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Pemphigus is a rare but serious autoimmune diseasethat causes blistering of the skin and oral cavity. Ifuntreated it is almost always fatal. It is caused byautoantibodies directed against antigens on the surfaceof keratinocytes, the cells of the epidermis. There aretwo basic forms of pemphigusvulgaris andfoliaceouswhich affect different layers of the skin,have different symptoms, and target differentantigens.1 In pemphigus vulgaris blisters develop justabove the basal-cell layer and are associated withautoantibodies to desmoglein 3, a keratinocyte cell-

surface adhesion molecule. In pemphigus foliaceousthe blisters are high in the epidermis, just below thestratum corneum, and are associated with antibodiesagainst desmoglein 1, another cell-surface adhesionmolecule. There are several subtypes of each form.

EpidemiologyPemphigus has an incidence of 0755 cases permillion per year.2 Incidence of the various forms of thedisease, however, varies from country to country.Pemphigus vulgaris is most common in Europe andthe USA, for example, whereas pemphigus foliaceousis more prevalent in Africa3 and in certain rural areas inunderdeveloped nations, where it affects up to 3% of

the population.4

Pemphigus vulgarisPemphigus vulgaris can develop at any age, but is mostcommonly diagnosed in the fourth to sixth decades oflife. Although the disease can affect anyone, it is mostprevalent in people of Mediterranean or Jewishancestry. Furthermore, individuals with certain HLAallotypes are predisposed to the disease, though thesusceptibility gene differs dependent on ethnic origin.Thus, HLA-DRB1*0402 is associated with the diseasein Ashkenazi Jews5 and DRB1*1401/04 andDQB1*0503 in non-Jewish patients of European or

Asian descent.

6,7

However, pemphigus rarely affectsmore than one family member and can arise in

individuals of various HLA types, so cannot beconsidered a hereditary disease.

Pemphigus foliaceousSporadic and endemic forms of pemphigus foliaceousexist. The sporadic form is most common in Europeand the USA, where its incidence is about a fifth to atenth that of pemphigus vulgaris, and is associatedwith HLA DRB1*0102 and 0404.7 Endemic pemphigusfoliaceous (also know as fogo selvagem and Brazilianpemphigus foliaceous) is a variant of the disease that is

frequently diagnosed in certain regions of Brazil andother underdeveloped areas of the world, includingTunisia and Colombia. The susceptibility genes forendemic pemphigus are HLA DRB1*0102, 0404, 1402,and 1406.8 Clinically and histologically, the disease issimilar to sporadic pemphigus foliaceous. However,the endemic form usually affects teenagers andindividuals in their 20s. Furthermore, it can affectmultiple members of the same family. Theepidemiology of the endemic form suggests anenvironmental cause, which remains unidentified9

though an insect vector is suspected.10 Endemicpemphigus typically arises at the interface betweendeveloping and non-developed areas; as an area

becomes urbanised, the disease disappears. The

Lancet 2005; 366: 6173

The Ronald O Perelman

Department of Dermatology

New York University School

Medicine, 5601st Avenue,

New York, NY 10016, USA

(Prof J-C Bystryn MD,

J L Rudolph MD)

Correspondence to:

ProfJean-ClaudeBystryn

[email protected]

PemphigusJean-Claude Bystryn, Jennifer L Rudolph

Pemphigus is a rare autoimmune disease that results in blistering of the skin and oral cavity. It is caused byautoantibodies directed against cell-surface antigens on keratinocytes, which when targeted lose their cellularadhesion properties and separate from one another to form blisters within the epidermis. Differences in theparticular antigens targeted by the antibodies and in the distribution of these antigens in the different regions ofthe body and in the separate layers of the epidermis result in different clinical manifestations of the disease. Thedisease is diagnosed based on its clinical manifestations (flaccid blisters and erosions on skin and oral mucosa),histology (epidermal acantholysis), and immunological abnormalities (circulating and tissue-fixed antibodiesagainst keratinocyte surface antigens). Pemphigus, which if left untreated is almost always fatal, is generallymanaged with topical, oral, or intralesional corticosteroids. Other options include plasmapheresis andintravenous immunoglobulin (IVIg), coupled with cytotoxic drugs. Immunosupressants, anti-inflammatorydrugs, and antibiotics are used as adjuvants, but apart from IVIg, these therapy options are non-specific and more

research is needed to develop treatments with improved side-effect profiles.

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.


