Bullous pemphigoïd

(Ref. Pathology of the skin, PH McKee, 3rd Ed. Elsevier-Mosby)

Clinical Features

Bullous pemphigoid is not a single disease entity. Rather, there are many subtypes, which have been classified into primary cutaneous and mucosal variants and into generalized and localized forms.

Generalized cutaneous pemphigoid

Bullous pemphigoid (BP) is the most frequently encountered autoimmune bullous dermatosis with an annual incidence of 6.6 new cases per one million of the population. Any age group may be affected, but the generalized variant demonstrates a predilection for the later years of life, showing a maximum incidence in the seventh decade and over. Rarely, however, children and even infants may be affected. The disease is associated with a worldwide distribution and shows no racial propensity. There are no significant human leukocyte antigen (HLA) associations and the sex incidence is approximately equal.

Prodromal events are numerous and include erythematous, urticarial and, rarely, eczematous phases. Erythroderma either preceding the bullous phase or occurring simultaneously is a very rare manifestation (erythrodermic pemphigoid). Similarly, patients may present with a history of generalized pruritus in the absence of visible skin lesions (pruritic pemphigoid). In such circumstances, immunofluorescence investigations are essential to establish the correct diagnosis.

The characteristic lesions of established disease are tense and often intact blisters arising on normal or erythematous skin. They may measure up to several centimeters in diameter and are typically dome-shaped . Often they contain clear or bloodstained fluid. Any area of the body may be affected, but the blisters are most commonly located about the lower abdomen, the inner aspect of the thighs and on the flexural surfaces of the forearms, the axillae and groins. Grouping of lesions as seen in dermatitis herpetiformis is not usually a feature and symmetry is characteristically absent. A cluster of jewels appearance of new blisters arising at the edge of resolving lesions as seen in linear IgA disease may, however, occasionally be a feature of bullous pemphigoid . The lesions are often pruritic and a burning sensation is sometimes a feature. Nikolsky's sign is usually negative. In contrast to cicatricial pemphigoid, generalized bullous pemphigoid is not associated with scarring.

Reported mucosal involvement (frequently as ulcers) is highly variable ranging from 8 to 58%. In a recent series of 115 patients, 24% had oral involvement and 7% had genital lesions. Lesions are found most often on the palate, the checks, lips and tongue . Other sites less commonly involved include mucosae of the nose, pharynx, conjunctiva and rarely the urethra and vulva . In contrast to cicatricial pemphigoid, mucosal involvement in generalized bullous pemphigoid is not associated with scarring.

Although bullous pemphigoid bas been reported in association with a variety of internal malignancies, this may just be coincidental, merely reflecting the age incidence of these two diseases. In a series of almost 500 patients from Sweden, no increased incidence of cancer was observed. More recent studies, however, have shown that there may be a positive correlation between internal malignancy and seronegative bullous pemphigoid patients.

Generalized bullous pemphigoid is a serious condition with a significant mortality ranging from 10 to 20%. Since the advent of steroid therapy and immunosuppressive agents, patients are more at risk of developing severe iatrogenic disorders than of dying from their disease .

Clinical variants of generalized pemphigoid

Urticarial bullous pemphigoid presents with large persistent erythematous plaques, which sometimes adopt an annular or gyrate peripheral comportment . Rarely small vesicles are also to be found.

Vesicular pemphigoid (case 052044) is a rare clinical variant in which the cutaneous manifestations show a striking overlap with dermatitis herpetiformis. Patients present with numerous small tense vesicles that may be symmetrical, intensely pruritic and therefore associated with conspicuous excoriation.

Polymorphic pemphigoid is a somewhat confusing entity, which is similar to vesicular pemphigoid, but probably shows overlap with linear IgA disease. Patients present with burning and itching lesions predominantly affecting the extensor aspects of the limbs, back and buttocks. Symmetry, grouping and a polymorphic clinical appearance of papules, vesicles and variably sized bullae emphasize similarity to dermatitis herpetiformis. It has been suggested that polymorphic pemphigoid is not an entity sui generis, but represents a pot-pourri of conditions including vesicular pemphigoid, linear IgA disease and mixed subepidermal bullous disease in which patients show both linear IgG and linear IgA or dermal papillary granular IgA on direct immunofluorescence.

