IMMUNOLOGICAL DISORDERS

OF CORNEADr.Adithya Phadnis

WHAT IS PERIPHERAL CORNEA? .

P

C

REF: WOLFF'S ANATOMY-8TH EDITION

HISTOLOGY Collagen fibrils arranged densely.

Chondroitin sulphate, dermatan sulphate and hyaluronic acid

Keratan sulphate

REF: WOLFF'S ANATOMY-8TH EDITION

Abundance of langerhans cells in epithelium of corneoscleral limbus.

Channels from subconjunctival lymphatic accompany capillaries into peripheral cornea

Drain into regional lymph nodes providing mechanism for afferent arm of corneal immunological reactions.

Basic immunology

PHASES OF IMMUNE RESPONSE Afferent phase Activation phase Effector phase

MAJOR COMPONENTS OF IMMUNE SYSTEM Antibodies Compliment system Cytokines

CELLS INVOLVED Neutrophil Eosinophil Lymphocytes

Dendritic cells

T lymphocytes

B lymphocyte

Helper T cellCytotoxic T cellSupressor T cellMemory T cell

Interdigitating follicular

IMMUNORECOGNITION MHC class 1- HLA-A, HLA-B,HLA-C- all

nucleated cells-(CD8-Endogenous-effector limb)

MHC Class 2- HLA-DP, HLA-DQ, HLA-DR- plasma membrane of APC(CD4-exogenous-affector limb)

ANTIGEN PROCESSING AND PRESENTATION

HYPERSENSITIVITYTYPES

SALIENT FEAUTURES DISEASES

1 Antigen with Ig E VKC and AKC

2 Compliment fixing antibodies and complement

Ocular cicatricial pemphigoid, dermatitis herpetiformis

3 Immune complex mediated response

Mooren’s ulcer ,RA,SLE,PAN, Wegener’s granulomatosis

4 Mediated by ‘T’ cells Phlyctenulosis, drug allergy, corneal transplant rejection

REF:CORNEAL DISORDERS-LEIBOWITZ, 2nd EDITION

TYPE 1

TYPE 2

TYPE 3

TYPE 4

ACAID?•The absence of an identifiable lymphatic drainage pathway led to the conclusion that antigenic material was sequestered in the immunologically priviledged site and was probably ignored by the immune system.

•However it was noted that cell mediated immunity is supressed and humoral immunity is promoted.

•ACAID depends on unique features of both spleen and eye for its initiation.

•Cells from iris and ciliary body are able to downregulate the earliest events of antigen presentation and lymphocyte activation, thereby initiating a selective impairment of delayed hypersensitivity.

- Leibowitz 2nd edition

TYPE 1 HYPERSENSITIVITY DISORDERS VERNAL KERATOCONJUNCTIVITIS Clinical features:

Pathogenesis:

Treatment:a) Control the symptomsb) Limit the sight threatening

complications

GRADINGmild moderate severe Blinding

Bulbar conj

congestion congestion Thickening H.T spots

granuloma

Tarsal/pal micropapillae

macropapillae

Giant papillae

Mega cobblestones

Cornea -- microerosions

macroersios

Shield ulcer

limbus -- Focal infl Diffuse inf

Limbal def

Grade Findings Treatment

0(quiescent) Absence of symptoms No treatment

1(mild) Symptoms but no corneal inv

Antiallergic e/d occassionally

2(moderate) Symptoms with photophobia but no corneal inv

Antiallergic e/d daily

3(severe) Symptoms, photophobia mild-mod spk

Antiallergic e/d daily with pulsed low dose topical steroid

Symptoms,photophobia, diffuse spk or corneal ulcer

Pulsed high dose steroid eventually asso with surgical removal of cornea

.

STEP LADDER APPROACH

Current Allergy & Clinical Immunology, June 2006 Vol 19, No. 2

TYPE 1 HYPERSENSITIVITY DISORDERS ATOPIC KERATOCONJUNCTIVITIS Epidemiology: 25 -42% ocular

involovement

Clinical features:- B/l involvement- Thick ropy discharge

Pathogenesis- defect in supressor T cell

cellular infiltration fibroblast activation

TYPE 2 HYPERSENSITIVITY DISORDERS OCULAR CICATRICIAL PEMPHIGOID Epidemiology

Pathogenesis: 2 hit hypothesis

Clinical features

Diagnosis

Cicatrising pemphigoidAtopic keratoconjunctivitisOcular rosaceaSclerodermaCorynebacterium conjunctivitisChemical burnTraumaSteven johnson syndromeLyell’s syndromeSarcoidosisTrachomaAdenoviral conjunctivitisSebaceous carcinomaSquamous cell carcinomaIntraepithelial epithelioma