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disease is so common in some rural areas of Brazil thatspecialised hospitals have been built to care for affectedindividuals.

PathophysiologyThe basic abnormality in all forms of pemphigus is theseparation of keratinocytes from one another, aprocess known as acantholysis. The primary event isthe dissolution of the intercellular substance followed

by separation of desmosomes. This process leads to theformation of a cleft within the epidermis, which thenenlarges into a bulla.

All forms of pemphigus are associated with thepresence of circulating and skin-fixed autoantibodiesreferred to as intercellular antibodiesagainstkeratinocyte cell-surface antigens (figure 1).11

Circulating intercellular antibodies are present inabout 80% of patients with active disease, and theirtitre usually correlates with disease activity. Tissue-fixed intercellular antibodies are present in lesions andadjacent healthy skin in about 90% of patients. Theyare usually IgG, though IgM, IgA, and the complementprotein C3 might also be deposited. Intercellular

antibodies are uncommon in individuals withoutpemphigus and can, therefore, be used in diagnosis.12

Intercellular antibodies are pathogenic, as evidencedby their ability to induce the histological changes ofpemphigus (acantholysis) in organ cultures of humanskin,13 and clinically and histologically typical lesions ofpemphigus when passively administered to neonatalmice.14,15 Furthermore, placental transfer of maternalautoantibodies can induce transient lesions of thedisease in newborn babies of women with activepemphigus vulgaris.16 The ability to passively transferthe disease in mice with pemphigus antibodies isabrogated by specifically absorbing out antibodiesagainst desmoglein 1 or desmoglein 3,17 confirmingthat pemphigus can be mediated by these antibodies.

Intercellular antibodies are directed against multiple

keratinocyte cell-surface antigens. Of these, theadhesion molecules desmoglein 1 and desmoglein 3are the best characterised.18,19 Both molecules aredesmosomal transmembrane proteins, which belong tothe cadherin gene family.20 The portion of thesemolecules targeted by pathogenic antibodies isexpressed on the external surface of the cells,21 andmultiple epitopes on the same molecule can betargeted.22 The antigens targeted in the two forms ofpemphigus differ.1 In pemphigus vulgaris, intercellularantibodies are predominantly directed againstdesmoglein 3 and less often against desmoglein 1. Inpemphigus foliaceous, they are predominantly directedagainst desmoglein 1. Serological analysis23 suggests

that antibodies are also directed to other antigens, anobservation confirmed by the induction of pemphigus-like lesions in mice given intercellular antibodies notdirected against desmoglein 1 or desmoglein 3.24 Theseadditional antigens seem to include acetylcholinereceptors on keratinocytes.25

Whether intercellular antibodies cause clinicaldisease seems to depend on the subclass of theantibody response. Thus, IgG1 antibodies againstdesmoglein 3 are present with equal frequency inindividuals with or without pemphigus vulgaris, butIgG4 antibodies are present almost exclusively inpatients with active disease.26 Likewise, IgG1 antibodies

against desmoglein 1 are present in a high proportionof individuals with or without endemic pemphigus andwith or without active disease in areas where thiscondition is common in Brazil, but IgG4 antibodiesagainst this same antigen are present in much higherconcentrations in patients with active disease than inthose with inactive disease or in unaffectedindividuals.9 As such, in endemic pemphigus, an as yetunknown environmental agent might trigger theproduction of non-pathogenic IgG1 antibodies againstdesmoglein 1, and the appearance of clinical diseasemight be triggered by the presence of an HLAsusceptibility gene required for the production of apathogenic IgG4 response.9 A similar subclass

switching might be involved in the clinical appearanceof the other forms of pemphigus. Whether the differentpathogenic activity of IgG1 and IgG4 antibodies is dueto differences in effector function or the differentsubclasses being directed to different epitopes on thetargeted antigens is unknown.

The exact process by which intercellular antibodiescause loss of cellular adhesion is unclear. Asmentioned, the subclass of the IgG response seems tobe important.9,22 Perhaps the antibodies physically blockadhesion sites on desmoglein27 or on other adhesionmolecules, or maybe they interfere with their structureor other functions or with the assembly ofdesmosomes.28,29 Another possibility is that theystimulate release of proteolytic enzymes. It is note-

Figure 1: Indirect immunofluorescence photomicrograph of the reaction of

intercellular antibodies in the serum of a patient with pemphigus againstantigens expressed on the surface of keratinocytes in normal human skin

Reproduced by permission of the New York University Department of

Dermatology.


