Cicatricial (Mucous Membrane) Pemphigoid 

Updated: May 03, 2017
Author: Manuel Valdebran, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, refers to a group of rare chronic autoimmune blistering diseases that predominately affect the mucous membranes, including the conjunctiva, and occasionally the skin. Patients with cutaneous involvement present with tense blisters and erosions, often on the head and the neck or at sites of trauma. Scarring of the mucous membranes is common, hence the designation cicatricial, which can lead to decreased vision, blindness, and supraglottic stenosis with hoarseness or airway obstruction. The first international consensus on mucous membrane pemphigoid was published in 2002.[1]

See the illustration below depicting ocular mucous membrane pemphigoid.

Ocular manifestations of cicatricial pemphigoid (m Ocular manifestations of cicatricial pemphigoid (mucous membrane pemphigoid) include symblepharon, demonstrated in this photograph by the tethering of the lower lid to the cornea.

Classification of mucous membrane pemphigoid patients has been difficult because some patients with other autoimmune blistering diseases, including bullous pemphigoid (BP),epidermolysis bullosa acquisita (EBA),and anti-p200 pemphigoid, may have mucosal involvement. Also, clinical heterogeneity exists in the clinical manifestations of this disease, with some patients presenting with ocular involvement and others with oropharyngeal involvement. The heterogeneity in clinical manifestations does not appear to be linked to the heterogeneity of the target antigens alone.

Pathophysiology

As in other autoimmune diseases, environmental factors combined with genetic susceptibility lead to development of autoantibodies. By direct immunofluorescence (DIF) study, antibodies bound in a linear band at the epidermal-dermal junction have been found in patients with mucous membrane pemphigoid (MMP), as depicted below. By immunoelectron microscopy, these antibodies are found in the lamina lucida. In some patients, autoantibodies extend to the lamina densa. When detectable, circulating autoantibodies are present in a low titer. See the image below.

By direct immunofluorescence, a linear band of imm By direct immunofluorescence, a linear band of immunoreactants at the epidermal-dermal junction is demonstrated by using a fluorescein-tagged antibody specific for human immunoglobulin G.

Different epithelial membrane zone components have been recognized by antibodies in patients with mucous membrane pemphigoid, including BP antigens 1 and 2 (BP230 and BP180), laminin-332, laminin-311, type VII collagen, b4 integrin subunit, and antigens with unknown identities (a 45-kd protein, uncein, a 168-kd epithelial protein, and a 120-kd epithelial protein). While circulating autoantibodies in a given patient tend to target a single antigen, sera of patients with same clinical features may target different autoantigens.

Epidemiology

Frequency

The incidence of mucous membrane pemphigoid (MMP) has been estimated to be 2 cases per million in studies performed in France and Germany.[2, 3, 4] Pure ocular mucous membrane pemphigoid occurs in less than 1 case per million in the United Kingdom.[5] . Among white patients in the United States, mucous membrane pemphigoid is associated with human leukocyte antigen DQB1*0301 (HLA-DQB1*0301).[6, 7]

Race

No racial predilection is known.

Sex

Most studies have demonstrated a female-to-male ratio of approximately 2:1

Age

Most patients with mucous membrane pemphigoid are elderly, with a mean age of 62-66 years.

Prognosis

Extensive studies on the long-term outcome of patients with mucous membrane pemphigoid (MMP) have not been performed.

In general, mucous membrane pemphigoid is a chronic, progressive disorder that responds poorly to therapy. Some patients may experience long-term remissions. The disease is characterized by intermittent exacerbations and waning of disease activity. Mucous membrane pemphigoid is a chronic blistering disease that frequently heals with scarring. Individual blisters may itch, and subsequent erosions are often painful. Depending on the sites affected, sequelae include decreased vision or blindness, hoarseness, esophageal stenosis, or upper airway compromise. This disease is often recalcitrant to therapy.

A cohort study of 35 patients with anti–laminin-332 mucous membrane pemphigoid indicated an increased risk of malignancy that approximates that for adults with dermatomyositis. The risk is particularly high in the first year of disease.

