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Fahd Anzaar, MD · C. Stephen Foster, MD, FACS, FACR
Mucous membrane pemphigoid (MMP) is a term first defined in 2002 (during the first international consensus on MMP) as "a heterogenous group of autoimmune, chronic inflammatory, subepithelial blistering diseases predominantly affecting mucous membranes characterized by linear deposition of IgG, IgA, or C3 along the epithelial basement membrane."1 Previously, this condition was referred to by other names like cicatricial pemphigoid, benign MMP, oral pemphigoid, ocular cicatricial pemphigoid (OCP), and, incorrectly, as ocular pemphigus. "Pemphigus" refers to a separate disease entity distinct from "pemphigoid." Both are autoimmune bullous diseases, but the difference lies in the location of the autoantigen-antibody complex: Pemphigus is characterized by intra-epithelial antibody deposition, and pemphigoid is characterized by subepithelial antibody deposition. This is reflected in histopathology specimens as intra-epithelial bullae in pemphigus, and subepithelial bullae in pemphigoid. The pemphigoid group of diseases includes bullous pemphigoid (skin more than mucosa), MMP (mucosa more than skin), linear IgA bullous disease, chronic bullous dermatosis of childhood, pemphigoid gestationis, and epidermolysis bullosa acquisita. The pemphigus group of diseases includes pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, pemphigus erythematosus, pemphigus herpetiformis, and drug-induced and paraneoplastic pemphigus.
Any mucous membrane may be affected in MMP, and membranes affected most frequently include the oral, ocular, nasal, nasopharyngeal, anogenital, skin, laryngeal, and esophageal mucosa, in descending order.2 When MMP involves only the conjunctiva, or when ocular involvement is prominent, the disease entity is referred to as ocular cicatricial pemphigoid (OCP).
OCP is an uncommon disease, but estimates may falsely under-represent the true prevalence because diagnosis in the early stages is difficult and patients with predominantly non-ocular manifestations are not included. OCP occurs in older individuals, with presentation typically occurring in the sixth or seventh decade of life. It occurs in younger populations as well, with isolated reports of occurrence in children. No racial or geographic predilection exists, and females are affected more than males.3
Ocular
The onset of OCP is typically asymmetric and unilateral, progressing to bilateral involvement in all cases, given sufficient time. This time interval varies from weeks to years. Patients complain of irritative symptoms such as foreign body sensation, tearing, burning, light sensitivity, redness, itching, pain, and discharge. At this point, the signs and symptoms of this chronic papillary conjunctivitis are indistinguishable from any other nonspecific conjunctivitis. Symptoms do not always correlate with disease severity, and the fibrosis, once initiated, continues relentlessly, even in asymptomatic patients.4 The earliest signs appearing on slit lamp examination are lacy white lines in the lower tarsal conjunctiva, typically perivascular, that represent subepithelial fibrosis, or stage I (Slide 1). Conjunctival bullae form, but are short-lived and ulcerate, healing with scarring. Medial canthal involvement results in the formation of shallow canthal recesses, with subsequent loss of the normal architecture and flattening of the caruncal plicae.
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Progressive scar formation in the conjunctiva results in fornix foreshortening, or stage II (Slide 2) and symblepharon formation, or stage III. Stage III consists of adhesions between the bulbar and tarsal conjunctiva, seen when the patient is asked to look upwards and the lower lid is retracted (Slide 3).5
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Scarring and contraction of the eyelid results in trichiasis, distichiasis and entropion. The inturned lashes rub against the cornea, irritating the corneal epithelium, which undergoes squamous metaplasia, neovascularization and keratinization. Pseudopterygium formation occurs, and the cornea progressively thins and may perforate. Secondary bacterial infections and ulceration of the corneal epithelium may occur, leading to further damage. Conjunctival fibrosis destroys goblet cells and obliterates or distorts the lacrimal ducts and the meibomian gland ductules, causing a severe dry eye syndrome with aqueous deficiency, increased evaporative loss from the reduced meibum secretion and mucin loss. Further scarring results in ankyloblepharon, or stage IV of OCP, which is permanent fusion of the lids to the bulbar conjunctiva (Slide 4). Due to the scarring and changes to the eyelid and globe structure, the outflow of aqueous humor is affected and patients may develop glaucoma and optic neuropathy.6 Without appropriate treatment, the natural history of the disease is one of slow progression to eventual bilateral blindness from diverse mechanisms including corneal damage, dry eye, lid/globe changes, and glaucoma. Diagnosis must be made early so that appropriate treatment may be initiated. However, diagnosis is often made in the later stages of the disease, when considerable damage has already occurred,7 which necessitates aggressive systemic therapy with potentially toxic medications. An older patient may be intolerant of such medications, resulting in vision loss despite the initiation of treatment.8
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Systemic
Oral lesions are the most common extraocular manifestation of MMP. Desquamative gingivitis may bleed and ulcerate. Painful vesico-bullous lesions may also form and rupture, but, in contrast with lesions elsewhere, do not heal with scarring. Erythematous patches and pseudomembrane-covered lesions may be seen on the palatal, labial, tongue, and buccal mucosa. Esophageal lesions may lead to heartburn, dysphagia, and aspiration.9 Laryngeal and tracheal stenosis may cause difficulty in breathing or hoarseness and may be severe enough to be fatal. Cutaneous manifestations may be of two types: recurrent vesico-bullous lesions in the inguinal areas and the extremities that do not result in scarring, or the localized, erythematous, pruritic plaques with bullae on the scalp and face that heal with scarring (known as Brusting-Perry dermatitis).
