Clinics in Dermatology
Volume 30, Issue 1 , Pages 34-37, January 2012

Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid)

Article Outline

Abstract 

Mucous membrane pemphigoid, a heterogeneous group of autoimmune blistering diseases, affects primarily the mucous membranes. Although oral and ocular mucosae can both be affected in a given patient, patients with involvement restricted to oral mucosae tend to have a benign outcome, whereas those with ocular disease commonly face treatment resistance, resulting in scarring and blindness. Diagnosis requires direct immunofluorescence microscopy to demonstrate a linear deposition of immunoglobulin (Ig) G or IgA, or complement component 3 (C3), at the epithelial basement membrane. Although the target antigens vary, subsets of patients affected exclusively by oral and ocular mucosal diseases have autoantibodies targeting α-6 and β-4 integrins, respectively.

 

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Introduction: Definition and etiology 

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid , is defined as a heterogeneous group of putative autoimmune subepithelial blistering diseases primarily affecting any mucous membranes, including the oral cavity, ocular mucosae, or mucous membranes of the nose, larynx, esophagus, rectum, penis, and vagina.1 Autoantibodies binding to the epithelial basement membrane zone have been demonstrated in these patients, and some of these autoantibodies can induce subepidermal separation in skin organ culture.1, 2, 3, 4, 5

Fab fragments antibodies against laminin-5 are able to induce subepithelial blisters of mucous membranes and skin in neonatal mice, lending more support for MMP being an autoimmune disease.6 Many clinical reports have also pointed to a possible involvement of a mechanism of “epitope spreading,” where a prior inflammatory event might expose the previously “hidden” epithelial basement membrane components to autoreactive T cells, leading to a secondary autoimmune phenomenon and the eventual development of MMP.7 In fact, ocular MMP subsequently developed in several patients who had suffered an episode of Stevens-Johnson syndrome affecting the ocular mucosae.8 Ocular MMP in the context of ocular Sjögren syndrome has also been reported.9

Many epithelial basement membrane components have been identified as potential targets of MMP. These include bullous pemphigoid antigen 2 (type XVII collagen),1 type VII collagen,1 laminin 332 (laminin-5),3 laminin-6,10 α-6 and β-4 integrin subunits,4 and a 120-kDa undefined epithelial antigen.8 Currently, there is no definite evidence pointing to the mechanism that links the binding of autoantibodies to the epithelial basement membrane and the subsequent scarring process, which actually post the single most difficult challenge to the physicians who care for these patients.

Investigators have attempted to subdivide this heterogeneous group of diseases into more unique subsets.2, 4, 11 For example, patients with exclusive involvement of ocular mucosae possess autoantibodies to an epithelial basement membrane antigen, β-4 integrin subunit, that is different from those who have other mucosal and skin diseases.2, 4 Other investigators also proposed that patients with exclusive oral mucosae involvement should be categorized as another distinct subset of disease (oral pemphigoid), with autoantibodies targeting the α-6 subunit of integrin.11 These “oral pemphigoid” patients tend to encounter a relative benign course compared with those with skin and other mucosal diseases.11 Several reports have documented the association of MMP with human leukocyte antigen (HLA) major histocompatibility class II HLA-DQB1⁎0301.12, 13, 14

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Clinical manifestations 

Although skin and multiple mucous membranes can be affected in a given patient,1 there are apparently distinct subsets of patients where the affected sites are restricted to the ocular or oral mucosae.2, 4, 11 Patients who have restricted oral mucosal lesions have an excellent prognosis, they tend to have a mild to moderate disease process,1, 11 and scarring usually does not occur.1 The individual lesions can be erythematous patches, blisters, erosions, or pseudomembrane-covered erosions.15 Any oral cavity locations, including attached gingivae, buccal mucosae, palate, pharynx, labia, and tongue, can be involved. Oral mucosal involvement is illustrated in Figure 1.

