eMedicine Specialties > Ophthalmology > Conjunctiva

Cicatricial Pemphigoid

Author: C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution
Coauthor(s): Rola Hamam, MD, Clinical Associate, Department of Ophthalmology, American University of Beirut; Erik Letko, MD, Fellow in Immunology and Uveitis Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School
Contributor Information and Disclosures

Updated: Dec 12, 2008

Introduction

Background

Ocular cicatricial pemphigoid (OCP) is one of the subsets of mucous membrane pemphigoid (MMP), a group of systemic autoimmune diseases characterized by T-lymphocyte dysregulation, the production of circulating autoantibodies directed against a variety of adhesion molecules in the hemidesmosome-epithelial membrane complex, and the production of proinflammatory cytokines and immune system activation markers. OCP can affect the skin and other mucous membranes (eg, oral mucosa, pharynx, larynx, trachea, esophagus, vagina, urethra, anus), in addition to its hallmark feature, chronic cicatrizing conjunctivitis.

Pathophysiology

The pathophysiologic mechanisms of OCP, as well as conjunctival fibrosis, are not completely understood. Clearly, a defect exists in immunoregulation, with production of autoantibodies directed against the beta 4 subunit of alpha 6 beta 4 integrin, and, reportedly, in some instances, against alpha 3, beta 3, or gamma 2 subunits of laminin 5.

A triggering agent in the genetically susceptible individual, leading to clinical manifestations of the disease, may occur in a "2-hit" mechanism. It is probably operative in some patients. Human leukocyte antigen DR2 (HLA-DR2), human leukocyte antigen DR4 (HLA-DR4 [HLA-DR*0401]), and human leukocyte antigen DQw7 (HLA-DQw7 [DQB1*0301]) genotypes have been identified as conferring increased susceptibility to the development of OCP.

In some patients, systemic practolol therapy and topical antiglaucoma drugs, such as pilocarpine, timolol, epinephrine, Humorsol, idoxuridine, and phospholine iodide, have triggered the onset of OCP. The term pseudopemphigoid or drug-induced pemphigoid may be used to describe these cases. Whether or not these cases associated with medication use are identical to OCP is not completely clear.

On the molecular level, the initial trigger may be a process by which the OCP antigen undergoes a conformational change that provides antigenic stimulation. This signal results in the generation of B-cell clones that produce antibodies against antigens located at the basement membrane zone (BMZ), initiating a type II Gell and Coombs hypersensitivity reaction. The antibodies of immunoglobulin G (IgG), immunoglobulin A (IgA), and/or immunoglobulin M (IgM) bind to the antigen and initiate complement activation.

Circulating autoantibodies are difficult to demonstrate by classic indirect immunofluorescence technique in patients with OCP. Specialized radioimmunoassay and immunoblot techniques allow the circulating autoantibodies to be seen in all patients with OCP who have active conjunctivitis. The resultant inflammatory mediators that are produced induce migration of lymphocytes, eosinophils, neutrophils, and mast cells to the BMZ. The separation of the epithelium from the underlying tissues within the BMZ may be the result of direct cytotoxic action or the effect of lysosomal proteolytic enzymes.

Fibroblast activation secondary to inflammatory cytokine influences, with collagen production and subsequent cicatrization, is the end result in the conjunctiva. Progressive fibrosis causes profound tear insufficiency, meibomian gland dysfunction, and mucin deficiency. Symblepharon formation, trichiasis, distichiasis, and keratinization cause corneal epitheliopathy, persistent corneal epithelial defects, stromal ulcers, corneal scarring, neovascularization, and even perforation.

OCP is a chronic, slowly progressive, bilateral blinding, systemic autoimmune disease. Multiple antigens in the BMZ of squamous epithelia may serve as targets for a spectrum of autoantibodies observed in OCP. Molecular definition of these autoantigens facilitates the classification and characterization of subsets of OCP. Sera from patients with OCP have been shown to recognize beta 4 integrin, which is a 205-kDa protein, also known as CD104. A subset of patients with clinical features similar to OCP also has been shown to have autoantibodies against epiligrin, which is identified as laminin 5, a ligand for alpha 6 beta 4 integrin, and autoantibodies to the alpha 6 integrin subunit. OCP probably is a spectrum of several different diseases associated with different target antigens, different triggers, and different therapeutic responses.

