The Clinical Potential of Influencing Nrf2 Signaling in Degenerative and Immunological Disorders
Immunological disorders of cornea
-
Upload
adithya-phadnis -
Category
Health & Medicine
-
view
12 -
download
0
Transcript of Immunological disorders of cornea
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