Elsevier

Clinics in Dermatology

Volume 30, Issue 1, January–February 2012, Pages 3-16
Clinics in Dermatology

Bullous pemphigoid: From the clinic to the bench

https://doi.org/10.1016/j.clindermatol.2011.03.005Get rights and content

Abstract

Bullous pemphigoid (BP) constitutes the most frequent autoimmune subepidermal blistering disease. It is associated with autoantibodies directed against the BP antigens 180 (BP180, BPAG2) and BP230 (BPAG1-e). The pathogenicity of anti-BP180 antibodies has been convincingly demonstrated in animal models. The clinical features of BP are extremely polymorphous. The diagnosis of BP critically relies on immunopathologic findings. The recent development of novel enzyme-linked immunosorbent assays has allowed the detection of circulating autoantibodies with relatively high sensitivity and specificity. Although potent topical steroids have emerged in the past decade as first-line treatment of BP, management of the disease may be challenging.

Introduction

The name “bullous pemphigoid” itself is a pleonasm: pemphigoid is derived from the Greek and means “form of a blister” (pemphix, blister; eidos, form); hence etymologically, the adjective “bullous” should reasonably not be added to designate the blistering in pemphigoid.1 Despite this redundancy, “bullous” pemphigoid (BP) has emerged as a paradigm for an organ-specific autoimmune disease.

BP belongs to the group of pemphigoids that further include gestational pemphigoid (also called pemphigoid gestationis or herpes gestationis), mucous membrane pemphigoid, and linear immunoglobulin (Ig) A bullous disease. It represents the most frequent autoimmune blistering disease of the skin in many geographic areas, such as in Europe, North America, Japan, and Australia. The disease typically affects the elderly and is associated with a significant morbidity and mortality. The cutaneous manifestations of BP are protean. BP is associated with an autoantibody response to BP180, also called BPAG2, or type XVII collagen, and BP230 (BPAG1-e), two components of hemidesmosomes. Although various in vitro and in vivo animal models have shown IgG autoantibodies to BP180 are pathogenic, the exact role of anti-BP230 antibodies remains to be clarified.

This contribution encompasses the clinical features of BP, the clinical context in which BP occurs and the associated conditions, a diagnostic algorithm, and a discussion of its practical management. Finally, recent advances of our insights into the physiopathology of BP are presented.

Section snippets

Epidemiology and clinical context

The annual incidence of BP was originally estimated in the first prospective studies to be at least 6 to 7 new cases/year per 1 million population.2, 3, 4 In our prospective study encompassing the entire Swiss population during a 2-year period, we found an incidence of 12 new cases/year per 1 million population,4 whereas another German prospective study from Lower Franconia reported a similar incidence of 13.4.5 As seen in some reports describing figures of up to 42.8 new cases/year per 1

Clinical features

The possibility of BP should be promptly considered in all elderly patients who present with a generalized pruritic bullous eruption.8, 9, 10

In the bullous stage, dozens to hundreds of vesicles and bullae can arise on apparently normal or erythematous skin together with urticarial and infiltrated papules and plaques or eczematous lesions. The blisters are tense, 1 to 3 cm in diameter or even larger, have a clear exudate, and may persist for several days, leaving eroded and crusted areas. In

Trigger factors and associated conditions

Numerous triggers have been implicated in the disease onset of individual BP patients, including trauma, burns, radiotherapy, ultraviolet (UV) radiation, and a large variety of drugs. A weak association with aldosterone antagonists and neuroleptics was found in a prospective case-control study37 and was recently confirmed by a larger study that showed that chronic use of spironolactone and, among neuroleptics, of phenothiazines with aliphatic side chains represents a risk factor for BP.38

Diagnosis of typical and atypical forms of BP

Diagnosis of BP is in principle derived from a combination of criteria, including clinical features and histopathologic and immunopathologic findings10 (Figure 3). In elderly patients with the classic generalized bullous eruption, the diagnosis is easy: clinical features (see below) together with findings of the direct immunofluorescence (IF) microscopy studies are sufficient to make the diagnosis of BP with a sensitivity of 90%, a specificity of 83%, and a high positive-predictive value.55, 56

Current diagnostic challenges

In localized and atypical variants, diagnosis of BP critically relies on direct IF microscopy studies and the detection of circulating autoantibodies directed against BP180 or BP230, or both. Although we usually make the diagnosis of early-stage of BP (pemphigoid incipiens, or prebullous BP) in patients with pruritic skin conditions in whom positive direct IF findings even when blisters are lacking, this approach is personal and questionable. A small number of these patients do not appear to

Prognosis

Although few data are available on the evolution of the disease, BP appears to have a chronic course with frequent exacerbations or relapse, even after successful treatment. A recent prospective study of 114 BP patients found up to 45% of the evaluable individuals experienced a relapse, which in most cases occurred within 6 months after cessation of therapy.80

Besides a significant effect on the quality of life because of the severe itch and potentially widespread inflammatory lesions, BP has a

Principles of therapy

The management of BP has undergone significant changes in the past decade.87, 88 A large multicenter study demonstrated that potent topical corticosteroids, such as clobetasol propionate, are superior than the previous gold therapy standard of oral corticosteroids in the control of the disease, side effect profile, and overall survival.89 In addition, a mild regimen with clobetasol propionate cream (10 to 30 g/d, tapered over 4 months) was not inferior to the original treatment protocol (40 g/d

Disease activity and relapse markers

In retrospective cohorts with a limited number of patients, IgG ELISA BP180 NC16A values appeared to parallel disease severity or activity, or both.99, 100 We were able to confirm in our recent prospective multicenter study with 49 BP patients that disease severity and activity of BP correlate not only with the levels of IgG against the BP180-NC16A domain but also against a COOH-terminal epitope of BP180.11 Two prospective studies recently showed that disease severity fluctuates in parallel

Targeted antigens and humoral immune response

BP180 and BP230 are components of hemidesmosomes, junctional complexes promoting adhesion of epithelial cells to the underlying BMZ in stratified and other complex epithelia, and are involved in the maintenance of dermoepidermal adhesion101 (Figure 4). BP180 is a transmembrane molecule with a large collagenous extracellular domain102, 103 (Figure 4). Mutations in the gene encoding BP180 underlie a form of nonlethal junctional epidermolysis bullosa characterized by skin blistering and fragility,

Conclusions

The autoimmune etiology of BP is now established:

  • 1.

    patients have autoantibodies and autoreactive T cells to well-characterized self-antigens

  • 2.

    tissue injury occurs where antibody-antigen complexes are found

  • 3.

    in vivo animal models of the disease have provided unequivocal evidence for the pathogenic role of autoantibodies and cellular immune response

  • 4.

    in gestational pemphigoid, the transplacental transfer of anti-BP180 autoantibodies from the mother into the neonate can cause a transient bullous eruption

  • 5.

Acknowledgments

This work was supported by grants of the European Community's FP7 (Coordination Theme 1-HEALTH-F2-2008-200515 to L.B. and G.Z.), the Swiss National Foundation for Scientific Research (31003A-121966 and 31003A-09811, to L.B.), the Swiss Foundation for Research in Muscle Diseases (SSEM, to L.B.) and by the Italian Ministry of Health. Naomi De Luca provided technical assistance in the IF studies.

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