Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid

INTRODUCTION — Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune subepithelial blistering diseases that most frequently arise in older adults and are characterized by the presence of cutaneous bullae and erosive mucosal lesions. Significant progress has been made in understanding the pathogenesis of these diseases. Multiple events, including the binding of immunoglobulins to basement membrane zone components, the subsequent activation of complement, and the migration of inflammatory cells into the subepithelial tissue, likely contribute to the clinical manifestations of bullous pemphigoid and MMP.

The epidemiology and pathogenesis of bullous pemphigoid and MMP will be reviewed here. The clinical features, diagnosis, and treatment of these disorders and greater detail on the ocular form of MMP (ocular cicatricial pemphigoid) are available separately. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Management and prognosis of bullous pemphigoid" and "Management of mucous membrane pemphigoid" and "Ocular cicatricial pemphigoid".)

CLASSIFICATION — Pemphigoid disorders, which include bullous pemphigoid, MMP, anti-laminin 332 pemphigoid (also known as anti-epiligrin cicatricial pemphigoid), pemphigoid gestationis, Brunsting-Perry pemphigoid, and anti-laminin gamma-1 (anti-p200) pemphigoid, are characterized clinically by the presence of inflammatory, blistering, and/or erosive mucocutaneous lesions and immunohistopathologically by subepithelial cleavage and immunoglobulin G (IgG) and/or complement deposits in a linear pattern at the epidermal basement membrane zone (picture 1A-B). The location of blistering and immunoglobulin deposition distinguishes pemphigoid disorders from pemphigus. In pemphigus, blister formation and antibody deposition occur within the epidermis/epithelium (picture 2A-B) [1]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

MMP is not a single disease, rather it represents a group of heterogeneous, chronic subepithelial blistering diseases that primarily affect mucosal surfaces [2]. Historically, because of the scarring sequelae that may develop clinically, the term cicatricial pemphigoid was ascribed to diseases now categorized as MMP.

Some authors also consider mucosal-predominant forms of linear IgA bullous dermatosis and epidermolysis bullosa acquisita as forms of MMP [2]. However, our preference is to consider these diagnoses as distinct disease entities. (See "Linear IgA bullous dermatosis" and "Epidermolysis bullosa acquisita".)

A table summarizing the major forms of pemphigoid and non-pemphigoid autoimmune blistering disorders is provided (table 1).

EPIDEMIOLOGY — Most of the data on the incidence of bullous pemphigoid are derived from European reports, in which studies documenting incidence rates of 4 to 22 cases per million individuals per year support the designation of bullous pemphigoid as an uncommon disorder [3-5]. The results of retrospective studies suggest that the incidence of bullous pemphigoid may be increasing [5-8]. One of the largest reported increases stems from a French, retrospective study that found that the annual incidence rate for bullous pemphigoid between 2000 and 2005 (22 cases per million inhabitants per year) was three times greater than the estimated incidence rate between 1986 and 1992 [5]. Multiple factors may be contributing to the increased incidence of this disease, including the aging population and associated increase in neurologic conditions (which may be pathogenically linked), increased use of drugs implicated in drug-induced disease, and an increase in the diagnosis of variant pemphigoid forms including localized bullous pemphigoid [7,8].

Bullous pemphigoid is considered the most common autoimmune blistering disorder in Europe. However, in locations such as Thailand and Malaysia, pemphigus may be more common [9,10].

Bullous pemphigoid is primarily a disease of older adults; the vast majority of cases occur in individuals over the age of 60 years and occurrence in children is rare [11-14]. In a retrospective study of 869 patients with bullous pemphigoid in the United Kingdom, the median patient age at the time of presentation was 80 years [15].

The increased risk of bullous pemphigoid with advancing age was illustrated in two European prospective studies that were based upon data collected in 2001 and 2002 [3,16]. In a German study, the estimated incidence rate in the general population was 13 cases per million individuals per year, but rose to 189 cases per million individuals per year among those over the age of 80 [16]. Similarly, a sharp rise in incidence was evident in a Swiss study in which the incidence of bullous pemphigoid increased from 12 cases per million individuals per year in the general population to 163 cases per million individuals among those over the age of 90 [3].

MMP is less common than bullous pemphigoid; in the German study cited above, the estimated incidence rate in the general population was two cases per million inhabitants per year [16]. Like bullous pemphigoid, MMP is most likely to occur in older individuals and is rare in children [11,17]. Patients with MMP most frequently are within the age range of 60 to 80 years [18].