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worthy that in staphylococcal scalded skin syndrome,

which is caused by a toxin that binds to and cleavesdesmoglein 1, patients develop blisters similar to thosecaused by pemphigus foliaceous.30 Last, we believeanother possibility for acantholysis is that theantibodies trigger a signalling event that causesreorganisation of the cytoskeleton of keratinocytes,causing the affected cells to shrink, pull away, and thusseparate from adjacent keratinocytes.

Little is also known about how intercellularautoantibodies arise. In most individuals, the disease isidiopathic. However, in some it is triggered by an

external cause, such as a drug (table).31,32 Different

drugs cause different forms of pemphigus.

33

Differences between pemphigus vulgaris, the deepform, and pemphigus foliaceous, the superficial form,seem to reflect regional variations in the expression ofantigens targeted by autoantibodies in the two forms ofthe disease, with lesions occurring in areas whereantigen expression is greatest.

Consider, for example, the striking difference in thelocation of lesions within the epidermis betweenpemphigus vulgaris and pemphigus foliaceous: blistersin pemphigus vulgaris occur deep in the epidermis,just above the basal-cell layer, whereas those inpemphigus foliaceous arise in the most superficiallayer, just below the stratum corneum (figure 2). There

is a parallel stratification in different layers of theepidermis of the antigens targeted by antibodies in thetwo forms of the disease.34 Desmoglein 1 is presentpredominantly in the superficial layers of theepidermis and is absent in the suprabasal layer,whereas desmoglein 3 is present predominantly in thedeeper layers and is absent in the most superficiallayer.35,36 These observations have led to the desmogleincompensation theory, which states that bothdesmoglein 1 and desmoglein 3 maintain adhesion ofkeratinocytes; in epidermal layers where both areexpressed, one desmoglein isotype compensates for theantibody-induced loss of function in the other.2,37

According to this notion, lesions only arise in thedeepest epidermal layers in pemphigus vulgarisbecause there is no desmoglein 1 there to compensatefor the action of the antibodies against desmoglein 3,and vice versa in pemphigus foliaceous, where there isno desmoglein 3 in the most superficial epidermallayer to compensate for the action of antibodies againstdesmoglein 1. Theoretically, blisters do not arise inother epidermal layers in either disease because bothdesmogleins are present. However, this theory does notexplain the absence of blisters throughout theepidermis in the substantial minority of patients withpemphigus vulgaris who have antibodies against bothdesmoglein 3 and desmoglein 1.

Another important difference between the two formsof pemphigus is in the distribution of lesions over thebody. Oral lesions are common in pemphigus vulgarisbut do not occur in pemphigus foliaceous, lesions onthe scalp, face, and upper torso are common in bothforms of pemphigus, and rare on the legs in both.There is a similar anatomical variation in theexpression of the antigens targeted by autoantibodiesin the two forms of the diseasethe mouth expresseshigh concentrations of antigen related to pemphigusvulgaris but low concentrations of those associatedwith pemphigus foliaceous, and the expression of bothtypes of antigens is high on the face, scalp, and uppertorso but low on the legs.38 Consequently, we believethe regional variation in the distribution of skin lesions

Thiols Angiotensin-converting O thers

enzyme inhibitorsPenicillamine Enalapril Aspirin

Benzylpenicillin Cilazapril Non-steroidal anti-inflammatory

drugs (NSAID)

Captopril Fosinopril Rifampicin

Tiopronin Ramipril Levodopa

Cephalosporin Phenobarbital

Pyritinol Pentachlorophenol

Interferon

Interleukin

Propranolol

Nifedipine

Table: Drugs implicated in pemphigus32

Figure 2: Photomicrograph of skin lesion of pemphigus vulgaris (upper) and

pemphigus foliaceus (lower)

Reproduced by permission of the New York University Department ofDermatology.


