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Shivani V. Reddy, M.D.Shivani V. Reddy, M.D.

University of LouisvilleUniversity of Louisville

Department of Ophthalmology and Department of Ophthalmology and Visual SciencesVisual Sciences

HistoryHistory CCCC: : “eyelashes turned in” “eyelashes turned in”

HPIHPI: : 72 y/o WM referred to oculoplastics 72 y/o WM referred to oculoplastics clinic for a progressive trichiasis over 3-4 clinic for a progressive trichiasis over 3-4 years. Patient states that growth is much years. Patient states that growth is much more pronounced in the left eye . Also c/o more pronounced in the left eye . Also c/o chronic tearing, irritation and yellowish-chronic tearing, irritation and yellowish-white discharge in both eyes, worse on the white discharge in both eyes, worse on the left. States that overall symptoms have left. States that overall symptoms have been progressing over about a 5 year span been progressing over about a 5 year span

HistoryHistoryPOHx:POHx: Retinal detachment OS 1997, CE + IOL OU Retinal detachment OS 1997, CE + IOL OU

PMHx:PMHx: Bullous Pemphigoid, Peripheral neuropathy, Bullous Pemphigoid, Peripheral neuropathy, Asthma,Asthma,

Hypothyroidism, HTNHypothyroidism, HTN

FAMHx:FAMHx: noncontributory noncontributory

ROS:ROS: joint pain, muscle aches and difficulty joint pain, muscle aches and difficulty swallowing swallowing

intermittentlyintermittently

MEDS:MEDS: dapsone, zioptan, avodart, bystolic, cymbalta, dapsone, zioptan, avodart, bystolic, cymbalta,

nexium, b12, synthroid,nexium, b12, synthroid,

NKDA NKDA

ExamExam

VA P

20/20-1

20/100+1 (PH: NI)

4→3

4→3+ RAPD OS

EOM: full OUCVF: superior field limitation OU

Anterior Segment Anterior Segment

OD OS Lids/Lashes mild entropion UL+LL entropian few trichiatic lashes trichiasis

Conj mild injection symblepharon 2+ injection

Cornea multiple SPE multiple SPE inferonasal corneal erosion

Iris WNL WNL

Lens PCIOL PCIOL

Physical ExamPhysical Exam

HENT: single tense vesicular lesion on soft palate

Thorax: 2 vesicular lesions on upper back

Extremities: single vesiculo-bullous lesion on right leg

Skin Lesion Skin Lesion

erupted bullous lesion on the right lower extremity

Summary Summary

DDx:oAutoimmune Cicatricial Conjunctivitis

o MMP, Sarcoidosis , SLE, Lichen Planus, IgA dermatosis

oAtopic Keratoconjunctivitis oOcular Rosacea o Chronic Infectious Conjunctivitis

o Adenovirus , streptococcusoPseudopemphigoid (drug-induced ) oConjunctival Trauma

72 y/o WM presents with trichiasis OU 2/2 entropion, decreased visual acuity OS, symblepharon OS , 2+ conjunctival injection OS with an inferonasal corneal erosion. Dermatologic exam reveals vesicular lesions on the soft palate, upper back and lower extremity

Treatment Treatment o Same day: UL + LL epilation OS,

aggressive lubrication

o OS cicatricial entropion repair + MMG of Upper and lower lid

o Pathology resultso Acutely inflamed tissue infiltrated

with histiocytes, lymphocytes and neutrophils. Sub-epithelial fibrosis lacking elastic fibers indicative of scarring

o Immunofixation not performed

One Month Post-Op Visit One Month Post-Op Visit

Grafts healing well, significant inflammation persistent, no residual trichiasis

Mucous Membrane Mucous Membrane PemphigoidPemphigoid

• Group of heterogeneous diseases characterized by inflammatory blistering of the oral, ocular, pharyngeal, laryngeal and genital mucosa

• Main pathological feature: linear deposits of IgG, IgA and C3 in the epithelial basement membrane zone

• When MMP presents as a chronic scarring conjunctivitis, it is known as Ocular Cicatricial Pemphigoid

Ocular Cicatricial Ocular Cicatricial PemphigoidPemphigoid

Clinical features Clinical features o Early on, signs of chronic or relapsing

conjunctivitis with vesicles detected on the conjunctiva

o Tearing , burning, mucous drainageo Loss of goblet cells

o As the disease progresses, conjunctival shrinkage can cause impaired eye movements and lagophthalmos

o Lid margin inflammation and scarring trichiasis

o Eventually trichiasis and gland loss lead to progressive corneal keratinization and scarring

