Scarring conjunctivitis: what the corneal specialist needs to know

2015-03-25
Scarring conjunctivitis: what the
corneal specialist needs to know
John Dart NIHR-BMRC for Ophthalmology
Moorfields Eye Hospital & The UCL Institute of Ophthalmology
7th International Symposium
Wisla 2015
Eye diseases with significant conjunctival scarring
Trachoma
How common is non - trachomatous
cicatrising conjunctivitis
Incidence in the UK (2008)
MMP SJS Other
Numbers 50
16 16
Incidence 0.8
0.2 0.2
per 106
All causes (n 82)
Incidence
1.2 per million
Radford C et al. Incidence, presenting features,
& diagnosis of cicatrising conjunctivitis in the
UK. Eye (2012) 1-10
Other: drug toxicity,
rosacea, atopic,
GVHD, lichen
planus, neoplasia,
Linear IgA, Sjögrens
Prevalence for MMP &
SJS/TEN about 20-30x
higher at
1: 50,000 – 1: 33,000
Diagnosing cicatrising conjunctivitis
Sebaceous carcinoma & CIN
Atopic keratoconjunctvitis
Ectodermal dysplasia
Stevens Johnson Syndrome
Rosacea
Mucous membrane pemphigoid
Major problems lie in the areas of:
• Diagnosis
• Understanding the pathogenesis
• Therapy for inflammation and scarring
Causes of static or slowly progressive
scarring
•
•
•
•
•
•
Trauma: chemical
Infection: trachoma, post-adenovirus
Allergic eye disease: atopic KC
Drug-induced†
Mucocutaneous: SJS & TEN†
Immunobullous disorders: Linear IgA
disease, Bullous pemphigoid etc.†
• Systemic disease: Rosacea, Sjögrens
• Is it progressive or static?
History
Photography and follow up
Fornix measurements
• Helpful clinical features?
Systemic or ocular
Unilateral or bilateral
• When to investigate & which ones?
Causes of progressive conj. scarring
• Neoplasia: Squamous & sebaceous
• Mucous membrane pemphigoid (MMP):
Ocular only or ocular with other features
• Ectodermal dysplasia, Stevens Johnson
Syndrome, Drug induced
• Other mucocutaneous & immunobullous
disorders with scarring: Lichen planus
† A subset develop autoantibody-positive
progressive conjunctival scarring similar to MMP
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2015-03-25
Mucous membrane pemphigoid (MMP)
Ocular cicatricial pemphigoid (OCP)
• Commonest cause of scarring
•
•
•
•
conjunctivitis (BOSU study)
50% have preceeding extraocular signs
Sexes equally affected in the UK
Mean age of onset 67 (range 20-90)
Mean diagnostic delay 2 years (range 1
week to 10 years)
Scarring in MMP is variable at extra-ocular sites
Oral mucosal scars rarely despite severe inflammation
Laryngeal & oesophageal scarring <1% but severe
What is Mucous Membrane Pemphigoid (MMP)?
MMP used to be
known as Cicatricial
Pemphigoid (CP)
Immunobullous
Diseases
Mucosal
dominated
Linear
IgA, Bullous
pemphigoid, and
Epidermal
disorders
bullosa acquisita
•Epidermolysis
Pemphigus vulgaris
may
now be foliaceus
reclassified as
• Pemphigus
MMP pemphigus
•having
Paraneoplastic
OCP is ocular CP
now termed MMP or
ocular MMP when
there is a major
ocular component
Subepidermal disorders
• Bullous pemphigoid
• Dermatitis herpetiformis
• Bullous SLE
• Pemphigoid gestationis
• Mucous membrane pemphigoid
• Epidermolysis bullosa acquisita
• Linear IgA bullous dermatosis
MMP is an
immunobullous
disorder
Diagnostic & presenting features in MMPO
Insidious or acute
Loss of plica
Subepithelial fibrosis
Forniceal shortening
Skin & genital mucosae scar
Symblepharon
Thanks to Jane Setterfield &
Mike Gleeson for the images
Scarring is a MAJOR problem in the eye
Investigations for CC
• Routine histopathology
For atopic disease
To exclude dysplasia: sebaceous and
squamous carcinoma (CIN) ALWAYS
do this for unilateral cicatrisation
LE
• Tests for MMP
Direct immunofluorescence
Indirect immunofluorescence
Entropion & trichiasis
Surface failure,
keratin, dry eye
Conjunctival Immunofluorescence (IF) may be both Direct (DIF)
& Indirect (IIF) also serology for autoantibodies to BM proteins
DIF
Autoantigens (epitopes) in MMP:
• NC16A domain of BP180 (type XVII collagen)
• LAD-1, LABD97 and a C terminal stretch of BP180
• Laminin 5 (MMP), laminin 6
• Integrin α6 subunit (oral pemphigoid)
• Integrin ß4 subunit in ocular MMP
integrin α6
and ß4 subunits
Serology:
By ELISA &
immunoblotting to
detect antibody to
specific epitopes
Not routinely
available
IIF
NC16A
Salt split skin
LAD
Laminin 5
MMP TESTS
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Proposed criteria for ocular MMP
• Patients with + conjunctival DIF or + DIF
from any site meet currently consensus
criteria for MMP
• Patients with negative DIF (any site) &
positive IIF can be diagnosed as having
MMP
• Patients with negative immunopathology can
be diagnosed as ocMMP providing the
phenotype is typical
• Detailed immunopathology findings must be
recorded for each case reported in research
studies
Problems for patients with cicatrising
conjunctivitis
Diagnostic criteria for patients with
presumed ocular MMP negative
immunopathology?