Pemphigoid vegetans is an exceedingly rare vegetative intertriginous variant that may be associated with chronic inflammatory bowel disease. Fewer than 10 cases have been documented. Patients present with vegetative, crusted purulent and sometimes eroded lesions in the groins, axillae, neck, hands, eyelids, inframammary and perioral regions . Vesicles and bullae may also be evident. The etiology of the vegetative lesions is unknown.

Seborrheic pemphigoid is a variant in which the clinical features are suggestive of pemphigus erythematosus.

Pemphigoid nodularis represents the extremely rare association of lesions of bullous pemphigoid with intensely pruritic papules and nodules of nodular prurigo predominantly affecting the trunk and extremities . Exceptionally, patients may show immunofluorescent evidence of bullous pemphigoid in the absence of clinical blistering. The cause of this unusual phenomenon is unknown although in some patients at least, chronic scratching probably damages the basement membrane region with exposure of bullous pemphigoid antigens. There is a female predilection (2: 1). The age range of this variant extends from 24 to 80 years but, as with classical bullous pemphigoid, the majority of patients are elderly.

Dyshidrosiform pemphigoid is a rare variant of pemphigoid in which patients develop 1-2 mm, tense 'sago-grain-like' vesicles on the palms and soles resembling dyshidrosiform dermatitis (pompholyx). Lesions may be localized, or precede or occur simultaneously with generalized disease.

Childhood pemphigoid exhibits lesions that are similar to their adult counterparts, but there is some tendency for lesions to be localized around the face, lower trunk, thighs and genitalia, reminiscent of linear IgA disease in childhood . Similarly, a 'cluster of jewels' appearance is sometimes evident. Palmar, plantar and oral lesions are often present and may be the sole site of involvement in infants . The mucous membranes may be affected but scarring is absent. A number of children with primary localized vulval lesions have also been described . This latter is of particular clinical importance since it may be mistaken for evidence of sexual abuse. Childhood pemphigoid has a good prognosis and, as in adults, is usually self‑limiting. Although generally the etiology is unknown, in some infant cases there appears to be a relationship to prior vaccination or immunization.

Localized cutaneous pemphigoid

Although classical bullous pemphigoid not uncommonly presents initially as localized lesions that after a few months generalize, occasional patients present with localized blisters that do not subsequently disseminate (localized bullous pemphigoid).Traditionally this group has been subdivided into two variants:

• Brunsting-Perry pemphigoid which predominantly affects the head and neck and is associated with scarring

• localized cutaneous non-scarring bullous pemphigoid (Eberhartinger and Niebauer variant) which predominantly affects the lower legs (in particular the pretibial region) of females.

The former variant is considered in the section on cicatricial pemphigoid. Although the latter non-scarring cutaneous form particularly affects the lower legs, it may also present at a variety of other sites including forearms and hands, breasts, chest, buttocks and umbilicus. Lesions in localized bullous pemphigoid may be related to trauma. This variant shows a peak incidence in the sixth decade. As with generalized bullous pemphigoid, patients present with tense sometimes hemorrhagic bullae that arise on normal or erythematous appearing skin. Localized cutaneous non-scarring bullous pemphigoid is generally associated with a good prognosis.

Mucosa pemphigoid desquamative gingivitis

Localized oral pemphigoid is a recently described variant of desqua­mative gingivitis. The latter, of multifactorial etiology by definition, affects the marginal and attached gingivae. It shows a female predominance (9:1) and presents most frequently in the middle aged. Desquamative gingivitis may also be a manifestation of lichen planus, cicatricial pemphigoid and pemphigus. The diagnosis of localized oral pemphigoid depends upon the presence of a linear band of immuno­reactants at the epithelial basement membrane region on direct immunofluorescence. Clinical features include erythema, edema, erosions and ulcers. The lesions are non‑scarring. Bullous pemphigoid­ associated desquamative gingivitis may remain confined to the gingiva (the localized oral pemphigoid type), but approximately equal propor­tions of patients go on to develop full‑blown cicatricial pemphigoid.