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is due to similar regional variations in the expression of

the antigens targeted by the autoantibodies in thedifferent forms of pemphigus.38 In support of thisconclusion is the fact that in bullous pemphigoid,another autoantibody mediated blistering diseasewhere the distribution of skin lesions differs markedlyfrom that in pemphigus, there is also a striking relationbetween the distribution of skin lesions and theexpression of the antigens targeted by theautoantibodies of that disease.39

The distribution of lesions could also be affected bythe profile of autoantibodies: oral lesions are morecommon in patients with antibodies only againstdesmoglein 3, mucosal and oral lesions are usuallyonly associated with the presence of antibodies against

both desmoglein 3 and desmoglein 1, and skin lesionswithout oral lesions are usually only present in patientswith antibodies against desmoglein 1 alone.40 Theserelations, however, are not universal. The desmogleincompensation theory has also been proposed to explainthis relation.41 According to that theory, oral lesionsarise only in pemphigus vulgaris, because only thosepatients have antibodies against desmoglein 3 and onlydesmoglein 3 is present in the oral cavity. However,this hypothesis does not explain why lesions do notappear in all layers of the oral mucosa, since there is nodesmoglein 1 to compensate for the inactivation ofdesmoglein 3. Furthermore, the theory does not

explain why both desmoglein 3 and desmoglein 1antibodies are, according to the hypothesis, requiredfor lesions to appear on skin in patients withpemphigus vulgaris, since the lesions arise only in thedeep layers of the epidermis where there is nodesmoglein 1 and where antibodies againstdesmoglein 1 should have no effect.

There is little inflammatory cell infiltrate in pem-phigus lesions, suggesting cellular immune mecha-nisms are not directly involved in the pathogenesis ofdisease. However, T-cell responses could play a part inregulating the formation of pathogenic auto-antibodies.42

Clinical featuresDeep forms of pemphigusThere are two deep forms of pemphiguspemphigusvulgaris and pemphigus vegetans. Pemphigus vulgarisis more common that pemphigus vegetans and usually,but not invariably, begins with painful, non-healingulcerations in the mouth. Blisters are rare, since theyrupture soon after forming, leaving an ulcerated area.Ulcerations are usually multiple, superficial, andirregular in shape, and arise from mucosa of healthyappearance. Although any surface can be involved, themost common sites are the buccal and labial mucosa,the palate, and the tongue. The ulcers of pemphigusvulgaris do not heal, by contrast with the oral lesions ofaphthmous stomatitis or viral infections that heal in a

matter of days or weeks. Ulcers are multiple; this factor

differentiates them from an ulcerated tumour, which issingle. Because the disease is rare, pemphigus is notoften diagnosed at a first examination, but ratherconsidered only after lesions have been present forweeks to months and after the patient has notresponded to antibiotic, antifungal, or antiviral therapy.Pemphigus should be considered in anyone who hasmultiple, non-healing oral ulcers that persist for longerthan a month.

After weeks to months, the condition progresses withlesions appearing on the skin (usually on the scalp,face, and upper torso) and with symptoms indicative ofnasal and oesophageal involvement. Occasionally, skinlesions are the initial manifestation of the disease. Skin

lesions usually begin as small blisters that are filledwith a clear fluid and that arise from normal appearingskin. The blisters are usually flaccid, because theoverlying epidermis is thin and cannot sustain muchpressure. Since they are thin, the blisters rupture inseveral days and are replaced by sharply outlined, coin-sized, superficial erosions with a collarette of looseepidermis (figure 3). Lesions appear most often on thescalp, upper chest, and back. They have a tendency toinvolve the medial or central portion of the torso ratherthan the sides. Other areas commonly involved are theface and neck, but any surface covered by stratifiedsquamous epithelium can be affected. Sites often

overlooked include: the periungual areas, the pharynx,and larynx, manifested by pain on swallowing food andby hoarseness; the nasal cavity, manifested by nasalcongestion and morning mucous discharge; and thecervix. Laryngeal and nasal involvement is morefrequent than usually believed. In one systematicstudy,43 49% of patients had symptoms of laryngeal ornasal involvement, or both. Because the symptoms oflaryngeal involvement are identical to those ofcandidiasis, an ear, nose, and throat (ENT) assessmentshould be done to differentiate between these twoconditions, which are treated very differently.

Figure 3: Characteristic skin lesions of pemphigus vulgaris



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A characteristic feature of all forms of active andsevere pemphigus is the Nikolsky sign, in which firm,sliding pressure on normal appearing skin causesseparation of the epidermis from the underlyingdermis. This sign is elicited most easily adjacent to anactive lesion. In its extreme forms, the pressure exertedon the skin simply by lifting a patient can shear offsubstantial portions of the epidermis.

