Background

This is also known as benign mucous membrane pemphigoid. This latter term should not be used since this disease may have severe blistering changes within the eye and esophagus. This chronic blistering disorder is characterized by tense bullae on an erythematous base which heal with scarring. The blisters characteristically recur in the same area. They occur in the oral cavity, cornea, conjunctiva, and to a lesser extent on the face, neck, scalp, axilla, and distal extremities. About 85% of patients present with oral involvement with a desquamative or erosive gingivitis the most common presentation. These lesions are slow to heal and may become secondarily infected. Lesions occurring in the upper aerodigestive tract may be life threatening, especially occurring in larynx.

It is a disease of older adult although childhood cases have been reported. There are occasional cases associated with carcinoma of the pancreas, systemic lupus erythematosus, rheumatoid arthritis, and ingestion of practolol and clonidine.

The pathogenesis reveals two antigenic sites. The first is a 180 kd protein which shows cross-reactivity to the bullous pemphigoid antigen (BPAg2). The second is uncommon and is epiligrin, a protein found at the junction of the lamina lucida and lamina densa and is associated with the anchoring filaments. It is identical to the alpha 3 subunit of laminin 5.

This is a subepidermal blister which begins with dermal papillary microabscesses. and progresses to subepidermal blisters. Scarring occurs early in the disease. Direct immunofluorescence (DIF) shows linear IgG and C3 along the dermoepidermal junction in 80% of cases. In the other 20% of cases, IgA may be the only immunoreactant present. Salt-split skin reveals two variants. In the anti-epiligrin type, the deposits are found on the dermal side while in the BPAg2 type, deposits are found in the epidermal side.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Benign mucous membrane pemphigoid
INCIDENCE	1/12,000-20,000 in general population 1/20,000-40,000 of patients seen by opthalmologists
AGE RANGE-MEDIAN	Mean 62-66 years 60-80 years
SEX (M:F)	1.5-2.27:1

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Malignancies	Carcinoma of the pancreas
Systemic lupus erythematosus
Rheumatoid arthritis
Drugs	Practolol Clonidine
HLA associations	DR4 DR5 DQw3 A2 B8 B35 B49
HLA-DQB1*0301	Presence of this allele appears to be a marker for increased susceptibility to ocular CP and not oral disease
Complement types	SC32 SC41 SC42

 

PATHOGENESIS	CHARACTERIZATION
Autoimmune disease with an environmental trigger	Higher incidence of other autoimmune diseases
Drugs as triggers	Topical anti-glaucoma medications Practolol Clonidine
Severe mucosal injury as trigger	May be precipitating factor in 5 cases following Stevens-Johnson syndrome
Role of autoantibodies	Anti-laminin Ab interfere with the adhesion of laminin-5 causing detachment of the keratinocytes from the basement membrane BP180 also forms a complex with laminin-5 and it spans the lamina lucida and interacts with the lamina densa-thus this may explain the scarring in this disease

 