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

Epidemiology Epidemiology

o Incidence: 1/8000 – 1/46000 ophthalmic patients

o Average age of diagnosis: 60 – 70 years

o Female:Male: 1.5:1 – 3:1

o No geographic or racial predilection

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

Pathogenesis Pathogenesis o Binding of circulating autoantibodies (IgG, IgA,

C3 and other complement factors) to the BMZ (lamina lucida of the dermal- epidermal junction)

o 205 kd β4 peptide of α6β4 integrin most frequent target

Why scarring instead of bullae formation? o Autoantibody binding to BMZ secretion of

cytokines (TNF-a, IL-1, migration inhibiting factor) recruitment of inflammatory cells release of pro-fibrotic cytokines such as TGF-beta and IFN-gamma scarring

o Inciting Event unknown

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

4 Stages 4 Stages Stage II – Shortening of the inferior fornix

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

4 Stages 4 Stages Stage III – Symblepharon formation

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

4 Stages 4 Stages Stage IV – End stage disease manifesting as

ankyloblepharon, severe sicca syndrome, severe ocular surface keratinization

Ocular Cicatricial Ocular Cicatricial PemphigoidPemphigoidDiagnosis Diagnosis

o Most cases are caught in stage 2 to 3 and beyond due to the often insidious nature of progression

o Diagnosis is based on:o Clinical Features o Tissue Biopsy

o Should be performed perilesionally o Conj biopsy best during active disease o Specimen handling is extremely

important as using the wrong specimen fixative can lead to false negative results

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

Hematoxylin & Eosin Staining

o inflammatory infiltrate of variable intensity . Contains neutrophils, macrophages, plasma cells, lymphocytes, and Langerhans cells

o Essentially nonspecific

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

Direct Immunofluorescence

o Characteristic finding : Linear deposition of IgG, IgA, and/or C3 in basement membrane

o However, diagnostic sensitivity is only around 50% . Therefore a negative result does not rule out a disease process

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid

1. Power WJ, Neves RA, Rodriguez A, Dutt JE, Foster CS. Increasing the diagnostic yield of conjunctival biopsy in patients with suspected ocular cicatricial pemphigoid. Ophthalmology. 1995;102(8):1158

Immunoperoxidase Assay

o Performed if immunofluorescence is negative but strong clinic suspicion

o Increases sensitivity of testing from 52- 83%1

Ocular Cicatricial Ocular Cicatricial PemphigoidPemphigoidTreatment Treatment

Mild to Moderate DiseaseoDapsone 50 – 200 mg/day for 12 weeks

o Important to check labs – hemolytic anemia risk

oMTX, mycophenolate, azathioprine can also be used, but more serious side effect profile

Severe Disease oCyclophosphamide +/- Prednisone for 12 months or less

o Must beware of leukopenia oNewer Therapies

o IVIG o Rituximab

Ocular Cicatricial Ocular Cicatricial Pemphigoid Pemphigoid Treatment Treatment

Surgical InterventionoEntropion repair oSymblepharon excision olimbal stem cell transplantation, PK, keratoprosthesis

Maintainence Measures oAggressive ocular lubrication oLid hygiene for infection prevention oEpilation

PROGNOSIS? Current literature shows long term remission in 1/3 of patients for an average of 34 months with IM therapy

ReferencesReferences1. BSCS Volume 8, External Diseases and Cornea . 2013 2. Pepose,Holland, Wilhelmus. Ocular Infection & Immunity. 1996 3. 1. Power WJ, Neves RA, Rodriguez A, Dutt JE, Foster CS. Increasing the diagnostic yield of conjunctival biopsy in patients with suspected ocular cicatricial pemphigoid. Ophthalmology. 1995;102(8):11584. Ahmed M, Zein G, Khawaja F, Foster CS. Ocular cicatricial pemphigoid: pathogenesis, diagnosis and treatment. Prog Retin Eye Res 2004; 23:579.5.Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am Acad Dermatol 2000; 43:571.6. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986; 84:527.7. Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol 2002; 138:370.8.Letko E, Bhol K, Foster SC, Ahmed RA. Influence of intravenous immunoglobulin therapy on serum levels of anti-beta 4 antibodies in ocular cicatricial pemphigoid. A correlation with disease activity. A preliminary study. Curr Eye Res 2000; 21:646.9. 60.Foster CS, Chang PY, Ahmed AR. Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report. Ophthalmology 2010; 117:861.

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