Left untreated, bullae and erosions spread (figure 4).As with burns, these lesions can be complicated when

widespread by severe infection or metabolicdisturbance, or both, leading to death. Before systemiccorticosteroids became available, about 75% of patientswho developed pemphigus vulgaris died within a year.44

However, improved diagnostic techniques now permitthe recognition of more subtle forms of disease,indicating that the severity of pemphigus can varywidely. Mild forms can regress spontaneously, and theprogression of even the most severe forms can almostalways be reversed with appropriate treatment.

With treatment, lesions heal with crusting followedby re-epithelialisation. There is no scarring, thoughthere can be residual hyperpigmentation at sites offormer lesions. This sign usually disappears in severalmonths. Most patients with pemphigus vulgaris

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 lesion-free and need no therapy. In a longitudinal study45 ofoutcome in 40 patients, half of patients were incomplete and long-lasting remission after 5 and three-quarters after 10 years.

As medications are tapered flares in disease activity,evidenced by new crops of lesions and itching, are notuncommon.45 Our personal experience of managingseveral hundred patients has highlighted severalfactors that can trigger a flare and that should be kept toa minimum. These include dental work, exposure tothe sun, cutaneous trauma, infection, and stress.

Pemphigus vegetans is a variant of pemphigusvulgaris in which healing is associated with vegetatingproliferation of the epidermis. Lesions usually appearin intertriginous areas such as the axillae, groin, andinframammary area. The disease is thought to arise inpatients with a less aggressive form of pemphigus or inthose in whom the intensity of therapy is sufficient toprevent new lesions but not sufficient to healestablished lesions. Because of their location, thelesions are generally secondarily infected, which slowshealing.

Superficial forms of pemphigus

Superficial forms of pemphigus include pemphigusfoliaceous, pemphigus erythematosus, and endemicpemphigus foliaceous. The pathology of these diseasesis so superficial that there is insufficient overlyingtissue to trap fluid 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 beendescribed as cornflakes. The crusts can easily beremoved, leaving superficial erosions. Untreatedlesions do not heal, and over weeks to months increasein number. In severe cases, the lesions become

Figure 4: Pemphigus vulgaris

Reproduced by permission of the New York University Department of

Dermatology.

Figure 5: Pemphigus foliaceous



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confluent and can resemble an exfoliative

erythroderma, involving the entire skin surface(figure 5). By contrast with the deep forms ofpemphigus, oral involvement is rare.

There are two clinical variants of pemphigusfoliaceouspemphigus erythematosus and fogoselvagem. In pemphigus erythematosus, the disease islocalised to the face and is characterised by anerythematosus scaly-to-crusted rash often in a butterflydistribution that resembles lupus erythematosus. Inaddition to the tissue-fixed intercellular deposits ofantibodies that are present in all forms of pemphigus,there are often granular deposits of immunoglobulin orcomplement, 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 alternateexplanation, therefore, which we favour, is that granulardeposits are common in pemphigus erythematosusbecause the face is generally the only site involved, andsuch deposits are common in that location.

Fogo Selvagem (endemic pemphigus, Brazilianpemphigus foliaceous) is unique in that it occurs inepidemic form in certain rural areas of the world.Clinically, histologically, and immunologically, it isotherwise identical to pemphigus foliaceous.47,48

The prognosis of untreated pemphigus foliaceous isbetter than that of pemphigus vulgaris, probablybecause lesions are more superficial and there is lessrisk of infection, fluid loss, and metabolic disturbance.However, the treatment is no easier, since the doses ofdrugs needed to control pemphigus foliaceous can besimilar to those used for pemphigus vulgaris.

Drug-induced pemphigusCertain drugs can trigger both pemphigus vulgaris andpemphigus foliaceous.31 Though uncommon, thispossibility should be excluded in all patients withnewly diagnosed disease.32 The clinical, histological,49

and immunofluorescence abnormalities50 of drug-

induced and idiopathic pemphigus are similar. Variousdrugs can act as triggers (table), and some31 havesuggested that the nature of the drug could affect boththe type of pemphigus triggered and the prognosis.The most commonly implicated drugs arepenicillamine, followed by angiotensin-convertingenzyme inhibitors, such as captopril.

Pemphigus in pregnancyPemphigus is associated with an increased risk ofpremature birth and fetal death.51 It is noteworthy that,as noted previously, the disease can be present inneonates as a result of the passive transfer ofpathogenic antibodies from the mother, in which casepemphigus will resolve spontaneously.

