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Pemphigus
Jean-Claude Bystryn, Jennifer L Rudolph

Pemphigus is a rare autoimmune disease that results in blistering of the skin and oral cavity. It is caused by autoantibodies directed against cell-surface antigens on keratinocytes, which when targeted lose their cellular adhesion properties and separate from one another to form blisters within the epidermis. Differences in the particular antigens targeted by the antibodies and in the distribution of these antigens in the different regions of the body and in the separate layers of the epidermis result in different clinical manifestations of the disease. The disease is diagnosed based on its clinical manifestations (accid blisters and erosions on skin and oral mucosa), histology (epidermal acantholysis), and immunological abnormalities (circulating and tissue-xed antibodies against keratinocyte surface antigens). Pemphigus, which if left untreated is almost always fatal, is generally managed with topical, oral, or intralesional corticosteroids. Other options include plasmapheresis and intravenous immunoglobulin (IVIg), coupled with cytotoxic drugs. Immunosupressants, anti-inammatory drugs, and antibiotics are used as adjuvants, but apart from IVIg, these therapy options are non-specic and more research is needed to develop treatments with improved side-effect proles. Pemphigus is a rare but serious autoimmune disease that causes blistering of the skin and oral cavity. If untreated it is almost always fatal. It is caused by autoantibodies directed against antigens on the surface of keratinocytes, the cells of the epidermis. There are two basic forms of pemphigusvulgaris and foliaceouswhich affect different layers of the skin, have different symptoms, and target different antigens.1 In pemphigus vulgaris blisters develop just above the basal-cell layer and are associated with autoantibodies to desmoglein 3, a keratinocyte cellsurface adhesion molecule. In pemphigus foliaceous the blisters are high in the epidermis, just below the stratum corneum, and are associated with antibodies against desmoglein 1, another cell-surface adhesion molecule. There are several subtypes of each form. individuals of various HLA types, so cannot be considered a hereditary disease.

Lancet 2005; 366: 6173 The Ronald O Perelman Department of Dermatology, New York University School of Medicine, 560 1st Avenue, New York, NY 10016, USA (Prof J-C Bystryn MD, J L Rudolph MD) Correspondence to: Prof Jean-Claude Bystryn bystryn@nyu.edu

Pemphigus foliaceous
Sporadic and endemic forms of pemphigus foliaceous exist. The sporadic form is most common in Europe and the USA, where its incidence is about a fth to a tenth that of pemphigus vulgaris, and is associated with HLA DRB1*0102 and 0404.7 Endemic pemphigus foliaceous (also know as fogo selvagem and Brazilian pemphigus foliaceous) is a variant of the disease that is frequently diagnosed in certain regions of Brazil and other underdeveloped areas of the world, including Tunisia and Colombia. The susceptibility genes for endemic pemphigus are HLA DRB1*0102, 0404, 1402, and 1406.8 Clinically and histologically, the disease is similar to sporadic pemphigus foliaceous. However, the endemic form usually affects teenagers and individuals in their 20s. Furthermore, it can affect multiple members of the same family. The epidemiology of the endemic form suggests an environmental cause, which remains unidentied9 though an insect vector is suspected.10 Endemic pemphigus typically arises at the interface between developing and non-developed areas; as an area becomes urbanised, the disease disappears. The
Search strategy and selection criteria We searched Medline with the keyword pemphigus for articles published in English between January, 1980, and October, 2004. Citations were used on the basis of relevance to the topic. Articles published before 1980 that we were aware of are included. The description of treatment approaches is based on review articles and key studies known to us. Non-peer reviewed publications and single case reports were not included. A limited number of abstracts, published in 19992003, were considered since they contain important information not available from alternative sources.

Epidemiology
Pemphigus has an incidence of 0755 cases per million per year.2 Incidence of the various forms of the disease, however, varies from country to country. Pemphigus vulgaris is most common in Europe and the USA, for example, whereas pemphigus foliaceous is more prevalent in Africa3 and in certain rural areas in underdeveloped nations, where it affects up to 3% of the population.4

Pemphigus vulgaris
Pemphigus vulgaris can develop at any age, but is most commonly diagnosed in the fourth to sixth decades of life. Although the disease can affect anyone, it is most prevalent in people of Mediterranean or Jewish ancestry. Furthermore, individuals with certain HLA allotypes are predisposed to the disease, though the susceptibility gene differs dependent on ethnic origin. Thus, HLA-DRB1*0402 is associated with the disease in Ashkenazi Jews5 and DRB1*1401/04 and DQB1*0503 in non-Jewish patients of European or Asian descent.6,7 However, pemphigus rarely affects more than one family member and can arise in
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Figure 1: Indirect immunouorescence photomicrograph of the reaction of intercellular antibodies in the serum of a patient with pemphigus against antigens expressed on the surface of keratinocytes in normal human skin Reproduced by permission of the New York University Department of Dermatology.

disease is so common in some rural areas of Brazil that specialised hospitals have been built to care for affected individuals.

