Mucous Membrane Pemphigoid (mucous membrane [cicatricial] Pemphigoid, cicatricial pemphigoid, anti-epiligrin cicatricial pemphigoid, benign mucous membrane pemphigoid, benign mucosal pemphigoid)

Are You Confident of the Diagnosis?

Mucous membrane pemphigoid (MMP) encompasses a group of rare autoimmune blistering diseases that can be relatively difficult to diagnose and manage, reflecting the potential diversity and severity of organ system involvement. The patient may need to consult with several doctors (dermatology, oral medicine, ophthalmology, and otolaryngology most frequently).

What you should be alert for in the history

It is important to determine the scope of epithelial involvement. Disease can affect the oral, ocular, genital, nasopharyngeal, esophageal and laryngeal mucosa, and rarely the skin. One to all sites can be involved. Ask about pain or difficulty eating or swallowing, a sensation of grittiness in the eyes, pain on urination or sexual intercourse, nasal lesions, hoarseness, or other symptoms of airway compromise.

Determine if the patient has a history that would support other conditions in the clinical differential diagnosis, such as primary herpes virus infection (do oral lesions recur in the same area?), erythema multiforme (recent medications or recurrent herpes?), contact mucositis (any recent dental work?), lichen planus (history of hepatitis?), or systemic lupus.

Because certain forms of MMP are thought to be associated with internal malignancy, ask if patients have undergone age-appropriate cancer screening.

Characteristic findings on physical examination

Oral mucosa, the site of most frequent involvement, often does not show evidence of scarring. A common finding is desquamative gingivitis (friability of gingiva with erosions, often at the interdental papillae) (Figure 1); however, erosions can occur throughout the oropharyngeal mucosa. Even if patients do not complain of eye symptoms, the conjunctiva should be examined. Any signs of conjuntival erythema and inflammation should be further evaluated by an ophthalmologist.

Expected results of diagnostic studies

Skin or mucosal biopsy for histology. Although skin lesions are rare, if they are present, biopsies are usually performed on skin before mucosa due to the greater ease of obtaining sufficient lesional and perilesional tissue. With only mucosal lesions, oral mucosa is biopsied before ocular mucosa for the same reasons. A punch or incisional biopsy for histology will ideally be obtained from the lateral edge of lesional tissue. Classic histology of MMP will show a subepithelial blister (Figure 2), often with mixed dermal inflammation. However, biopsy of a blister or erosion is not always possible, particularly in ocular lesions, so biopsies may only show mixed inflammation. Demonstration of a subepidermal blister on routine light microscopy is not an absolute criterion for diagnosis, based on consensus guidelines.

Mucosal biopsy of mucous membrane pemphigoid demonstrates subepithelial cleavage. (Courtesy of Faizan Alani, MD)

Tissue biopsy for direct immunofluorescence (DIF) is considered the current gold standard for diagnosis of MMP, although the procedure is technically difficult. Again, skin lesions are usually biopsied before oral mucosa then ocular mucosa. A punch or other incisional biopsy should be obtained from normal-appearing perilesional tissue and submitted in Michel’s or ideally, sterile saline then Michel’s, for direct immunofluorescence analysis.

MMP will demonstrate linear basement membrane zone staining for one or more of the following: IgG, C3, or IgA (Figure 3). Dermis usually has a strong background on DIF testing due to the high concentration of IgG in blood, which extravasates into the dermis during the biopsy, potentially masking the detection of immune reactants at the dermal-epidermal junction. Incubation of the tissue sample in sterile saline at 4 degrees C for up to 24 hours prior to transfer to Michel’s fixative will help to wash out unbound dermal IgG and increase the sensitivity of DIF detection. Immune reactants are typically destroyed within lesional tissue, leading to false negative results if samples for DIF are taken from blistered or inflamed epithelia.

Direct Immunoflourescense of perilesional mucosa showing linear IgA of the basement membrane zone.

Studies such as indirect immunofluorescence with salt split skin analysis and BP180 ELISA may aid in the diagnosis but is not considered to be absolute criteria for diagnosis due to their decreased sensitivity. One major advantage of these studies are that they are performed on blood. A good scenario for using these tests would be on a patient with a typical clinical presentation of MMP, with non-specific light microscopy biopsy findings such as mixed dermal inflammation, and who does not want to undergo further mucosal biopsy for diagnosis.

