AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal, blistering skin disease that rarely involves mucous membranes. BP is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific for the hemidesmosomal BP antigens BP230 (BPAg1) and BP180 (BPAg2).

In spontaneous animal models, BP has been reported to occur in dogs (canine) and horses (equine). Recently, BP has been found to occur in domestic cats (feline) and Yucatan minipigs (porcine).

In experimental animal models, passive transfer of antibodies to mouse BPAg2 causes blistering in newborn mice similar to that seen in humans. Active induction of anti-BPAg1 antibodies in rabbits enhances inflammation and deposition of immunoreactants at the basement membrane but does not result in spontaneous blistering.

In canine BP, histologic analysis reveals a subepidermal blistering process with prominent eosinophil infiltration identical to the classic pathology of humans. Similar findings have been observed in feline, porcine, and equine BP.

As in humans with BP, the sera from dogs with BP bind to the epidermal roof of salt-split skin and BP180. The antigenic epitopes of BP180 identified by the canine BP IgG map to the same epitopes as human BP autoantibodies. Similar findings were observed in cats, pigs, and horses with BP.

Pathophysiology

IgG autoantibodies bind to the skin basement membrane in patients with BP. The binding of antibodies at the basement membrane activates complement and inflammatory mediators. Activation of the complement system is thought to play a critical role in attracting inflammatory cells to the basement membrane. These inflammatory cells are postulated to release proteases, which degrade hemidesmosomal proteins and lead to blister formation. Eosinophils are characteristically present in human patients' blisters as demonstrated by histopathologic analysis, although their presence is not an absolute diagnostic criterion.

The precise role of BP antigens in the pathogenesis of BP is not completely clear. BPAg1 (BP230) is an intracellular component of the hemidesmosome; BPAg2 (BP180, type XVII collagen) is a transmembranous protein with a collagenous extracellular domain. Passive transfer experiments in newborn mice have demonstrated that rabbit antibodies against mouse BPAg2 can induce subepidermal blisters similar to those observed in patients with BP. However, the eosinophil infiltration that is frequently observed in human BP lesional skin was not detected in the passive transfer experimental model. Furthermore, anti-BP180 NC16A domain autoantibodies purified from patients with BP are capable of inducing dermal-epidermal separation in cryosections of normal human skin.

Studies from 2006 on autoreactive T and B cells from 35 patients with acute-onset BP revealed that the percentage of T- cell and B-cell reactivity from these BP patients against the BPAg2 is much higher than that against BPAg1, further suggesting a more prominent role of BPAg2 in disease development.

Serum levels of autoantibodies against BPAg2 are reportedly correlated with disease activity in some studies. Induction of antibodies against BPAg1 in rabbits does not induce primary blistering, but it can enhance the inflammatory response at the basement membrane. The role of autoantibodies specific for BP antigens in the initiation and the perpetuation of disease is unknown.

Although BPAg2 has been identified as the major antigen involved with BP disease development, in 2005, autoantibodies against alpha 6 integrin and laminin-5, 2 other skin basement membrane components, were identified in human patients affected by BP.

Currently, no active experimental model is available to dissect the induction phase of the disease. Nevertheless, the autoantibody response can be induced in healthy BALB/c mice by immunizing the mice with synthetic peptides of the mouse type XVII collagen NC16A domain, the target region of autoantibodies in human patients affected with BP.

Eotaxin, an eosinophil-selective chemokine, is strongly expressed in the basal layer of the epidermis of lesional BP skin and parallels the accumulation of eosinophils in the skin basement membrane zone area. It may play a role in the recruitment of eosinophils to the skin basement membrane area.

Other cytokines and chemokines have also been studied in BP. Interleukin 16, a major chemotactic factor responsible for recruiting CD4⁺ helper T cells to the skin and for inducing functional interleukin 2 receptors for cellular activation and proliferation, was found to be expressed strongly by epidermal cells and infiltrating CD4⁺ T cells in lesional BP skin. Significantly higher levels of interleukin 16 were detected in sera and blisters of BP patients compared with healthy subjects. These data (reported in 2004 and involved 39 BP patients with active disease) suggest a role of interleukin 16 in BP development. In other study of 27 BP patients (reported in 2006), serum levels of monokine induced by interferon gamma (MIG, a Th1-type chemokine) and serum levels of CCL17 and CCL22 (Th2-type chemokines) were significantly increased in BP patients compared with healthy subjects.