Gender also may play a role in risk for bullous pemphigoid and MMP. Multiple studies have reported at least a slight female predominance in these disorders [3,9,19]. The reasons for this observation are unknown.

PATHOGENESIS — The mechanisms that lead to bullous pemphigoid and MMP are not fully understood, but most likely involve autoantibody-mediated damage to epithelial basement membrane zone, a complex structure that mediates adhesion, permeability, and cellular organization and differentiation (figure 1A-B) [20-23]. The binding of antibodies to antigens within the epithelial basement membrane zone stimulates a destructive inflammatory cascade that results in separation of the epidermis from the dermis in skin and epithelium from subepithelial tissue in mucous membranes with the formation of characteristic cutaneous and mucosal lesions. Innate immune cells producing interleukin 17 (IL-17) may be important in the maintenance and extent of disease [24].

Antigenic targets — Antibodies to several antigens have been identified as potential contributors to bullous pemphigoid and MMP.

Bullous pemphigoid — In bullous pemphigoid, autoantibodies against two principal hemidesmosomal proteins are strongly linked to clinical disease: bullous pemphigoid antigen 180 (BP180), a 180 kilodalton protein also known as bullous pemphigoid antigen 2 (BPAg2) and type XVII collagen, and bullous pemphigoid antigen 230 (BP230), a 230 kilodalton protein also referred to as bullous pemphigoid antigen 1 (BPAg1).

BP180 — Antibodies against BP180, a transmembrane protein that extends from the hemidesmosomal dense plaque in basal keratinocytes into the lamina densa of the basement membrane zone (figure 1A) [25], are present in the majority of patients with bullous pemphigoid. Antibodies against the noncollagenous extracellular domain of BP180 known as NC16A (the primary site for antibody binding in bullous pemphigoid) are detected via enzyme-linked immunosorbent assay (ELISA) in 80 to 90 percent of affected patients [21,26-31]. The production of antibodies to other epitopes of BP180 also occurs in bullous pemphigoid, and may have clinical significance. As an example, antibodies directed against epitopes in the C-terminal end of BP180 have been associated with the presence of mucosal disease [32,33].

An important role for antibodies against BP180 in bullous pemphigoid is supported by animal models in which the transfer of BP180 immunoglobulin (Ig)G antibodies resulted in the development of skin lesions that resemble bullous pemphigoid [34-36] (see 'Animal models' below). Additional support is derived from the observation that serum levels of antibodies against the NC16A epitope correlate with disease activity [37,38].

The predominant subclass of antibodies that react with the basement membrane zone in bullous pemphigoid is immunoglobulin G4 (IgG4) [39,40]. IgG4 antibodies also are present in the prodromal phase of bullous pemphigoid that often precedes cutaneous blistering [40]. IgG1 and IgG2 antibodies may be present in bullous pemphigoid but are less frequently detected than IgG4 antibodies. IgG3 antibodies are usually absent [39].

Although BP180 antibodies of the IgG class are most frequently detected in bullous pemphigoid, IgA and IgE BP180 antibodies also may be present [20,39-43]. The relevance of IgA antibodies in bullous pemphigoid remains uncertain. Cases in which a predominance of IgA basement membrane zone localization is detected actually may represent linear IgA bullous dermatosis (see "Linear IgA bullous dermatosis", section on 'Pathogenesis'). There is some evidence to support a pathogenic role for IgE basement membrane zone antibodies, including a small, retrospective study that identified an association with severe disease [37,44-48]. In addition, a study in which anti-BP180 NC16A serum IgE was detected in 47 of 117 patients with BP (40 percent) found a correlation between serum levels of these autoantibodies and disease activity [43].

Of note, antibodies against BP180 also occur in other subepidermal autoimmune blistering diseases. IgG BP180 antibodies may be detected in patients with MMP and characteristically develop in pemphigoid gestationis. (See 'Mucous membrane pemphigoid' below and "Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)

BP230 — BP230 is an intracellular hemidesmosomal protein in the plakin family that is found in basal keratinocytes (figure 1A). In conjunction with plectin, another hemidesmosomal plakin, BP230 links keratin intermediate filaments to hemidesmosomes [25]. Antibodies to BP230 are detected in approximately 60 to 70 percent of patients with bullous pemphigoid [20,42]. The primary site of antibody binding on BP230 is the globular C-terminal domain [20,42].