Pathophysiology
The basic abnormality in all forms of pemphigus is the separation of keratinocytes from one another, a process known as acantholysis. The primary event is the dissolution of the intercellular substance followed by separation of desmosomes. This process leads to the formation of a cleft within the epidermis, which then enlarges into a bulla. All forms of pemphigus are associated with the presence of circulating and skin-xed autoantibodies referred to as intercellular antibodiesagainst keratinocyte cell-surface antigens (gure 1).11 Circulating intercellular antibodies are present in about 80% of patients with active disease, and their titre usually correlates with disease activity. Tissuexed intercellular antibodies are present in lesions and adjacent healthy skin in about 90% of patients. They are usually IgG, though IgM, IgA, and the complement protein C3 might also be deposited. Intercellular antibodies are uncommon in individuals without pemphigus and can, therefore, be used in diagnosis.12 Intercellular antibodies are pathogenic, as evidenced by their ability to induce the histological changes of pemphigus (acantholysis) in organ cultures of human skin,13 and clinically and histologically typical lesions of pemphigus when passively administered to neonatal mice.14,15 Furthermore, placental transfer of maternal autoantibodies can induce transient lesions of the disease in newborn babies of women with active pemphigus vulgaris.16 The ability to passively transfer the disease in mice with pemphigus antibodies is abrogated by specically absorbing out antibodies against desmoglein 1 or desmoglein 3,17 conrming that pemphigus can be mediated by these antibodies.
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Intercellular antibodies are directed against multiple keratinocyte cell-surface antigens. Of these, the adhesion molecules desmoglein 1 and desmoglein 3 are the best characterised.18,19 Both molecules are desmosomal transmembrane proteins, which belong to the cadherin gene family.20 The portion of these molecules targeted by pathogenic antibodies is expressed on the external surface of the cells,21 and multiple epitopes on the same molecule can be targeted.22 The antigens targeted in the two forms of pemphigus differ.1 In pemphigus vulgaris, intercellular antibodies are predominantly directed against desmoglein 3 and less often against desmoglein 1. In pemphigus foliaceous, they are predominantly directed against desmoglein 1. Serological analysis23 suggests that antibodies are also directed to other antigens, an observation conrmed by the induction of pemphiguslike lesions in mice given intercellular antibodies not directed against desmoglein 1 or desmoglein 3.24 These additional antigens seem to include acetylcholine receptors on keratinocytes.25 Whether intercellular antibodies cause clinical disease seems to depend on the subclass of the antibody response. Thus, IgG1 antibodies against desmoglein 3 are present with equal frequency in individuals with or without pemphigus vulgaris, but IgG4 antibodies are present almost exclusively in patients with active disease.26 Likewise, IgG1 antibodies against desmoglein 1 are present in a high proportion of individuals with or without endemic pemphigus and with or without active disease in areas where this condition is common in Brazil, but IgG4 antibodies against this same antigen are present in much higher concentrations in patients with active disease than in those with inactive disease or in unaffected individuals.9 As such, in endemic pemphigus, an as yet unknown environmental agent might trigger the production of non-pathogenic IgG1 antibodies against desmoglein 1, and the appearance of clinical disease might be triggered by the presence of an HLA susceptibility gene required for the production of a pathogenic IgG4 response.9 A similar subclass switching might be involved in the clinical appearance of the other forms of pemphigus. Whether the different pathogenic activity of IgG1 and IgG4 antibodies is due to differences in effector function or the different subclasses being directed to different epitopes on the targeted antigens is unknown. The exact process by which intercellular antibodies cause loss of cellular adhesion is unclear. As mentioned, the subclass of the IgG response seems to be important.9,22 Perhaps the antibodies physically block adhesion sites on desmoglein27 or on other adhesion molecules, or maybe they interfere with their structure or other functions or with the assembly of desmosomes.28,29 Another possibility is that they stimulate release of proteolytic enzymes. It is notewww.thelancet.com Vol 366 July 2, 2005

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Thiols Penicillamine Benzylpenicillin Captopril Tiopronin Cephalosporin Pyritinol

Angiotensin-converting enzyme inhibitors Enalapril Cilazapril Fosinopril Ramipril

Others Aspirin Non-steroidal anti-inammatory drugs (NSAID) Rifampicin Levodopa Phenobarbital Pentachlorophenol Interferon Interleukin Propranolol Nifedipine

Table: Drugs implicated in pemphigus32

worthy that in staphylococcal scalded skin syndrome, which is caused by a toxin that binds to and cleaves desmoglein 1, patients develop blisters similar to those caused by pemphigus foliaceous.30 Last, we believe another possibility for acantholysis is that the antibodies trigger a signalling event that causes reorganisation of the cytoskeleton of keratinocytes, causing the affected cells to shrink, pull away, and thus separate from adjacent keratinocytes. Little is also known about how intercellular autoantibodies arise. In most individuals, the disease is idiopathic. However, in some it is triggered by an

Figure 2: Photomicrograph of skin lesion of pemphigus vulgaris (upper) and pemphigus foliaceus (lower) Reproduced by permission of the New York University Department of Dermatology.