Serum sample for indirect immunofluorescence (IIF). Mild or localized disease may be associated with negative indirect immunofluorescence findings, which is why this test is not considered essential for diagnosis. Serum is incubated with epithelial substrates (monkey esophagus, normal human skin, or normal human skin pre-incubated with 1 M NaCl). On non-salt split substrates, IIF will classically demonstrate IgG, C3, and/or IgA basement membrane zone staining, and should remain positive for at least several weeks after skin lesions have healed. On salt split skin, IIF findings may vary due to the heterogeneous nature of autoantigens in this disease.

Antibodies against BP180 and BP230 will stain the roof or epidermal side of the blister, while antibodies against beta-4 integrin, laminin 5, and laminin 6 will stain the base or dermal side of the blister. If only IgA antibodies are observed on the roof/epidermal side of the blister, a diagnosis of linear IgA bullous dermatosis should be considered. Staining of the base or dermal side of the blister can also be seen in epidermolysis bullosa acquisita.

Serum sample for bullous pemphigoid ELISA. Antigen-specific ELISAs (BP180 and BP230) are sensitive and specific for the diagnosis of bullous pemphigoid, but their clinical utility in diagnosing MMP has not been well studied, and some national reference laboratories do not offer these tests. BP180 and BP230 are two of the several possible antigens in MMP; therefore a negative test does not rule out disease, although a positive result could confirm disease.

Diagnosis confirmation

The clinical differential diagnosis for mucous membrane pemphigoid includes lichen planus, chronic herpesvirus infection, contact mucositis, erythema multiforme, Stevens Johnson syndrome, ocular pseudopemphigoid (ocular scarring reactions resulting from severe inflammation, such as contact dermatitis), and other autoimmune blistering diseases such as pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis.

Who is at Risk for Developing this Disease?

MMP is a rare disease. Prior reports suggest an incidence in Western Europe of one case per million. The incidence of MMP is difficult to assess accurately as there is currently no clinical molecular test for the disease. Some cases previously diagnosed as MMP have subsequently been reclassified as epidermolysis bullosa acquisita or linear IgA bullous dermatosis after disease autoantigens were identified for research purposes.

Using the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) database, one cohort study of 35 MMP patients whose autoantibodies targeted laminin 5 (cases previously known as anti-epiligrin cicatricial pemphigoid) showed a 6.8 fold relative risk in the development of cancer (10 developed solid tumors, 7/10 within the first 14 months after MMP diagnosis).

What is the Cause of the Disease?

Etiology

Multiple autoantigens have been identified in MMP, almost all of which are part of the hemidesmosomal-basement membrane zone complex. Autoantigens include BP230 (bullous pemphigoid antigen or BPAg 1), BP180 (type XVII collagen or BPAg2), laminin 5 (epiligrin), laminin 6, the integrin beta-4 subunit, and a few other poorly characterized proteins or protein fragments.

Pathophysiology

As with most autoimmune diseases, the reasons for the loss of immune tolerance in MMP are unknown. Like bullous pemphigoid, the MHC class II allele DQB1*0301 is overrepresented in MMP patients. In experimental models, there are data to support pathogenicity of the BP180, laminin 5, and integrin beta-4 autoantibodies.

Disease pathophysiology has best been studied for the anti-BP180 antibodies in bullous pemphigoid. Anti-BP180 IgG binds to the basement membrane zone. Complement fixation and activation causes leukocyte chemotaxis and degranulation of mast cells, which promotes chemotaxis of eosinophils. Release of proteolytic enzymes by inflammatory cells (such as neutrophil elastase and eosinophil gelatinase) causes cleavage of basement membrane zone proteins including BP180, leading to blister formation.

Monovalent (Fab) fragments of BP IgG do not cause blisters, and mice deficient in components of complement, neutrophils, or neutrophil elastase do not develop blisters, indicating that the effector functions of BP autoantibodies are required for disease. This may underlie the therapeutic efficacy of dapsone, which is thought to impair neutrophil chemotaxis.