It is unclear whether BP230 antibodies have a pathogenic role in bullous pemphigoid or whether they occur as a secondary event related to keratinocyte injury [20,49]. Serum levels of antibodies against BP230 do not reveal consistent correlation with disease activity [50-53]. In addition, the intracellular location of BP230 likely limits access of BP230 antibodies to the antigen.

Nevertheless, there is a subset of pemphigoid patients with increased serum BP230 antibody levels and normal BP180 antibody levels [53,54]. This finding may be more common in patients with nonbullous pemphigoid, a variant characterized by the absence of bullae, compared with patients with classic bullous pemphigoid [54].

Mucous membrane pemphigoid — Antibodies against several basement membrane zone antigens have been detected in patients with MMP, some of which correlate with distinctive clinical features. The major basement membrane zone proteins targeted in MMP include (figure 1A) [2,55-57]:

●BP180 (C terminal domain)

●BP230

●Laminin 332 (also known as laminin 5 or epiligrin)

●Alpha-6 beta-4 integrin

●Type VII collagen

The precise location of antibody binding can have clinical relevance in MMP:

●Scarring – The site of antibody binding may account for the frequent development of scarring in MMP lesions, a feature that typically is not observed in bullous pemphigoid. In contrast to bullous pemphigoid, in which antibody binding occurs to epitopes located in hemidesmosomes and the upper lamina lucida, antibody-binding in MMP is primarily located in the lower lamina lucida and lamina densa [58]. This deeper location of antibody binding may increase the risk for scarring. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid'.)

●Sites of disease – Ocular involvement is associated with antibodies to the beta-4 integrin subunit of alpha-6 beta-4 integrin, whereas antibodies to the alpha-6 subunit have been linked to oral disease [59,60]. (See "Ocular cicatricial pemphigoid", section on 'Pathogenesis'.)

A systematic review with pooled analysis found statistically significant associations between the detection of autoantibodies against laminin 332 with ELISA and both pharyngo-laryngeal and oro-pharyngo-laryngeal involvement in patients with MMP [61]. However, publication bias may have contributed to this finding.

●Risk for associated malignancy – Antibodies to laminin 332, which are estimated to occur in approximately 25 percent of patients with MMP, are associated with an increased risk for internal malignancy [62]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Malignancy'.)

In addition to the specific epitope or epitopes targeted, the number and type of autoantibodies that bind to the basement membrane zone may be clinically relevant in MMP. Autoantibodies to multiple basement membrane antigens or multiple epitopes on BP180, as well as the combined presence of IgG and IgA basement membrane zone antibodies have been associated with severe disease [59,63].

Anti-p200 (laminin gamma-1) pemphigoid — Laminins are heterotrimers composed of one of five alpha chains, one of four beta chains, and one of three gamma chains. The laminins are named based on their polypeptide chain assortment [64]; for example, laminin 311 is composed of the laminin alpha-3, beta-1, and gamma-1 chains. At least 16 laminins are described of which at least three are important extracellular matrix glycoproteins in the basement membrane zone, laminin 311 (laminin 6), laminin 332 (laminin 5 or epiligrin), and laminin 551 (formerly known as laminin 10) [65].

Anti-p200 (laminin gamma-1) pemphigoid is a type of pemphigoid that clinically resembles bullous pemphigoid [66,67]. This type of pemphigoid is distinguished by the presence of antibodies to a 200 kilodalton protein that, in most patients, corresponds with the gamma-1 subunit of laminin 311 in the epithelial basement membrane zone (figure 1A) [66,68-70]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Anti-p200 (laminin gamma-1) pemphigoid'.)

Role of pathogenic antibodies — Antibody-mediated activation of the complement cascade by antibodies bound to specific antigens in the basement membrane zone has been proposed as a principal mechanism for lesion formation in bullous pemphigoid and MMP [20,21,71,72]. The activation of complement may stimulate the local recruitment of inflammatory cells that release proinflammatory mediators as well as proteases that directly damage the basement membrane zone [73,74]. In bullous pemphigoid, mast cells and eosinophils may contribute significantly to clinical disease [75-80].