Other systemic conditions, such as rheumatoid arthritis, systemic lupus erythematosus and Wegener's granulomatosis, may co-exist with MMP. A common immune mechanism may be responsible for these conditions.
Pathogenesis and Histopathology
MMP is an autoimmune disease characterized by the production of autoantibodies to antigens present within the basement membrane zone (BMZ) of epithelial cells, secondary complement activation from the antigen-antibody complex deposition and T cell alteration.10,11
A genetic susceptibility to MMP is suggested by increased frequencies of the HLA antigens DQB1*0301 (DQw7), DR-2, and DR-4 in patients,12,13 the result of an environmental trigger, acting on a susceptible individual (defined by genetic makeup), which starts an immune response that secondarily attacks the host's own tissues. This sets up a self-perpetuating cycle that continues unabated. Some identified triggers include systemic practolol (a beta-blocker no longer on the market), ocular epinephrine, idoxuridine, and phospholine iodide.
The most frequent and consistently reported autoantigen in patients with OCP is the β4 peptide of the α6β4 integrin molecule.14-16 Integrins, a class of transmembrane protein, anchor epithelial cells to the basement membrane. Other known MMP autoantigens include epilirin 17 (α3 subunit of laminin 5, a ligand for α6β4 integrin), α3 chain of laminin 6, type VII collagen, bullous pemphigoid antigen 1 (BP230) and bullous pemphigoid antigen 2 (BP180).18,19 Antigens that have yet to be identified also exist and are referred to by their molecular weight because they have no name (e.g., 45 kd, 120 kd, and 168 kd epithelial proteins).
Binding of the antibody to the antigen results in deposition of immune complexes in the BMZ, which may lead to the activation of the classic and alternate complement pathways. Secondary effector cells such as lymphocytes, plasma cells, dendritic cells, neutrophils, macrophages, eosinophils, and mast cells are then recruited and their influx results in the release of many inflammatory mediators, which cause further tissue damage. All of this occurs at the level of the hemidesmosome (which binds epithelial cells to the basement membrane), and tissue destruction (or alterations in cell signaling) results in the separation of epithelial cells from the BMZ, forming the subepithelial bullae characteristic of pemphigoid. The mediators and cytokines released by the incoming cells include TGF-β, IFN γ, PDFG, bFGF, TNF-α and β, IL-5, IL-1 and IL-4, ICAM-1, and VCAM-1.20-25 These are found in increased amounts, whereas both IL-6 and IL-1 receptor antagonist levels are lower than normal. Some of these are fibrogenic and are responsible for the progressive fibrosis and scarring that is the hallmark of MMP. However, in chronic progressive MMP, some of these cytokines are not detected, supporting the idea that fibroblasts in the conjunctiva of MMP patients remain active and abnormal (i.e., continue to lay down collagen) even after the cytokines are withdrawn.
Conjunctival biopsy in MMP shows increased numbers of the inflammatory cells mentioned above in the substantia propria, with the numbers of macrophages and neutrophils correlating with disease severity. Squamous metaplasia, keratinization, and parakeratosis is also shown in conjunctival biopsy in MMP, with reduced numbers of goblet cells. Mononuclear cells, especially T lymphocytes, are greatly increased, as are the numbers of conjunctival fibroblasts.26,27
Diagnosis is frequently delayed because of the nonspecific nature of the early signs and symptoms, and this delay in recognition and initiation of treatment may sometimes lead to permanent visual (or other) disability. The ophthalmologist may be the first to make the diagnosis of this potentially fatal disease because ocular manifestations may be the first to develop. Therefore, a careful medical history and review of symptoms should be obtained in every patient presenting with signs of chronic conjunctivitis. The clinician should specifically ask for the more ominous and potentially life-threatening symptoms, such as difficulty breathing or swallowing and a history of oral lesions.