Patient Education

Be certain that patients understand the chronic nature of this disorder.

Help patients in identifying factors that precipitate disease activity, and instruct them to avoid conditions that exacerbate the condition.

Discuss the medications, including the dose, the adverse effects, and the symptoms of toxicity, with the patient.

Teach patients appropriate wound care.

 

Presentation

History

Patients with mucous membrane pemphigoid (MMP) (cicatricial pemphigoid) typically present with persistent, painful erosions on the mucous membranes. The clinical manifestations are dependent on the sites involved. A majority of patients demonstrate oral mucosal findings, including erosions and desquamative gingivitis.

Patients with ocular involvement may present with pain or the sensation of grittiness in the eye and conjunctivitis. Erosions may be seen on the conjunctival surface. Early changes include keratinization of the conjunctiva and shortening of the fornices. Later, patients develop entropion with subsequent trichiasis.

Patients often present after ocular surgery, especially for cataracts, with severe inflammation of the eye or eyes and scar formation. With progressive scarring, patients develop symblepharon (fibrous tracts that tether bulbar and conjunctival epithelium), synechiae (adhesion of the iris to the cornea or the lens), and ankyloblepharon (a fixed globe). See the images below.

Ocular manifestations of cicatricial pemphigoid (m Ocular manifestations of cicatricial pemphigoid (mucous membrane pemphigoid) include symblepharon, demonstrated in this photograph by the tethering of the lower lid to the cornea.
With advanced disease, ankyloblepharon (a fixed gl With advanced disease, ankyloblepharon (a fixed globe) develops.
In a patient with more advanced ocular scarring, n In a patient with more advanced ocular scarring, note the thickening of the lid margins, shortening of the conjunctival sulcus, and scarring. The eyelashes have been epilated after entropion developed.

Lacrimal gland and duct involvement leads to decreased tear and mucus production. Diminished tear formation leads to ocular dryness and further trauma.

The end result of ocular involvement is opacification and blindness. Some patients with ocular disease may represent a subset of patients with  mucous membrane pemphigoid who do not develop oropharyngeal, other mucous membrane, or cutaneous disease.

Mouth involvement presents as recurrent, painful erosions. The gingivae are most commonly involved, followed by the palate and the buccal mucosa; however, any mucosal site in the mouth may blister. Involvement of the oropharynx may present with hoarseness or dysphagia. Pharyngeal involvement has been associated with the anti–laminin-332 subset of mucous membrane pemphigoid.[8] Progressive scarring disease may lead to esophageal stenosis requiring dilatation procedures. Supraglottic involvement may lead to airway compromise requiring tracheostomy.

Nasal involvement may manifest as epistaxis, bleeding after blowing the nose, nasal crusting, and discomfort. Other mucosal sites, such as the perianal area or the genitalia, may be involved.

Skin lesions develop in approximately one third of patients with  mucous membrane pemphigoid, manifesting as tense vesicles or bullae that may be hemorrhagic. Blisters may heal with scarring or milia. Scalp involvement may lead to alopecia. Pruritus at the sites of blisters or generalized pruritus may be present.

Cutaneous cicatricial pemphigoid involving the head and the neck without mucosal involvement is known as the Brunsting-Perry variant of localized BP. Patients are predominately elderly and male. Patients present with a chronic, recurrent vesiculobullous eruption on the head and the neck that heals with atrophic scarring. Patients with this disorder have histologic immunofluorescent and immunoelectron microscopic features similar to other patients with mucous membrane pemphigoid.

Physical Examination

Early ocular lesions may manifest as conjunctivitis, progressing to keratinization of the corneal epithelium and shortening of the corneal sulcus (see first image below). Progressive ocular disease leads to entropion (see first image below) and progressive corneal injury secondary to trichiasis. With persistent disease activity, synchesis and symblepharon occur (see second image below). Long term, ankyloblepharon (a fixed globe) may occur (see third image below). Patients with pure ocular involvement may constitute a distinct subset of patients with mucous membrane pemphigoid. These patients are distinct from patients with classic BP because they have a lower frequency of immunoglobulin G (IgG) and C3 as depicted by direct immunofluorescence (DIF), and they are usually negative for circulating autoantibodies as depicted by indirect immunofluorescence (IIF). These patients do not have detectable reactivity to BP antigens.