Diagnosis

Diagnosis is based on three independent sets of criteria:clinical features, histology, and immunological tests. Theclassic clinical findings of pemphigus vulgaris aremultiple flaccid blisters arising from healthy skin,multiple chronic oral ulcers, and a positive Nikolsky sign.Histologically, there is an intraepidermal blisterassociated with acantholytic cells. The blister isimmediately above the basal-cell layer in pemphigusvulgaris and vegetans and just below the strateumcorneum in pemphigus foliaceous and erythematosus.Acantholytic cells can also be seen in other conditions,such as Hailey-Hailey disease and impetigo. Establishinga diagnosis depends on the findings of clinical,histological, and immunological tests being in agreement.

Immunologically, all forms of pemphigus areassociated with circulating and tissue-fixed intercellularantibodies against keratinocyte surface antigens.12,52

Circulating intercellular antibodies are detected byindirect immunofluorescence assays on serum, andtissue-fixed intercellular antibodies by direct immuno-fluorescence assays on skin biopsies. In both instances, alace-like pattern of fluorescence within the epidermis isseen (figure 1). Circulating antibodies can also be presentin low titres in patients with antibodies to ABO bloodgroup antigens or with burns, fungal infections, orallergic drug reactions. ELISA assays are available todetect antibodies to desmoglein 1 and desmoglein 3. The

presence of antibodies against desmoglein 3 sometimestogether with those against desmoglein 1 is associatedwith pemphigus vulgaris, whereas antibodies todesmoglein 1 alone are associated with pemphigusfoliaceous.22 ELISA is more specific and somewhat moresensitive than indirect immunofluorescence. However,the results are not quantitative if antibody concentrationsare high because the assay plates become saturated.53 Thepresence and concentration of these antibodies isnormally related to the activity of the disease, and theyusually disappear in patients in remission. Serialmeasurements of intercellular antibodies can be helpfulin guiding therapy since they usually decrease withsuccessful treatment, while disease is more likely to

remain active or be exacerbated in patients withpersistently raised concentrations.

Tissue-fixed intercellular antibodies are present inlesions and adjacent healthy skin in about 90% of patientswith pemphigus.12,52 These antibodies are more sensitiveand specific for the diagnosis of pemphigus thancirculating antibodies. They are usually IgG; but IgM andIgA with or without C3 might also be deposited.

Pemphigus should be differentiated from the manyother conditions that also cause skin blisters. Theseconditions can often be excluded clinically by the historyof the illness, the appearance of the individual lesions,and their distribution. However, because of theseriousness of the disease, the diagnosis should beconfirmed by pathology and by immunofluorescence or


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ELISA assays for pemphigus antibodies. Blisters that

follow an injury to the skin, such as those resulting fromburns, frostbite, or contact dermatitis, can be excluded bythe patients history, and blisters due to viral or bacterialinfections by their brief duration.

Blisters arise as a sign of many autoimmune, genetic,and metabolic diseases. In most of these cases theblisters occur within or below the dermal-epidermaljunction and can readily be excluded by skin biopsy.These conditions include bullous and cicatricialpemphigoid, herpes gestationis, linear IgA bullousdermatosis, epidermolysis bullosa, porphyria cutaneatarda, and erythema multiforme. To maximise theinformation that can be obtained, a biopsy should bedone at the edge of an active lesion and include some

adjacent healthy skin so that the level of the blister can beaccurately identified. Additionally, the antibodies presentin autoimmune subepidermal blistering diseases reactagainst antigens at the dermal-epidermal junction ratherthan within the epidermis.

In several other diseases associated with blistering, suchas impetigo, staphylococcal scalded-skin syndrome,Hailey-Hailey disease, and subcorneal bullous disease,the blisters are situated within the epidermis. Differentialdiagnosis is especially difficult with chronic impetigo,since the clinical and histological appearance of these skinlesions is almost identical to those of pemphigusfoliaceous. However, there are normally fewer lesions in

impetigo and they are asymmetrically distributed andgenerally heal rapidly with antibiotic therapy. In theseconditions, circulating or tissue-fixed intercellularantibodies are absent.

