Seminar Pemphigoid diseases Enno Schmidt, Detlef Zillikens Lancet 2013; 381: 320–332 Pemphigoid diseases are a group of well defi ned autoimmune disorders that are characterised by autoantibodies Published Online against structural proteins of the dermal–epidermal junction and, clinically, by tense blisters and erosions on skin or December 11, 2012 mucous membranes close to the skin surface. The most common of these diseases is bullous pemphigoid, which http://dx.doi.org/10.1016/ mainly aff ects older people and the reported incidence of which in Europe has more than doubled in the past decade. S0140-6736(12)61140-4 Prognosis and treatments vary substantially between the diff erent disorders and, since clinical criteria are usually not Department of Dermatology (Prof E Schmidt MD, suffi cient, direct immunofl uorescence microscopy of a perilesional biopsy specimen or serological tests are needed Prof D Zillikens MD) and for exact diagnosis. In eight pemphigoid diseases the target antigens have been identifi ed molecularly, which has Comprehensive Centre for allowed the development of standard diagnostic assays for detection of serum autoantibodies—some of which are Infl ammation Medicine commercially available. In this Seminar we discuss the clinical range, diagnostic criteria, diagnostic assay systems, (Prof E Schmidt), University of Lübeck, Lübeck, Germany and treatment options for this group of diseases. Correspondence to: Prof Enno Schmidt, Department Introduction necessary. However, the diff erent diseases cannot usually of Dermatology, University of Pemphigoid diseases are characterised by the presence of be distinguished on clinical grounds alone, so an assess- Lübeck, Ratzeburger Allee 160, autoantibodies against distinct structural components of ment of skin-bound or mucous membrane-bound auto- 23538 Lübeck, Germany [email protected] the dermal–epidermal junction (fi gure 1). Junction pro- antibodies and serum autoanti bodies is needed. teins link the cytoskeleton of the basal keratinocytes to In 1953, Lever4 diff erentiated pemphigoid diseases from the extracellular matrix of the dermis. Binding of pemphigus clinically and histopathologically. He described pemphi goid autoantibodies leads to the separation of intraepidermal split formation and loss of cell adherence the epidermis and dermis by a complex, yet fairly well between keratinocytes (acantholysis) as hallmarks of understood process. pemphigus, and coined the term pem phigoid for disorders The pemphigoid diseases include eight disorders for characterised by subepidermal splitting. About 10 years which the molecular target antigens have been identifi ed later, Jordon and colleagues5 (including Lever) fi rst (table). In addition to the seven named diseases listed in described serum and skin-bound autoantibodies in the table, a few patients have a pemphigoid disease that bullous pemphigoid. Since then, detection of skin-bound is characterised by renal insuffi ciency and autoantibodies or epithelium-bound and serum autoantibodies have against the α5 chain of type IV collagen.1 IgG and IgA become diagnostic cornerstones for pemphigoid diseases, autoantibodies that target several not-fully-characterised alongside clinical characteristics (table). antigens (including 105 kDa, 125 kDa, and 168 kDa proteins) have also been detected in serum samples Bullous pemphigoid from patients with pemphigoid disorders.2,3 Dermatitis Incidence herpetiformis, another subepidermal im munobullous In a prospective study of bullous pemphigoid that disease, is not regarded as a pemphigoid disorder since encompassed the entire Swiss population, the inves- the autoantigen epidermal transgluta minase is not a tigators calculated an incidence of 12·1 new cases per structural component of the dermal–epidermal junction. 1 million people per year.6 In Germany, Scotland, and Pemphigoid diseases share some clinical characteristics, France, incidences of 13·4, 14, and 21·7 per 1 million people such as tense blisters and erosions and, by contrast with per year, respectively, have been reported.7–9 A 2008 report10 pemphigus, a negative Nikolsky sign—ie, friction of non- from the UK calculated a higher incidence of 66 new lesional skin does not lead to intra epidermal disruption cases per 1 million people per year, on the basis of a data and visible erosion. The disorders are, however, hetero- registry established in general practice. In the UK, geneous with respect to overall clinical presentation, target Germany, and France, incidence has increased sub- antigens, and autoantibody isotype. Importantly, prognosis stantially (two to fi ve times) in the past 10 years,7,9,10 a and treatment can vary substantially, so exact diagnosis is fi nding that might be related to the increasing age of the general