See the images below.

In a patient with more advanced ocular scarring, n In a patient with more advanced ocular scarring, note the thickening of the lid margins, shortening of the conjunctival sulcus, and scarring. The eyelashes have been epilated after entropion developed.
Ocular manifestations of cicatricial pemphigoid (m Ocular manifestations of cicatricial pemphigoid (mucous membrane pemphigoid) include symblepharon, demonstrated in this photograph by the tethering of the lower lid to the cornea.
With advanced disease, ankyloblepharon (a fixed gl With advanced disease, ankyloblepharon (a fixed globe) develops.

Nasal involvement can be detected as erosions and crusting in the nasal vestibule, best seen by nasal speculum examination.

Oral erosions often begin on the gingiva, particularly near the teeth. Erosions can also be seen on the palate, the buccal mucosa, the lips, the posterior part of the pharynx, the tongue, and the floor of the mouth. Intact blisters are rarely seen, but they may appear flaccid or tense.

On the genitalia, painful erosions involving the clitoris, labia, glans, or shaft of the penis may be seen. Perianal involvement manifests as perianal blisters and erosions.

On the skin, tense blisters or erosions may be seen on either normal-appearing skin or erythematous plaques. Common sites include the scalp, head, neck, distal extremities, or trunk. In patients with active disease, erosions may be persistent and difficult to heal. Scarring and milia frequently develop in this condition and are helpful in clinically differentiating  mucous membrane pemphigoid from BP and linear immunoglobulin A (IgA) bullous dermatosis, both of which do not tend to scar.

Localized mucous membrane pemphigoid on the head and the neck is known as Brunsting-Perry mucous membrane pemphigoid. This disease heals with scarring and milia.

Causes

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease associated with autoantibodies directed against basement membrane zone target antigens. Autoantibodies of the IgG subclass, particularly IgG4, are associated with mucous membrane pemphigoid; however, IgA antibodies have also been detected. The two major antigens associated with mucous membrane pemphigoid are BP180 and laminin-332. Patients with clinical features of mucous membrane pemphigoid may have antibodies directed against BP230 or type VII collagen. BP180 is a 180-kd hemidesmosomal protein with multiple extracellular collagenous domains.[9] BP180 is also a major target antigen for patients with BP and linear IgA bullous dermatosis. Patients with mucous membrane pemphigoid react with epitopes on BP180 distinct from those associated with BP and linear IgA bullous dermatosis, particularly the C-terminal of the protein. Given this reaction with the C-terminal epitope, routine serology for BP180 may fail to detect patients with circulating autoantibodies.[8]

A subset of patients with mucous membrane pemphigoid reacts with laminin-332. These patients have circulating autoantibodies that bind to the dermal side of salt-split skin as depicted by IIF study. By immunoelectron microscopy, these autoantibodies deposit at the lower lamina lucida, extending to the lamina densa. Laminin-332 contains disulfide-linked alpha, beta, and gamma chains, of which the alpha subunit is the major site of mucous membrane pemphigoid reactivity. Laminin-332 plays a major role in the adhesion of human keratinocytes to the dermis by binding alpha-6-beta-4 integrin. Because defects in laminin-332 are associated with junctional epidermolysis bullosa, one group has suggested calling mucous membrane pemphigoid associated with anti–laminin-332 autoantibodies acquired junctional epidermolysis bullosa; however, most clinicians refer to this disease as antiepiligrin or anti–laminin-332 mucous membrane pemphigoid.

