Bullous Pemphigoid

Practice Essentials

Bullous pemphigoid is a chronic, inflammatory, subepidermal, blistering disease. If untreated, it can persist for months or years, with periods of spontaneous remissions and exacerbations. The disease can be fatal, particularly in patients who are debilitated.

Signs and symptoms

Bullous pemphigoid may present with several distinct clinical presentations, as follows:

• Generalized bullous form: The most common presentation; tense bullae arise on any part of the skin surface, with a predilection for the flexural areas of the skin
• Vesicular form: Less common than the generalized bullous type; manifests as groups of small, tense blisters, often on an urticarial or erythematous base
• Vegetative form: Very uncommon, with vegetating plaques in intertriginous areas of the skin, such as the axillae, neck, groin, and inframammary areas
• Generalized erythroderma form: This rare presentation can resemble psoriasis, generalized atopic dermatitis, or other skin conditions characterized by an exfoliative erythroderma
• Urticarial form: Some patients with bullous pemphigoid 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 bullous pemphigoid associated with vaccination, the bullous lesions predominantly affect the palms, soles, and face
• Infant form: In infants affected by bullous pemphigoid, the blisters tend to occur frequently on the palms, soles, and face, affecting the genital areas rarely; 60% of these infant patients have generalized blisters^[1]

See Clinical Presentation for more detail.

Diagnosis

To establish a diagnosis of bullous pemphigoid, the following tests should be performed:

• Histopathologic analysis: From the edge of a blister; 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
• Direct immunofluorescence (DIF) studies: Performed on normal-appearing, perilesional skin (see the image below)^[2]

  View Image

  Direct immunofluorescence study performed on a perilesional skin biopsy specimen from a patient with bullous pemphigoid detects a linear band of immun....

   

  

   
• Indirect immunofluorescence (IDIF) studies: Performed on the patient’s serum, if the DIF result is positive (see the image below)

  View Image

  Indirect immunofluorescence study performed on salt-split normal human skin substrate with the serum from a patient with bullous pemphigoid detects im....

   

  

   

DIF tests in patients with bullous pemphigoid usually demonstrate immunoglobulin G (IgG) and complement C3 deposition in a linear band at the dermal-epidermal junction, with IgG in salt-split skin found on the blister roof (epidermal side of split skin).

IDIF studies document the presence of circulating IgG autoantibodies in the patient's serum that target the skin basement membrane component. Seventy percent of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin.

See Workup for more detail.

Management

As in other autoimmune bullous diseases, the goal of therapy in bullous pemphigoid is as follows:

• Decrease blister formation
• Promote healing of blisters and erosions
• Determine the minimal dose of medication necessary to control the disease process

The most commonly used medications for bullous pemphigoid are anti-inflammatory agents (eg, corticosteroids, tetracyclines, dapsone) and immunosuppressants (eg, azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide).^{[3, 4]} Initial treatment with doxycycline was found to be effective and was associated with a lower incidence of adverse effects compared with prednisone.^{[5, 6, 7]}

Most patients affected with bullous pemphigoid 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 bullous pemphigoid occurs secondary to the effects of medications used in treatment. For example, the population at risk for bullous pemphigoid is at an increased risk for comorbid conditions, such as hypertension, diabetes mellitus, and heart disease, which treatment may exacerbate.

See Treatment and Medication for more detail.

• References

Background

Bullous pemphigoid is a chronic, autoimmune, subepidermal, blistering skin disease that rarely involves mucous membranes. Bullous pemphigoid is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific for the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2). BP antigen 2 is the usual pathogenic antibody. Occasionally, sublamina densa deposits are noted, related to anti-p200 antibody.

In spontaneous animal models, bullous pemphigoid has been reported to occur in dogs (canine)^{[8, 9]} and horses (equine).^[10] Bullous pemphigoid has been found to occur in domestic cats (feline) and Yucatan minipigs (porcine).^[11]

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.^{[12, 13, 14]}

In canine bullous pemphigoid, 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,^[15] porcine, and equine bullous pemphigoid.^[10]

As in humans with bullous pemphigoid, the sera from dogs with bullous pemphigoid bind to the epidermal roof of salt-split skin and BP180. The antigenic epitopes of BP180 identified by the canine bullous pemphigoid IgG map to the same epitopes as human bullous pemphigoid autoantibodies. Similar findings were observed in cats,^[15] pigs, and horses^[10] with bullous pemphigoid.