Systemic Implications and Complications

Mucosal involvement in cicatricial pemphigoid is associated with the potential for significant morbidity and rarely mortality due to mucosal inflammation and adhesions leading to cataracts, blindness, chronic sinusitis, esophageal stricture, and airway compromise.

A small cohort study suggested an increased risk of solid tumors in patients with anti-laminin 5 antibodies.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Medical treatment	Surgical treatment
Topical corticosteroids	Epilation
Dapsone	Punctal occlusion
Cyclophosphamide	Lid surgery
Oral corticosteroids	Fornix reconstruction
Azathioprine	Corneal surgery
Mycophenolate mofetil	Cataract surgery
Subconjunctival mitomycin C
Rituximab
Intravenous immunoglobulin
Etanercept

Optimal Therapeutic Approach for this Disease

Treatment of MMP must be extremely aggressive at the first signs of ocular involvement due to the potential for rapid progression of disease leading to blindness. Involvement of only the oral mucosa is associated with a more indolent course. Medical treatment is pursued first to control disease. After active disease has subsided, surgical intervention to ameliorate complications of scarring can be pursued.

Medical Treatment

-Topical steroids are most useful in mild to moderate cases of oral mucosal disease and typically are not used in ocular disease. Class I steroids such as clobetasol can be applied twice daily to new oral lesions. Dexamethasone elixir, swish and spit 5 cc once to twice daily, is easy to use. Clobetasol ointment or gel can also be applied directly to mucosal erosions. Dental trays (fitted by oral medicine) facilitate occlusion of topical steroids to the gingiva at night. Corticosteroid nasal sprays and inhalers may help nasal, pharyngeal, and upper esophageal disease.

-For moderate to severe oral disease, dapsone (50-200 mg/day) is considered first-line therapy. If symptoms are not controlled by 12 weeks, more aggressive therapy is warranted. Dapsone can also be considered for early mild ocular disease. Glucose-6-phosphate dehydrogenase (G6PD) activity should ideally be measured before starting therapy, particularly in men of African-American and Middle Eastern descent. Most patients will experience a 1-2 g/dL drop in hemoglobin due to hemolysis, although some patients can experience a severe pancytopenia with or without systemic hypersensitivity reaction. Laboratory monitoring should be performed at least every other week for the first 8 weeks. As an advantage, dapsone 100 mg daily provides Pneumocystis prophylaxis.

-For severe or rapidly progressing disease, cyclophoshamide (1-2 mg/kg/day) plus oral corticosteroids (0.5-1.5mg/kg/day) are indicated. Cyclophosphamide is among the fastest agents for treating disease. However, counseling is important given its risk of blood count and liver test abnormalities, infertility, and long-term risk of lymphoma and hemorrhagic cystitis with bladder carcinoma. Oral corticosteroid monotherapy is typically not as useful in MMP.

Before starting high-dose steroids, tuberculosis screening should be performed (via tuberculin skin testing or Quantiferon-gold blood assay). If patients will be on chronic corticosteroids (at least 5mg daily prednisone equivalent for at least 3 months), osteoporosis counseling and prevention is indicated. Additionally, Pneumocystis prophylaxis should be considered for patients on chronic prednisone, particularly with daily prednisone doses of 15mg or higher. Patients should remain on high-dose steroids until new lesions cease to form, and then the dose can be gradually tapered to the minimum required to control disease.

-Azathioprine or mycophenolate mofetil may substitute for dapsone or cyclophosphamide. Azathioprine can be started at 50mg daily and titrated upward by 50mg every 1-2 weeks until side effect, therapeutic effect, or the target dose of 2.5 mg/kg/day occurs. Measurement of serum thiopurine methyltransferase (TPMT) level prior to start of azathioprine therapy can be performed, although some studies suggest that TPMT levels do not correlate with the incidence of adverse effects or efficacy of azathioprine therapy. Nevertheless, if serum TPMT levels are very low or very high, azathioprine may not be a good choice for therapy, due to an increased likelihood for adverse effects or lack of effect, respectively. The active metabolites for azathioprine do not significantly accumulate until 6-8 weeks after initiation of therapy, leading to a delayed therapeutic effect.

