Bullous pemphigoid (BP) represents the most common autoimmune subepidermal blistering disease. BP typically affects the elderly and is associated with significant morbidity. It has usually a chronic course with spontaneous exacerbations. The cutaneous manifestations of BP can be extremely protean. While diagnosis of BP in the bullous stage is straightforward, in the non-bullous stage or in atypical variants of BP signs and symptoms are frequently non-specific with eg, only itchy excoriated, eczematous, papular and/or urticarial lesions that may persist for several weeks or months. Diagnosis of BP critically relies on immunopathologic examinations including direct immunofluorescence microscopy and detection of serum autoantibodies by indirect immunofluorescence microscopy or BP180-ELISA.
Bullous pemphigoid (BP) belongs to the group of autoimmune subepidermal blistering diseases, which are characterized by an autoantibody response directed against distinct components of the dermoepidermal junction of skin and adjacent mucous membranes. Besides BP, this group, which has overlapping clinical and immunopathologic features, also comprises pemphigoid gestationis (also called gestational pemphigoid), mucous membrane pemphigoid, linear IgA disease, anti-p200/laminin γ1 pemphigoid, and epidermolysis bullosa acquisita.
Pemphigoid diseases were first differentiated from pemphigus in 1953 by Lever who described intraepidermal split formation and loss of cell adherence between keratinocytes (acantholysis) as the histopathologic hallmark of pemphigus, whereas he coined the term pemphigoid for conditions in which a subepidermal split formation was typically present. A decade later, Jordon and colleagues showed that patients with BP had tissue-bound and circulating autoantibodies directed against the dermoepidermal junction. Further milestones in the understanding of BP included the immunochemical characterization of the hemidesmosomal target proteins BP180 (also called BPAG2 or type XVII collagen) and BP230 (BPAG1-e), the cloning of their genes, and the demonstration that autoantibodies to BP180 are pathogenic.
Epidemiology
The incidence of BP has been estimated at between 4.5 and 14 new cases per million per year. In a recent prospective study encompassing the entire Swiss population, the incidence was found to be 12.7 new cases per million per year. These data are consistent with a recent prospective study in Lower Franconia, a well-defined region in southern Germany, where the incidence of BP was estimated to be 13.4/1 million/y. A higher incidence of 42.8/1 million/y has recently been reported in Great Britain based on a data registry established on the general practitioner level. However, the British study, in which the immunopathologic criteria used were not specified, did not differentiate the various pemphigoid diseases and most likely also included bullous drug eruptions. In Lower Franconia, Germany, and Great Britain the incidence of BP has considerably increased within the last 10 years (twofold and 4.8-fold, respectively), an observation that may be related to either the increasing age of the general population or a better knowledge of the disease with proper diagnosis.
BP is probably the only autoimmune diseases of which the incidence increases with age. BP is typically a disease of the elderly and its diagnosis is usually made in patients aged between 75 and 81 years. In the population older than 80 years of age, the incidence is 150 to 180 new patients/1 million/y.
Clinical features
The name BP itself is a pleonasm. Pemphigoid is derived from Greek and means a form of blister (pemphix, blister, and eidos, form). Hence, from a purely etymologic point of view, the adjective bullous should not be added to designate the blistering in pemphigoid. However, the spectrum of clinical presentations is extremely broad ( Boxes 1 and 2 ).
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Papular and/or urticarial lesions
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Eczematous lesions
- •
Prurigo-like lesions
- •
Excoriations, hemorrhagic crusts
- •
Localized vesicles or erosions
- •
Dyshidrosiform pemphigoid
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Intertrigo-like pemphigoid
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Prurigo-nodularis-like pemphigoid
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Papular pemphigoid
- •
Lymphomatoid papulosis–like
- •
Vesicular/eczematous pemphigoid
- •
Erythrodermic pemphigoid
- •
Localized forms
- ○
pretibial
- ○
peristomal
- ○
umbilical
- ○
stump pemphigoid
- ○
on paralyzed body sites
- ○
on irradiated/traumatized body sites
- ○
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Brunsting-Perry form (variant of cicatricial pemphigoid)
Characteristically, BP is an intensely pruritic eruption with widespread blister formation. In this bullous stage, vesicles and bullae develop on apparently normal or erythematous skin together with urticated and infiltrated plaques with an occasionally annular or figurate pattern ( Fig. 1 ). The blisters are tense with a clear, sometimes hemorrhagic, exudate; the Nikolsky sign is negative. Pruritus, which may be invalidating, is almost constantly present. Blisters are typically symmetrically distributed and may persist for several days, leaving eroded and crusted areas. Predilection sites involve the flexural aspects of the limbs and abdomen. In our own prospective Swiss cohort of patients encompassing 164 patients with BP for a 2-year period, the clinical presentation at time of diagnosis consisted of typical blisters localized on the trunk and on the extremities in about 80% of cases. In the intertriginous spaces, vegetating plaques may occur, and oral lesions develop in 10% to 20% of cases. The mucosae of eyes, nose, pharynx, esophagus, and anogenital areas are rarely affected (reviewed in Refs. ).