external cause, such as a drug (table).31,32 Different drugs cause different forms of pemphigus.33 Differences between pemphigus vulgaris, the deep form, and pemphigus foliaceous, the supercial form, seem to reect regional variations in the expression of antigens targeted by autoantibodies in the two forms of the disease, with lesions occurring in areas where antigen expression is greatest. Consider, for example, the striking difference in the location of lesions within the epidermis between pemphigus vulgaris and pemphigus foliaceous: blisters in pemphigus vulgaris occur deep in the epidermis, just above the basal-cell layer, whereas those in pemphigus foliaceous arise in the most supercial layer, just below the stratum corneum (gure 2). There is a parallel stratication in different layers of the epidermis of the antigens targeted by antibodies in the two forms of the disease.34 Desmoglein 1 is present predominantly in the supercial layers of the epidermis and is absent in the suprabasal layer, whereas desmoglein 3 is present predominantly in the deeper layers and is absent in the most supercial layer.35,36 These observations have led to the desmoglein compensation theory, which states that both desmoglein 1 and desmoglein 3 maintain adhesion of keratinocytes; in epidermal layers where both are expressed, one desmoglein isotype compensates for the antibody-induced loss of function in the other.2,37 According to this notion, lesions only arise in the deepest epidermal layers in pemphigus vulgaris because there is no desmoglein 1 there to compensate for the action of the antibodies against desmoglein 3, and vice versa in pemphigus foliaceous, where there is no desmoglein 3 in the most supercial epidermal layer to compensate for the action of antibodies against desmoglein 1. Theoretically, blisters do not arise in other epidermal layers in either disease because both desmogleins are present. However, this theory does not explain the absence of blisters throughout the epidermis in the substantial minority of patients with pemphigus vulgaris who have antibodies against both desmoglein 3 and desmoglein 1. Another important difference between the two forms of pemphigus is in the distribution of lesions over the body. Oral lesions are common in pemphigus vulgaris but do not occur in pemphigus foliaceous, lesions on the scalp, face, and upper torso are common in both forms of pemphigus, and rare on the legs in both. There is a similar anatomical variation in the expression of the antigens targeted by autoantibodies in the two forms of the diseasethe mouth expresses high concentrations of antigen related to pemphigus vulgaris but low concentrations of those associated with pemphigus foliaceous, and the expression of both types of antigens is high on the face, scalp, and upper torso but low on the legs.38 Consequently, we believe the regional variation in the distribution of skin lesions
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is due to similar regional variations in the expression of the antigens targeted by the autoantibodies in the different forms of pemphigus.38 In support of this conclusion is the fact that in bullous pemphigoid, another autoantibody mediated blistering disease where the distribution of skin lesions differs markedly from that in pemphigus, there is also a striking relation between the distribution of skin lesions and the expression of the antigens targeted by the autoantibodies of that disease.39 The distribution of lesions could also be affected by the prole of autoantibodies: oral lesions are more common in patients with antibodies only against desmoglein 3, mucosal and oral lesions are usually only associated with the presence of antibodies against both desmoglein 3 and desmoglein 1, and skin lesions without oral lesions are usually only present in patients with antibodies against desmoglein 1 alone.40 These relations, however, are not universal. The desmoglein compensation theory has also been proposed to explain this relation.41 According to that theory, oral lesions arise only in pemphigus vulgaris, because only those patients have antibodies against desmoglein 3 and only desmoglein 3 is present in the oral cavity. However, this hypothesis does not explain why lesions do not appear in all layers of the oral mucosa, since there is no desmoglein 1 to compensate for the inactivation of desmoglein 3. Furthermore, the theory does not explain why both desmoglein 3 and desmoglein 1 antibodies are, according to the hypothesis, required for lesions to appear on skin in patients with pemphigus vulgaris, since the lesions arise only in the deep layers of the epidermis where there is no desmoglein 1 and where antibodies against desmoglein 1 should have no effect. There is little inammatory cell inltrate in pemphigus lesions, suggesting cellular immune mechanisms are not directly involved in the pathogenesis of disease. However, T-cell responses could play a part in regulating the formation of pathogenic autoantibodies.42

matter of days or weeks. Ulcers are multiple; this factor differentiates them from an ulcerated tumour, which is single. Because the disease is rare, pemphigus is not often diagnosed at a rst examination, but rather considered only after lesions have been present for weeks to months and after the patient has not responded to antibiotic, antifungal, or antiviral therapy. Pemphigus should be considered in anyone who has multiple, non-healing oral ulcers that persist for longer than a month. After weeks to months, the condition progresses with lesions appearing on the skin (usually on the scalp, face, and upper torso) and with symptoms indicative of nasal and oesophageal involvement. Occasionally, skin lesions are the initial manifestation of the disease. Skin lesions usually begin as small blisters that are lled with a clear uid and that arise from normal appearing skin. The blisters are usually accid, because the overlying epidermis is thin and cannot sustain much pressure. Since they are thin, the blisters rupture in several days and are replaced by sharply outlined, coinsized, supercial erosions with a collarette of loose epidermis (gure 3). Lesions appear most often on the scalp, upper chest, and back. They have a tendency to involve the medial or central portion of the torso rather than the sides. Other areas commonly involved are the face and neck, but any surface covered by stratied squamous epithelium can be affected. Sites often overlooked include: the periungual areas, the pharynx, and larynx, manifested by pain on swallowing food and by hoarseness; the nasal cavity, manifested by nasal congestion and morning mucous discharge; and the cervix. Laryngeal and nasal involvement is more frequent than usually believed. In one systematic study,43 49% of patients had symptoms of laryngeal or nasal involvement, or both. Because the symptoms of laryngeal involvement are identical to those of candidiasis, an ear, nose, and throat (ENT) assessment should be done to differentiate between these two conditions, which are treated very differently.

Clinical features
Deep forms of pemphigus
There are two deep forms of pemphiguspemphigus vulgaris and pemphigus vegetans. Pemphigus vulgaris is more common that pemphigus vegetans and usually, but not invariably, begins with painful, non-healing ulcerations in the mouth. Blisters are rare, since they rupture soon after forming, leaving an ulcerated area. Ulcerations are usually multiple, supercial, and irregular in shape, and arise from mucosa of healthy appearance. Although any surface can be involved, the most common sites are the buccal and labial mucosa, the palate, and the tongue. The ulcers of pemphigus vulgaris do not heal, by contrast with the oral lesions of aphthmous stomatitis or viral infections that heal in a
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Figure 3: Characteristic skin lesions of pemphigus vulgaris Reproduced by permission of the New York University Department of Dermatology.