Frequency

United States

Incidence is estimated between 1 in 8,000 and 1 in 46,000 ophthalmic patients. It is likely that early stages of OCP are not reflected in these estimates because of difficulties in making the correct diagnosis. The real frequency of the disease is probably higher.

International

Distribution appears to be worldwide. No geographical predilection is reported.

Mortality/Morbidity

Oral lesions occur in 75-100% of patients with OCP. Skin involvement (eg, face, neck, scalp) occurs in approximately 25% of patients with OCP.

Race

OCP can occur in all races.

Sex

Females predominate patients diagnosed with OCP. The female-to-male ratio is estimated to be 1.5:1 to 3:1.

Age

Average age of onset is 50-60 years; however, the exact age of onset may be younger, since most patients with early stages of OCP remain undiagnosed. Some cases have been diagnosed as early as 12 and 19 years.

Clinical

History

• Ocular symptoms
  • Red eye
  • Tearing
  • Dry eye
  • Blepharospasm
  • Itching
  • Grittiness
  • Heavy eyelid
  • Foreign body sensation
  • Decreased vision
  • Burn sensation
  • Photophobia
  • Diplopia
• Other symptoms
  • Skin lesions
  • Oral lesions
  • Esophageal lesions
  • Pharyngeal lesions
  • Laryngeal lesions
  • Anal lesions
  • Tracheal lesions
  • Vaginal lesions
  • Urethral lesions

Physical

• External examination
  • Conjunctival hyperemia (red eye)
  • Quiet eye
  • Entropion
  • Skin lesions
  • Nasal lesions
  • Mouth lesions
  • Discharge (ie, catarrhal, mucous, membranous)
• Slit lamp examination
  • Eyelids
    • Trichiasis
    • Distichiasis
    • Meibomian gland dysfunction
    • Blepharitis
  • Conjunctiva
    • Papillae
    • Follicles
    • Keratinization
    • Subepithelial fibrosis
    • Conjunctival shrinkage
    • Foreshortening of fornices
    • Symblepharon
    • Ankyloblepharon
  • Cornea
    • Superficial punctate keratitis
    • Epithelial defect
    • Stromal ulcer
    • Neovascularization
    • Keratinization
    • Limbitis
    • Conjunctivalization
    • Stromal opacity
    • Perforation
• Based on clinical findings, progression of disease can be divided into 4 stages.
  • Stage I is characterized by chronic conjunctivitis with mild conjunctival and/or corneal epitheliopathy with subepithelial conjunctiva fibrosis, best seen at the tarsal conjunctiva as fine, white striae.
  • Stage II is characterized by cicatrization with conjunctival shrinkage, distorted anatomy, and foreshortening of fornices.
  • Stage III is characterized by the presence of symblepharon. Subepithelial scarring alters the orientation of lashes, causing aberrant lash growth. In addition, cicatricial entropion may occur.
  • Stage IV is the end stage, consisting of a dry eye with keratinization of the cornea and ankyloblepharon, which immobilizes the globe. Profound keratopathy can develop secondary to eyelid disorders, tear insufficiency, and corneal exposure. Corneal epitheliopathy, persistent epithelial defects, stromal ulceration, and neovascularization may be present. The cornea may become completely scarred, vascularized, and keratinized.

Causes

The cause of OCP is unknown. Genetic factors and several triggers can increase the likelihood of the onset of OCP.

• Individuals with HLA-DR2, HLA-DR4 (HLA-DR*0401), and HLA-DQw7 (DQB1*0301) are more susceptible to OCP.
• In some patients, systemic practolol therapy and topical antiglaucoma drugs (eg, pilocarpine, timolol, epinephrine, Humorsol, idoxuridine, phospholine iodide) have been identified as triggers of OCP.

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