BASICS

DESCRIPTION

• Mucous membrane pemphigoid (MMP) or cicatricial pemphigoid (CP) encompasses a number of systemic autoimmune diseases that involve cicatrization or scarring of mucous membranes and the skin. Traditionally, when there is primarily ocular involvement the term ocular cicatrizing pemphigoid (OCP) is used (1).

– Extraocular mucosal involvement: Oral (up to >60%), nasal mucosa, sinuses, pharynx, larynx, esophagus, bowel, anus, urethra, and genitals.

EPIDEMIOLOGY

Incidence

• 1/15,000–1/16,000 (possibly an underestimation as these are advanced cases at the time of diagnosis) (2)

• Mean age of onset sixth to seventh decade (2)

• 2:1 female:male ratio (2)

RISK FACTORS

• Increased incidence of autoimmune disease such as rheumatoid arthritis (17%) (2)

• Mean duration of symptoms to diagnosis is 2.8 years.

Genetics

Increased frequency in HLA-DR4 and HLA-Dqw3 (3).

PATHOPHYSIOLOGY

• Systemic autoimmune disease where circulating antibodies bind to antigens of the basement membrane zone (BMZ), activating a complement cascade, recruitment of inflammatory cells and hydrolytic enzymes leading to digestion of the lamina lucida and activation of fibroblasts with eventual scar tissue formation (1,4)

• Linear deposition of antibodies IgG, IgA, or C3 along the epithelial BMZ

ETIOLOGY

• Idiopathic autoimmune disease

• “Pseudopemphigoid”: Medication induced (see Differential Diagnosis)

COMMONLY ASSOCIATED CONDITIONS

• Cicatrizing conjunctivitis

• Skin involvement

• Desquamative gingivitis

• Esophageal or laryngeal involvement may be fatal if adhesions and/or strictures develop.

DIAGNOSIS

HISTORY

• Targeted history of onset, duration, location, quality of symptoms, associated conditions, and oral/topical medications. Early ocular symptoms include redness, foreign body sensation, burning, tearing, and mucus discharge.

• Review of systems (ROS):

– Skin/Mucocutaneous: Rash on face, scalp, or extremities (flat erythematous plaques) or inguinal area (small vesicobullous lesions), oral ulcers, bleeding gums (desquamative gingivitis)

– ENT: New onset sinus disease, epistaxis (nose bleeds)

– Respiratory: Hoarseness or dysphonia (laryngeal/vocal cords), laryngeal adhesions, and strictures causing difficulty breathing (tracheostomy)

– Gastrointestinal: Dysphagia, heartburn

– Genitourinary: Genital ulcers

PHYSICAL EXAM

Classic signs include:

• In early disease, nonspecific papillary conjunctivitis, conjunctival vesicles and ulcers, fine (“lacy”) subepithelial scarring on tarsal conjunctiva, shrinkage of inferior fornix, and symblepharon formation, trichiasis, corneal scarring. In later disease, obliteration of fornix and lacrimal gland ductules, and keratinization of ocular surface.

• Stages (Foster/Mondino)^2.5

– Stage I: Subepithelial fibrosis

– Stage II: Fornix

– a) 0–25%

– b) 25–50%

– c) 50–75%

– d) 75–100%

– Stage III: Symblepharon

– a) 0–25%

– b) 25–50%

– c) 50–75%

– d) >75% involvement of symblepharon

– Stage IV: Ankyloblepharon & keratinization

• External exam: Rashes and oral ulcers

• Eyelids: Keratinization of lid margin, trichiasis, distichiasis, scarring of meibomian glands, entropion, lagophthalmos, and ankyloblepharon

• Conjunctiva/Sclera: Papillary conjunctivitis, conjunctival vesicles, and ulcers, subepithelial conjunctival fibrosis (use red-free broad beam on slit-lamp), limbitis, shrinkage of inferior/superior fornix, symblepharon, obliteration of lacrimal gland ductules (late), keratinization (late)

• Cornea: Punctate epithelial keratitis, epithelial defect, corneal ulcer, neovascularization or scarring, keratinization, perforation

• Remainder of anterior and posterior segment examination typically unremarkable

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Direct immunofluorescence (DIF) microscopy or immunoperoxidase.

• Sensitivity DIF alone: 52% (5)

• Sensitivity DIF and immunoperoxidase: 83% (5)

• Specimen incubated with fluorescein labeled anti-human immunoglobulins directed at IgA, IgG, IgM, IgD, IgE, C3, C4, and fibrinogen

Diagnostic Procedures/Other

• Gold Standard: Conjunctival biopsy

– Choose an area of inflamed conjunctiva adjacent to limbus in interpalpebral fissure. Do not perform biopsy in fornix–can promote symblepharon formation

– Place topical anesthetic drop and apply cotton swab soaked with 4% lidocaine over the intended area for conjunctival biopsy. Inject 0.5 cc of 2% lidocaine with epinephrine subconjunctivally and excise 1.5 × 1.5 mm area of conjunctiva for biopsy. Must be processed fresh (no formalin) (1)

Pathological Findings

• A line of homogenous linear fluorescence at the BMZ

• Eosinophils may be found on conjunctival scrapings

DIFFERENTIAL DIAGNOSIS

Cicatrizing conjunctivitis (1)

• Infectious conjunctivitis:

– Bacterial (Corynebacterium diphtheriae, Beta- hemolytic streptococcus, Neisseria gonorrhea)

– Viral (Adenovirus (8&19), Herpes Simplex Conjunctivitis)

– Chlamydia (Trachoma, Lymphogranuloma venereum)

• Medication Induced: “Pseudopemphigoid”

– Systemic: Practolol, D-penicillinamine

– Topical: Epinephrine, Echothiophate iodide, Pilocarpine, Idoxuridine

• Dermatobullous:

– Toxic Epidermal Necrolysis

– Dermatitis Herpetiformis

– Epidermolysis bullosa

– Pemphigus vulgaris

– Linear IgA

– Porphyria cutanea tarda

• Autoimmune

– Graft—versus–host disease

– OCP

– Sjögren’s syndrome

– Stevens-Johnson Syndrome

– Systemic lupus erythematosus

• Trauma

– Chemical/thermal burn

– Conjunctival surgery

– Radiation

• Other

– Atopic Keratoconjunctivitis

– Rosacea blepharoconjunctivitis

– Ligneous conjunctivitis

– Sarcoidosis

– Paraneoplastic ocular cicatricial pemphigoid (POCP)

TREATMENT

Overall Approach to Treatment (1)

• Address systemic findings and consult Internal Medicine and/or Dermatology depending on comorbidities

• Initiate systemic treatment with immunosuppressives and consult Rheumatology or Hematology/Oncology for dosage/patient monitoring

• Management of local eyelid and ocular surface disease

MEDICATION

• Begin systemic chemotherapy when conjunctival/oral mucosa biopsy proven or overwhelming clinical suspicion with documented progression of conjunctival scarring and/or symblepharon

• Prior to initiation of any systemic therapy, obtain baseline CBC, liver enzymes, Basic Metabolic panel, Hepatitis panel, Urinalysis, pregnancy test, or sperm banking (if applicable).

First Line

• Mild Disease: Dapsone, a sulfone derivative, for early, active but non-progressive disease

• Least effective treatment. Should discontinue if no result after 4 weeks and switch to cyclophosphamide

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