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 1 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 2 2015-03-25 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 3 2015-03-25 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: j.dart@ucl.ac.uk for a copy of this 4
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