Key Features
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Subepithelial bulla formation, rupture, and scarring of mucous membranes and skin.
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Female-to-male ratio of 2 : 1.
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Type II immune linear deposition of immunoglobulin A (IgA), IgG, IgM, and/or complement (C3) on the conjunctival epithelial basement membrane.
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Systemic immunosuppressive treatment is critical in suppressing conjunctival inflammation and disease progression.
Introduction
Ocular cicatricial pemphigoid (OCP) is an autoimmune disease characterized by chronic progressive conjunctival inflammation and scarring. This condition belongs to a heterogeneous group of chronic, systemic, inflammatory, subepithelial, blistering diseases termed mucous membrane pemphigoid. They share the similar manifestations of subepithelial bulla formation, rupture, and scarring of mucous membranes and skin.
The incidence of mucous membrane pemphigoid varies between 1 in 20 000 to 1 in 46 000 in the ophthalmic literature, with a female-to-male ratio of approximately 2 : 1. The average age of diagnosis is in the seventh decade of life (age range 30–90 years), and an average diagnostic lag of 2.8 years has been reported because of the nonspecific nature of early disease. No racial or geographical predilection has been reported. Oral involvement in mucous membrane pemphigoid occurs in up to 84% of cases. The risk of ocular disease in patients seen with only extraocular manifestations is estimated to be 5% per annum for the first 5 years of follow-up with eventual involvement in up to 80% of cases. Approximately 50% of patients presenting with OCP will have extraocular lesions. The clinical presentation and frequency of extraocular tissue involvement is listed in Table 4.10.1 .
| Site | Clinical Features | Frequency (%) |
|---|---|---|
| Oral mucosa and pharynx | Oral mucosal vesicles/bullae Desquamative gingivitis Pharyngitis and scarring | 30–84 |
| Conjunctiva | Conjunctivitis and progressive scarring | 60–80 |
| Nose/sinus | Epistaxis Nasal mucosa/turbinate ulcers | 18–50 |
| Skin | Localized, erythematous plaques with recurrent vesicles and bullae on the scalp and face that heal with atrophic scars Recurrent vesiculobullous eruptions of the inguina and/or extremities | 17–23 |
| Esophagus | Dysphagia Esophageal strictures | 7–27 |
| Larynx | Intermittent hoarseness or dysphonia Supraglottic inflammation and scarring | 5–30 |
| Anus/vagina | Blisters, erosions, and scarring with or without fusion of tissues | 5–11 |
Pathogenesis
Although the cause of mucous membrane pemphigoid remains unknown, research continues to unravel more clues as to the pathogenesis of this complex condition. The hallmark of this autoimmune disease is the type II immune linear deposition of immunoglobulin A (IgA), IgG, IgM, and/or complement (C3) on the conjunctival epithelial basement membrane. Autoantibodies form against different components of the basement membrane, with certain autoantigens being more specific for particular mucosal regions in the body. This likely explains the clinical heterogeneity seen in mucous membrane pemphigoid. Multiple target autoantigens, including BP180, BP230, α 6 β 4 integrin, laminin 5, and type VII collagen, have been identified in patients with mucous membrane pemphigoid. In particular, α 6 β 4 integrin has been strongly linked with OCP. This antigen is an important component of hemi-desmosomes required for epithelial cell attachment to the basement membrane, and its targeting may explain the formation of subepithelial bullae seen in OCP. Recent studies have shown abnormal serum levels of interleukin-4 (IL-4), IL-5, IL-6, tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) during the active phase of the disease, suggesting an abnormal immune system regulation. Further support for the autoimmune nature of mucous membrane pemphigoid comes from the observed association with other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and polyarteritis nodosa. A genetic predisposition for developing mucous membrane pemphigoid also has been postulated by linkage studies. Specific human leukocyte antigen (HLA) class II alleles, such as the DQB1*0301, are significantly associated with severe disease phenotype and anti–basement membrane zone IgG antibody response in mucous membrane pemphigoid.
The histopathology of OCP demonstrates local infiltration by macrophages, neutrophils, T cells, mast cells, and eosinophils into the conjunctiva. The presence of these cells in conjunction with antibody/complement deposition results in the inflammatory response with subsequent bullae formation, rupture, and eventual scarring.
Clinical Findings
Ocular cicatricial pemphigoid presents with nonspecific symptoms of irritation, burning, and tearing and can manifest as recurrent papillary conjunctivitis. In some cases, patients do not experience ocular symptoms even with advanced signs of conjunctival scarring. The ocular involvement initially can be unilateral but progresses, usually within 2 years, to bilateral involvement with asymmetry in the severity and rate of evolution.
The disease progression of OCP has classically been documented into one of four stages ( Figs. 4.10.1–4.10.4 ). Stage I denotes chronic conjunctivitis with subepithelial fibrosis and an unstable tear film. This leads to dryness and exacerbation of the cicatrization process. Stage II refers to inferior fornix foreshortening. Stage III describes symblepharon formation typically starting with the inferior fornix. As a result of the cicatrizing process, lid abnormalities become a major confounder in the overall prognosis. Trichiasis, entropion, and lagophthalmos contribute to the exposure and abrasion of the corneal surface. Damage to mucin-producing goblet cells, meibomian glands, and lacrimal glands leads to keratinization, which along with ankyloblepharon formation and corneal scarring define the end-stage, which is stage IV. As such, in addition to staging disease progression, the extent of conjunctival inflammation should be graded from inactive (0) to severe (4+). By assessing the stage of the disease process and degree of conjunctival inflammation, appropriate therapy for these patients can be determined more accurately.
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