Autoantibodies specific for laminin-332 and BP180 are believed to be important in blister formation. Lazarova et al[10] have developed an animal model of anti–laminin-332 mucous membrane pemphigoid in which passive transfer of rabbit anti–laminin-332 into neonatal mice leads to a subepidermal blistering disease with features consistent with mucous membrane pemphigoid. Passive transfer of anti–laminin-332 antibodies to mast cell and complement-deficient neonatal mice can also induce blistering, suggesting a direct effect of the circulating autoantibodies in inducing dermal-epidermal cleavage.

The incidence of the HLA haplotype HLA-DQB1*0301 is increased in patients with ocular mucous membrane pemphigoid. This HLA haplotype may be important in the presentation of specific epitopes on target antigens in the generation of an autoimmune response; however, the precise events relevant in the initiation of autoantibody production in patients with this disease are unknown.

Complications

The following complications have been described in mucous membrane pemphigoid (MMP)[11] :

  • Eye - Conjunctival scarring, trichiasis, corneal epithelial defects, sterile and infectious ulcers and scars, keratinization of the cornea, foreshortening of the fornices, trichiasis, synechia, symblepharon, ankyloblepharon, diminished tear formation, glaucoma, visual loss or blindness
  • Skin and extraocular mucous membranes - Oral mucosa, gingivitis, secondary infection, loosening, cutaneous blistering with scarring and milia formation
  • Anogenital region - Fusion of the labia, vaginal stenosis, urethral stenosis, phimosis, constriction of the anal canal
  • Nose and pharynx - Hoarseness, loss of voice, stenosis
  • Esophagus - Dysphagia, strictures, stenosis
 

DDx

 

Workup

Laboratory Studies

The histologic findings, DIF results, and IIF results of mucous membrane pemphigoid (MMP) (cicatricial pemphigoid), BP, and EBA are similar; differentiation between these three entities depends on the clinical presentation.

Criteria for the diagnosis of  mucous membrane pemphigoid include an appropriate clinical presentation, histology demonstrating a subepidermal blistering process (as described below), and DIF results showing continuous deposits of any one or the combination of the following along the epithelial basement membrane zone: IgG, IgA, and/or C3. DIF study can be used to categorize the process as an autoimmune blistering disease, but it cannot be used to discriminate between  mucous membrane pemphigoid, BP, EBA, or anti-p200 pemphigoid.

IIF study of patients' sera depicts circulating antibasement membrane zone specific for IgG in 20% of patients, and, when present, it usually has a low titer (1:10-1:20).

Imaging Studies

For evaluation of the upper airway or the esophagus, CT scans, barium swallows, or other imaging studies may be helpful. In patients with anti–laminin-332 mucous membrane pemphigoid (MMP), imaging may be required as part of a malignancy search.

Other Tests

DIF study should be performed on noninvolved perilesional skin or mucous membranes. Patients with mucous membrane pemphigoid (MMP) typically demonstrate linear deposits of complement and IgG at the dermoepidermal junction. The most commonly assayed complement component is C3; however, C4, properdin, and other complement components have been described. Linear deposits of IgG are detectable in 25% of patients. Linear deposits of IgA, in addition to IgG, have been reported in 20% of patients in one series. This pattern of DIF is also seen in patients with BP and EBA, and DIF assay cannot be used to differentiate among these disorders. Conjunctival specimens have been reported to be less sensitive than biopsy specimens of oral mucosa on DIF results.

IIF assay detects the presence of circulating antibodies directed against normal epithelial basement membrane in the sera of patients who are affected. In patients with  mucous membrane pemphigoid, IIF assay reveals circulating IgG in 20% of patients, typically a low titer. When healthy human skin preincubated in 1 mol/L sodium chloride (salt-split skin) is used as a substrate, autoantibodies in patients with  mucous membrane pemphigoid associated with reactivity to BP180 bind to the epidermal roof. IIF results demonstrate a similar localization in patients with BP. Patients with autoantibodies associated with laminin-332 have circulating autoantibodies that bind to the blister floor, similar to that in patients with EBA. One laboratory has reported an increased sensitivity by IIF study by concentrating serum samples prior to assay.