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eventually enter a phase of partial remission in which they can be maintained, lesion-free, with minimum ( 15 mg per day prednisone) doses of corticosteroids, or go into complete remission in which they are lesionfree and need no therapy. In a longitudinal study45 of outcome in 40 patients, half of patients were in complete and long-lasting remission after 5 and threequarters after 10 years. As medications are tapered ares in disease activity, evidenced by new crops of lesions and itching, are not uncommon.45 Our personal experience of managing several hundred patients has highlighted several factors that can trigger a are and that should be kept to a minimum. These include dental work, exposure to the sun, cutaneous trauma, infection, and stress. Pemphigus vegetans is a variant of pemphigus vulgaris in which healing is associated with vegetating proliferation of the epidermis. Lesions usually appear in intertriginous areas such as the axillae, groin, and inframammary area. The disease is thought to arise in patients with a less aggressive form of pemphigus or in those in whom the intensity of therapy is sufcient to prevent new lesions but not sufcient to heal established lesions. Because of their location, the lesions are generally secondarily infected, which slows healing.

Supercial forms of pemphigus


Figure 4: Pemphigus vulgaris Reproduced by permission of the New York University Department of Dermatology.

A characteristic feature of all forms of active and severe pemphigus is the Nikolsky sign, in which rm, sliding pressure on normal appearing skin causes separation of the epidermis from the underlying dermis. This sign is elicited most easily adjacent to an active lesion. In its extreme forms, the pressure exerted on the skin simply by lifting a patient can shear off substantial portions of the epidermis. Left untreated, bullae and erosions spread (gure 4). As with burns, these lesions can be complicated when widespread by severe infection or metabolic disturbance, or both, leading to death. Before systemic corticosteroids became available, about 75% of patients who developed pemphigus vulgaris died within a year.44 However, improved diagnostic techniques now permit the recognition of more subtle forms of disease, indicating that the severity of pemphigus can vary widely. Mild forms can regress spontaneously, and the progression of even the most severe forms can almost always be reversed with appropriate treatment. With treatment, lesions heal with crusting followed by re-epithelialisation. There is no scarring, though there can be residual hyperpigmentation at sites of former lesions. This sign usually disappears in several months. Most patients with pemphigus vulgaris
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Supercial forms of pemphigus include pemphigus foliaceous, pemphigus erythematosus, and endemic pemphigus foliaceous. The pathology of these diseases is so supercial that there is insufcient overlying tissue to trap uid and allow for blister formation. Lesions usually begin with multiple, pruritic, crusted, coin-sized patches on the upper torso, face, and scalp. They arise from healthy looking skin and have been described as cornakes. The crusts can easily be removed, leaving supercial erosions. Untreated lesions do not heal, and over weeks to months increase in number. In severe cases, the lesions become

Figure 5: Pemphigus foliaceous Reproduced by permission of the New York University Department of Dermatology.

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conuent and can resemble an exfoliative erythroderma, involving the entire skin surface (gure 5). By contrast with the deep forms of pemphigus, oral involvement is rare. There are two clinical variants of pemphigus foliaceouspemphigus erythematosus and fogo selvagem. In pemphigus erythematosus, the disease is localised to the face and is characterised by an erythematosus scaly-to-crusted rash often in a buttery distribution that resembles lupus erythematosus. In addition to the tissue-xed intercellular deposits of antibodies that are present in all forms of pemphigus, there are often granular deposits of immunoglobulin or complement, or both, at the dermal-epidermal junction. Thus, pemphigus erythematosus might be a crossover syndrome between pemphigus and lupus. However, granular deposits of immunoglobulin or complement, or both, are not uncommon in normal facial skin, particularly if exposed to a lot of sun.46 An alternate explanation, therefore, which we favour, is that granular deposits are common in pemphigus erythematosus because the face is generally the only site involved, and such deposits are common in that location. Fogo Selvagem (endemic pemphigus, Brazilian pemphigus foliaceous) is unique in that it occurs in epidemic form in certain rural areas of the world. Clinically, histologically, and immunologically, it is otherwise identical to pemphigus foliaceous.47,48 The prognosis of untreated pemphigus foliaceous is better than that of pemphigus vulgaris, probably because lesions are more supercial and there is less risk of infection, uid loss, and metabolic disturbance. However, the treatment is no easier, since the doses of drugs needed to control pemphigus foliaceous can be similar to those used for pemphigus vulgaris.

Diagnosis
Diagnosis is based on three independent sets of criteria: clinical features, histology, and immunological tests. The classic clinical ndings of pemphigus vulgaris are multiple accid blisters arising from healthy skin, multiple chronic oral ulcers, and a positive Nikolsky sign. Histologically, there is an intraepidermal blister associated with acantholytic cells. The blister is immediately above the basal-cell layer in pemphigus vulgaris and vegetans and just below the strateum corneum in pemphigus foliaceous and erythematosus. Acantholytic cells can also be seen in other conditions, such as Hailey-Hailey disease and impetigo. Establishing a diagnosis depends on the ndings of clinical, histological, and immunological tests being in agreement. Immunologically, all forms of pemphigus are associated with circulating and tissue-xed intercellular antibodies against keratinocyte surface antigens.12,52 Circulating intercellular antibodies are detected by indirect immunouorescence assays on serum, and tissue-xed intercellular antibodies by direct immunouorescence assays on skin biopsies. In both instances, a lace-like pattern of uorescence within the epidermis is seen (gure 1). Circulating antibodies can also be present in low titres in patients with antibodies to ABO blood group antigens or with burns, fungal infections, or allergic drug reactions. ELISA assays are available to detect antibodies to desmoglein 1 and desmoglein 3. The presence of antibodies against desmoglein 3 sometimes together with those against desmoglein 1 is associated with pemphigus vulgaris, whereas antibodies to desmoglein 1 alone are associated with pemphigus foliaceous.22 ELISA is more specic and somewhat more sensitive than indirect immunouorescence. However, the results are not quantitative if antibody concentrations are high because the assay plates become saturated.53 The presence and concentration of these antibodies is normally related to the activity of the disease, and they usually disappear in patients in remission. Serial measurements of intercellular antibodies can be helpful in guiding therapy since they usually decrease with successful treatment, while disease is more likely to remain active or be exacerbated in patients with persistently raised concentrations. Tissue-xed intercellular antibodies are present in lesions and adjacent healthy skin in about 90% of patients with pemphigus.12,52 These antibodies are more sensitive and specic for the diagnosis of pemphigus than circulating antibodies. They are usually IgG; but IgM and IgA with or without C3 might also be deposited. Pemphigus should be differentiated from the many other conditions that also cause skin blisters. These conditions can often be excluded clinically by the history of the illness, the appearance of the individual lesions, and their distribution. However, because of the seriousness of the disease, the diagnosis should be conrmed by pathology and by immunouorescence or
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Drug-induced pemphigus
Certain drugs can trigger both pemphigus vulgaris and pemphigus foliaceous.31 Though uncommon, this possibility should be excluded in all patients with newly diagnosed disease.32 The clinical, histological,49 and immunouorescence abnormalities50 of druginduced and idiopathic pemphigus are similar. Various drugs can act as triggers (table), and some31 have suggested that the nature of the drug could affect both the type of pemphigus triggered and the prognosis. The most commonly implicated drugs are penicillamine, followed by angiotensin-converting enzyme inhibitors, such as captopril.