Matrix metalloproteinase (MMP)–2, MMP-9, and MMP-13 were significantly increased in lesional BP skin compared with that of healthy skin, with T cells comprising the majority of MMP cellular sources. These data (reported in 2006) suggest a role of MMP in the blistering of BP.

In another study of 39 BP patients (reported in 2006), a cytokine named BAFF (B-cell activating factor belonging to the tumor necrosis factor family) that functions to regulate B-cell proliferation and survival was found to be significantly increased in sera of BP patients compared with healthy subjects, although no significant association was noted between serum BAFF levels and titers of anti-BPAg2 antibodies.

Frequency

United States

BP is uncommon, and its frequency is unknown.

International

BP has been reported to occur throughout the world. In France and Germany, the reported incidence is 6.6 cases per million people per year. In Europe, BP was identified as the most common subepidermal autoimmune blistering disease.

Mortality/Morbidity

BP is a chronic inflammatory disease. If untreated, the disease can persist for months or years, with periods of spontaneous remissions and exacerbations. In most patients who are treated, BP remits within 1.5-5 years. Patients with aggressive or widespread disease, those requiring high doses of corticosteroids and immunosuppressive agents, and those with underlying medical problems have increased morbidity and risk of death. Because the average age at onset of BP is about 65 years, patients with BP frequently have other comorbid conditions that are common in elderly persons, thus making them more vulnerable to the adverse effects of corticosteroids and immunosuppressive agents.

• BP may be fatal, particularly in patients who are debilitated. The proximal causes of death are infection with sepsis and adverse events associated with treatment. Patients receiving high-dose corticosteroids and immunosuppressants are at risk for peptic ulcer disease, GI bleeds, agranulocytosis, and diabetes.
• BP involves the mucosa in 10-25% of patients. Patients who are affected may have limited oral intake secondary to dysphagia. Erosions secondary to rupture of the blisters may be painful and may limit patients' daily living activities. Blistering on the palms and the soles can severely interfere with patients' daily functions.
• BP lesions typically heal without scarring or milia formation.

Race

No racial predilection is apparent.

Sex

The incidence of BP appears to be equal in men and women.

Age

• BP primarily affects elderly individuals in the fifth through seventh decades of life, with an average age at onset of 65 years.
• BP of childhood onset has been reported in the literature.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

The onset of BP may be either subacute or acute, with widespread, tense blisters. Significant pruritus is frequently present. In some patients, the blisters arise after persistent urticarial lesions.

• BP has been reported following several nonbullous, chronic, inflammatory skin diseases, such as lichen planus and psoriasis.
• BP has been reported to be precipitated by ultraviolet irradiation, x-ray therapy, and exposure to some drugs.
• Drugs associated with BP include furosemide, ibuprofen and other nonsteroidal anti-inflammatory agents, captopril, penicillamine, and antibiotics.
• BP has been reported to develop shortly after vaccination, particularly in children.

Physical

BP may present with several distinct clinical presentations, as follows: generalized bullous, vesicular, vegetative, generalized erythroderma, urticarial, and nodular variants.