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Pathophysiology

IgG autoantibodies bind to the skin basement membrane in patients with bullous pemphigoid. 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 bullous pemphigoid antigens in the pathogenesis of bullous pemphigoid 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.^[16] 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 bullous pemphigoid. However, the eosinophil infiltration that is frequently observed in human bullous pemphigoid lesional skin was not detected in the passive transfer experimental model.^[17] Furthermore, anti-BP180 NC16A domain autoantibodies purified from patients with bullous pemphigoid are capable of inducing dermal-epidermal separation in cryosections of normal human skin.^[18]

Studies from 2006 on autoreactive T and B cells from 35 patients with acute-onset bullous pemphigoid revealed that the percentage of T- cell and B-cell reactivity from these bullous pemphigoid patients against the BPAg2 is much higher than that against BPAg1, further suggesting a more prominent role of BPAg2 in disease development.^[19]

Serum levels of autoantibodies against BPAg2 are reportedly correlated with disease activity in some studies.^[20] 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 bullous pemphigoid antigens in the initiation and the perpetuation of disease is unknown.

Although BPAg2 has been identified as the major antigen involved with bullous pemphigoid disease development, in 2005, autoantibodies against alpha 6 integrin^[21] and laminin-5,^[22] 2 other skin basement membrane components, were identified in human patients affected by bullous pemphigoid.

Although no perfect active experimental model is available currently, an active animal model was generated by transferring splenocytes from wide-type mice that had been immunized by grafting human BP180-transgenic mouse skin into Rag-2(-/-)/BP180-humanized mice.^[23] The recipient immunodeficient mice developed antihuman BP180 antibodies, manifested with blisters that are consistent with the clinical, histological, and immunopathological features of human bullous pemphigoid, except eosinophil infiltration.^[23] In addition, 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 bullous pemphigoid.^[24]

Eotaxin, an eosinophil-selective chemokine, is strongly expressed in the basal layer of the epidermis of lesional bullous pemphigoid 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 bullous pemphigoid. 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 bullous pemphigoid skin. Significantly higher levels of interleukin 16 were detected in sera and blisters of bullous pemphigoid patients compared with healthy subjects. These data (reported in 2004 and involved 39 bullous pemphigoid patients with active disease) suggest a role of interleukin 16 in bullous pemphigoid development.^[25]

In other study of 27 bullous pemphigoid 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 bullous pemphigoid patients compared with healthy subjects.^[26]

Matrix metalloproteinase (MMP)–2, MMP-9, and MMP-13 were significantly increased in lesional bullous pemphigoid 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 bullous pemphigoid.^[27]

In another study of 39 bullous pemphigoid 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 bullous pemphigoid patients compared with healthy subjects, although no significant association was noted between serum BAFF levels and titers of anti-BPAg2 antibodies.^[28]

In 2008, a role for IgE class of autoantibodies, particularly those that target BP180, has been established. The higher level of IgE anti-BP180 was correlated with a more severe clinical phenotype.^[29]

In an animal model in which C57BL/6 type of mice engrafted with syngeneic mouse skin transgenically expressed human BPAg2 in the epidermal basement membrane zone, antibodies against the human BPAg2 extracellular domain developed first, followed by the occurrence of antibodies to the intracellular domain of the same human BPAg2. Interestingly, the development of later antibodies was associated with the loss of the graft.^[30]

IgG autoantibodies from bullous pemphigoid patients are found to deplete cultured keratinocytes of the BPAg2 and weaken cell attachment in vitro, which further supports the pathogenic role of these autoantibodies.^[31]

The coagulation cascade is found to be activated in bullous pemphigoid patients, and such activation is found to be correlated with the disease severity and with eosinophilia, suggesting a role of eosinophils in this activation of coagulation, which may contribute to the potential thrombotic risk, as well as inflammation, tissue damage, and blister formation.^[32]

A 2010 report of finding anti-BP180 antibodies in unaffected subjects is provides interesting data for further study of the pathogenesis of bullous pemphigoid.^[33]

A 2009 report of bullous pemphigoid developed after adalimumab treatment for psoriasis raises some question about whether biologics can play a role in inducing the disease or it may just suggest the association of bullous pemphigoid with psoriasis.^[34]

Bullous pemphigoid has been associated with PD-1 inhibitors used as targeted therapy for malignancy. Some patients developed both pemphigoid and keratoacanthomas.^{[35, 36, 37]}

A retrospective case-control study reports that certain dipeptidyl peptidase 4 (DPP-4) inhibitors, specifically vildagliptin and linagliptin (but not sitagliptin), used to treat type 2 diabetes may confer a significant but small risk of developing bullous pemphigoid.^{[38, 39]}

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Epidemiology

United States

Bullous pemphigoid is uncommon, and its frequency is unknown.

