Elsevier

The Lancet

Volume 381, Issue 9863, 26 January–1 February 2013, Pages 320-332
The Lancet

Seminar
Pemphigoid diseases

https://doi.org/10.1016/S0140-6736(12)61140-4Get rights and content

Summary

Pemphigoid diseases are a group of well defined autoimmune disorders that are characterised by autoantibodies against structural proteins of the dermal–epidermal junction and, clinically, by tense blisters and erosions on skin or mucous membranes close to the skin surface. The most common of these diseases is bullous pemphigoid, which mainly affects older people and the reported incidence of which in Europe has more than doubled in the past decade. Prognosis and treatments vary substantially between the different disorders and, since clinical criteria are usually not sufficient, direct immunofluorescence microscopy of a perilesional biopsy specimen or serological tests are needed for exact diagnosis. In eight pemphigoid diseases the target antigens have been identified molecularly, which has allowed the development of standard diagnostic assays for detection of serum autoantibodies—some of which are commercially available. In this Seminar we discuss the clinical range, diagnostic criteria, diagnostic assay systems, and treatment options for this group of diseases.

Introduction

Pemphigoid diseases are characterised by the presence of autoantibodies against distinct structural components of the dermal–epidermal junction (figure 1). Junction proteins link the cytoskeleton of the basal keratinocytes to the extracellular matrix of the dermis. Binding of pemphigoid autoantibodies leads to the separation of the epidermis and dermis by a complex, yet fairly well understood process.

The pemphigoid diseases include eight disorders for which the molecular target antigens have been identified (table). In addition to the seven named diseases listed in the table, a few patients have a pemphigoid disease that is characterised by renal insufficiency and autoantibodies against the α5 chain of type IV collagen.1 IgG and IgA autoantibodies that target several not-fully-characterised antigens (including 105 kDa, 125 kDa, and 168 kDa proteins) have also been detected in serum samples from patients with pemphigoid disorders.2, 3 Dermatitis herpetiformis, another subepidermal immunobullous disease, is not regarded as a pemphigoid disorder since the autoantigen epidermal transglutaminase is not a structural component of the dermal–epidermal junction.

Pemphigoid diseases share some clinical characteristics, such as tense blisters and erosions and, by contrast with pemphigus, a negative Nikolsky sign—ie, friction of non-lesional skin does not lead to intraepidermal disruption and visible erosion. The disorders are, however, heterogeneous with respect to overall clinical presentation, target antigens, and autoantibody isotype. Importantly, prognosis and treatment can vary substantially, so exact diagnosis is necessary. However, the different diseases cannot usually be distinguished on clinical grounds alone, so an assessment of skin-bound or mucous membrane-bound autoantibodies and serum autoantibodies is needed.

In 1953, Lever4 differentiated pemphigoid diseases from pemphigus clinically and histopathologically. He described intraepidermal split formation and loss of cell adherence between keratinocytes (acantholysis) as hallmarks of pemphigus, and coined the term pemphigoid for disorders characterised by subepidermal splitting. About 10 years later, Jordon and colleagues5 (including Lever) first described serum and skin-bound autoantibodies in bullous pemphigoid. Since then, detection of skin-bound or epithelium-bound and serum autoantibodies have become diagnostic cornerstones for pemphigoid diseases, alongside clinical characteristics (table).

Section snippets

Incidence

In a prospective study of bullous pemphigoid that encompassed the entire Swiss population, the investigators calculated an incidence of 12·1 new cases per 1 million people per year.6 In Germany, Scotland, and France, incidences of 13·4, 14, and 21·7 per 1 million people per year, respectively, have been reported.7, 8, 9 A 2008 report10 from the UK calculated a higher incidence of 66 new cases per 1 million people per year, on the basis of a data registry established in general practice. In the

Mucous membrane pemphigoid

An international consensus conference87 has defined mucous membrane pemphigoid as immunobullous disease with autoantibodies against components of the dermal–epidermal junction and predominant mucosal involvement. Previously, the term cicatricial pemphigoid was used synonymously for mucous membrane pemphigoid. Now, cicatricial pemphigoid refers only to the rare clinical variant in which mucous membranes are not predominantly affected and skin lesions heal with scarring.87 Incidence of mucous

Pemphigoid gestationis

Pemphigoid gestationis, previously known as herpes gestationis, is a pregnancy-associated immunobullous disease with autoantibodies against BP180 NC16A. An annual incidence of between 0·5 and 2·0 cases per 1 million people has been reported in France, Germany, and Kuwait.7, 88, 114 A much higher incidence than in these countries was noted in two English tertiary referral centres, with the disease reportedly occurring in 4·2% of pregnancies.115 Pemphigoid gestationis usually occurs in the second

Linear IgA disease

Linear IgA disease is named for its main immunopathological feature, which is the linear binding of IgA at the dermal–epidermal junction. Some overlap is seen with bullous pemphigoid (patients with dual IgG and IgA deposition along the junction), with mucous membrane pemphigoid (patients with predominant mucosal involvement), and IgA epidermolysis bullosa acquisita. Incidences between 0·25 and 1·0 per 1 million people per year have been reported in central Europe, Singapore, and Kuwait.7, 88,

Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita is a clinically heterogeneous disease characterised by autoantibodies against type VII collagen. Incidence reportedly ranges between 0·2 and 0·5 new cases per 1 million people per year.7, 88, 123 The disease is associated with HLA-DR2—notably the DRB1*15:03 allele—and African descent.130 Clinically, epidermolysis bullosa acquisita can either be the classic form or an inflammatory variant.131, 132 The classic mechanobullous form presents with tense blisters and

Anti-p200/anti-laminin γ1 pemphigoid and lichen planus pemphigoides

Both anti-p200 pemphigoid and lichen planus pemphigoides are rare, with fewer than 100 reported cases of each worldwide. Anti-p200 pemphigoid clinically mimics bullous pemphigoid, although patients tend to be younger and concurrent psoriasis is seen in about a third of cases.146, 147 Serum samples from 90% of patients react with laminin γ1.148 Diagnosis is made by detection of autoantibodies against the 200 kDa protein of the dermal–epidermal junction by immunoblotting with extract of dermis or

Search strategy and selection criteria

We searched PubMed using the terms “pemphigoid”, “linear IgA”, “herpes gestationis”, and “epidermolysis bullosa acquisita”. Our search covered articles published in English between Jan 1, 2000, and May 31, 2012. We identified additional reports from the reference lists of selected articles. Some important older publications are cited either directly or indirectly through review articles.

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