Mechanisms other than complement-mediated pathways may also contribute to bullous pemphigoid and MMP. A case report describes a patient with nonbullous pemphigoid who was negative for BP180 antibodies but positive for BP230 and in whom direct and indirect immunofluorescence studies demonstrated deposition of only the IgG4 subclass of antibodies at the basement membrane zone [53]. IgG4 antibodies are incapable of activating complement, supporting a complement-independent mechanism for the development of bullous pemphigoid.

With respect to anti-p200 (laminin gamma-1) pemphigoid, an increasingly recognized form of pemphigoid [81], ex vivo and in vivo studies were unable to show pathogenic activity of laminin gamma-1 antibodies [82]. Such antibodies appear to be a useful biomarker for anti-p200 (laminin gamma-1) pemphigoid, but their pathogenic role is yet to be understood.

The acceptance of basement membrane zone antibodies as the exclusive cause of bullous pemphigoid is complicated by the observation that some patients with positive circulating basement membrane zone antibodies lack clinical signs of disease [83,84]. In one study, BP180, BP230, or both antibody levels determined by ELISA were increased in 5 out of 15 older adult patients with pruritus and no other clinical or laboratory evidence of bullous pemphigoid [85]. It is unclear whether these results represented the identification of a prodromal phase of bullous pemphigoid or coincidental findings unrelated to the disease.

Animal models — Studies utilizing animal models have contributed significantly to the understanding of the pathogenesis of bullous pemphigoid and MMP. The pathogenic role of BP180 antibodies is supported by animal models of bullous pemphigoid that indicate that IgG antibodies to a basement membrane zone antigen analogous to BP180 in the animal species are capable of activating complement and inducing features consistent with bullous pemphigoid, including blister development and mast cell degranulation [34-36]. Moreover, passive transfer experiments in which human BP180 antibodies are delivered to mice humanized with BP180 antigen demonstrate basement membrane separation that is dependent upon complement, neutrophils, and mast cells [86].

However, the observations that animal models of bullous pemphigoid primarily demonstrate neutrophil infiltration (similar to that seen in linear IgA disease), rather than eosinophil infiltration and eosinophil degranulation, which are characteristic of human bullous pemphigoid, indicate that pathogenic mechanisms in bullous pemphigoid remain incompletely understood [75,77,78]. It is likely that additional factors not present in the passive transfer models are responsible for eosinophil infiltration in humans. A murine model of bullous pemphigoid with IgE antibodies recapitulates the inflammatory infiltrate in pemphigoid more closely [87]. Additional study is necessary to define the pathogenic role that IgE plays in bullous pemphigoid [88].

Other factors — Although further study is necessary to elucidate the pathways that lead to bullous pemphigoid and MMP, genetic factors, environmental exposures, and the phenomenon of epitope spreading are considered potential contributory factors.

Genetics — Certain human leukocyte antigen (HLA) alleles may play a role in bullous pemphigoid and MMP. In MMP, increased prevalence of the HLA-DQB1*0301 allele is reported in multiple studies [89-92], and the same allele is associated with bullous pemphigoid in a small series of patients in the United States and Germany [90,93]. However, these findings may not be applicable to all populations, as this allele was not associated with bullous pemphigoid in two studies performed in Japanese and Chinese patients [94,95]. In the Japanese study, several other potential susceptibility alleles were identified [94].

The proposed mechanism through which certain HLA alleles might contribute to risk for bullous pemphigoid or MMP involves the facilitation of antigen presentation of basement membrane zone antigens to T cells [72]. Further studies are necessary to explore the role of genetic factors in the development of these diseases.

Infections and drugs — Autoimmune reactions triggered by exposure to infections or drugs may play a role in bullous pemphigoid and MMP. In theory, these disorders could occur as a result of cross-reactivity of antibodies that target infectious agents or drugs with antigens in the basement membrane zone. Although no specific infectious disorder has been definitively associated with pemphigoid, in a small case-control study, antibodies against hepatitis B, hepatitis C, Helicobacter pylori, Toxoplasma gondii, and cytomegalovirus were more prevalent among patients with bullous disease (pemphigus or bullous pemphigoid) [21].

The possibility that pemphigoid is a rare side effect of vaccination against infectious agents is raised by reports of more than 25 patients with BP and at least 1 patient with MMP that describe the development of pemphigoid shortly after vaccination [96,97]. However, a causal relationship between vaccination and pemphigoid is unconfirmed.