TYPE 2 HYPERSENSITIVITY DISORDERS Treatment Systemic: Dapsone 25mg bd(max 150mg/kg) or

weekly methotrexate 7.5mg/week(max 15mg/week) or daily azathioprine

treat with high dose systemic prednisolone and oral or iv cyclophosphamide 2-3mg/kg/day daily prednisolone is tapered and changed to alternate day and discontinued over 3months subcut cytosine arabinoide 0.2-0.3 mg/kg 5days a month

If fails

Once inflamtn is controlled

If fails

Local therapy Epilation Topical retinoids Lid margin mucous membrane grafting Punctal occlusion with lubricants Tarsorrhaphy If good lid function; then penetrating

keratoplasty.

MOOREN’S ULCERFewer than 300 cases in the world’s literature- History -Definetion:mooren’s ulcer is idiopathic, occuring in the absence of any systemic disorder that could be responsible for progressive destruction of the cornea. It is also strictly a PUK, with no associated scleritis.- Epidemiology: - Patterns

Partial peripheralComplete peripheralTotal corneal ulceration

-By srinivasan et al

MOOREN’S ULCER Etiology Type 3 hypersensitivity Autoimmunity to calgranulin-c Cross immunity with helminths 83% are HLA-DR17 and HLA-DQ2

positive Association with hepatitis C,hepatitis B,

syphillis, TB, Trauma, foreign body, cataract surgery

-www.eyewiki.org

.Trauma, cross

immunity, surgery

Recognition of hidden antigen plus genetically predisposed

Deposition of immune

complexes

Activation of lymphocytes and

recruitment of neutrophils puk

HISTOPATHOLOGY

High levels of proteolytic enzymes

Sup stroma-vascularization+ infiltration of plasma cells and lymphocytes

Mid stroma- disorganized collagen lamellae+ hyperactive fibroblats

Deep stroma- macrophage infiltrate

Leading edge of ulcer has neutrophil infiltration

TYPES Type 1: excesive painful Seen in elderly Affected eyes are red and congested but

inflammation doesnot extend 3mm beyond limbus. Vascularization of ulcer bed is seen alomg with

leakage at tips of new vessels Ulceration extends around the globe and leaves

thick opaque central cornea Fluroscein angio: venular occlusion of local

episcleral and conjunctival blood vessels along with disruption of limbal arcade and vascular leakage from deep vessels at limbus and base of ulcer, vasoobliteration of sup vascular arcades is characteristic --Watson et al

Type 2- bilateral, occurs in young Pain is less severe , pain in one eye and

congestion in other eventually progress to develop grey patches within corneal stroma and 2mm from edge of limbus.

FA : shows vascular leakage and new vessel formation that reaches base of ulcer, also shows change in architecture of episcleral vessels and blockage in addition to break up of limbal arcade

Type 3- indolent, affects mid age Corneal guttering in both eyes with little

inflammation. Disease more severe in one eye and

patient complain of discomfort. Most cases are progressive but some

heal spontaneously. Few may be quiscient.

FA- vascular architecture is normal except new vessel may extend upto base of ulcer.

ON EXAMINATIONThere is a cresent shaped peripheral corneal ulcer with an undermined central edge

Puk in collagen vascular disease Puk in mooren’ ulcer

DIFFERENTIAL DIAGNOSIS

Terrien’s marginal degeneration Mooren’ ulcer

Pellucid marginal degeneration Mooren’s

Senile furrow degeneration Mooren’ ulcer

MOOREN’S ULCER MANAGEMENT Investigations Chest x ray, sinus x ray, complete

hemogram, rft,lft,mantaoux test,ANA, complement fixation, ANCA, Hep-b,Hep-c,HIV, Serum electrophoresis,VDRL,Stool examination

TREATMENT Historically Subconj dichloride of mercury, carbonic

and nitric acid Formalin, tincture iodine, subconj

heparin Galvanocautery, vit B1 injections,

tuberculin injection, irradiation, paracentesis

-Mooren's ulcer : Current concepts in managementVS Sangwan, P Zafirakis, CS FosterMassachusetts Eye and Ear Infirmary, Department of Ophthalmology, Boston, USA