Mycophenolate mofetil (30mg/kg/day divided twice daily) is generally well tolerated, although side effects of fatigue, gastrointestinal upset, and tremor are not uncommon, particularly at higher doses, and there is a small long-term risk of lymphoma and fatal infection or reactivation from JC virus with progressive multifocal leukencephalopathy. Reduction of corticosteroid dose can be initiated as early as one month after starting mycophenolate mofetil, although maximal effect is not achieved until 2-3 months.

-One study has reported the efficacy of subconjunctival mitomycin C for reduction of mucosal fibrosis.

In patients who have severe or persistent disease that is unable to be controlled with dapsone or cyclophosphamide, other therapies such as rituximab, intravenous immunoglobulin, and plasmapheresis can be considered.

-B-cell depletion therapy with rituximab (anti-CD20 monoclonal antibody) is anecdotally effective for the treatment of ocular cicatricial pemphigoid (dosed in conjunction with intravenous immunoglobulin). For the treatment of another autoimmune blistering disease pemphigus vulgaris, both lymphoma (375 mg/m² IV weekly x 4 weeks) and rheumatoid arthritis (1000mg IV on days 1 and 15) dosing regimens can be used. In vivo studies from lymphoma patients indicate that peripheral blood B cells disappear from the circulation within days, although antibody production by plasma cells (which are not well targeted by rituximab) can persist for months; therefore, maximal results are typically not observed until 3-6 months after infusion, and reinfusion every 6 months may be required. Fatal infection has occurred with rituximab therapy, including bacterial sepsis, hepatitis B reactivation, and progressive multifocal leukencephalopathy from JC virus, although fatal infection is also a potential side effect of other therapies for MMP, including prednisone.

-Intravenous immunoglobulin (IVIG, 2mg/kg, divided over 3-5 days) can be provided by hospital or home infusion. IVIG is thought to induce catabolism of endogenous serum antibodies and offers the advantage of being immunoprotective. A disadvantage of IVIG is that the temporary serum viscosity associated with the infusion can cause stroke or other complications from clotting. The serum half life of IVIG has been reported to range from 8-39 days (average 3-4 weeks). Treatment guidelines for autoimmune blistering disease with IVIG suggest an initial frequency of every 4 weeks until disease remits, increasing to 6, 8, 10, 12, 14, then 16 weeks, the latter being the proposed end point for an initial course of therapy.

-Successful treatment of mucous membrane (cicatricial) pemphigoid with etanercept, 25 to 50 mg twice weekly, has been reported, including recalcitrant cases with severe ocular disease.

Surgical Treatment

Surgical treatment should not be pursued until disease inflammation is controlled; however, it can initiate while the patient is stably tapering off systemic corticosteroids and immunosuppressives. In fact, systemic corticosteroids are indicated to reduce post-operative inflammation, which increases risk for scarring. Interventions include epilation to remove misdirected eyelashes that can perpetuate ocular mucosal inflammation, punctal occlusion to slow the drainage of tears from the eyes, surgical procedures to release adhesions and reconstruct the conjunctival fornices, and in some cases, corneal or cataract surgery to help restore vision.

Patient Management

The goal of treatment is to avoid permanent complications from scarring and to ultimately obtain a complete remission off therapy, although many patients may only achieve a partial remission off therapy, or a complete remission on minimal therapy. When starting patients on therapy, risks of medications should be discussed. There is no systemic medication that is 100% safe. However, with severe or rapidly progressive disease the sequelae can be devastating; therefore, the risk-benefit ratio favors treatment.

At every visit, the patient history should be carefully reviewed to determine whether mucosal strictures are a potential concern (pain or difficulty eating or swallowing, a sensation of grittiness in the eyes, pain on urination or sexual intercourse, nasal lesions, hoarseness, or other symptoms of airway compromise). If the patient notes any of these symptoms, urgent referral to the appropriate specialty is appropriate (otolaryngology, ophthalmology, urology), and one may consider empiric start of cyclophosphamide therapy for rapid disease control pending evaluation.