Tests negative in 20-40% of ocular MMP
• Progressive conjunctival scarring - not static
e.g. trauma, trachoma or adenovirus
• Excluding Sjögren’s syndrome, ocular
rosacea, Stevens-Johnson syndrome, atopic
keratoconjunctivitis, ectodermal dysplasia,
sarcoidosis, scleroderma, drug induced
pseudo-pemphigoid & ocular surface
neoplasia.
Progression in Cicatrising Conjunctvitis
Infection
• Mean diagnostic delay of 2 years (range
1 week to 10 years) for patients without
extra-ocular disease
• Some cases can progress very fast:
delay in implementing appropriate
therapy leads to irreversible problems
• Refer early for specialised advice
Infection
Infection is a constant threat and may
be difficult to identify; treat expectantly
Surface disease
Immune mediated
inflammation
Trichiasis and entropion
Blepharitis & dry eye
Persistent epithelial defect
Surface failure
Manage
secondary
inflammation due
Toxicity
to surface
disease, infection
& toxicity first
Leading to:
Dry eye
Surface failure
Corneal blindness
Trichiasis & entropion
Surface
disease
Blepharitis
Toxicity
Avoid iatrogenic toxicity due to
topical therapy in ocular MMP
Persistent epithelial
defect & surface failure
Dry eye
Keratinisation
Use unpreserved
drops where
possible
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Immunosuppression for Cicatrising
Conjunctivitis: when should you use it?
AS 09.06.03
Poor control, or failure to control, disease after an
adequate trial of intensive topical therapy:
• Mucous membrane pemphigoid (MMP): topical therapy
seldom works for inflammation control
• Atopic keratoconjunctivitis (AKC)
• Ectrodactyly Ectodermal Dysplasia (EEC)
• Ocular Rosacea and rarely GVHD
Fulminating disease requiring rapid control to prevent
loss of eye: acute exacerbations of MMP and in acute
SJS, rarely in late SJS
3 months of cyclophosphamide, prednisolone
bilateral amnion grafts, & 7 visits later
AS 18.09.03
1.10.03 CL’s issued VA 6/9 RE &
6/60 LE (cataract)
• Cyclophosphamide 100 mg od
• G Prednisolone 0.5%
unpreserved qds & lubricants
Summary
• Prompt diagnosis is critical to outcomes
Use a diagnostic protocol (supplied)
• Manage surface disease problems
• Most patients with these diseases
respond to topical therapy
• For those who don’t, and for most
Mucous Membrane Pemphigoid (MMP)
patients, use systemic therapy
2.6.03 Emergency referral to MEH
• VAR 2/60 VAL HM’s
• Bilateral PED’s with stromal loss & severe conj. inflammation
2004 Cyclophosphamide discontinued
Switched to Azathioprine 100 mg daily
Topical Lubricants
2006 L phaco & IOL
VA 6/9 in each eye with RGP lenses
Azathioprine 50 mg daily
AS 3.08.06
References
• Radford C et al. Incidence, presenting features, & diagnosis of cicatrising
conjunctivitis in the UK. Eye (2012) 1-10
• Guglielmetti, S., Dart, J. K., Calder, V. (2010). Atopic keratoconjunctivitis
and atopic dermatitis. Curr Opin Allergy Clin Immunol 10(5), 478-485
• Dart JKG, Saw VS Immune Modulation in Ocular Mucous Membrane
Pemphigoid. Immune Modulation and Anti-Inflammatory Therapy in
Ocular Disorders. IOIS Guidelines. Eds. Pleyer U, et al. Springer, Heidelberg
2014 19-40
• Saw VP, Dart JK. Ocular mucous membrane pemphigoid: diagnosis and
management strategies. Ocul Surf 2008;6:128-142
• Saw VPJ, Dart JKG, Rauz S et al. Immunosuppressive Therapy for Ocular
Mucous Membrane Pemphigoid: Strategies and Outcomes.
Ophthalmology 2008 115:253-261
• Schmidt E, Zillikens D. Pemphigoid Diseases (Seminar). Lancet
2013:381:320-32. (update on immunobullous diseases)
Contact: [email protected] for a copy of this
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