However, before the development of tense generalized blisters, BP is typically preceded by a prodromal nonbullous phase. In this stage, diagnosis is difficult. Mild to intractable pruritus, alone or in association with excoriated, eczematous, popular, and/or urticarial lesions are found that may persist for several weeks or even months (see Box 1 ; Fig. 2 ). These unspecific skin findings may remain the only signs of the disease. In this same context, several clinical variants of BP (see Box 2 ) (reviewed in Ref. ) have been described with a variety of different denominations, such as prurigo nodularis–like, prurigo-like, erythrodermalike, ecthyma gangrenosum–like, intertrigolike, and toxic epidermolysis–like lesions. Localized forms have been described confined to areas affected by radiotherapy, surgery, trauma, and burns, as well as lesions limited around stomata, hemodialysis fistulae, the pretibial ( Fig. 3 ) or umbilical area, the palmoplantar region (mimicking dyshidrotic eczema), and the genital area.
Clinical features
The name BP itself is a pleonasm. Pemphigoid is derived from Greek and means a form of blister (pemphix, blister, and eidos, form). Hence, from a purely etymologic point of view, the adjective bullous should not be added to designate the blistering in pemphigoid. However, the spectrum of clinical presentations is extremely broad ( Boxes 1 and 2 ).
- •
Papular and/or urticarial lesions
- •
Eczematous lesions
- •
Prurigo-like lesions
- •
Excoriations, hemorrhagic crusts
- •
Localized vesicles or erosions
- •
Dyshidrosiform pemphigoid
- •
Intertrigo-like pemphigoid
- •
Prurigo-nodularis-like pemphigoid
- •
Papular pemphigoid
- •
Lymphomatoid papulosis–like
- •
Vesicular/eczematous pemphigoid
- •
Erythrodermic pemphigoid
- •
Localized forms
- ○
pretibial
- ○
peristomal
- ○
umbilical
- ○
stump pemphigoid
- ○
on paralyzed body sites
- ○
on irradiated/traumatized body sites
- ○
- •
Brunsting-Perry form (variant of cicatricial pemphigoid)
Characteristically, BP is an intensely pruritic eruption with widespread blister formation. In this bullous stage, vesicles and bullae develop on apparently normal or erythematous skin together with urticated and infiltrated plaques with an occasionally annular or figurate pattern ( Fig. 1 ). The blisters are tense with a clear, sometimes hemorrhagic, exudate; the Nikolsky sign is negative. Pruritus, which may be invalidating, is almost constantly present. Blisters are typically symmetrically distributed and may persist for several days, leaving eroded and crusted areas. Predilection sites involve the flexural aspects of the limbs and abdomen. In our own prospective Swiss cohort of patients encompassing 164 patients with BP for a 2-year period, the clinical presentation at time of diagnosis consisted of typical blisters localized on the trunk and on the extremities in about 80% of cases. In the intertriginous spaces, vegetating plaques may occur, and oral lesions develop in 10% to 20% of cases. The mucosae of eyes, nose, pharynx, esophagus, and anogenital areas are rarely affected (reviewed in Refs. ).
However, before the development of tense generalized blisters, BP is typically preceded by a prodromal nonbullous phase. In this stage, diagnosis is difficult. Mild to intractable pruritus, alone or in association with excoriated, eczematous, popular, and/or urticarial lesions are found that may persist for several weeks or even months (see Box 1 ; Fig. 2 ). These unspecific skin findings may remain the only signs of the disease. In this same context, several clinical variants of BP (see Box 2 ) (reviewed in Ref. ) have been described with a variety of different denominations, such as prurigo nodularis–like, prurigo-like, erythrodermalike, ecthyma gangrenosum–like, intertrigolike, and toxic epidermolysis–like lesions. Localized forms have been described confined to areas affected by radiotherapy, surgery, trauma, and burns, as well as lesions limited around stomata, hemodialysis fistulae, the pretibial ( Fig. 3 ) or umbilical area, the palmoplantar region (mimicking dyshidrotic eczema), and the genital area.
Trigger factors and associated diseases
Several triggers have been implicated in the disease onset of individual patients, including trauma, burns, radiotherapy, and ultraviolet radiation. In addition, various autoimmune disorders, psoriasis, and neurologic disorders have also been described in association with BP. A large variety of drugs have been anecdotally reported to induce BP. A weak association with aldosterone antagonists and neuroleptics was found and, most recently, with spironolactone and phenothiazines with aliphatic side chains. Based on these data, the use of latter drugs should be carefully evaluated in BP. In 2 case-control studies including more than 1700 patients with BP and age-matched controls in Sweden and Japan, a low association with gastric cancer was identified in the Japanese cohort. The previously described higher incidence of malignancies in patients with BP was probably biased by the lack of appropriate age-matched controls and the intensive work-up of affected patients in an hospital setting. Nevertheless, patients who develop BP at less than 60 years of age may be at higher risk for an underlying malignancy. We usually perform an age-related cancer screen based on patient’s history and clinical examination without a systematic and extensive cancer screening.