Pemphigus in pregnancy
Pemphigus is associated with an increased risk of premature birth and fetal death.51 It is noteworthy that, as noted previously, the disease can be present in neonates as a result of the passive transfer of pathogenic antibodies from the mother, in which case pemphigus will resolve spontaneously.
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ELISA assays for pemphigus antibodies. Blisters that follow an injury to the skin, such as those resulting from burns, frostbite, or contact dermatitis, can be excluded by the patients history, and blisters due to viral or bacterial infections by their brief duration. Blisters arise as a sign of many autoimmune, genetic, and metabolic diseases. In most of these cases the blisters occur within or below the dermal-epidermal junction and can readily be excluded by skin biopsy. These conditions include bullous and cicatricial pemphigoid, herpes gestationis, linear IgA bullous dermatosis, epidermolysis bullosa, porphyria cutanea tarda, and erythema multiforme. To maximise the information that can be obtained, a biopsy should be done at the edge of an active lesion and include some adjacent healthy skin so that the level of the blister can be accurately identied. Additionally, the antibodies present in autoimmune subepidermal blistering diseases react against antigens at the dermal-epidermal junction rather than within the epidermis. In several other diseases associated with blistering, such as impetigo, staphylococcal scalded-skin syndrome, Hailey-Hailey disease, and subcorneal bullous disease, the blisters are situated within the epidermis. Differential diagnosis is especially difcult with chronic impetigo, since the clinical and histological appearance of these skin lesions is almost identical to those of pemphigus foliaceous. However, there are normally fewer lesions in impetigo and they are asymmetrically distributed and generally heal rapidly with antibiotic therapy. In these conditions, circulating or tissue-xed intercellular antibodies are absent. Some judge paraneoplastic pemphigus a variant of pemphigus, because it is associated with acantholysis and with antibodies against desmoglein 3 and desmoglein 1. In our opinion, paraneoplastic pemphigus, which is usually associated with an underlying lymphoproliferative neoplasm, is a separate disease. As with pemphigus vulgaris, skin lesions can arise both in the oral mucosa and skin, and there is histological acantholysis and intercellular antibodies both on direct and indirect immunouorescence.54 But it differs in various clinical, histological, and immunological features from other forms of pemphigus. Oral lesions in paraneoplastic pemphigus, for example, characteristically involve the vermilion border of the lips, the skin lesions often resemble those of erythema multiforme or toxic epidermal necrolysis, and histologically there are interface changes at the dermal-epidermal junction. Furthermore, on direct immunouorescence abnormal deposits of immunoglobulin or complement, or both, are also present at the dermal-epidermal junction, the intercellular antibodies also react against columnar and transitional epithelia, and, most importantly, the antibodies are also directed against plakin proteins (such as envoplakin and periplakin).54 None of these abnormalities occurs in pemphigus.
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Assessment and management


Before treatment is initiated, the diagnosis of pemphigus should be conrmed by review of the clinical, histological, and immunouorescence data, since the disease usually requires long-term therapy with potentially serious side-effects. Involvement of the pharynx, larynx, and nasal cavity should be assessed by ENT examination if there are symptoms to suggest involvement of these areas. The patients overall medical status should also be assessed to identify whether they are at greater risk of developing complications from corticosteroids or other systemic medications that could be used, and to provide a baseline against which to monitor potential treatmentinduced complications. There are no real absolute contraindications to systemic steroids, which are life saving in this disease. The presence of diabetes, hypertension, duodenal ulcers, cataracts, osteoporosis, psychiatric illness, and other risk factors mandates closer observation and use of preventive measures, and is an indication for adjuvant therapy to hopefully reduce the total dose of steroids needed. If the patient is to be treated with systemic corticosteroids, a tuberculin test and chest radiograph should be done to look for evidence of exposure to tuberculosis; if present, prophylactic therapy should be administered. Baseline bone density studies and ophthalmological assessment should be undertaken and repeated periodically while the patient is on corticosteroids. Other investigations recommended before the initiation of therapy are haematocrit, complete blood cell count and differential, serum urea creatinine, and electrolytes, liver function tests, fasting glucose test, urinalysis, and assessment of thiopurine methyl transferase concentrations if azathioprine is to be used and of glucose-6-dehydrogenase and reticulocyte count if dapsone is to be used.55 The patients worries or lack of concern about their illness should also be addressed. Some patients believe that pemphigus is fatal. They should be reassured that their outlook is far better than it used to be, and that eventually a state of remission that needs little or no therapy is often reached. Other patients are under the impression that skin diseases are never serious. They should be made to understand that untreated pemphigus is dangerous and they must undergo a lengthy and potentially dangerous treatment to attain remission or cure.