MMP patients with ocular disease generally tend to follow a progressive disease process.1, 16 A recurrent conjunctiva inflammatory process usually results in subepithelial fibrosis that leads to fornix shortening, symblepharon, and ankyloblepharon formation, and then, subsequently, trichiasis and entropion. Blisters are rarely observed. Ocular involvement is illustrated in Figure 2. Later in the disease stage, limbal stem cell deficiency, tear deficiency, and lid malposition can occur, ending in total keratinization of the entire ocular surface.1, 16

The epidemiologic data for MMP are not very well established. A survey of a large series of 28 MMP patients (61% women) who were a mean age of 73 years, found 64% had ocular disease.17 This survey documented many complications of ocular disease, including entropion, recurrent epithelial erosions, corneal ulcers, keratitis, and corneal perforation.17 Despite the control of inflammation, visual loss occurred in 53% of eyes and reading visual acuity was maintained in only 35% of eyes.17

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Diagnostic workups 

Differential diagnoses of MMP include pemphigus vulgaris, paraneoplastic pemphigus, and Stevens-Johnson syndrome. The disease is documented by direct immunofluorescence microscopy before the patient is committed to long-term immunosuppressive treatments. An international consensus meeting recommends that a mucosal biopsy specimen should be obtained from the oral mucosa for the test.1 This consensus also recommends against biopsy of the ocular mucosa tissue because it may aggravate the existing inflammation.

The finding of linearly deposited IgG, IgA, or complement component 3 (C3) at the epithelial basement membrane (Figure 3) is considered to be sufficient for the diagnosis in the context of consistent clinical findings. Histopathologic study of a lesion is recommended only if a biopsy specimen can be obtained in nonocular mucosae such as the oral mucosae or skin.

  • View full-size image.
  • Fig. 3. 

    Direct immunofluorescence microscopy of a biopsy specimen obtained from oral mucosa illustrates the linear deposit of C3 along the epithelial basement membrane (original magnification × 40).

Some physicians may also perform an indirect immunofluorescence (IIF) microscopy to identify the presence and characteristics of autoantibodies, using the patient’s sera on a normal human skin substrate split by 1.0 mol/L NaCl or 20 mmol/L of Na-ethylenediaminetetraacetic acid. Although the sensitivity is low in IIF, a positive finding of autoantibodies binding to the roof or the floor of the split will allow physicians to subdivide patients with autoantibodies targeting upper lamina lucida antigens (bullous pemphigoid antigen 2, α6β4 integrins) or lower lamina lucida/sublamina densa antigens (laminin-5, laminin-6, type VII collagen), respectively.

An enzyme-linked immunosorbent assay (ELISA) for the target antigen is a more sensitive test, but its availability is currently limited to a few academic centers. Because a subset of patients with MMP and antilaminin-5 autoantibodies also developed internal malignancies near the time of MMP onset,18 it is essential that this subgroup of patients undergo an age-appropriate cancer screening.

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Therapeutic strategies 

An international consensus meeting recommended that patients should be subdivided into two clinical categories for the purpose of strategic therapy: (1) patients with mucosal lesions restricted to oral mucosae and (2) patients with ocular, laryngeal, esophageal, or genital lesions.1, 15

For the first group of patients with milder disease, an initial treatment of topical corticosteroid should be tried.1, 11, 15 In patients with moderate to severe of oral mucosal disease, dapsone (50-200 mg/d) and a low dose of prednisone (0.5 mg/kg/d) should be initiated.1, 11, 15 If satisfactory response is not obtained by dapsone and prednisone, then an immunosuppressive, such as azathioprine (100-150 mg/d) or mycophenolate mofetil (1 g/d), could be added to the regimens.

A more aggressive starting treatment plan is recommended for the second group of patients.1, 15 The available medications for these patients include dapsone, systemic corticosteroids, azathioprine, mycophenolate mofetil, and cyclophosphamide. For patients with slow to moderate progression of disease, dapsone (50-200 mg/d), plus systemic corticosteroids (1 mg/kg/d) and an immunosuppressive with azathioprine (100-150 mg/d) or mycophenolate mofetil (1-1.5 g/d) should be initiated. For patients with rapid progression of disease, cyclophosphamide (1-2 mg/kg/d) plus systemic corticosteroids (1-1.5 mg/kg/d) is preferred because cyclophosphamide has a faster onset of action.1, 15 When patients are being treated with immunosuppressive agents, careful monitoring of the medication side effects is an essential part of the management. Azathioprine and mycophenolate mofetil can cause severe liver toxicity; cyclophosphamide can cause hemorrhagic cystitis, and all of these immunosuppressive agents can induce severe bone marrow suppression.