 

Pathogenesis and histological features

The histological features of bullous pemphigoid depend to some extent upon the age of the lesion biopsied. Early erythematous and urticarial lesions most often show upper dermal edema associated with a perivascular lymphohistiocytic infiltrate accompanied by usually conspicuous eosinophils . Eosinophilic spongiosis is sometimes evident and occasionally, if eosinophils are present in sufficient numbers, flame figures may be a feature. Mild interface changes characterized by basal cell hydropic degeneration can be seen in early or prodromal lesions.

If the biopsy is taken from an established blister, the changes are most often those of an inflammatory (cell-rich) variant. The blister, which is subepidermal, is typically unilocular and covered by attenuated epithelium . In early lesions the roof epidermis may appear unaffected or show occasional to even confluent necrotic basal keratinocytes. The blister contents include coagulated serum, fibrin strands and large numbers of inflammatory cells including conspicuous eosinophils . Variable numbers of neutrophils may be present.

A typical finding in bullous pemphigoid is retention of the dermal papillary outline (festooning) which project like sentries into the vesicle cavity . The underlying dermis is inflamed and usually shows widespread severe edema. An infiltrate of eosinophils and mononuclears surrounds the blood vessels and extends between the adjacent collagen bundles. Leukocytoclasis is not seen and features of vasculitis are not present. The adjacent papillary dermis is often edematous and, very occasionally, eosinophil microabscesses are a feature . Exceptionally rarely, neutrophil microabscesses may be seen (see vesicular pemphigoid), raising diagnostic confusion with dermatitis herpetiformis. Eosinophilic spongiosis is also sometimes evident in the adjacent epidermis.

Cell-poor (non-inflammatory) (case 051873) features are occasionally seen if biopsies are taken from lesions arising on non-inflamed skin . Because inflammatory cells are sparse or, exceptionally, even absent in such cases, problems with the differential diagnosis may be considerable, particularly if adequate clinical information and immunofluorescence findings are not available.

Vesicular/polymorphic pemphigoid is characterized by subepidermal vesicles with features suggesting either bullous pemphigoid or dermatitis herpetiformis or both . Neutrophil dermal papillary micro­abscesses, which are often regarded as pathognomonic of dermatitis herpetiformis, may be seen in this variant .

Pemphigold vegetans is characterized by acanthosis, often with pseudoepitheliomatous hyperplasia, papillary dermal edema with subepidermal clefting or frank vesicle formation and an inflammatory cell infiltrate of eosinophils, mononuclears and occasional neutrophils.

Pemphigold nodularis exhibits pruriginous lesions which are characterized by hyperkeratosis, acanthosis, and which may amount to pseudoepitheliomatous hyperplasia and dermal fibrosis . In the dermis a perivascular infiltrate of lymphocytes and eosinophils is present. The blisters show typical features of bullous pemphigoid .

Localized non-scarring (pretibial) bullous pemphigoid usually shows the histology of cell-rich bullous pemphigoid. Localized oral pemphigoid is typified by a subepithelial vesicle (when present) and cannot be distinguished histologically from oral involvement in cicatricial pemphigoid.

Ultrastructurally, in early lesions of bullous pemphigoid, the dermoepidermal cleavage is seen to have developed between the plasma membrane of the basal keratinocyte and the lamina densa, through the lamina lucida.The lamina densa is therefore located along the floor of the blister. Degenerative changes in the basal cells, including villous process formation, mitochondrial swelling and cytoplasmic vacuolization,are frequently found. Hemidesmosomes may appear reduced in number or may even be absent. Intercellular edema between adjacent basal cells is a common finding. If specimens are examined froin established inflammatory lesions the lamina densa may be fragmented or entirely absent.

Bullous pemphigoid is characterized by a linear anti-basement membrane zone antibody using the indirect immunofluorescent technique. Although IgG is invariably present (and most commonly of the IgG4 subclass), other immunoglobulins, including IgE, may be represented. Such antibodies are present in around 75-80% of patients. Sensitivity can however be increased to 90% if split skin is used as substrate. Although the antibody titer does not correlate with disease activity, more recently it has been shown that serum antibodies to BP180 NC16A (a subunit of the bullous pemphigoid antigen) do correlate with disease activity.