International

Bullous pemphigoid 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, bullous pemphigoid was identified as the most common subepidermal autoimmune blistering disease.

In a population-based cohort study, the incidence of bullous pemphigoid was found to be 4.3 cases per 100,000 person-years in the United Kingdom.^[40]

Race

No racial predilection is apparent.

Sex

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

Age

Bullous pemphigoid primarily affects elderly individuals in the fifth through seventh decades of life, with an average age at onset of 65 years. Bullous pemphigoid of childhood onset has been reported in the literature. It is suggested that the childhood-onset bullous pemphigoid may be more self-limited.^[41] One puzzling finding, however, is a report of rising incidence of infant-onset bullous pemphigoid.

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Prognosis

Most patients affected with bullous pemphigoid 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 bullous pemphigoid occurs secondary to the effects of the medications. Data suggest that high serum levels of IgG1 and IgG4 targeting the noncollagenous 16A domain of BP180 correlate with more serious disease and a worse prognosis.^[42] Age and the presence of circulating antibodies are also associated with poor outcome.^[43]

The population at risk for bullous pemphigoid is at an increased risk for comorbid conditions, such as hypertension, diabetes mellitus, thromboembolism, and heart diseases, which treatment may exacerbate.^[44] Bullous pemphigoid may be linked (directly or indirectly) to neurological disorders.^{[45, 46]} An increase in the occurrence of neurological disorders has been reported in patients affected by bullous pemphigoid, relative to the age-matched and sex-matched general population.^[47] However, these findings need to replicated in different populations to clarify this proposed relationship.

In a multicenter, prospective cohort in France, a high titer of anti-BPAg2 autoantibodies by ELISA and a positive direct immunofluorescence finding were found to be good indicators of further clinical relapse of bullous pemphigoid and may correlate with overall morbidity and mortality.^{[48, 49, 50]}

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Mortality/Morbidity

Bullous pemphigoid 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, bullous pemphigoid 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 bullous pemphigoid is about 65 years, patients with bullous pemphigoid 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.

Bullous pemphigoid 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.

Bullous pemphigoid 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.

Bullous pemphigoid lesions typically heal without scarring or milia formation. In a survey of patients conducted in a Midwest United States university medical center, no difference was noted in expected mortality in bullous pemphigoid 223 patients compared with the general population.^[51] In a population-based cohort study in the United Kingdom, however, the risk of death for bullous pemphigoid patients was found to be twice as great as that for controls.^[40] Furthermore, a Swiss prospective study confirmed a high-case fatality rate, with increased 1-year mortality compared with the expected mortality rate for age-adjusted and sex-adjusted general population.^[52]

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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.

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History

The onset of bullous pemphigoid may be either subacute or acute, with widespread, tense blisters. Significant pruritus is frequently present and may be the only manifestation of the disease, especially in older patients.^[53] In some patients, the blisters arise after persistent urticarial lesions.

Bullous pemphigoid has been reported following several nonbullous, chronic, inflammatory skin diseases, such as lichen planus and psoriasis.

Bullous pemphigoid has been reported to be precipitated by ultraviolet irradiation, x-ray therapy, and exposure to some drugs.

Drugs associated with bullous pemphigoid include furosemide, ibuprofen and other nonsteroidal anti-inflammatory agents, captopril, penicillamine, and antibiotics.

Bullous pemphigoid has been reported to develop shortly after vaccination, particularly in children.^[54]

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Physical Examination

Bullous pemphigoid may present with several distinct clinical presentations, as follows:

• Generalized bullous form of bullous pemphigoid: 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 of bullous pemphigoid: The vesicular form is less common. It manifests as groups of small, tense blisters, often on an urticarial or erythematous base.
• Vegetative form of bullous pemphigoid: 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 bullous pemphigoid closely resembles pemphigus vegetans.
• Generalized erythroderma form of bullous pemphigoid: 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 of bullous pemphigoid: Some patients with bullous pemphigoid initially present with persistent urticarial lesions that subsequently convert to bullous eruptions. In some patients, urticarial lesions are the sole manifestations of the disease. In a report from China, about 30% of bullous pemphigoid patients were recorded with initial nonbullous forms of clinical presentation, such as erythema, papules, and plaques.^[55]
• Nodular form of bullous pemphigoid: 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 of bullous pemphigoid: In childhood-onset bullous pemphigoid associated with vaccination, the bullous lesions predominantly affect the palms, the soles, and the face.
• Infant form of bullous pemphigoid: For the infant patients affected by bullous pemphigoid, the blisters tend to occur frequently on the palms, soles, and face, affecting the genital areas rarely. Sixty percent of these infant patients have generalized blisters.^[1]