1. Topical steroids 2. Conjuctival resection 3.Sytemic immunosupressives 4. Additional surgical procedures 5. Visual rehabilitation

Goals of therapy- halt the destructive process

Promote healing and re epitheliasation of cornea

DOS Times - Vol. 11, No. 7

TOPICAL STEROIDS Prednisolone acetate/phophate 1%

hourly +cycloplegic +prophylactic antibiotics

TOPICAL IMMUNOSUPRESSION 0.5% cyclosporine

If no healing in 2-3days If healsContinue steroids half hourly

Taper the steroids over several months

•Oral pulse therapy(oral prednisolone 60-100mg daily for 7-10days)•Topical teracycline/medroxyprogesterone drops,BCL

DOS Times - Vol. 11, No. 7

CONJUNCTIVAL RESECTION Conjunctival excision to bare sclera

extending atleast 2 clock hour to either side of peripheral ulcer approx 4mm posterior to limbus and parallel to ulcer

Overhanging lip of the cornea to be removed

Tissue adhesives and BCL Keratoepithelioplasty- donor cornea

lenticules are sutured onto scleral bed after conjunctival resection

SYSTEMIC IMMUNOSUPPRESSION Cyclophosphamide 2mg/kg/day Methotrexate 7.5mg/week Azathioprine 2mg/kg/day

Oral cyclosporine 10mg/kg/day (loading dose of 8 mg/kg in two divided doses for 2 days, thereafter being reduced to 3-4 mg/kg/d to maintain serum level of 200-400 ng/ml).

ADDITIONAL SURGICAL PROCEDURES Resection of the overhanging lip of the

ulcerating cornea and application of tissue adhesive with bandage soft contact lens application or amniotic membrane has been described in a study healed 34 out of 40 eyes.

For an ulcer smaller than half circle of the limbus and the central 7-8 mm of the cornea uninvolved crescent shaped lamellar graft can be used.

For an ulcer larger than 2/3 of a circle of the limbus where the central 7-8 mm of cornea is intact, a doughnut shaped lamellar graft is recommended.

A full lamellar graft is used tomaintain useful vision.

.. Double lamellar grafts (a fresh thin inner

graft with corneal endothelial cells is used to repair the perforation, on which another lamellar graft shaped in accordance with the shape of the ulcer is placed) can be

used for perforations of the peripheral cornea.

5. REHABILITATION Once the active ulceration has ceased

and remaining cornea has been opacified it is possible to perform penetrating keratoplasty on these patients.

First a 13mm tectonic corneal graft is sutured in place with interupted sutures and then therapeutic graft is placed.

(should be done under immunosupression)

COMPLICATIONS Uveitis (6.8%) Glaucoma Complicated cataract(2-3%) Perforation (limbus>peripheral>central) Postop recurrence(25% in 2weeks to

15years)

RHEUMATOID ARTHRITIS Prevalence-0.5-1% Anti cyclic citrullinated peptides are

specific for diagnosis Systemic : articular:joint deformity and

joint destruction, Non articular:subcutaneous

nodules,vasculitis, pericarditis,pulmonary nodules or

interstitial fibrosis

OCULAR MANIFESTATIONS Keratoconjunctivitis sicca

Keratoconjuct

ivitis sicca

xerostomia

Sicca syndro

me

RA/CVD

SICCA SYNDROME

SECONDARY

SJOGREN’S

SYNDROME

CONTD…Severe keratoconjunctivitis sicca, drying of

epithelium from tear deficiency,Chronic exposure of cornea

Epithelial pathology, epithelial cell loss

Formation of central epithelial defect

Note: Unlike peripheral ulcerative keratitis this is not an immune mediated vaculitis and is not indicative of systemic vasculitis

PUK IN RHEUMATOID ARTHRITISThere is an obliterative Microangiitis at the level of limbal vascular arcades

Deposition of Immune complexes in limbal vessels

Causes an immune microangiopathy and obliterative microangiitis

Leakage of inflammatory cells and proteins

Collagenases and proteases are released by neutrophils Corneal melting

TREATMENT After wide conjunctival resection, ulcer

debridement, and application of tissue adhesive and soft contact lens adminiter systemic immunosuppressive therapy.