Treatment
The treatment of pemphigus has been the subject of many reviews.5558 Drug trials for pemphigus are difcult. The disease is rare and its severity and response to therapy vary greatly from patient to patient. Although there are many therapies available, few have been assessed in randomised trials.59,60 A further difculty in the assessment and comparison of results of the trials
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Panel 1: Therapies for pemphigus Rapid effect: to control disease activity Systemic steroids IVIg Megadose pulse steroids Plasmapheresis Delayed effect: to decrease need for steroids Immunosuppressive drugsazathioprine, methotrexate, cyclophosphamide, cyclosporine, mycophenolic acid Gold Dapsone Antibiotics

that have been done is that there is no common denition of the terms and endpoints used to describe the extent, activity, and therapeutic response of pemphigus. Hence, the best way to treat the disease remains uncertain, as does the effectiveness of the available therapies. The recommendations made here are based on existing published work and our experience with several hundred patients with the disease. The therapies used to control pemphigus can be divided into those that act rapidly and are usually used to control the activity of the disease, and those with a delayed effect that are generally used in chronic management to decrease the need for systemic corticosteroids (panel 1). The aim of treatment is to induce a complete remission with minimum side-effects that permits all therapy to be discontinued or to use the lowest drug doses that prevent disease activation. Treatment is usually divided into three phases: control, consolidation, and maintenance (panel 2). Since there is much heterogeneity in the manifestations of the disease and its response to therapy, treatment is tailored to the needs of the individual patient.56

Control phase
The control phase of treatment is the period in which the intensity of therapy is rapidly escalated until a level is reached that suppresses disease activity as evidenced
Panel 2: Treatment phases Control phase Intensity of therapy rapidly escalated until disease activity is brought under control, as evidenced by cessation of formation of new lesions, commencement of healing of established lesions, and decrease in pruritus Consolidation phase Intensity of therapy needed to control disease maintained until about 80% of established lesions have healed Maintenance phase Intensity of therapy gradually reduced to lowest level needed to prevent appearance of new lesions

by a pronounced reduction or complete suppression of new lesion formation, absence of itching, and the beginning of healing of established lesions. The importance of treating the disease intensely enough to suppress disease activity cannot be over emphasised, because if not achieved tapering of treatment will probably not be possible. The length of the control phase is measured in weeks.61 Pemphigus responds rapidly to treatment (within 2 weeks) in most instances if the right dose of medication is used. Continued disease activity indicates inadequate treatment or a complicating factor. The initial treatment is identied by the extent and rate of progression of lesions.56 If they are few and progressing slowly, individual lesions can be treated topically with high-potency corticosteroid ointments or with intralesional injections of corticosteroids. New lesions that continue to appear in numbers that cannot easily be managed topically should be controlled with a low dose of oral prednisone (2040 mg per day). Patients who do not respond, or those who initially have extensive or rapidly progressive disease, are treated with a moderately high dose of prednisone (7090 mg daily). This dose is escalated every 12 weeks (depending on disease activity and severity) in 50% increments until disease activity is controlled. If only corticosteroids are used, this dose might have to be escalated in resistant patients to 240 mg per day or more. If patients do not respond to prednisone 120 mg daily or more, other treatment options should be tried. Plasmapheresis62,63 can be used to physically remove pathogenic intercellular antibodies. The procedure is normally done three times a week, removing about 2 L of plasma on every occasion. Plasmapheresis is most effective if coupled with the administration of a cytotoxic drug, such as azathioprine or cyclophosphamide, to prevent the rebound in antibody concentrations that otherwise occurs.64,65 Plasmapheresis can, however, be complicated by severe infections, and is being increasingly replaced by administration of intravenous immunoglobulin (IVIg).5154 IVIg is an interesting option, because it seems to work in pemphigus by selectively and rapidly decreasing circulating concentrations of pathogenic pemphigus antibodies.66 Serum concentrations of the antibodies have been reported66 to decrease by more than half within 12 weeks of initiation of IVIg. The decrease is selective, because total concentrations of IgG increase rather than decrease.66 This treatment is, therefore, different from all other treatments, which non-specically suppress immune function. We believe IVIg works by rapidly increasing the catabolism of immunoglobulin molecules as a response to the pronounced increase in the serum concentrations that follow the procedure. This reaction results in the selective depletion of only pemphigus antibodies, since serum concentrations of other antibodies are replaced
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by those in the administered immunoglobulin. IVIg is generally administered at a dose of 2 g per kg bodyweight over 35 days.67,68 Within 12 weeks, IVIg can control disease activity unresponsive to high doses of systemic corticosteroids in many patients.64 However, multiple cycles given every 24 weeks are usually needed.69 As with plasmapheresis, the effectiveness of IVIg seems to be improved by the concomitant administration of a cytotoxic drug, such as cyclophosphamide or azathioprine.70 With both plasmapheresis and IVIg, serum intercellular antibody concentrations should be monitored, to ensure the patient is responding. The procedure has not been assessed in randomised trials. Pulse therapy with intravenous methylprednisolone 1 g per day for 5 days71 is another option. No comparative studies have been done to assess the relative effectiveness of these procedures. Patients who do not respond to these approaches could have secondary bacterial, fungal, or viral (herpes simplex) contamination of skin lesions, which should be treated. This possibility can be excluded only by appropriate culture of skin lesions, since the clinical appearance of infected lesions does not differ from those that are not infected.

