphi Approach to Treatment Recommendations - 17 international specialists on dry eye in Delphi Panel Pupose ▶ current classification of aqueous-deficient versus evaporative dry eye failed to incorporate inflammatory mechanisms Proposes a new terminology for dry eye disease from recent pathophysiologic findings ▶ DTS (Dysfunctional Tear Syndrome) More accurately reflected pathophysiological events in dry ey Severity levels of dry eye disease relied on symptoms & signs Treatment recommendations for severity levels in a stepwise approach Easier approach for general eye care practitioners Behrens A et al. Cornea 2006

International Dry Eye Work Shop (2007) Multi factorial disease Symptoms of Discomfort & Visual Disturbance Tear Film Instability Results in Multi factorial disease Increased Osmolarity of the Tear Film Accompanied by Inflammation Of the Ocular Surface 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. The Definition and Classification of Dry Eye Disease: Report of the definition and classification subcommittee of the international Dry Eye Workshop(2007) The Ocular Surface 2007;5:75-92

Classification of Dry Eye National Eye Institute (1994)

Delphi Panel Dry Eye Classification Dysfunctional Tear Syndrome With Lid Margin Disease Tear Distribution Without Lid Margin Disease Anterior Posterior Conjunctivochalasis Lid and Lash Malposition Elevated Surface Lesion Reduced or Incomplete Blinking Others Severity Level I Severity Level II Severity Level III Severity Level IV Behrens A et al., Cornea 2006;25:900-907

Delphi Panel Dry Eye Classification Level Sign & Symptom I Mild to moderate symptoms Mild to moderate conjunctival staining Unstable tear film II Visual signs Mild corneal punctate staining Conjunctival staining III Severe symptoms Marked corneal punctate staining Central corneal staining Filamentary keratitis IV Severe corneal staining, erosions Conjunctival scarring

International Dry Eye Work Shop (2007) 3 Classification A. Etiopathogenic B. Causative mechanism C. Severity Pflugfelder SC, et al, The Ocular Surface, 2007

Etiopathogenic Classification 2007 DEWS DRY EYE Aqueous deficient Evaporative Sjogran Syndrome Dry eye Intinsic Extrinsic Non-Sjogren Dry eye Meibomian Oil Deficiency Vit.A Deficiency Topical Drugs Preservatives Primary 병인적 분류 Lacrimal Dificiency Disorders of Lid Aperture Secondary Contact Lens Wear Lacrimal G. Duck Obstruction Low Blink Late Ocular Surface Disease (ex.Allergy) Reflux block Drug Action Accutane Systemic drugs

Causative Mechanism of Dry Eye

Severity Classification 2007 DEWS The Definition and Classification of Dry Eye Disease: Report of the definition and classification subcommittee of the international Dry Eye Workshop(2007) The Ocular Surface 2007;5:75-92

Delphi Panel Treatment Guideline Eliminate Environmental/Drug Factors Preserved Tears Control Allergy Dietary Modification (↑ Omega-3,6 FA) LEVEL 1 Unpreserved Tears Gels / PM Ointment Cyclosporin A Steroids Secretagogues LEVEL 2 Oral Tetracyclines Autologous Serum Punctal Plugs (after inflammation controlled) LEVEL 3 Systemic Immunosuppressives Topical Vitamin A Contact Lenses Moisture Goggles Surgery (tarsorrhapy, AMT) LEVEL 4

2007 DEWS Treatment Guideline Eliminate Environmental/ Dietary Modification Elimination of offending systemic medications Artificial tear substitutes, gels/ointments Eye lid therapy LEVEL 1 Anti-inammatories (Cyclosporin A, Steroids) Tetracyclines (for meibomianitis, rosacea) Punctal plugs Secretogogues Moisture chamber spectacles LEVEL 2 Serum Contact lenses Permanent punctal occlusion LEVEL 3 Systemic anti-inammatory agents Surgery (lid surgery, tarsorrhaphy; mucus membrane, salivary gland, amniotic membrane transplantation) LEVEL 4

One treatment used most frequently for dry eye Nichols JJ, CLSO, 2010

Treatment Guideline 한국형 가이드라인에 의한 분류 (가안)

Treatment Guideline 한국형 가이드라인에 의한 분류 (가안)

Treatment Guideline 한국형 가이드라인에 의한 분류 (가안)

NEI / Industry workshop 건성안의 개념 및 치료방침의 변화 눈물샘의 기능적 단위 NEI / Industry workshop / Delphi Panel 안구표면 시스템 Ocular Surface System Dry Eye Workshop 개념의 변화 FROM TO 염증요소를 제거 눈물성분의 자연적인 생성을 자극 - 안구표면상피의 건강과 방어기능 을 유지 단순히 인공누액으로 안구표면에 수분을 공급, 윤활작용을 호전 Paradigm Shift Management & Therapy of Dry Eye Disease. The Ocular Surface 2007;5:163-178

Molecualr Mechanism of Ocular Surface Disease in Dry Eye

Causative Mechanism of Dry Eye

Hyperosmolarity in Tear Fluid Hyperosmolarity has been recognized as a key factor in the pathogenesis of keratoconjunctivitis sicca (KCS) for decades Elevated tear fluid osmolarity has been referred to as the “gold standard” for diagnosis of dry eye Farris RL. Tear osmolarity--a new gold standard? Adv Exp Med Biol. 1994;350:495-503. The exact mechanism by which hyperosmolarity induced pathologic changes and irritation symptoms remained a mystery

Tear Osmolarity – A New Gold Standard? R. Linsy Farris, Adv Exp Med Biol. 1994;350:495-503.

Hyperosmolarity and Inflammation Hyperosmolarity has been reported to significantly increase production of inflammatory cytokines (such as IL-1) chemokines (such as IL-8) in human peripheral blood leukocytes, bronchial epithelial cells Shapiro L, Dinarello CA. Hyperosmotic stress as a stimulant for proinflammatory cytokine production. Exp Cell Res. 1997;231(2):354-62.. Hashimoto S, Matsumoto K, Gon Y, Nakayama T, Takeshita I, Horie T. Hyperosmolarity-induced interleukin-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase. Am J Respir Crit Care Med. 1999;159(2):634-40.

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