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Anti-epiligrin cicatricial pemphigoid: clinical findings, immunopathogenesis, and significant associations. Egan CA, Lazarova Z, Darling TN, Yee C, Yancey KB. Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.	Medicine (Baltimore). 2003 May;82(3):177-86. Abstract quote We report the clinical and immunopathologic findings in a cohort of 35 patients with anti-epiligrin cicatricial pemphigoid (AECP). These patients have a mucosal predominant subepithelial blistering disease that is clinically indistinguishable from other forms of cicatricial pemphigoid. The mucosal surfaces of the mouth and eye are most commonly involved. The skin is also involved in most patients, but usually this is less severe than mucosal involvement. AECP is characterized by the binding of circulating IgG autoantibodies to the dermal side of 1M NaCl split human skin on indirect immunofluorescence microscopy. These IgG antibasement membrane autoantibodies target laminin 5, a heterotrimeric protein consisting of alpha3, beta3, and gamma2 subunits. IgG autoantibodies predominantly target the G domain within the alpha subunit. The presence of circulating IgG autoantibodies are specific for the diagnosis of AECP and are not seen in patients with other autoimmune blistering diseases or normal volunteers. Furthermore, we expand on data previously reported on the finding of an increased relative risk for solid cancer in patients with AECP, especially in the first year after blister onset. The majority of cancers documented in a cohort of 35 patients assembled over 12 years of study were adenocarcinomas that were at an advanced stage at their time of detection. This circumstance is thought to account for a high incidence of mortality among AECP patients who develop an associated cancer. AECP patients also demonstrate a significant risk for mortality as a consequence of treatment with systemic immunosuppressives. The current longitudinal study suggests that only a minority of AECP patients go into remission.
The First International Consensus on Mucous Membrane Pemphigoid Definition, Diagnostic Criteria, Pathogenic Factors, Medical Treatment, and Prognostic Indicators Lawrence S. Chan, MD; A. Razzaque Ahmed, MD; Grant J. Anhalt, MD; Wolfgang Bernauer, MD; Kevin D. Cooper, MD; Mark J. Elder, MD; Jo-David Fine, MD; C. Stephen Foster, MD; Reza Ghohestani, MD, PhD; Takashi Hashimoto, MD; Thanh Hoang-Xuan, MD; Gudula Kirtschig, MD; Neil J. Korman, MD, PhD; Susan Lightman, PhD; Francina Lozada-Nur, DDS, MPH; M. Peter Marinkovich, MD; Bartly J. Mondino, MD; Catherine Prost-Squarcioni, MD, PhD; Roy S. Rogers III, MD; Jane F. Setterfield, MD; Dennis P. West, PhD; Fenella Wojnarowska, MD; David T. Woodley, MD; Kim B. Yancey, MD; Detlef Zillikens, MD; John J. Zone, MD	Arch Dermatol. 2002;138:370-379 Abstract quote Objective We aimed to develop consensus-based recommendations for streamlining medical communication among various health care professionals, to improve accuracy of diagnosis and treatment, and to facilitate future investigations for mucous membrane pemphigoid. Participants Because of the highly specific nature of this group of diseases, the 26 invited participants included either international scholars in the field of mucous membrane pemphigoid or experts in cutaneous pharmacology representing the 3 medical disciplines ophthalmology, oral medicine, and dermatology. Evidence The first author (L.S.C.) conducted a literature search. Based on the information obtained, international experts who had contributed to the literature in the clinical care, diagnosis, and laboratory investigation for mucous membrane pemphigoid were invited to participate in a consensus meeting aimed at developing a consensus statement. Consensus Process A consensus meeting was convened and conducted on May 10, 1999, in Chicago, Ill, to discuss the relevant issues. The first author drafted the statement based on the consensus developed at the meeting and the participants' written comments. The draft was submitted to all participants for 3 separate rounds of review, and disagreements were reconciled based on literature evidence. The third and final statement incorporated all relevant evidence obtained in the literature search and the consensus developed by the participants. The final statement was approved and endorsed by all 26 participants. Conclusions Specific consensus-based recommendations were made regarding the definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators for mucous membrane pemphigoid. A system of standard reporting for these patients was proposed to facilitate a uniform data collection.
Ocular cicatricial pemphigoid	Linear deposition of IgG and IgA along the dermoepidermal junction of the conjunctiva-directed against a 45 kd protein The Modified Foster Staging System has been used (Cornea 1992;11:446-451)
Stage	Characteristics
I	Subconjunctival scarring and fibrosis
II	Forniceal shortening (letters a-d indicate degree to which fornix is shortened)
IIa	0-25%
IIb	25-50%
IIc	50-75%
IId	75-100%
III	Presence of symblephara (letters a-d indicate percentage of horizontal involvement by sympblephara)
IIIa	0-25%
IIIb	25-50%
IIIc	50-75%
IIId	75-100%
IV	Presence of ankyloblephara and a frozen globe
SKIN DISEASE VARIANTS
Localized cicatricial pemphigoid (Brunsting-Perry type)	Scarring plaque-like lesions on the head and neck, sparing the mucous membranes, and healing with scarring Generalized bullous eruption may occur called disseminated cicatricial pemphigoid.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Non-specific findings with subepidermal bulla with diffuse, perivascular mixed inflammatory cell infiltrate with neutrophils, eosinophils, lymphocytes, and histiocytes Fibrosis and scarring may occur in chronic lesions
	Presence of sebaceous glands in the blister may be a clue

 

SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER	CHARACTERIZATION
Electron microscopy	Variable with the basement membrane zone (BMZ) present on either the dermal or epidermal side of the blister Immunoelectron microscopy has localized deposits over the lamina densa and within the lamina lucida
Direct immunofluorescence (DIF)	80-100% of patients have linear continuous band at BMZ usually with IgG, C3, and less commonly IgA-usually in perilesional skin or mucosa Linear IgA with the other two are more commonly seen in this disease rather than bullous pemphigoid
antiepiligrin CP (anti-laminin type 5)	IgG binds to the dermal side of salt-split skin
anti-beta4 integrin	IgG in predominantly ocular cases
INDIRECT IMMUNUFLUORESCENCE	Circulating IgG binds to epidermal side of the blister cavity with IgG1 and IgG4 the predominant subclasses
Anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita: Differentiation by use of indirect immunofluorescence microscopy. Vodegel RM, De Jong MC, Pas HH, Yancey KB, Jonkman MF. Departments of Dermatology, Groningen University Hospital and Medical College of Wisconsin.	J Am Acad Dermatol 2003 Apr;48(4):542-7 Abstract quote Binding of autoantibodies to laminin 5 and type VII collagen causes anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita, respectively. Differentiation between these two dermal-binding autoimmune bullous dermatoses is not yet possible by indirect immunofluorescence microscopy. In this study we tested whether two recently described immunofluorescence techniques, "knockout" skin substrate and fluorescent overlay antigen mapping, can differentiate between anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita. A total of 10 sera were tested: 4 with antilaminin 5, and 6 with antitype VII collagen autoantibodies, as characterized by either immunoblot or immunoprecipitation analysis. Differentiation between anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita was possible in all 10 sera by indirect immunofluorescence using either knockout skin substrate or fluorescent overlay antigen mapping technique.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Bullous pemphigoid
Epidermolysis bullosa acquisita
Linear IgA disease
Bullous SLE
Paraneoplastic pemphigus
Anti-p105 pemphigoid
Pseudo-ocular cicatricial pemphigoid