Immunohistochemistry of conjunctival biopsy specimens is the standard of diagnosis for MMP. Bulbar conjunctiva is obtained from the actively inflamed eye and divided into three equal pieces for light microscopy, electron microscopy, and immunohistochemical studies. Linear immunoreactant deposition at the BMZ confirms the diagnosis. Immunoreactants may be IgG, IgA or C3 (Slide 5).28 This immunofluorescence pattern is not specific for MMP, however, and false positives are seen in bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and paraneoplastic and drug-induced pemphigoid.29 False-negative results may also occur, which may be overcome by using the direct immunofluorescence or immunoperoxidase avidin-biotin complex technique and immunoelectron microscopy.30,31
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The goals of therapy are to control the underlying systemic immune disease and to prevent ocular surface disturbances as much as possible. The failures of topical and subconjunctival therapies (e.g., mitomycin C, cyclosporine, and corticosteroids) have been well documented,32 and only systemic immunomodulatory therapy abrogates the chronic cicatricial process.33,34 In advanced cases, visual loss may continue despite the initiation of therapy, and several combinations of immunomodulators may be insufficient to adequately control the inflammation.
Systemic therapy with dapsone, corticosteroids, azathioprine, cyclophosphamide and intravenous immunoglobulin has shown good results. A standard treatment protocol has not been proposed, and the appropriate institution of therapy should be guided by the sites involved, the severity of involvement, the speed of progression and the patient's age and health. Dapsone (25 mg twice daily) is used as the initial agent for patients with mild to moderate disease, slowly progressive forms or elderly patients. It is contraindicated in patients with sulfa allergy or glucose 6 phosphate dehydrogenase (G6PD) deficiency. Side effects include hemolytic anemia, methemoglobinemia, agranulocytosis, aplastic anemia, hepatitis and peripheral neuropathy. The highest dose given is approximately 75 mg twice daily; if unresponsive, methotrexate (7.5-15 mg weekly), azathioprine (2-3 mg/kg) or mycophenolate mofetil (1-2 g daily) therapy may be initiated.35 For severe or rapidly progressive forms, prednisone (1 mg/kg per day) and cyclophosphamide (2 mg/kg per day) are used as combination therapy. Patients should be counseled about the importance of adequate fluid intake to minimize the potential for hemorrhagic cystitis. Due to the nature of the disease, high doses of corticosteroids for long periods were used in the past, but were associated with an unacceptably high side-effect profile and even higher mortality. According to some authors, the complications of systemic corticosteroid therapy may be even more devastating than the disease they were intended to cure.36 According to recommendation, corticosteroids should never be used alone and should always be tapered within 6 weeks of initiation. Intravenous immunoglobulin (IVIg, 2-3 g/kg/cycle, divided over 3 days, and repeated every 2-6 weeks) may be used as an alternative.37,38 Intravenous daclizumab (1 mg/kg/cycle, repeated every 2 weeks for the first 12 weeks, every 3 weeks for the next 12 weeks, and every 4 weeks for the next 28 weeks) may also be used. It is chimeric, humanized IgG antibody to the anti-IL-2 receptor (specifically CD 25) that is expressed preferentially on activated T lymphocytes.
Follow-up must be continued for life, as relapses occur in patients who are considered to be in remission.39
In addition to systemic therapy, the ocular condition may necessitate further local treatment. Dry eye syndrome may be treated with artificial tears, lubricating ointments, or punctal occlusion. Gas-permeable scleral lenses create an oxygen-rich micro-environment around the cornea and protect the epithelium from exposure to air and the eyelids (during blinking), enhancing vision and reducing the incidence of epithelial defects, ocular pain, and photophobia. Epithelial keratinization predisposes a patient to bacterial and other microbial colonization (which may place patients at risk for blepharoconjunctivitis or keratitis), and, subsequently, cultures of the ocular surface should be taken frequently and patients should be started on topical antibiotics if the culture is positive for microbial contamination.
All surgeries should be strictly avoided during active conjunctival inflammation, as the trauma can induce further inflammation and scarring that sabotage the outcome of surgery. Procedures should be delayed until the conjunctival inflammation has been completely controlled and has been stable for at least 3 months,40 with some authors advocating 6 months.3 The preferred method of cataract surgery for patients with MMP is phacoemulsification with a clear corneal incision.41 In cases of corneal pathology, penetrating or lamellar keratoplasty (with or without limbal stem cell transplantation or amniotic membrane grafting)42 may be performed, but only after trichiasis, distichiasis, or dry eye has been controlled. These factors reduce the success of the procedure because they continue to irritate and damage the new cornea. Keratoprostheses are a last resort in patients with the most severe disease, but visual acuity may be suboptimal and the potential for complications (glaucoma, retinal detachment, extrusion and endophthalmitis) is considerable.43