Effective drug: Cyclophosphamide 2mg/kg/day Methotrexate 7.5mg/week a one dose Daily azathioprine 2mg/kg/day Cyclosporine 5mg/kg/day

SYSTEMIC LUPUS ERYTHEMATOSUS Antinuclear antibodies Anti ds DNA, anti Ro SYSTEMIC: hematologic,

arthritic,dermatologic, fever,fatigue,weight loss

Corneal manifestations: 6.5% incidence of keratitis in SLE 88% of SLE pts have superficial punctate

keratitis 62.5% have keratoconjuctivitis sicca Treatment: control underlying disease Topical corticosteroids

POLYARTERITIS NODOSA Systemic, necrotrizing vasculitis that

involves small and medium sized muscular arteries.

Segmental, acute and chronic inflammatory cell infiltration of all layers of vessel wall and infiltration of perivascular areas.

Granuloma formation wuth multinucleated giant cells.

Incidence is 5-220 per million

OCULAR MANIFESTATIONS

Pathogenesis

neutrophil

Eosinophils,Plasma cells and Lymphocytes in substantia propria

Treatment: Treat the underlying disease Conjunctival resection, ulcer debridement,

application of cyanoacrylate tisue adhesive to ulcer bed and to a small rim of surrounding normal cornea and sclera

Application of continuous wear bandage soft contact lens

Use of topical corticosteroids Medroxyproesterone drops, N-acetylcysteine

drops and ytemic tetracycline Systemic therapy- cyclophosphamide and

prednisolone.

WEGENER’S GRANULOMATOSISCharacterised by Peripheral ulcerative keratitis is the initial ocular manifestation (50-60%)- Sometimes maybe preceded by

conjunctivitis or episcleritis- Crescentic peripheral corneal ulcer that

resembles Mooren’s ulcer - Scleral involvement is invariably present- this helps to differentiate it from

Moorens

WEGENER’S GRANULOMATOSIS HISTOPATHOLOGY – lymphocytes and plasma

cells predominate the substantia propria- The sclera and episclera may show a - Granulomatous reaction with epithelioid cells

and giant cells,fibrinoid necrosis- Areas of active collagen degradation can be

seen- ANCA testing is positive (sensitivity-96%n for

active generalised ds, 67%-local regional ds,32%-pts in remission)

- MANAGEMENT – Systemic immunosuppression with cyclophosphamide and steroids is highly effective

PROGRESIVE SYSTEMIC SCLEROSIS Fibrosis of the skin and visceral organs c/f: keratoconjunctivitis sicca, shortening

of fornices, mucosal subepithelial fibrosis, vascular congestion, telangiectasia, and varicosities.

RELAPSING POLYCHONDRITIS Autoimmunity to type2 collagen(sclera) Ocular involvement in 50% of cases and

in 19% ocular involvemnt is initial presentation.

Necrotising scleritis with or without peripheral ulcerative keratitis.

Treatment:

MOOREN’S ULCER CONCLUSION- TAKE AWAY HOME MESSAGE Mooren's ulcer although a distinct clinical entity, remains

a diagnosis of exclusion. One should always look for associated scleritis,limbal

involvement, corneal sensation, associated blepharitis and keratitis, lipid deposition, ulcerated corneal epithelium and stroma,and so on, to rule out other causes of peripheral ulcerative keratitis, including infections, collagen vascular diseases anddegenerative processes.

The precise pathophysiology of Mooren's ulcer remains uncertain.

Advances have been made in its management, but significant percentage of cases still remain refractory to available therapies and result in severe visual morbidity

TYPE 4 HYPERSENSITIVITY PHLYCTENULOSIS

STAPHYLOCOCCAL HYPERSENSITIVITY

CONTACT LENS-ASSOCIATED INFILTRATES

Graft vs host disease

DIFFERENTIAL DIAGNOSIS OF PUK-A REVISION OCULAR NONINFECTIOUS - Acne rosacea -Mooren s ulcer -Traumatic ,post surgical -Exposure keratopathy -Terrien’s Marginal degeneration

OCULAR INFECTIONS - Staphylococcal -Viral – Herpes -Acanthamoeba

-Leibowitz 2nd edi pp568

ETIOLOGIES SYSTEMIC NONINFECTIOUS - Rheumatoid Arthritis - Wegener’s Granulomatosis - PAN - SLE -Microscopic polyangiitis -Relapsing polychondritis -Churg strauss syndrome -Systemic sclerosis and Sjogren’s syndrome -Cicatricial pemphigoid/IBD/Sarcoidosis

SYSTEMIC INFECTIOUS – tuberculosis , Borreliosis Gonorrhea,dysentery Varicella zosterREF:CORNEAL DISORDERS-