More recently, a few cases of MMP treated successfully with a new biologic, rituximab, with or without combination of intravenous immunoglobulin have been reported.19, 20, 21 In one report, combined treatment of rituximab and intravenous immunoglobulin arrested disease progression and prevented total blindness in patients with recalcitrant disease, whereas those treated aggressively with other immunosuppressive regimens became totally blind.19

From time to time, surgical interventions are used for MMP patients with ocular diseases. These procedures include entropion surgery (eye lash ablation), tarsorrhaphy, mucous membrane grafting, amniotic membrane transplantation, tectonic keratoplasty, and keratoprosthesis.17 These surgical procedures aim to achieve temporary symptom relieve and are not curative. After receiving a procedure called “Boston keratoprosthesis,” patients with end-stage ocular disease secondary to MMP suffered numerous corneal meltdowns and required multiple repeat implantations.22 Because tear deficiency is a major cause of symptoms in these MMP patients with ocular disease, systemic treatment to control inflammation should be augmented with a lubricant, without a preservative, to improve the dry eye. The accompanying blepharitis should be treated with tetracycline and lid hygiene.23

Besides medical and surgical treatments, physicians who care for these patients need to address a potential association of MMP with internal malignancies. A survey of 35 patients who developed MMP with autoantibodies to laminin 332 showed a relative cancer risk of 6.8, which appears to be increased.18 Other surveys of MMP patients who have exclusively oral mucosal disease (with autoantibodies to α-6 integrin) and who have exclusive ocular mucosal disease (with autoantibodies to β-4 integrin) showed a lower than expected relative cancer risk of 0.34 and 0.29, respectively.24, 25

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Conclusions 

One of the major practice gaps regarding the therapeutic options for MMP is the current lack of any medication or procedure that can be used to reverse the scarring/fibrotic process once it is established. This is particularly detrimental to those with ocular lesions. Future therapeutic interventions should be geared toward learning about reversing the scarring/fibrotic process. Another area of research interest would be the link between antilaminin 332 autoantibodies and the increased cancer development.18 Is laminin 332 important in preventing the development of certain cancers?

There are some encouraging research data, however. One recent publication reported an increased conjunctiva expression of tumor necrosis factor-α (TNF-α) in ocular MMP and suggests that a systemic TNF-α antagonist could be effective in controlling severe MMP cases unresponsive to conventional immunosuppressant.26 TNF-α stimulated conjunctiva fibroblast matrix metalloproteinase-9 production and upregulated CD40 and intercellular adhesion molecule 1 expressions, without a significant effect on fibroblast proliferation or collagen lattice contraction.26 In fact, several cases of MMP, some of them affecting ocular mucosae, have been successfully controlled by anti-TNF-α medication after failure of the conventional treatment with immunosuppressive agents.27, 28, 29 A controlled trial in the future is needed to establish the true effectiveness of this regimen.

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References 

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  2. Chan LS, Yancey KB, Hammerberg C, et al. Immune-mediated subepithelial blistering diseases of mucous membranes. Pure ocular cicatricial pemphigoid is a unique clinical and immunopathological entity distinct from bullous pemphigoid and other subsets identified by antigenic specificity of autoantibodies. Arch Dermatol. 1993;129:448–455
  3. Domloge-Hultsch N, Gammon WR, Briggaman RA, et al. Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease. J Clin Invest. 1992;90:1628–1633
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PII: S0738-081X(11)00083-6

doi:10.1016/j.clindermatol.2011.03.007

Clinics in Dermatology
Volume 30, Issue 1 , Pages 34-37, January 2012

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