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Laboratory Studies

To establish a diagnosis of bullous pemphigoid, the following tests should be performed: histopathologic analysis from the edge of a blister and DIF studies on normal-appearing perilesional skin.^[2] 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

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 bullous pemphigoid and may be seen in cicatricial pemphigoid and epidermolysis bullosa acquisita. Bullous pemphigoid 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 bullous pemphigoid, 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. See the image below.

View Image

Direct immunofluorescence study performed on a perilesional skin biopsy specimen from a patient with bullous pemphigoid detects a linear band of immun....

Indirect immunofluorescence

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 bullous pemphigoid 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. See the image below.

View Image

Indirect immunofluorescence study performed on salt-split normal human skin substrate with the serum from a patient with bullous pemphigoid detects im....

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Other Tests

Experimental procedures available in research laboratories include direct and indirect immunoelectron microscopy, immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA), as follows:

• 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^[57] : 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 bullous pemphigoid 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.^[58] ELISA kits for testing bullous pemphigoid 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.^[59] 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 bullous pemphigoid.
• Immunohistochemistry: If freshly frozen tissue is not available for direct immunofluorescence microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone, for the confirmation of the diagnosis.^[60]

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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 bullous pemphigoid).

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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.

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Consultations

Treatment of patients with bullous pemphigoid 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.

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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.^[61]

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).

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Activity

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

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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 bullous pemphigoid have failed to detect an increased incidence of malignancy in patients with bullous pemphigoid 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. Associated neurodegenerative disease may be antibody-mediated.^[62]

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Medication Summary

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). Evidence suggests that strong topical corticosteroid treatment may achieve disease control while avoiding systemic adverse effects from systemic corticosteroids.^{[4, 3, 63, 64]} Omalizumab has been used as a corticosteroid-sparing agent.^[65]

Initial treatment with doxycycline was found to be effective and was associated with a lower incidence of adverse effects compared with prednisone.^{[5, 6, 7]}

Proper treatments of bullous pemphigoid depend on the severity of the disease. For localized disease, topical steroids plus the systemic anti-inflammatory (tetracycline and nicotinamide) may be sufficient. Effects of monotherapy with nicotinamide are unknown. For more severe cases, systemic steroids along with immunosuppressives may be needed to control the disease. If the disease is difficult to control, consider treatment with an anti-CD20 antibody (rituximab), which is relatively specific in targeting the antibody-producing B cells.^{[66, 67, 68, 69, 70, 71, 72, 73, 74]}

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Prednisone (Deltasone)

• Dosing, Interactions, etc.

Clinical Context:  Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. When taken orally, it is used alone or in conjunction with other immunosuppressive agents for treating bullous pemphigoid.

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Tetracycline (Sumycin)

• Dosing, Interactions, etc.

Clinical Context:  Although an antibiotic, tetracycline has proven effective in some cases of bullous pemphigoid either alone or in conjunction with niacinamide (2 g/d). Efficacy may be due to anti-inflammatory properties.

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Clobetasol (Temovate)

• Dosing, Interactions, etc.

Clinical Context:  Clobetasol is a class I superpotent topical steroid; it suppresses mitosis and increases the synthesis of proteins that decrease inflammation and cause vasoconstriction. It is useful in treating localized bullous pemphigoid or in conjunction with low-dose systemic corticosteroids to treat the generalized disease.

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Class Summary

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.

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Azathioprine (Imuran)

• Dosing, Interactions, etc.

Clinical Context:  Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of lymphocytes. It is for use alone or in conjunction with prednisone.

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Class Summary

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.

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Rituximab (Rituxan)

• Dosing, Interactions, etc.

Clinical Context:  Rituximab is a genetically engineered chimeric murine/human monoclonal antibody against human CD20, a molecule present in normal and malignant B lymphocytes. It is described in case reports as a promising biological treatment for B-lymphocyte–mediated diseases (eg, pemphigus vulgaris).

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