population, the availability of more sensitive and specifi c diagnostic assay systems, or both. Search strategy and selection criteria Bullous pemphigoid mainly aff ects older people, with We searched PubMed using the terms “pemphigoid”, “linear onset usually in the late 70s. Incidence rises substantially IgA”, “herpes gestationis”, and “epidermolysis bullosa to 150–330 per 1 million people per year in people older 6–11 acquisita”. Our search covered articles published in English than 80 years. With the changing age structure of between Jan 1, 2000, and May 31, 2012. We identifi ed the European population, the incidence is likely to rise. additional reports from the reference lists of selected articles. Bullous pemphigoid rarely occurs in individuals Some important older publications are cited either directly or younger than 50 years (incidence <0·5 cases per 6,7,10,11 indirectly through review articles. 1 million people per year). Few cases in infants, children, and ado lescents have been reported, and 320 www.thelancet.com Vol 381 January 26, 2013 Seminar treatment responses in these patient groups do not diff er greatly from those in adults.12 Corneal layer Mortality, risk factors, and associated diseases 1-year mortality for patients with bullous pemphigoid Epidermis ranges from 20% to 40%, which is about two to three times higher than that of age -matched and sex- Dermis matched controls.9,10,13 Old age, widespread disease, a low Karnofsky score, and, importantly, high doses of oral corticosteroids are key risk factors for death.14,15 Patients with bullous pemphigoid are also three times more likely Keratin Plectin to develop pneumonia and pulmonary embolism than Cell filaments are matched controls.10 membrane In the past 5 years, researchers have learned of an Hemidesmosomal BP230 association between bullous pemphigoid and neuro- plaque logical disorders. Between a third and half of all bullous pemphigoid patients have neurological diseases (odds 16–19 ratios from 2·4 to 10·6). In particular, major cognitive α6 impairment, Parkinson’s disease, stroke, epilepsy, and β4 NC16A domain multiple sclerosis have been associated with bullous Lamina integrin lucida 16–19 pemphigoid in controlled studies. These fi ndings are BP180 Laminin γ1 Laminin 332 especially intriguing since both bullous pemphigoid target antigens, BP180 (also termed type XVII collagen, COL17, or bullous pemphigoid antigen 2, BPAG2) and Lamina BP230 (dystonin or BPAG1), are expressed in the central densa nervous system. BP180 expression has been reported in Dermal the cerebellum of rats and in autopsy samples of various collagens Type VII collagen neuroanatomical regions of human brain,20,21 and the Sublamina antigen is predominantly seen in lipofuscin granules of densa ageing, post-mitotic neurons.20 Mice with mutations in the dystonin gene that encodes for various isoforms of Figure 1: Schematic diagram of the dermal–epidermal junction BPAG1, including the epithelial isoform BP230, develop Only molecules that are targeted by autoantibodies in pemphigoid diseases are shown. severe dystonia and sensory nerve degeneration.22 Investigators discovered an independent association of with urticarial plaques (fi gure 2). Blisters often arise on bullous pemphigoid with psoriasis in a population-based the fl exural aspects of the limbs and on the abdomen and study based on data from the national health insurance can persist for several days, leaving erosions and crusts. In database in Taiwan.17 Various autoimmune disorders and almost all patients, severe pruritus is present. Mild oral cancer have also been linked with the disease. However, lesions develop in 10–20% of patients, but other mucosal investigators of a case-control study23 did not report any areas are rarely aff ected.29 Before development of blisters, increased risk for other autoimmune disorders and the disease is typically preceded for several weeks and investigators of two case-control studies into bullous even months by a prodromal phase in which pruritus pemphigoid and cancer risk reported no association24 or alone or in association with excoriated, eczematous, and only a weak association with gastric cancer25 in Swedish papular or urticarial lesions occur (fi gure 2). In some and Japanese cohorts, respectively, compared with age- patients, these non-bullous skin symptoms persist and are matched controls. defi ned as several clinical variants—eg, prurigo-like, Several triggers have been implicated in disease onset erythroderma-like, ecthyma gangrenosum-like, intertrigo- in individual patients, including trauma, burns, radio- like, and toxic epi dermolysis-like bullous pemphigoid.29 therapy, ultraviolet radiation, and vaccination—most Localised forms of the disease frequently aff ect the frequently