Immunoblot (Western blot), immunoprecipitation, and immunoelectron microscopy are investigational tools used to better define target antigens. By immunoblot (Western blot) and immunoprecipitation, patients with  mucous membrane pemphigoid can have autoantibodies directed against BP180 (180 kd), BP230 (230 kd), and laminin-332. Enzyme-linked immunoassays using recombinant target antigens may ultimately be available to characterize autoantibody reactivity.

Routine laboratory studies are not helpful in establishing the diagnosis of  mucous membrane pemphigoid. Most hematologic studies are within the reference range. Laboratory values that may be elevated include immunoglobulins, erythrocyte sedimentation rate, and acute phase reactants.

Histologic Findings

Biopsies specimens can be taken from a vesicle or perilesional tissue adjacent to an erosion. In oral lesions, it is recommended to avoid gingival biopsies.

Histopathologic features typically include the following[12, 13] :

  • Subepithelial blister
  • Infiltrate containing plasma cells, neutrophils, and eosinophils localized in the lamina propria
  • DIF showing linear deposits of IgG and C3 in basement membrane zone; sometimes, linear deposition of Ig A can also be present along with IgG and C3, which suggests mucous membrane pemphigoid (MMP).
  • Scar tissue may be seen in older or recurrent lesions

These histologic features can also be seen in other autoimmune subepidermal blistering diseases, including cell-poor BP, EBA, and linear IgA bullous dermatosis. The histologic features of porphyria cutanea tarda and variegate porphyria also may resemble  mucous membrane pemphigoid.

 

Treatment

Medical Care

The goal of treatment in mucous membrane pemphigoid (MMP) (cicatricial pemphigoid) is to suppress extensive blister formation, promote healing, and prevent scarring. The lowest dose of medication to suppress disease activity and to minimize the risk for the patient should be used. This disorder is extremely difficult to treat. Even with optimum control, blisters may continue to develop in some patients. The risks and the benefits of therapy must always be evaluated for each patient.

Wound care of erosions includes daily gentle cleaning or compresses, topical agents to promote wound healing, and biologic dressings. The goals of wound care are to minimize trauma to the surrounding skin, to promote healing, and to diminish scarring.

Increased risk of malignancies has been documented in patients with anti–laminin-332  mucous membrane pemphigoid, especially in the first year of disease; hence, appropriate screening is warranted.

Surgical Care

Surgical intervention may be required to improve functioning or to prevent further morbidity. Such intervention is directed at the sequelae of chronic blistering.

Patients with mucous membrane pemphigoid (MMP) and ocular involvement require ongoing ophthalmologic care. Surgical intervention to ablate ingrown eyelashes prevents further ocular damage. Procedures to release entropion have been successful. Tsubota et al[14] reported the long-term outcome in patients with cicatricial ocular disorders treated with limbal allografts. The transfer of epithelial stem cells restored useful vision in these patients, including several patients with ocular  mucous membrane pemphigoid. Care should be taken to control the inflammatory component of the disease before and immediately after surgery because patients with  mucous membrane pemphigoid frequently experience flare-ups after surgery.

Patients with upper airway disease may develop respiratory compromise requiring tracheostomy.

Patients with esophageal obstruction may require dilatation procedures.

Consultations

The management of mucous membrane pemphigoid (MMP) requires a coordinated team approach. Specific consultations are dictated by the phenotype of the disease and the target organ or organs involved.

The patient management team typically includes a dermatologist with expertise in this area; an internist to assist with monitoring therapy, adverse effects of medications, and the patient's overall health; an ophthalmologist for ocular disease; an otolaryngologist for upper airway evaluation and management; and a dentist for oral disease.

Additional specialists, such as a gynecologist (vulvar disease), a gastroenterologist (esophageal involvement), and an endocrinologist (prophylaxis of osteoporosis in patients receiving long-term systemic corticosteroids), may be indicated.

Diet

Although no dietary restrictions are necessary, patients with oral disease may benefit from avoiding foods high in acid, such as tomatoes and orange juice, and foods with hard surfaces that may mechanically traumatize the oral epithelium, such as chips, nuts, raw vegetables, and uncut fruit.