Consolidation phase
During this phase the type and dose of medication(s) needed to control disease activity are maintained until most lesions have healed. The length of this period is also measured in weeks, not months. If lesions are slow to heal, the intensity of therapy is inadequate and should be increased. Treatment should not be tapered until most lesions (about 80%) have healed to reduce the chances of a subsequent are in disease activity. A major unanswered question is whether ares in disease activity can be cut by more intensive or longterm therapy during the control or consolidation phase of treatment, or both, or by use of adjuvant therapies.

Maintenance phase
The maintenance phase begins once most lesions have healed. The doses of medications are gradually tapered to the lowest concentration needed to suppress the appearance of new lesions. The aim is to eventually discontinue all systemic medication. This goal can be achieved over time in most patients.45 If the patient is on multiple drugs, these should be tapered one at a time. The rate of dose reduction is an essential part of the art of treating this diseasetapering too rapidly increases the chances of a are, while tapering too slowly leads to unnecessary exposure to the side-effects of medication. One approach is to reduce prednisone doses by about a quarter every one to two weeks, and to gradually convert to an alternate day schedule once the daily dose is at 8090 mg. The rate at which medications are tapered is based on the clinical manifestations of disease. Because there is a
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correlation between serum intercellular antibody concentrations and disease activity, tapering should proceed more slowly if the concentration of these antibodies does not continue to fall. If a few (one to ve) new lesions appear while medications are being tapered, these can be treated with intralesional corticosteroids or high potency topical corticosteroids, maintaining the patient on their current dose of systemic medications. If many new lesions appear, however, then we believe the dose of corticosteroids should be increased in 2550% increments until control is re-established. Systemic corticosteroids are the mainstay of treatment for pemphigus, but the high and prolonged doses needed can have side-effects that can be serious. Alternative treatments are therefore continually being sought. Because other drugs are generally used together with, rather than instead of, steroids, they are normally referred to as adjuvant therapies.44 Although widely used, the role of adjuvant therapies in the treatment of pemphigus remains uncertain, since objective data on their effectiveness in the form of randomised clinical trials are mostly lacking. In the few instances in which an adjuvant treatment cyclophosphamide,59 cyclosporin60has been studied in a randomised trial, they were ineffective. The following indications for their use are reasonable: presence of relative contraindications to the use of systemic corticosteroids, development of serious side-effects to corticosteroids, or inability to reduce corticosteroid doses without repeated ares in disease activity. Agents used as adjuvants include various immunosuppressive drugssuch as cyclophosphamide, azathioprine, cyclosporin, methotrexate, and mycophenolic acidanti-inammatory drugssuch as gold, dapsone, and antimalarialsand antibioticssuch as tetracycline and minocycline.57 There is thought to be a lag phase of 46 weeks before most of these agents become effective. Because there is no hard data on their relative effectiveness, the choice of a particular agent is based on the doctors experience with that drug and the patients underlying medical condition(s), which might make the side-effect prole of one agent more desirable than that of another. As an example, the chronic use of immunosuppressive agents, such as cyclophosphamide, is associated with loss of fertility and an increased risk of cancer; thus, they should be avoided in patients wanting to have children. In our experience, the two adjuvant treatments that have most consistently permitted systemic corticosteroids to be tapered without a are in disease activity have been mycophenolate mofetil7274 and methotrexate.75 Mycophenolate mofetil is used at a dose of 23 g a day. We use methotrexate at a dose of 255 mg that is given orally every 12 h for three doses, once every week. Methotrexate should not be given to patients who are on high doses of corticosteroids, since this
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combination has been associated with sepsis. Detailed summaries of the activity of these agents and their method of use in the treatment of pemphigus have been published.76 Based on the response of a few patients with pemphigus foliaceous treated with dapsone only,77 this drug is a preferred adjuvant for the treatment of this form of pemphigus. The mechanism of action of these drugs in pemphigus is not known. They do not necessarily work by suppressing the formation of autoantibodies, since patients can improve while intercellular autoantibodies remain in the circulation. They might work locally at the site of the lesion by blocking the processes that cause acantholysis, by suppressing local inammatory response, or by increasing the adhesive properties of keratinocytes. Topical treatment is used to reduce pain to a minimum and to prevent and treat secondary infections, which can delay response to therapy. Pain and the sticking of clothing to lesions can be reduced with a light coating of an ointment such as vaseline. Lesions can be kept clean with compresses of normal saline or diluted bacteriostatic solutions, such as silver nitrate or potassium permanganate. Recalcitrant individual lesions can be treated with topical high potency corticosteroids, such as clobetasol, or with intralesional corticosteroid injections. Intralesional corticosteroids are more effective when given in high concentrationseg, 20 g/L triamcinolone acetonide. This dose can, however, cause local and temporary atrophy of the skin. This complication is acceptable since it might permit more rapid reduction of systemic corticosteroids, whose potential side-effects are far more serious. Individual lesions of pemphigus have been reported to also respond to topical tacrolimus,7881 but in our opinion this agent is of limited use. Lesions that do not respond to therapy should be cultured to exclude secondary infections such as candidiasis or herpes simplex, which are often unsuspected. Oral lesions are a challenge because they respond to therapy much more slowly than lesions on the skin. High-potency topical corticosteroids such as clobetasol, steroids in an adherent base such as triamcinolone acetonide in gelatin, letting tablets of corticosteroids dissolve in the oral cavity rather than swallowing, and rinsing with dexamethesone solution can all be useful. Probably most effective is intralesional injection of triamcinolone acetonide at a concentration of 20 g/L. Secondary infection with candida is a recurrent problem that can be managed with clortimazole troches or similar antifungal medications. Good oral hygiene and the treatment of periodontal disease is important, but should be weighed against the known propensity of dental trauma to exacerbate oral disease. Pain in the throat after swallowing should be assessed by laryngoscopy to ascertain whether it is due to recurrent pemphigus or secondary candidiasis.
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An important element of management is the regular monitoring of patients for side-effects. Summaries of the side-effects of the drugs used to treat pemphigus are available.76,82 The side-effects of corticosteroid can be reduced by prophylactic use of antacids, calcium, vitamin D, exercise, avoidance of smoking, and a low salt and low sugar diet. Guidelines for the prevention of steroid-induced osteoporosis should be followed.83 Patients should be closely followed-up, especially while their disease is active and while medications are being tapered, because pemphigus is a dynamic disease that responds rapidly to appropriate therapy. In our opinion, doses of medication should be adjusted frequently, increasing them if there is little or no response and decreasing them if the patient is responding well.