• Generalized bullous form
• • The generalized bullous form is the most common presentation.
  • Tense bullae arise on any part of the skin surface, with a predilection on the flexural areas of the skin. Oral and ocular mucosa involvement rarely occurs and, when seen, is of minor clinical significance.
  • The bullae can occur on normal-appearing, as well as erythematous, skin surfaces.
  • The bullae usually heal without scarring or milia formation.
• Vesicular form
• • The vesicular form is less common.
  • It manifests as groups of small, tense blisters, often on a urticarial or erythematous base.
• Vegetative form
• • The vegetative form is very uncommon, with vegetating plaques in intertriginous areas of the skin, such as the axillae, the neck, the groin, and inframammary areas.
  • This form of BP closely resembles pemphigus vegetans.
• Generalized erythroderma form
• • This rare presentation can resemble psoriasis, generalized atopic dermatitis, or other skin conditions characterized by an exfoliative erythroderma.
  • Patients with this variant may develop vesicles or bullae.
• Urticarial form
• • Some patients with BP initially present with persistent urticarial lesions that subsequently convert to bullous eruptions.
  • In some patients, urticarial lesions are the sole manifestations of the disease.
• Nodular form: This rare form, termed pemphigoid nodularis, has clinical features that resemble prurigo nodularis, with blisters arising on normal-appearing or nodular lesional skin.
• Acral form: In childhood-onset BP associated with vaccination, the bullous lesions predominantly affect the palms, the soles, and the face.

Causes

The cause of BP is not known; however, several potentially relevant factors have been identified.

• Immunogenetics
• • Immunogenetic analyses have identified that the human leukocyte antigen (HLA) haplotype, DQB1*0301, is increased in patients with BP.
  • In one study, peripheral blood lymphocytes from patients with BP who are positive for HLA-DQB1*0301 proliferated in the presence of the BP180 antigen. In these studies, the ability of the patient's T cells to respond to the target BP antigen was restricted by the HLA haplotype. This HLA haplotype is postulated to be important in the presentation of the target antigen by antigen-presenting cells in the initial development of the autoimmune response.
• Age
• • BP is most common in patients in their fifth to seventh decades of life. Investigators have postulated that intrinsic changes in the immune system with aging may be a factor in the initiation of an autoimmune response against BP antigens.
  • Alternately, repeated trauma to the skin may lead to the development of an immune response against normal skin proteins.
• Epitope spreading
• • Anecdotal reports of BP arising in patients with inflammatory skin diseases, such as psoriasis and lichen planus, or after trauma, such as drug reactions, suggest that inflammation may expose sequestered skin basement membrane proteins and BP antigens and lead to the development of an autoimmune response.
  • The autoimmune reaction may extend by an immunologic phenomenon termed epitope spreading, whereby a relatively restricted immune response spreads to involve different sites on the same autoantigen and to involve different autoantigens.
  • This phenomenon has been well documented in animal models of autoimmune diseases. Epitope spreading may explain the presence of an immune response against 2 target antigens (BPAg1 and BPAg2) as well as multiple epitopes on the target antigens.
• Complement activation
• • BP autoantibodies bind to the hemidesmosome/upper lamina lucida areas of the skin basement membrane. Complement activation follows this binding as detected by direct immunofluorescence (DIF) studies that demonstrate in situ deposition of complement components (typically C3) at the basement membrane in patients with BP.
  • Complement activation leads to the recruitment of inflammatory cells to the basement membrane zone. The enzymes released by these inflammatory cells cleave BPAg2 in vitro and are postulated to be important in blister formation.
• Chemokines
• • The histologic hallmark for BP is the prominent eosinophil infiltration at the skin basement membrane area. Eosinophil migration and activation is likely induced by chemokines.
  • The expression of eotaxin, a chemokine associated with eosinophil migration, is increased in the epidermis of BP lesions. Similarly, eotaxin expression is increased on endothelial cells in biopsy samples obtained from the skin of patients with BP. This increased epidermal and endothelial expression of eotaxin may be important in the recruitment of eosinophils to the basement membrane in patients with BP.
  • At the skin basement membrane, eosinophils can release proteolytic enzyme 92-kd gelatinase, which cleaves BPAg2 in vitro.
  • Interleukin 5, an interleukin with eosinophil chemoattractant and activation properties, has also been found in the skin of patients with BP. It may play a role in eosinophil recruitment to the skin.