Patients on oral prednisone should maintain adequate calcium and vitamin D intake through diet and supplements. The daily calcium requirement in patients with no history of kidney stones is 1.5 g/d, and the daily minimum dose of vitamin D is 800 IU/d.

Activity

Patients are encouraged to lead as normal a life as possible; however, cutaneous and mucosal blisters may be induced by trauma. Contact lenses, dental plates, or bridges may precipitate or exacerbate mucosal disease. Patients may benefit by minimizing activities, such as contact sports, that traumatize the skin and precipitate blistering. Nontraumatic exercises, such as swimming or aquatic exercises, may be beneficial.

 

Medication

Medication Summary

Patients with mild localized mucous membrane pemphigoid (MMP) (cicatricial pemphigoid) may benefit from topical steroids (eg, triamcinolone [Kenalog in Orabase]) in gel-based topical agents for oral disease or in ointment-based topical steroids for cutaneous disease. Intralesional steroids can be administered as triamcinolone acetonide (Kenalog susp) 10 mg/mL injected weekly or biweekly for oral and cutaneous lesions. Patients with more extensive disease and progressive scarring require systemic therapy with prednisone and/or steroid-sparing agents, such as cyclophosphamide, azathioprine, cyclosporin, or mycophenolate mofetil. Evidence from two small randomized controlled trials indicates that ocular  mucous membrane pemphigoid responds best to cyclophosphamide, while mild-to-moderate disease seems effectively suppressed by treatment with dapsone.

Rituximab is a therapeutic option for refractory cases. Maley and colleagues retrospectively studied 24 patients treated with rituximab and 25 with conventional immunosuppressants. One hundred percent of patients treated with rituximab achieved control of the disease, compared with 40% of the patients treated with conventional therapy.[15]

High-dose intravenous immune globulin has been used successfully in the treatment of  mucous membrane pemphigoid in patients whose disease was refractory to other therapies. This therapy can be very helpful in patients who have severe adverse effects from conventional therapy.[16] Immunosuppressive agents should be prescribed and monitored by physicians familiar with these medications. The 2002 consensus statement on mucous membrane pemphigoid reports expert panel opinion on the management of the disease.[1]

Anti-inflammatory Agents

Class Summary

These agents decrease the inflammatory response.

Triamcinolone topical (Kenalog, Kenalog in Orabase)

Triamcinolone topical is an agent for mild disease or is used as an adjuvant in patients receiving concurrent systemic therapy. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Dapsone (Avlosulfon)

Dapsone is the drug of choice for ocular mucous membrane pemphigoid and is often beneficial in patients with oral mucosal disease. It is bactericidal and bacteriostatic against mycobacteria. Its mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Prednisone (Deltasone, Orasone, Sterapred)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Immunosuppressants

Class Summary

These agents inhibit immune reactions resulting from diverse stimuli.

Azathioprine (Imuran)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine has demonstrated to be helpful in a variety of skin disorders. It is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight.

Cyclophosphamide (Cytoxan, Neosar)

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Mycophenolate (CellCept)

Mycophenolate inhibits purine synthesis and the proliferation of human lymphocytes.

Antineoplastics, Anti-CD20 Monoclonal Antibodies

Class Summary

Antineoplastic agents act by inhibiting the key factors responsible for neoplastic transformation of cells. The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Immune Globulins

Class Summary

Intravenous immunoglobulins have proven beneficial in achieving rapid disease control in patients with immunobullous diseases.

Immune globulin IV (IGIV) (Bivigam, Carimune, Carimune NF)

Immune globulin intravenous consists of IgG collected from a pool of thousands of blood donors (virus-free), thus providing a wide range of immunologically different IgG. Theoretically, they bind and neutralize pathogenic autoantibodies.

Cost and availability limit its use. Immune globulin intravenous is expensive. It is generally used in resistant and severe bullous diseases in addition to immunosuppressive therapy or as monotherapy in patients with contraindications for immunosuppressive drugs.