Split skin indirect studies are essential in the investigation of a patient in whom a linear IgG anti-basement membrane antibody bas been detected. Such antibodies are also characteristic of cicatricial pem­phigoid, herpes (pemphigoid) gestationis, inflammatory epidermolysis bullosa and bullous systemic lupus erythematosus. The antibodies in pemphigoïd variants (with the exception of the anti-pl05 and anti-p2OO variants discussed below) bind to the epidermal side of 1 M NaCl-split skin whereas those of inflammatory epidermolysis bullosa and bullous systemic lupus erythematosus bind to the floor.

In those patients in whom indirect fluorescent studies are not available, similar information may be obtained through the localization of lamina densa constituents such as type IV collagen or laminin-1 using paraffin-embedded direct immunoperoxidase techniques. In pemphigoid, the staining is found along the floor of the blister whereas in inflamma­tory epidermolysis bullosa and bullous systemic lupus erythematosus, it is located along the roof.

Bullous pemphigoid antibodies are capable of complement fixation in as many as 75% of patients. Most of complement fixation in bullous pemphigoid antibody resides in the IgG4 subclass.

Linear, in vivo-bound immunoglobulin at the epidermodermal interface on direct immunofluorescence is present in 90% or more of patients. Complement (C3) is also usually present and is sometimes the sole immunoreactants. Other immunoglobulin subclasses including IgM, IgA and IgE may be detected occasionally. In addition to C3, the other components of the classical complement pathway, in particular C5b-9 (the membrane attack complex) and members of the alternative complement pathway, including properdin, factor B and B-IH-globulin, may also be identified. There is therefore evidence that both the classical and alternate complement pathways are. The classical involved in the pathogenesis of bullous pemphigoid complement pathway, however, predominates.

The immunofluorescence findings in erythematous, pruritic, urticarial and eczematous prodromal lesions and childhood, dyshidrosiform, vesicular, nodular and vegetans variants are similar to those seen in the conventional generalized disease. In polymorphic pemphigoid either linear IgG or IgA deposits may be identified along the basement membrane region. The serum may contain either IgG or IgA antibodies.

Immunofluorescence findings in localized cutaneous disease are variable. In some reports, patients show positive direct immunofluores­cence for IgG and C3 at the epidermodermal junction and a positive indirect immunofluorescent test for bullous pemphigoid antibody, while others may be positive for in vivo-bound complement, but negative on indirect examination. A recent series has shown that almost 70% of sera from patients with localized pemphigoid have circulating IgG antibodies.

By direct immunoelectron microscopy, the immunoreactants (IgG and C3) are located within the hemidesmosomal plaque and upper lamina lucida. Indirect immunoelectron microscopic studies show that the bullous pemphigoid antigen is most often detected intracellularly in the region of the cytoplasmic face of the hemidesmo­some.

The immunoelectron microscopic observations in childhood bullous pemphigoid, vesicular pemphigoid, polymorphic pemphigoid, pemphigoid nodularis, pemphigoid vegetans and localized pemphigoid, are identical to those of classical bullous pemphigoid.

Two principal bullous pemphigoid antigens are recognized by western blot and immunoprecipitation studies: one is 230 kD (BPAG1) and the other is approximately 180 kD (BPAG2). These represent distinct gene products.

BP230 maps to the short arm of chromosome 6, locus 6pll-12. It belongs to the plakin family and shows homology with plectin and the desmogleins. It is wholly intracellular and localizes to the hemidesmosome. BP230 is not involved in the early stages of the pathogenesis of blistering but is of importance as a secondary event.

BP180 is the major pathogenic antigen in bullous pemphigoid. It maps to the long arm of chromosome 10, locus lOq24.3. It is a transmembrane adhesion molecule comprising an intracytoplasmic N-terminal fragment, a transmembrane region and a collagenous extracellular C-terminal ectodomain. The latter constitutes part of the anchoring filament and distally merges with the lamina densa.The antibodies directed against BP180 in bullous pemphigoid most commonly react with a short extracellular non-collagenous locus NC16A (regions MCWO-MCW3) located within the upper lamina lucida proximal to the collagenous segment. Antibodies, however, may also target BP180 non-NC16A domains.

Between 50 and 90% of patients with generalized bullous pemphigoid have antibodies that react with BP230 and 35-50% have antibodies that react with BP180. If, however, patients sera are reacted with a BP180 NC16A domain recombinant protein, the yield for the latter is 100%.