A variety of drugs have been associated with the development of bullous pemphigoid [98,99], although the strength of these associations is uncertain [100]. A listing of many of the reported agents is provided (table 2).

In particular, there is increasing support for an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the development of BP and MMP [101-106]. A case-control study of 82 patients with BP and diabetes and 328 age- and sex-matched controls with diabetes but without BP found an association between DPP-4 inhibitor intake and the development of BP (adjusted odds ratio [OR] 3.2, 95% CI 1.9-5.4) [107]. BP was associated with use of vildagliptin (adjusted OR 10.7, 95% CI 5.1-22.4) and linagliptin (adjusted OR 6.7, 95% CI 2.2-19.7), but not sitagliptin. Patients younger than 70 years and males exhibited the strongest associations between DPP-4 inhibitor use and BP. Mucosal involvement in BP was more common in DPP-4 inhibitor-exposed patients. Patients who discontinued DPP-4 inhibitors appeared to have better outcomes from standard BP therapy than those who continued DPP-4 inhibitor use.

Checkpoint inhibitors, including programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) blocking agents used for the treatment of cancer, constitute another class of drugs with pemphigoid as a dermatologic side effect [99,108]. Various theories have been put forth to explain the pathophysiology underlying immune-related adverse events with this therapy. Generally, it is believed to be related to the role that checkpoints play in maintaining immunologic homeostasis.

Epitope spreading — The term epitope spreading has been used to describe the induction of an autoimmune response against normally tolerated host antigens and epitopes as a consequence of the exposure of these antigens and epitopes during immune-mediated tissue inflammation [109]. Epitope spreading has been proposed as an explanation for cases in which pemphigoid occurred in the setting of other diseases. As examples, ocular cicatricial pemphigoid has developed following conjunctival inflammation due to Stevens-Johnson syndrome [110] and, in lichen planus pemphigoides (a variant of bullous pemphigoid), the onset of bullous lesions occurs weeks to months after the development of lichen planus [111]. Bullous pemphigoid also develops after radiation therapy possibly through exposure of basement membrane zone antigens in the course of the treatment [112]. (See "Ocular cicatricial pemphigoid", section on 'Pathogenesis' and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of bullous pemphigoid'.)

Spreading of the immune response against epidermal basement membrane zone antigens to or from similarly structured proteins in other body sites also may occur. The development of bullous pemphigoid in several renal transplant patients has been attributed to the concept that autoantibody formation against the glomerular basement membrane zone may have contributed to the development of bullous disease [113]. This phenomenon also has been proposed as a contributor to the observed link between bullous pemphigoid and certain neurologic disorders [114-118]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Neurologic disorders'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bullous pemphigoid".)

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●Basics topic (see "Patient education: Bullous pemphigoid (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune subepithelial bullous disorders that classically present with blistering and/or erosive cutaneous and mucosal lesions but also may present as urticaria, eczema, and/or pruritus (table 1). (See 'Classification' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

●Bullous pemphigoid and MMP primarily occur in the older population. Most patients affected by these disorders are over the age of 60 years. Bullous pemphigoid and MMP are rare in children. (See 'Epidemiology' above.)

●The clinical manifestations of bullous pemphigoid and MMP likely result from the destructive and inflammatory consequences related to antibody binding in the epithelial basement membrane zone in skin and mucous membranes. (See 'Pathogenesis' above.)

●Bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230) are two principal basement membrane zone antigens targeted by antibodies in patients with bullous pemphigoid (figure 1A). Although antibodies formed against BP180 are likely pathogenic, a pathogenic role for BP230 antibodies is uncertain. (See 'Bullous pemphigoid' above.)

●Multiple antigenic targets have been linked to MMP. Of note, antibodies against laminin 332 (also known as laminin 5 or epiligrin) are associated with an increased risk for malignancy, and antibodies against the beta-4 subunit of alpha-6 beta-4 integrin are linked to ocular disease (ocular cicatricial pemphigoid). (See 'Mucous membrane pemphigoid' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Malignancy' and "Ocular cicatricial pemphigoid", section on 'Pathogenesis'.)

●Genetic factors, environmental exposures, and the phenomenon of epitope spreading may impact the development of bullous pemphigoid and MMP. Additional studies are necessary to explore the relationships of these factors to disease expression. (See 'Other factors' above.)