Dry Eye 여의도성모병원 R4 김태경/ Pf. 주천기

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

OSDI (Ocular Surface Disease Index) 2 OSDI (Ocular Surface Disease Index) LEVEL 1 LEVEL 2 LEVEL 3 LEVEL 4 Symptoms (OSDI score) 12-15 16-30 31-45 >45

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

- 건성안 연구 전문가들로 Delphi Panel구성 01, 안구건조증 이란? 새로운 건성안의 Delphi 개념 (2006) - 건성안 연구 전문가들로 Delphi Panel구성 ▶ 기존정의 (눈물부족 또는 증발) 가염증기전을설명하지못함 용어의 재정의필요 목적 ▶ DTS (Dysfunctional Tear Syndrome) 최근 건성안 연구에서 밝혀진 새로운 사실 반영 눈물기능 이상증에 대해 통일된 치료 방법의 알고리즘을 제시

- 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

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

Classification of Dry Eye National Eye Institute (1994)

Causative Mechanism of Dry Eye

J Fr. Ophtalmol., 2007; 30, 3, 239-246

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.

9 -2. Tear osmolarity 대상자 확인 measured by TearlabTM 1회용 disposable chip 사용 Lateral canthal area에서 tear meniscus에 접촉 Most significant single test for dry eye diagnosis Dry eye cut off value = 316 mosm 이상 Tear osmolarity : OD ( ) mosm / OS ( ) mosm TearlabTM

Desiccating stress demonstrated the evolution of hyperosmolarity in tear fluid. Hyperosmolarity stimulates a cascade of inflammatory events in the epithelial surface cells, involving MAP kinases and NFkB signalling pathways and the generation of inflammatory cytokines (IL-1α; -1β; TNF-α) and MMPs (MMP-9), which arise from or activate inflammatory cells at the ocular surface. There is evidence that these inflammatory events lead to apoptotic death of surface epithelial cells, including goblet cells; thus, goblet cell loss may be seen to be directly related to the effects of chronic inflammation. Goblet cell loss is a feature of every form of dry eye, and consistent with this is the demonstration of reduced levels of the gel mucin MUC5AC in dry eye.

Goblet Cell Density in Dry Eye Syndromes Normal Grade 1 Grade 2 Grade 3 Grade 4 Ralph RA. Conjunctival goblet cell density in normal subjects and in dry eye syndromes. Invest Ophthalmol 1975;14:299-302 Gilbard JP, Rossi SR. Tear lm and ocular surface changes in a rabbit model of neurotrophic keratitis. Ophthalmology 1990;97:308-12 MURUBE J, RIVAS L. Impression cytology on conjunctiva and cornea in dry eye patients establishes a correlation between squamous metaplasia and dry eye clinical severity. Eur J Ophthalmol 2003; 13: 115 - 127 Mantelli F, Moretti C, Micera A, B onini S. Conjunctiv al mucin de ciency in comp lete androgen insensitiv ity syndrome (CAIS). G raefes Arch Clin E x p Op h th alm o l 2006 Nov 2; [Ep ub ahead of p rint]

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

7 Lid & MG evaluation Blepharitis 1) Anterior blepharitis Telangiectasia ( ) Erythema or Hyperemia ( ) Scales or crust ( ) 2) Posterior blepharitis (MGD) MG orifice metaplasia or plugging ( ) MG expression ; clear ( ), cloudy ( ), granular ( ), solid ( ) Lid anatomy and lash malposition Entropion ( )/ Ectropion ( ) Lagophthalmos ( ) Trichiasis ( ) Lid surgery history ( ) Reduced or incomplete blink Lid margin telangiectasia MG orifice plugging Scales or crusts on lid lash

Ocular surface disease 8 Ocular surface disease Elevated surface lesions Pterygium ( ) Pingueculum ( ) Cicatrical scar tissue ( ) Others ( ) Conjunctivochalasis ( ) redundant lower bulbar conjunctiva가 limbus를 넘을 정도 Chronic allergic conjunctivitis ( ) Previous keratitis or conjunctivitis ( ) Active state, 약물치료 중인 환자는 제외 Contact lens wearer ( ) 최근 3개월간 지속적으로 사용한 경우 Ocular surface surgery history ( ) Ocular surface에 damage가 가능한 모든 종류의 ocular surgery Pingueculum Conjunctivochalasis

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

Cyclosporin A: Mechanism of action 04, 레스타시스의 임상효과 Cyclosporin A: Mechanism of action Immunomodulation Selective inhibition of the signal transduction cascade of T cell action Limitation of the activation of CD4+/CD8+ T-cells by the blockage of the transcription and production of IL-2 Anti-inflammation Inhibition of NF-B activation Upregulation of anti-inflammatory TGF- expression Inhibition of the expression of high-affinity IL-2 receptor by the blockage of the production of other lymphokines(IFN-γ) Differential Effects on Apoptosis Facilitation of lymphocyte apoptosis Inhibition in epithelial cell apoptosis

Goblet cell numbers in the conjunctiva of DES patients treated with CsA Baseline Treatment 0.05% CsA for 6 months Fewer goblet cells at baseline in DES Increase in goblet cells in both Non-SS and SS groups after Tx. CsA NSS Goblet cell Vehicle CsA SS Vehicle Normal PAS staining Kunert KS, et al. Arch Ophthalmol (2008)

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