DIFFERENTIALS

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Other Problems to be Considered

Chronic bullous dermatosis of childhood
Dyshidrosis
Bullous eruption of systemic lupus erythematosus
Pemphigus vegetans
Urticaria
Herpes gestationis

WORKUP

Section 5 of 11  

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Lab Studies

• To establish a diagnosis of BP, the following tests should be performed: histopathologic analysis from the edge of a blister and DIF studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed using the patient's serum. The preferred substrate for IDIF is salt-split normal human skin substrate.
• Direct immunofluorescence studies (see Image 1)
• • DIF studies demonstrate in vivo deposits of antibodies and other immunoreactants, such as complement. DIF tests usually demonstrate IgG (70-90% of patients) and complement C3 deposition (90-100% of patients) in a linear band at the dermal-epidermal junction. This pattern of immunoreactants is not specific for BP and may be seen in cicatricial pemphigoid and epidermolysis bullosa acquisita. BP can be differentiated from these conditions by incubating the patient's skin biopsy sample in 1 mol/L salt prior to performing the DIF technique. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals IgG on the blister roof (epidermal side of split skin) in patients with BP, while, in CP and EBA, the IgG localizes to the blister floor (dermal side of split skin).
  • The optimal location for DIF testing is normal-appearing perilesional skin. False-positive results can be observed when it is performed on lesional skin. Rarely, skin biopsy samples placed in transport media may yield false-negative results. This observation makes the use of fresh tissue the preferred substrate for DIF studies.
• Indirect immunofluorescence (see Image 2)
• • IDIF studies document the presence of IgG circulating autoantibodies in the patient's serum that target the skin basement membrane component. Seventy percent of patients with BP have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course.
  • IDIF studies can be used to detect the patient's IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate.

Other Tests

• Experimental procedures available in research laboratories include direct and indirect immunoelectron microscopy, immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA).
• Direct and indirect immunoelectron microscopy
• • Direct and indirect immunoelectron microscopy (immunoEM) ultrastructurally localize in vivo–bound IgG autoantibodies (direct immunoEM) or the binding site of circulating IgG autoantibodies (indirect immunoEM) at the basement membrane.
  • IgG autoantibodies are detected at the hemidesmosome/upper lamina lucida areas of the skin basement membrane.
• Immunoblotting
• • Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin.
  • The sensitivity of immunoblotting varies. In 75% of patients, a reaction occurs with the BP230 antigen, while, in 50% of patients, a reaction occurs with the BP180 antigen.
• Immunoprecipitation
• • Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, immunoprecipitation is performed with native, rather than denatured, protein and is more sensitive. Immunoprecipitation is more difficult to perform and generally less available than immunoblotting.
  • In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180.
• Enzyme-linked immunosorbent assay
• • The ELISA technique analyzes the BP antigen-specific IgG autoantibodies in the patients' sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. In several reports, ELISA has been demonstrated to be highly sensitive and specific. ELISA kits for testing BP antigen-specific IgG autoantibodies are now available commercially. However, only a few medical centers currently offer this service.
  • ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed. These assays are not commercially available, but they offer promise as investigational tools. An ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients with BP.

Histologic Findings

The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor BP).

TREATMENT

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Medical Care

• As in other autoimmune bullous diseases, the goal of therapy is to decrease blister formation, to promote healing of blisters and erosions, and to determine the minimal dose of medication necessary to control the disease process.
• Therapy must be individualized for each patient, keeping in mind preexisting conditions and other patient-specific factors.

Consultations

Treatment of patients with BP requires coordination of care between the dermatologist and the patient's primary care provider.

• Patients with oral disease may require an otolaryngologist and/or a dentist for evaluation and care.
• An ophthalmologist should evaluate patients with suspected ocular involvement and those requiring prolonged high-dose steroids.

Diet

• The lesions may flare in patients with oral disease after eating hard and crunchy foods, such as chips, raw fruits, and vegetables.
• For patients treated with systemic corticosteroid for longer than 1 month, a combined supplement of calcium and vitamin D should be instituted to prevent osteoporosis. The dosage and the frequency are stated in the recommendations established by the American College of Rheumatology Task Force in 1996.
• In addition to calcium and vitamin D supplementation, patients on long-term treatment with systemic corticosteroids should be taking bisphosphonate, a specific inhibitor for osteoclast-mediated bone resorption (eg, alendronate).