LEIBOWITZ, 2nd EDITION p:568

Thank you

ANTIHISTAMINES Antistine,Levocabastine(0.5%),emadasti

ne 0.05% Act on H1 receptors in conjunctiva. Adverse effects: systemic- nausea,

vomiting, diarrhoea,dryness of mucous membranes,sedation

Local- precipitates narrow angle glaucoma, ciliary muscle paresis

MAST CELL STABILIZERS Cromolyn sodium 4%, nedocromil 2%,

Iodoxamide 0.1% Act by stabilizing membrane of mast

cells by preventing influx of calcium thereby preventing degranulation of the enzymes.

Adverse effect- systemic-direct irritant, dermatitis, gastroenteritis, myositis, urethral burning

Local- transient stinging and conjunctival injection.

DUAL ACTION Olapatadine 0.1%- reduces level of

histamine and cellular infiltrate and ICAM expression.

Ketotifen inhibits release of inflammatory mediators from mast cells, basophils, and neutrophils to inhibit the production and release of LTC4 LTB4, PAF,

Azelastine, Epinastine

Newer therapy for ocular allergy- HEPP(Pentyde)

CORTICOSTEROIDS MECHANISM OF ACTION WHY PHOSPHATES AND WHY ACETATES? SIDE EFFECTS

CYCLOPHOSPHAMIDE Most potent therauptic alkylating agent MOA- reacts with DNA resulting in DNA

breaks and subsequent cell death Cytotoxic for lymphoid cells(B=T),

inhibits delayed hypersensitivity and induces immunologic tolerance towards particular antigen.

Indications- wegener’s granulomatosis, PAN, Rheumatoid arthritis,bullous pemphigoid, mooren’s ulcer

Adverse effects- systemic-bone marrow supression, gastroenteritis, hemorrhagic colitis,oral mucosal ulceration, hemorrhagic cystitis,alopecia, gonadal supression, pulm fibrosis

AZATHIOPRINE Purine analogues that interfere with the

metabolism of DNA, RNA and protein Dose-2-3mg/kg/day, acts within 48hours

of antigen priming. Side effects- hepatotoxicity, bone

marrow supression, gastrointestinal distress,rash, fever, athralgia

METHOTREXATE Folic acid analogue which blocks

conversion of dihydrofolic acid to terahydrofolic acid thereby interfering with thymidine synthesis in turn inhibiting DNA synthesis.

Dose-2.5-7.5mg/week upto 50mg/week Adverse effects-hepatotoxicity,bone

marrow supression

CYCLOSPORINE Is a fungal metabolite isolated from

cultures of tolypocladium inflatum and cylindrocarpon lucidum

MOA-they block the helper t cell response to IL-1 and block IL-2 release.

Adverse effect- systemic-B cell lymphomas, interstitial pneumonitis, renal tubular necrosis

CYANOACRYLATE GLUE Applied to the area of perforation after careful debridement. The

surface is dried with a sponge & a small drop of tissue adhesive from the undersurface of a bent iris repositer or a hypodermic needle is placed immediately over the perforation. Drying takes 5-10 minutes after which anterior chamber reforms. Following this, continuous wear soft contact lens may be applied.

Advantage: good tensile strength Drawback: it may form a solid, impermeable mass in situ and may

require removal.

FIBRIN GLUE Blood derived product that is

absorbable, easy to use and can be kept at room temperature or refrigerator.

Can be prepared at a blood bank, or from patients own blood or commercially available preparation.

Advantage: forms a smooth seal along the perforation, less postop discomfort.

Technique of Glue Application

Part preparation (paint and drapes), application of topical anesthetics and speculumDebridement of necrotic tissue from ulcer crater

As tissue adhesive glue adheres best to basement membrane, 1-2 mm of normal epithelium should be debride to allow the glue to properly adhere

Dry the site by methyl cellulose spearAs application in small amount to seal the perforation

Tissue adhesive solidify in few minutes via polymerization

Send this material for culture and sensitivity

A large heaped up mound is not required

Check the evidence Check for anterior chamber Apply bandageof leakage by Seidel’s test maintenance (Air bubble contact lens

can also be used)

Tissue adhesive remains in place for weeks to months until the perforation seals, it can be removed or dislodges of its own

TISSUE ADHESIVES-COMPLICATIONS Iridolenticular adhesion Cataract formation Rise in iop Giant papillary conjunctivitis