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Dependent upon the extent and severity of the disease In general, this is one of the most difficult blistering diseases to control Poor prognostic factors for visual prognosis include: Persistent epithelial defects Limbal inflammation Ongoing conjunctival inflammation Patients with high titers of IgG and IgA have highest likelihood of requiring systemic treatement
Survival	Dependent upon the extent and severity of the disease
Recurrence	1/3 of patients maintained prolonged remission after treatment with one or more immunosuppressive agents
TREATMENT
GENERAL
Interventions for Mucous Membrane Pemphigoid/Cicatricial Pemphigoid and Epidermolysis Bullosa Acquisita A Systematic Literature Review Gudula Kirtschig, MD; Dédée Murrell, FAAD; Fenella Wojnarowska, DM; Nonhlanhla Khumalo	Arch Dermatol. 2002;138:380-384 Abstract quote Objective To identify and critically evaluate evidence from randomized controlled trials for the efficacy of treatments for mucous membrane pemphigoid (MMP)/cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Search Strategy Review of MEDLINE from 1966 through March 2000, EMBASE from 1980 through March 2000, and the Cochrane Controlled Trials Register (February 28, 2001) to identify randomized controlled trials for the efficacy of treatments in MMP/CP and EBA. Selection Criteria All randomized controlled trials of therapeutic interventions that included patients with MMP/CP or EBA confirmed by immunofluorescence study findings. All age groups were included. Results We found 2 small randomized controlled trials of MMP/CP, both conducted in patients with severe eye involvement. We were not able to identify a randomized controlled trial of therapeutic interventions in EBA. Conclusions There is evidence from 2 small trials that severe ocular CP responds best to treatment with cyclophosphamide, and mild to moderate disease seems effectively suppressed by treatment with dapsone. No treatment recommendations can be made for EBA because to our knowledge no randomized controlled trials are published. Even though systemic corticosteroids are regarded as the gold standard in the treatment of MMP/CP and EBA, there is poor evidence from the literature that they are the best treatment for these diseases.
MEDICAL	Sulfapyridine Minocycline Intravenous immunoglobulins Subconjunctival mitomycin
Treatment-Topical	Limited disease may respond to local therapy with debridement of dead mucosal tissue and potent topical corticosteroids-helpful in oral lesions Topical steroids ineffective in ocular lesions-topical cyclosporine has been beneficial associated with frequent lubrication. However, overal, these patients require systemic therapy
Treatment-Systemic	Ocular, laryngeal, esophageal, or oral or cutaneous disease unresponsive to topical measures Controversial with some ophthalmologists treating with combination prednisone and cyclophosphamide (sometimes administered in pulse) Azathioprine has also been used Others have advocated dapsone with or without corticosteroids
Treatment-Surgical	Surgical intervention in cases of severe ocular CP, esophageal or laryngeal strictures, should not be performed until the disease is fully controlled by medical therapy-otherwise the trauma will create more scarring Newer techniques including allograft limbal transplantation, amniotic membrane transplantation, and trasorrhaphy followed by serum-derived tears Severe tracheal involvement may require elective tracheostomy
ETANERCEPT
Treatment of recalcitrant cicatricial pemphigoid with the tumor necrosis factor antagonist etanercept Christopher Sacher, MD, etal. Cologne, Germany	J Am Acad Dermatol 2002;46:113-5. Abstract quote The treatment of cicatricial pemphigoid is generally regarded as difficult and usually relies on individual clinical experience. Corticosteroids, as drugs of first choice, often have to be combined with steroid-sparing agents to prevent hazardous, long-term side effects. We describe a 72-year-old woman with long-standing cicatricial pemphigoid recalcitrant to established treatment regimens who responded rapidly and lastingly to therapy with the tumor necrosis factor antagonist etanercept. To our knowledge, this is the first report of its use in the treatment of a bullous autoimmune disease.
IMMUNOGLOBULIN
Cicatricial pemphigoid with circulating IgA and IgG autoantibodies to the central portion of the BP180 ectodomain: Beneficial effect of adjuvant therapy with high-dose intravenous immunoglobulin Martin Leverkusa, etal Germany, and Kurume, Japan	J Am Acad Dermatol 2002;46:116-22 Abstract quote Cicatricial pemphigoid (CP) is an autoimmune subepidermal blistering disease characterized by deposits of IgG, IgA, or C3 at the cutaneous basement membrane zone. CP may present with considerable variation regarding age, morphology of lesions, and mucosal involvement, which may heal with or without scarring. We describe a patient with CP who presented with circulating IgA and IgG autoantibodies to the epidermal side of salt-split human skin. By immunoblot analysis, the patient's IgA reacted with the soluble ectodomain of BP180 (LAD-1). This reactivity was mainly directed to the central portion of the BP180 ectodomain, a site that, to date, has not been described as the target of IgA autoantibodies. Different immunosuppressive treatment regimens including steroids and mycophenolate mofetil did not control this patient's disease, and severe scarring of the conjunctivae occurred with impairment of vision. Addition of adjuvant intravenous immunoglobulin (1 g/kg body weight on 2 consecutive days) every 4 weeks led to a dramatic improvement of conjunctivitis and gingivitis. Clinical improvement correlated with the serum's IgA immunoblot reactivity against LAD-1. Further studies on a larger number of patients with CP should try to correlate the specificity of autoantibodies in CP with the response to certain therapeutic regimens. \
MYCOPHENOLATE
Treatment of cicatricial pemphigoid with mycophenolate mofetil as a steroid-sparing agent M. Megahed, MD S. Schmiedeberg, MD J. Becker, MD T. Ruzicka, MD Düsseldorf, Germany	J Am Acad Dermatol 2001;45:256-9 Abstract quote Background: Cicatricial pemphigoid (CP) is a rare autoimmune bullous disease that affects the skin and mucous membranes. It commonly ends by serious complications such as blindness, stenosis, and stricture formation and is difficult to treat. Mycophenolate mofetil has been reported to be effective in the treatment of pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid either as monotherapy or as a steroid-sparing agent. Objective: Our purpose was to evaluate the effectiveness of mycophenolate mofetil as a steroid-sparing agent in treating patients with CP. Methods: Three patients with CP were treated with mycophenolate mofetil and prednisolone. Results: All 3 patients responded very well to the therapy. None of them showed relapse of the disease for a follow-up period of 6 to 14 months after complete cessation of mycophenolate mofetil and prednisolone. No side effects were seen. Conclusion: Mycophenolate mofetil appears to be a safe and effective steroid-sparing agent in the treatment of CP.
THALIDOMIDE
Thalidomide therapy for cicatricial pemphigoid. Duong DJ, Moxley RT 3rd, Kellman RM, Pincus SH, Gaspari AA. Department of Neurology, State University of New York at Syracuse, USA.	J Am Acad Dermatol 2002 Aug;47(2 Suppl):S193-5 Abstract quote Cicatricial pemphigoid is a chronic, presumed autoimmune, blistering disease of the mucous membranes and occasionally of the skin. The characteristic feature is scarring at the sites of healing. We report the use of thalidomide as a therapeutic agent to control previously resistant disease.

J Am Acad Dermatol 2000;43:571-591.

Collagen VII-Collagen variant present in the skin basement membrane within the anchoring fibrils.

Salt split skin assay-Normal skin incubated with 1M NaCl which separates the epidermis from dermis. The epidermal half contains the upper lamina lucida, hemidesmosomes, and BP antigen. The dermal half contains laminin 5, lamina densa, and anchoring fibrils.

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