Circulating antibodies against BP180 or BP230 have been also been defined in many of the other variants of bullous pemphigoid, including localized and vesicular forms, pemphigoid vegetans, erythrodermic pemphigoid and pemphigoid nodularis.

In childhood pemphigoid, the antibodies also react against these same antigens. In addition, there rarely may also be antibodies reacting with the linear IgA 120 kD antigen. The BP180 antigen is most often targeted and immunoblot analyses have shown that the antibodies react specifically with the NC16A domain as in adult patients. In some children at least, the IgG subclasses differ from adult disease, consisting of all IgG subclasses or IgG2 in isolation. IgE antibodies are not a feature of childhood disease.

More recently, two patients with a non-scarring, bullous pemphigoid­like illness characterized by neutrophil-rich subepidermal blisters resembling dermatitis herpetiformis and antibodies to a unique 105 kD protein so-called anti-pl05 pemphigoid have been documented. This antigen localizes to the dermal side of split skin on indirect immunofluorescence. Its precise nature has not yet been determined.

Anti-p200 pemphigoid is characterized by antibodies to a lower lamina lucida basement membrane antigen. Patients generally present with a non-scarring bullous pemphigoid-like illness although linear IgA disease-like and dermatitls herpetiformis-like variants have also been documented. The disease has also been described in association with psoriasis. With split skin indirect IMF, the antibodies bind to the floor of the blister cavity. With indirect immunoelectron microscopy, the antibodies bind to the lower lamina lucida. The identity of the 200 kD antigen bas yet to be determined but it is neither laminin nor type VII collagen.

Anti-p450 pemphigoid bas been documented in a single patient. The antigen, which bas been localized to the basal keratinocyte, belongs to the plectin family. Its precise nature has yet to be determined.

Exceptionally bullous pemphigoid may be associated with antiplectin antibody.

Bullous pemphigoid has been described following PUVA therapy for mycosis fungoides.

A mechanism for blister development in bullous pemphigoid has been proposed and is outlined as follows. Following antibody-antigen interaction and complement fixation, various chemo­tactic agents including C3a and C4a are produced. Mast cells degranulate under the influence of the latter or IgE, and release ECFA, NMW-NCF, ESM, histamine and enzymes. Eosinophils and neutrophils, so recruited, bind (possibly via C3b receptors) to the basement membrane region. By direct cytotoxic action (eosinophils are capable of antibody-dependent cellular cytotoxicity) or via released proteases, particularly elastase, damage at the basement membrane regions results in the development of a vesicle. Lymphocytes elaborate histamine-releasing factor (HRF), which increases mast cell degranu­lation and perpetuates the process. A broad range of cytokines are involved in this inflammatory reaction including interleukin (ILI, IL4, IL8, IL10, IL13, IL15 and interferon gamma (IFN,y).123 As yet their relative importance and time sequences are unknown.

Bullous pemphigoid is therefore a true autoimmune disease in which antigen-antibody reaction and complement fixation results in a characteristic and reproducible train of events, which is inevitably accompanied by the development of subepidermal blister formation. The etiology or initiator (other than those associated with drugs or PUVA rherapy, the minority) is unknown.

 

Differential diagnosis

The inflammatory cell-rich variant of bullous pemphigoid must be distinguished from other subepidermal blistering dermatoses in which a heavy inflammatory cell comportent is a typical finding. These include dermatitis herpetiformis, linear IgA disease, inflammatory epidermolysis bullosa acquisita and bullous systemic lupus erythematosus . Successful differentiation depends upon careful clinicopathological correlation and immunofluorescent studies. Split skin indirect immuno­fluorescence or lamina densa antigen mapping by type IV collagen or laminin-1 direct immunoperoxidase are essential to determine the level of the split. Although electron microscopy, immunoelectron microscopy and immunoprecipitation or western blotting provide definitive informa­tion, in the majority of cases, such techniques are not necessary.

The cell-poor variant of bullous pemphigoid has a very wide range of differential diagnoses including epidermolysis bullosa (congenital and acquired), porphyria cutanea tarda, bullous amyloidosis, bullosa diabeticorum and autolysis.