Patients should receive regularly scheduled dental cleaning from a hygienist experienced with oral blistering disease. Patients often avoid cleanings due to painful mucosal disease; however, over time plaque buildup leads to chronic gingival inflammation that aggravates disease.

Patients should ideally be maintained in complete remission for at least 1 year before all immunosuppressive therapy is discontinued. Often patients want to taper off their medications quickly, but then flare and have to go back on high doses of medications for disease control, which may reduce the chance for disease remission. Typically, corticosteroids are typically tapered off first, then adjunctive immunosuppressants are slowly tapered over the course of one year. However, the tapering regimen should be tailored for each patient depending on side effects and response to therapy. It is common for patients to have a small flare with each dose taper; as long as lesions heal within one week and no further lesions form, the taper can be continued.

The Centers for Disease Control recommends that all patients on immunosuppressive therapy receive influenza and other regularly scheduled vaccinations. While on immunosuppressive therapy, patients should be reminded that they should not receive live vaccines (e.g. nasal influenza or zoster.)

Unusual Clinical Scenarios to Consider in Patient Management

The timing of rituximab with intravenous immunoglobulin has not been well worked out. If rituximab infusion is administered immediately before IVIG, IVIg may hasten the catabolism of rituximab. However, rituximab is thought to rapidly bind and deplete circulating B cells (within days), and peripheral B cell counts may begin to recover as early as 8 days after infusion.

Theoretically therefore, IVIG could be considered as early as 1-4 weeks after completion of rituximab infusion, although studies indicate that rituximab half-life progressively increases with subsequent weekly infusions (suggesting saturation of in vivo binding sites), and that a higher serum concentration is associated with better treatment outcome in B cell lymphomas. Conversely, the ideal timing of rituximab infusion after a course of IVIG is unknown, with recommendations ranging from 1-6 weeks based on the serum half life of IVIG.

What is the Evidence?

Borradori, L, Bernard, P, Bolognia, JL, Jorizzo, JL, Rapini, RP. Dermatology. 2003. (A more complete review of the clinical presentation and management of mucous membrane/cicatricial pemphigoid.)

Chan, LS, Ahmed, AR, Anhalt, GJ, Bernauer, W, Cooper, KD, Elder, MJ. “The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators”. Arch Dermatol. vol. 138. 2002. pp. 370-379. (An important document reflecting the consensus of international experts on the heterogeneity of disease and guidelines for diagnosis and treatment.)

Vodegel, RM, de Jong, MCJM, Meijer, HJ, Weytingh, MB, Pas, HH, Jonkman, MF. “Enhanced diagnostic immunofluorescence using biopsies transported in saline”. BMC Dermatol. vol. 4. 2004. pp. 10(An informative visual comparison of Michel’s fixative, snap freeze, and saline for diagnostic immunofluorescence testing with pemphigus and pemphigoid. Saline is the preferred medium for pemphigoid, although samples must be processed (or otherwise fixed) within 24 hours.)

Egan, CA, Lazarova, Z, Darling, TN, Yee, C, Cote, T, Yancey, KB. “Antiepiligrin cicatricial pemphigoid and relative risk for cancer”. Lancet. vol. 357. 2001. pp. 1850-1. (Cohort study of 35 patients with anti-epiligrin cicatricial pemphigoid using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry suggests a 6.8 relative risk of cancer in cicatricial pemphigoid patients. Cancers were all solid tumors, seven out of the 10 affected patients were diagnosed with cancer within 14 months after their diagnosis of cicatricial pemphigoid.)

Foster, CS, Chang, PY, Ahmed, AR. “Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report”. Ophthalmology. vol. 1117. 2010. pp. 861-9. (Retrospective case series of 12 patients with ocular cicatricial pemphigoid refractory to immunosuppressive therapy suggests that rituximab and IVIG therapy halted disease progression and prevented total blindness, although its safety and efficacy compared to monotherapy with either agent remains unknown.)

Ahmed, AR, Dahl, MV. “Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases”. Arch Dermatol. vol. 139. 2003. pp. 1051-9. (Provides guidelines for the use of IVIG, including indications, prescreening, premedications, dose, frequency, monitoring, and therapeutic endpoints.)

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