Future treatments
Various treatment avenues are being explored, involving more potent, but non-specic, approaches to suppress the production of pemphigus antibodies, and selective procedures that remove or prevent the production of only those antibodies that are pathogenic. Most of the approaches have been assessed in limited numbers of patients so their effectiveness, toxicity, and ultimate role in the management of pemphigus remain uncertain. Complicating the assessment of these new approaches is the fact that patients are often treated concurrently with other therapies known to be effective in pemphigus. The most radical approach for non-specic suppression of the formation of pemphigus antibodies is the administration of immunoablative doses of cyclophosphamide (50 mg per kg bodyweight daily for 4 days) without stem-cell rescue. This option has been tried in three patients with pemphigus.84,85 Slow healing of skin lesions over several months was noted in two patients, and no response in the third. All patients had febrile neutropenia. There was no evidence that this treatment was safer or more efcacious than daily oral cyclophosphamide.84 A more selective but still nonspecic approach is to attempt to suppress the formation of pemphigus antibodies with rituximab. Rituximab is a chimeric murine-human monoclonal antibody against CD20, an antigen expressed on the surface of pre-B and mature B cells, but absent on plasma cells that actually synthesise antibodies. The drug reduces circulating B cells and prevents their maturation into antibodysecreting plasma cells. It suppresses the production of all plasma cells, not just those making pathogenic antibodies. Rituximab has been used at a dose of 375 mg/m2 weekly for 4 weeks to treat a few patients with pemphigus.8690 In most individuals, previously unresponsive skin lesions cleared in 14 months, and some patients eventually entered complete remission that permitted withdrawal of all therapy. Not all patients responded. About half of those treated developed severe
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infections, one of which was fatal.86 Another selective but still non-specic approach is to remove serum pemphigus antibodies with extracorporeal immunoadsorption columns that bind IgG antibodies. Such columns can be constructed from several absorbents. Those assessed in pemphigus include protein A91 and tryptophan-linked polyvinyl alcohol.92 Immunoadsorption is similar to plasmapheresis in that it physically and non-specically removes IgG antibodies. By contrast with plasmapheresis, immunoadsorption does not remove albumin and non-IgG serum proteins, and thus might have fewer side-effects. However, the capacity of the available immunoadsorption columns to remove large amounts of IgG is limited. Even though pemphigus results from abnormal antibodies directed against a limited set of antigens, therapies such as systemic corticosteroids and cytotoxic agents non-specically suppress all immune responsesgood and bad. The toxicity of the treatment is therefore increased and its intensity limited. Future therapies need to be selective, and there is evidence that this aim can be achievedIVIg is such an approach. Another approach involves the intravenous administration of high-dose desmoglein 3 peptides, which are recognised by immunomodulatory T cells, in an effort to induce high-dose tolerance. This procedure is safe and is being assessed in clinical trials. A third approach is to selectively block the acantholytic activity of pemphigus antibodies with cholinergic agonists such as pyridostigmine bromide. This approach is also being assessed in clinical trials. Finally, the formulation of acantholysis and blisters is an active process that depends on energy and enzymatic activity. Drugs that block these pathways could prove therapeutically helpful.

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Prevention
Several factors can exacerbate pemphigus, such as dental work, exposure to the sun, radiographs, stress, and trauma. All should be avoided. In our experience, ares in disease activity after dental work are sufciently common to warrant prophylactic administration of 20 mg per day prednisone in addition to the patients normal requirement for 57 days, beginning with every dental procedure that is associated with trauma to the gums. Patients should be told to avoid exposure to the sun as much as possible and to use broad-spectrum sunprotective creams and clothing.
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Vecchietti G, Kerl K, Hugli A, Samson J, Borradori L. Topical tacrolimus (FK 506) for relapsing erosive stomatitis in paneoplastic pemphigus. Br J Dermatol 2003; 148: 83334. Hodgson TA, Malik F, Hegarty AM, Porter SR. Topical tacrolimus: a novel intervention for recalcitrant labial pemphigus vulgaris. Eur J Dermatol 2003; 13: 14246. Lester RS, Knowles SR, Shear NH. The risks of systemic corticosteroid use. Dermatol Clin 1998; 16: 27778. Nishimura J, Ikuyama S. Glucocorticoid-induced osteoporosis: pathogenesis and management. J Bone Min Metabol 2000; 18: 35052. Nousari CH, Brodsky R, Anhalt GJ. Evaluating the role of immunoablative high-dose cyclophosphamide therapy in pemphigus vulgaris. J Am Acad Dermatol 2003; 49: 14850. Hayag MV, Cohen JA, Kerdel FA. Immunoablative high-dose cyclophosphamide without stem cell rescue in a patient with pemphigus vulgaris. J Am Acad Dermatol 2000; 43: 106569. Morrison LH. Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (Rituximab). J Am Acad Dermatol 2004; 51: 81719.

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