Bullous Pemphigoid

5/11/2009 · Kategori: Dermatology

Bullous Pemphigoid

Author: Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine

Introduction

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)^1,2 and horses (equine).³  BP has been found to occur in domestic cats (feline) and Yucatan minipigs (porcine).⁴

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.^5,6,7

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,⁸ porcine, and equine BP.³

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,⁸ pigs, and horses³ 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.⁹ 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.¹⁰ Furthermore, anti-BP180 NC16A domain autoantibodies purified from patients with BP are capable of inducing dermal-epidermal separation in cryosections of normal human skin.¹¹

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.¹²

Serum levels of autoantibodies against BPAg2 are reportedly correlated with disease activity in some studies.¹³ 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 integrin¹⁴ and laminin-5,¹⁵ 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.¹⁶

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.¹⁷ 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.¹⁸

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.¹⁹

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.²⁰

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.²¹

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.
• One puzzling finding, however, is the recent report of rising incidence of infant-onset BP.

Clinical

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.²²

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 an 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.
• Infant form: For the infant patients affected by BP, 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.²³

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 spreading²⁴
  • 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.²⁵
  • 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.
• IgE class autoantibodies
  • The higher level of IgE class of autoantibodies against BP180 was associated with more extensive skin lesions.
  • The higher level of IgE class of autoantibodies against BP230, however, was not associated with more extensive skin lesions.