keratoprosthesis (KPro; Massachusetts Eye and Ear Infirmary, Boston) has also been reported to be effective. Unfortunately, many patients who have this condition are young and are left with lifelong ocular morbidity.
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Mucous Membrane Pemphigoid
PATHOGENESIS The exact mechanism of mucous membrane pemphigoid (MMP), formerly called ocular cicatricial pemphigoid, remains unknown, although it may represent a cytotoxic (type II) hypersensitivity in which cell injury results from 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 a (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 MHC, has been associated with this condition, but not all affected individuals are positive for this background; hence, HLA typing is not useful.
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 principal difference between pseudopemphigoid and true pemphigoid is that in the former, progression of the disease generally ceases once the offending agent is recognized and removed.
CLINICAL PRESENTATION MMP is a chronic cicatrizing conjunctivitis of autoimmune etiology. Although it is a chronic vesiculobullous disease primarily involving the conjunctiva, it frequently affects other mucous membranes, including the mouth and oropharynx, genitalia, and anus. Difficulty swallowing may be an important early symptom. The skin is involved as well in approximately 15% of cases.
MMP affects women more than men by a 2:1 ratio. Patients are usually older than 60 years and rarely younger than 30. They frequently present with recurrent attacks of mild and nonspecific conjunctival inflammation with an occasional mucopurulent discharge. In its early phases, MMP may
present with conjunctival hyperemia, edema, ulceration, and tear dysfunction.
Close examination of the conjunctiva in early stages of the disease (stage I) reveals subepithelial fibrosis (Fig 7-11). Fine gray-white linear opacities, best seen with an intense but thin slit beam, appear in the deep conjunctiva. However, in many cases insidious 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.
Figure 7-11 Ocular mucous membrane pemphigoid (MMP) showing subepithelial fibrosis. (Courtesy of Charles S. Bouchard, MD.)
Transient bullae of the conjunctiva rupture, leading to subepithelial fibrosis. Loss of goblet cells, shortening of the fornices (stage II), symblepharon formation (stage III; Fig 7-12), 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 should therefore watch for an inferior forniceal depth of less than 8 mm, which is abnormal and should prompt further evaluation. Subtle inferior symblephara can be detected when the lower eyelid is pulled down while the patient looks up.
Figure 7-12 Patient with MMP showing subepithelial fibrosis, symblepharon, and shortening of the inferior fornix. (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. 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 (Table 7-2):
1.postinfectious conditions that follow severe episodes of trachoma, adenoviral conjunctivitis, or streptococcal conjunctivitis
2.autoimmune or autoreactive conditions such as sarcoidosis, scleroderma, lichen planus, SJS, dermatitis herpetiformis, epidermolysis bullosa, atopic blepharoconjunctivitis, or graft-vs-host disease
3.prior conjunctival trauma
4.severe blepharokeratoconjunctivitis caused by rosacea or other disorders that are associated with conjunctival shrinkage (eg, atopic keratoconjunctivitis)
Table 7-2
The diagnosis of unilateral MMP should be made with caution, because other diseases, including many of those just listed, may masquerade as MMP. Finally, linear IgA dermatosis, a rare dermatologic condition, can result in an ocular syndrome that is clinically identical to MMP and requires similar treatment.
LABORATORY EVALUATION Although MMP is a bilateral disease, 1 eye may be more severely involved than the other. Pathologic support for a diagnosis of pemphigoid can be obtained from a conjunctival biopsy sent for direct immunofluorescent or immunoperoxidase staining. 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 BMZ of the conjunctiva in pemphigoid (Fig 7- 13). Circulating anti–basement membrane antibody has been identified in the sera of some patients with pemphigoid. End-stage disease may produce negative results because of the destruction of basement membrane.
Figure 7-13 Immunofluorescent staining of basement membrane in a patient with MMP.
MANAGEMENT A multidisciplinary approach is often required in the management of this disease, with the involvement of ophthalmologists, dentists, dermatologists, oral surgeons, primary care physicians, gynecologists, otolaryngologists, and gastroenterologists. Classifying patients into highrisk and low-risk groups is valuable when determining appropriate therapy. Patients with MMP involving ocular, genital, nasopharyngeal, esophageal, and laryngeal mucosae, as well as patients with rapidly progressing disease, should be treated using the high-risk algorithm. Dapsone, a drug previously used to treat leprosy (Hansen disease) and dermatitis herpetiformis, has been advocated by most authorities as the initial drug of choice in mild cases. It must be avoided in patients with glucose- 6-phosphate dehydrogenase (G6PD) deficiency or sulfa allergy; therefore, testing for G6PD deficiency is recommended before treatment is initiated. However, even those without this enzymatic deficiency may develop hemolytic anemia. Cyclophosphamide remains a mainstay of therapy in severe disease. The usual therapeutic dose is 1.5–2.0 mg/kg per day in divided doses. The therapeutic target is a reduction in white blood cell count to the range of 2000–3000 cells/µL. Cytotoxic therapy can bring about disease remission. Consultation with an internist, dermatologist, or oncologist experienced in cytotoxic therapy is recommended when administering immunosuppressive agents such as cyclophosphamide.
Patients who fail to respond to conventional therapies may be treated with intravenous immunoglobulin or biologic agents such as rituximab, infliximab, or etanercept. This therapy should be considered an alternative treatment option for patients who would otherwise require aggressive systemic treatments, such as cyclophosphamide, corticosteroids, or azathioprine.
Low-risk patients include those with disease occurring only in the oral mucosa or oral mucosa and skin. These patients have a much lower incidence of scarring; thus, they can be treated more conservatively. Because progression is often slow, careful clinical staging of the disease and photodocumentation in differing positions of gaze are generally recommended in evaluating the disease course and response to therapy. Severity of pemphigoid can be judged by measuring the shortening of the inferior forniceal depth (for stage II disease) and the extent of symblepharon along the inferior fornix in quartiles (0%–25%, 25%–50%, 50%–75%, and 75%–100% for stage III–IV disease) (see Fig 7-12).
Topical vitamin A has been shown to reverse, to some extent, the keratinization resulting from the squamous metaplasia associated with this condition, but it is not currently commercially available as an ophthalmic preparation.