Several autoimmune disorders, such as rheumatoid arthritis, Hashimoto thyroiditis, dermatomyositis, lupus erythematosus, and autoimmune thrombocytopenia, have been reported in BP. However, a case-control study did not find any increased risk for autoimmune disorders in BP, but a genetically determined susceptibility to develop autoimmune diseases is likely. BP has also been found in association with certain inflammatory dermatoses, such as psoriasis and lichen planus ; a statistically significant link has not been provided. It is conceivable that the inflammatory process at the dermoepidermal junction in these disorders raises a secondary immune response leading to autoimmunity against the target antigens of BP (epitope-spreading phenomenon).
Most recently, the association between BP and neurologic disorders has been highlighted, such as stroke (odds ratio 2.1), Parkinson disease (odds ratio 3.0 and 2.2), major cognitive impairment (odds ratio 2.2), psychiatric disorders such unipolar and bipolar disorders (odds ratio 5.3), epilepsy (odds ratio 1.7), and most strongly with multiple sclerosis (odds ratio 6.7 and 10.7). These findings are particularly intriguing because some evidence has been provided suggesting that both antigens BP180 and BP230 are expressed in the central nervous system, and mice with either target disruption of or inherited mutations in the dystonin (DST) gene encoding for various isoforms of BPAG1 (including the epithelial isoform BP230/BPAG1-e) develop severe dystonia and sensory nerve degeneration.
Target antigens
In BP, autoantibodies recognize BP180 (also known as type XVII collagen or BP antigen 2) and BP230 (also known as BPAG1-e or BP antigen 1). These proteins are components of junctional adhesion complexes called hemidesmosomes, which are expressed in stratified and complex epithelia, such as skin, mucous membranes, and the ear, nose, and throat area. BP180 is a transmembrane glycoprotein of about 1500 amino acids. Ultrastructurally, it spans the lamina lucida before kinking back from the lamina densa into the lamina lucida (reviewed in Refs. ). The juxta-membrane domain of the extracellular portion of BP180 called NC16A was identified as the immunodominant region of BP180 in BP. BP180 interacts with the β4 chain of α6β4 integrin, plectin, BP230, and most likely with laminin 332 ). It provides a structural link between the intermediate filaments of the cytoskeleton and dermal collagen fibers. The importance of BP180 for the structural integrity of the skin is attested to by the observation that pathogenic mutations in its gene, COLXVII, lead to nonlethal junctional epidermolysis bullosa.
In contrast, BP230 is an intracellular constituent of the hemidesmosomal plaque and belongs to the plakin family of cytolinkers. Its globular C-terminal domain mediates the anchorage of keratin filaments to the cell membrane. Targeted inactivation of the DST gene encoding BP230 in mice resulted in mild skin fragility. Unexpectedly, affected mice developed neurologic defects with sensory neuron degeneration. The phenotype was identical to those observed in mice suffering from dystonia musculorum, with a spontaneous mutation in the so called DST gene. Better understanding of the phenotype of these animals has led to characterization of several tissue-specific isoforms of BP230, including at least a neuronal and a muscle-specific variant. These findings, together with the recently highlighted increased association between BP and neurologic disorders, may suggest that autoimmunity to BP230 is involved in the development of neurologic diseases. Recently, mutations in the DST gene have been identified in a patient with epidermolysis bullosa exhibiting mild, localized blistering.
Diagnosis
Diagnosis of BP is based on a combination of clinical features and immunopathologic findings ( Fig. 4 ). In atypical and nonbullous variants, diagnosis of BP critically relies on the findings of direct immunofluorescence (IF) microscopy together with the characterization of the specificity of circulating autoantibodies and/or findings from other approaches ( Fig. 4 ).
Clinical Criteria
The typical patient with BP is older than 75 years and presents with a pruritic eczematous, urticarial eruption with or without frank blistering. Mucous membranes and the face and neck region are usually not affected. In many patients, there are simply excoriated lesions. Knowledge of the wide spectrum of clinical presentations and atypical variants is important to consider the diagnosis of BP. Vaillant and colleagues showed that the diagnosis of BP can be made with high specificity and sensitivity in patients with linear immunoglobulin G (IgG) and/or C3 deposits along the dermoepidermal junction when 3 of the 4 clinical criteria are present: age greater than 70 years, absence of atrophic scars, absence of mucosal involvement, and absence of predominant bullous lesions on the neck and head.
Histopathology and Immunohistochemistry
Histopathology is not essential for the diagnosis of BP. Findings may be either typical or suggestive, or at least useful, for the differential diagnosis. When BP is suspected, the biopsy specimen should ideally include a macroscopically visible vesicle, a bulla, or at least the edge of a larger bulla. Light microscopy studies of an early bulla typically reveal a subepidermal blister formation with a superficial dermal inflammatory infiltrate rich in eosinophils ( Fig. 5 ) In early nonbullous phases, subepidermal clefts and eosinophilic spongiosis can be found. Recently, immunohistochemical studies have suggested that the detection of C3d deposits at the dermoepidermal junction in formalin-fixed tissue is useful for the diagnosis.
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