The exact mechanism of mucous membrane pemphigoid (MMP), formerly called ocular cicatricial pemphigoid, remains unknown, although MMP may represent a cytotoxic (type II) hypersensitivity, in which cell injury results from the action of autoantibodies directed against a cell surface antigen in the basement membrane zone (BMZ). Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains have been identified as possible autoantigens. Antibody activates complement, with a subsequent breakdown of the conjunctival membrane. A number of proinflammatory cytokines, such as IL-1 and tumor necrosis factor α (TNF-α), are overexpressed. TNF-α has been shown to induce the expression of migration inhibition factor, a cytokine found to have elevated levels in the conjunctival tissues of patients with MMP. Macrophage colony-stimulating factor has also been shown to have an increased expression in the conjunctival tissue of patients with active MMP.
Cellular immunity may also play a role. HLA-DR4, a special genetic locus in the major histocompatibility complex (MHC), has been associated with this condition, but not all affected individuals are positive for this background; hence, HLA typing is not useful for diagnosis.
Pseudopemphigoid, which has a clinical picture similar to that of pemphigoid, has been associated with the long-term use of certain topical ophthalmic medications. Case reports have implicated pilocarpine, epinephrine, timolol, idoxuridine, echothiophate iodide, and demecarium bromide. The main difference between pseudopemphigoid and true pemphigoid is that in the former, disease progression generally ceases once the offending agent is recognized and removed. The clinical findings of pseudopemphigoid are similar to those of ocular MMP, and immunohistologic evaluation of biopsied tissue can be helpful.
Mucous membrane pemphigoid is a chronic cicatrizing conjunctivitis of autoimmune etiology. Although it is a vesiculobullous disease primarily involving the conjunctiva, it frequently affects other mucous membranes, including those of the mouth and oropharynx, genitalia, and anus. Difficulty swallowing may be an important early symptom. Skin involvement can occur in some cases.
Patients with MMP are usually older than 60 years at the time of diagnosis. They often present with recurrent attacks of mild and nonspecific conjunctival inflammation with an occasional mucopurulent discharge. Patients with early MMP may present with conjunctival hyperemia, edema, ulceration, and tear dysfunction.
According to the Foster staging system, close examination of the conjunctiva in the early stages of the disease (stage I) reveals subepithelial fibrosis (Fig 11-11). Fine gray-white linear opacities, best seen with an intense but thin slit beam, appear in the deep conjunctiva. However, in many cases, the disease in its early stages produces nonspecific symptoms with minimal overt physical findings, such as chronic red eye. Oral mucosal lesions may be a clue that can lead to early diagnosis.
Transient bullae of the conjunctiva rupture, leading to subepithelial fibrosis. Loss of goblet cells, shortening of the inferior fornices (stage II), symblepharon formation (stage III; Fig 11-12), and, on occasion, restricted ocular motility with extensive adhesions between the eyelid and the globe (stage IV) can follow. Ophthalmologists should attempt to diagnose this condition in its early stages and watch for an inferior fornix depth of less than 8 mm, which is abnormal and should prompt further evaluation. A subtle inferior symblepharon can be detected when the lower eyelid is pulled down while the patient looks up.
Figure 11-11 Ocular mucous membrane pemphigoid (MMP) showing subepithelial fibrosis.
(Courtesy of Charles S. Bouchard, MD.)
Figure 11-12 Subepithelial fibrosis, symblepharon, and shortening of the inferior fornix in MMP are demonstrated.
(Courtesy of Charles S. Bouchard, MD.)
Recurrent attacks of conjunctival inflammation can lead to destruction of goblet cells and eventually obstruction of the lacrimal gland ductules. The resultant aqueous and mucous tear deficiency leads to keratinization of the already thickened conjunctiva. Entropion and trichiasis may develop as scarring progresses, leading to abrasions, corneal vascularization, further scarring, ulceration, and epidermalization of the ocular surface. Corneal abrasions in these patients are emergencies and must be treated immediately to minimize progression to perforation, scarring, and ankyloblepharon formation. Although the clinical course varies, progressive deterioration usually occurs in untreated cases. Remissions and exacerbations are common. Surgical intervention can incite further scarring but may be essential in managing entropion and trichiasis.
The differential diagnosis of cicatrizing conjunctivitis includes 4 major categories, which are listed in Table 11-1. The diagnosis of unilateral MMP should be made with caution because other diseases, including many of those listed in Table 11-1, may masquerade as MMP. Also, linear IgA dermatosis, a rare dermatologic condition, can result in an ocular syndrome that is clinically identical to MMP and requires similar treatment.