Activity

Patients should be instructed to avoid direct physical trauma to their skin surfaces. For example, localized BP has rarely been described peristomally.

MEDICATION

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Treatment is directed at reducing the inflammatory response and autoantibody production. Although target-specific therapy is the "Holy Grail" for immunodermatologists, non–target-specific treatments are currently used. The most commonly used medications are anti-inflammatory agents (eg, corticosteroids, tetracyclines, dapsone) and immunosuppressants (eg, azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide). A recent article from Europe provided evidence that strong topical corticosteroid treatment may achieve disease control while avoiding systemic adverse effects from systemic corticosteroids.

Drug Category: Anti-inflammatory agents

These agents inhibit the inflammatory process by inhibiting specific cytokine production and vascular permeability. They may also stabilize granulocyte membranes and prevent release of key enzymes.

Drug Category: Immunosuppressive agents

For patients in whom steroids or other anti-inflammatory agents have not caused a response or for those unable to tolerate prednisone, immunosuppressants are useful adjuvants.

Drug Category: Biologicals

FOLLOW-UP

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Complications

• Secondary infection may occur because of the presence of multiple erosions and immunosuppressants used to control the disease. These infections may be either systemic or localized to the skin. Cutaneous infection increases the risk of scarring and delays wound healing.
• Malignancies due to immunosuppressants have been reported. Case-control series in patients with BP have failed to detect an increased incidence of malignancy in patients with BP when compared with age- and sex-matched controls
• Bone marrow suppression may occur in patients receiving immunosuppressants.
• Growth retardation may occur in children receiving systemic corticosteroids and immunosuppressants.
• Adrenal insufficiency may occur following prolonged use of glucocorticoids.
• Osteoporosis and bone fractures may result following the use of systemic corticosteroids.

Prognosis

• Most patients affected with BP require therapy for 6-60 months, after which many patients experience long-term remission of the disease. However, some patients have long-standing disease requiring treatment for years.
• Most mortality associated with BP occurs secondary to the effects of the medications.
• The population at risk for BP is at an increased risk for comorbid conditions, such as hypertension, diabetes mellitus, and heart diseases, which treatment may exacerbate.

Patient Education

• Patients should avoid trauma to the skin. Patients' skin is fragile from the disease, as well as from the use of topical and systemic steroids.
• Patients should be educated about their disease and treatments, so that they can report adverse effects to their physicians.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Appropriate testing, both routine histologic analysis and immunofluorescence testing, should be performed to confirm the correct diagnosis.
• Patients on systemic therapy must be appropriately monitored for adverse effects, toxicity, and response to therapy.

Special Concerns

• Elderly patients with BP who have other significant health problems, such as diabetes mellitus, hypertension, or heart disease, may require treatment with a more conservative approach, using topical corticosteroids (clobetasol), tetracyclines, and/or low doses of systemic corticosteroids (prednisone 10-20 mg/d). In all patients, the goal of treatment is to achieve disease control with minimal symptoms and adverse effects from treatment.

MULTIMEDIA

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Media file 1:  Direct immunofluorescence study performed on a perilesional skin biopsy specimen from a patient with bullous pemphigoid detects a linear band of immunoglobulin G deposit along the dermoepidermal junction.
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Media type:  Photo

Media file 2:  Indirect immunofluorescence study performed on salt-split normal human skin substrate with the serum from a patient with bullous pemphigoid detects immunoglobulin G class circulating autoantibodies that bind to the epidermal (roof) side of the skin basement membrane.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
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• Liu Z, Diaz LA, Troy JL, et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest. Nov 1993;92(5):2480-8. [Medline].
• Liu Z, Giudice GJ, Swartz SJ, et al. The role of complement in experimental bullous pemphigoid. J Clin Invest. Apr 1995;95(4):1539-44. [Medline].
• Morrison LH. Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (rituximab). J Am Acad Dermatol. Nov 2004;51(5):817-9. [Medline].
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Article Last Updated: Apr 19, 2007