Table 11-1 Differential Diagnosis of Cicatricial Conjunctivitis
In patients with unexplained persistent epithelial defects (ie, after cataract surgery), MMP should be considered in the differential diagnosis and the patient carefully examined for any other signs of the disease.
Williams GP, Radford C, Nightingale P, Dart JK, Rauz S. Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom. Eye (Lond). 2011;25(9):1207–1218.
Although MMP is a bilateral disease, one eye may be more severely involved than the other. Pathologic support for a diagnosis of pemphigoid can be obtained from direct immunofluorescence or immunoperoxidase staining of conjunctival biopsy specimens. False-negative results are not uncommon, however.
Biopsy specimens should be obtained from an actively affected area of the conjunctiva or, if involvement is diffuse, from the inferior conjunctival fornix. Oral mucosal biopsies may be useful, especially in the presence of an active lesion. In pseudopemphigoid, conjunctival biopsies may or may not be positive for immunoreactants. Immunohistochemical staining techniques can demonstrate complement 3, IgG, IgM, and/or IgA localized in the epithelial BMZ of the conjunctiva in pemphigoid (Fig 11-13). Circulating anti–basement membrane antibody has been identified in some patients with pemphigoid. End-stage disease may produce negative results because of the destruction of basement membrane. (See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors.)
Figure 11-13 Immunofluorescent staining of basement membrane in a patient with MMP.
Radford CF, Rauz S, Williams GP, Saw VP, Dart JK. Incidence, presenting features, and diagnosis of cicatrizing conjunctivitis in the United Kingdom. Eye (Lond). 2012;26(9):1199–1208.
A multidisciplinary approach is required in the management of MMP. It is helpful to involve an ophthalmologist who specializes in the treatment of this disease, and collaboration with other providers who have experience using systemic treatment is recommended to maximize patient outcome. Classifying patients according to their risk for disease progression (low or high) is valuable when appropriate therapy is being determined. Because progression is often slow, careful clinical staging of the disease and photo documentation (with the patient in differing positions of gaze) are generally recommended in evaluation of the disease course and response to therapy. Different staging systems to determine disease severity have been developed. Mondino and Brown staged MMP by the amount of inferior fornix depth lost. The Foster staging system is based on the presence or absence of specific clinical findings. Tauber proposed a modification to these staging systems (Table 11-2).
Table 11-2 Staging Systems for Mucous Membrane Pemphigoid
It is important to remember that MMP is a systemic disease. Topical treatments (steroids, cyclosporine A, tacrolimus) may help alleviate symptoms but will not prevent disease progression. Systemic therapy is required. Several systemic therapies have been reported for the treatment of MMP, with regimens varying depending on the severity of the disease and the presence or absence of sight-threatening complications. Cyclophosphamide remains a mainstay of therapy for severe disease when sight is threatened. The use of intravenous immunoglobulin, anti-TNF-α medications, and rituximab has been reported in patients who were unresponsive to or who experienced complications from conventional treatments.
These systemic treatments have significant adverse effects, including death; thus, it is critical for the ophthalmologist to partner with providers who are experienced in the administration and management of these treatments (ie, rheumatologists, hematologists, oncologists).
Any procedure or surgery (eyelid, intraocular) can cause disease flare, so adequate immunosuppression therapy is necessary. Also, surgical correction of eyelid deformities or treatment of trichiasis is important. In severe cases, hard palate and buccal mucosal grafting can be useful techniques in fornix reconstruction. Punctal occlusion, which may have already resulted from cicatrization, can be useful in the management of any associated dry eye condition. In general, patients with cicatrizing conjunctivitis have a higher rate of spontaneous extrusion of silicone punctal plugs; thus, permanent punctal occlusion with cautery is often required. Standard penetrating keratoplasty in MMP patients with severe corneal disease is generally associated with a very guarded prognosis. In patients who become blind due to MMP, keratoprosthesis surgery, performed as a last resort, has achieved some success. It is often difficult to distinguish sequelae of uncontrolled disease from inflammation secondary to structural and mechanical problems related to prior active disease. Careful examination is critical to determine whether there is active disease requiring further control.
Foster CS, Chang PY, Ahmed AR. Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report. Ophthalmology. 2010;117(5):861–869.
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Saw VP, Dart JK, Rauz S, et al. Immunosuppressive therapy for ocular mucous membrane pemphigoid: strategies and outcomes. Ophthalmology. 2008;115(2):253–261.
Srikumaran D, Tzu JH, Akpek EK. Cicatrizing conjunctivitis. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2011, module 1.
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Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.