Some judge paraneoplastic pemphigus a variant ofpemphigus, because it is associated with acantholysis andwith antibodies against desmoglein 3 and desmoglein 1.In our opinion, paraneoplastic pemphigus, which isusually associated with an underlying lymphoproliferativeneoplasm, is a separate disease. As with pemphigusvulgaris, skin lesions can arise both in the oral mucosaand skin, and there is histological acantholysis andintercellular antibodies both on direct and indirectimmunofluorescence.54 But it differs in various clinical,

histological, and immunological features from otherforms of pemphigus. Oral lesions in paraneoplasticpemphigus, for example, characteristically involve thevermilion border of the lips, the skin lesions oftenresemble those of erythema multiforme or toxicepidermal necrolysis, and histologically there are interfacechanges at the dermal-epidermal junction. Furthermore,on direct immunofluorescence abnormal deposits ofimmunoglobulin or complement, or both, are alsopresent at the dermal-epidermal junction, theintercellular antibodies also react against columnar andtransitional epithelia, and, most importantly, theantibodies are also directed against plakin proteins (suchas envoplakin and periplakin).54 None of theseabnormalities occurs in pemphigus.

Assessment and management

Before treatment is initiated, the diagnosis ofpemphigus should be confirmed by review of theclinical, histological, and immunofluorescence data,since the disease usually requires long-term therapywith potentially serious side-effects. Involvement of thepharynx, larynx, and nasal cavity should be assessed byENT examination if there are symptoms to suggestinvolvement of these areas. The patients overallmedical status should also be assessed to identifywhether they are at greater risk of developingcomplications from corticosteroids or other systemicmedications that could be used, and to provide abaseline against which to monitor potential treatment-induced complications. There are no real absolute

contraindications to systemic steroids, which are lifesaving in this disease. The presence of diabetes,hypertension, duodenal ulcers, cataracts, osteoporosis,psychiatric illness, and other risk factors mandatescloser observation and use of preventive measures, andis an indication for adjuvant therapy to hopefullyreduce the total dose of steroids needed.

If the patient is to be treated with systemiccorticosteroids, a tuberculin test and chest radiographshould be done to look for evidence of exposure totuberculosis; if present, prophylactic therapy should beadministered. Baseline bone density studies andophthalmological assessment should be undertaken

and repeated periodically while the patient is oncorticosteroids. Other investigations recommendedbefore the initiation of therapy are haematocrit,complete blood cell count and differential, serum ureacreatinine, and electrolytes, liver function tests, fastingglucose test, urinalysis, and assessment of thiopurinemethyl transferase concentrations if azathioprine is tobe used and of glucose-6-dehydrogenase andreticulocyte count if dapsone is to be used.55

The patients worries or lack of concern about theirillness should also be addressed. Some patients believethat pemphigus is fatal. They should be reassured thattheir outlook is far better than it used to be, and thateventually a state of remission that needs little or no

therapy is often reached. Other patients are under theimpression that skin diseases are never serious. Theyshould be made to understand that untreatedpemphigus is dangerous and they must undergo alengthy and potentially dangerous treatment to attainremission or cure.

TreatmentThe treatment of pemphigus has been the subject ofmany reviews.5558 Drug trials for pemphigus are difficult.The disease is rare and its severity and response totherapy vary greatly from patient to patient. Althoughthere are many therapies available, few have beenassessed in randomised trials.59,60 A further difficulty inthe assessment and comparison of results of the trials


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that have been done is that there is no commondefinition of the terms and endpoints used to describethe extent, activity, and therapeutic response ofpemphigus. Hence, the best way to treat the diseaseremains uncertain, as does the effectiveness of theavailable therapies. The recommendations made hereare based on existing published work and our experiencewith several hundred patients with the disease.

The therapies used to control pemphigus can bedivided into those that act rapidly and are usually used tocontrol the activity of the disease, and those with adelayed effect that are generally used in chronicmanagement to decrease the need for systemic

corticosteroids (panel 1). The aim of treatment is toinduce a complete remission with minimum side-effectsthat permits all therapy to be discontinued or to use thelowest drug doses that prevent disease activation.Treatment is usually divided into three phases: control,consolidation, and maintenance (panel 2). Since there ismuch heterogeneity in the manifestations of the diseaseand its response to therapy, treatment is tailored to theneeds of the individual patient.56

Control phaseThe control phase of treatment is the period in whichthe intensity of therapy is rapidly escalated until a levelis reached that suppresses disease activity as evidenced

by a pronounced reduction or complete suppression of

new lesion formation, absence of itching, and thebeginning of healing of established lesions. Theimportance of treating the disease intensely enough tosuppress disease activity cannot be over emphasised,because if not achieved tapering of treatment willprobably not be possible. The length of the controlphase is measured in weeks.61 Pemphigus respondsrapidly to treatment (within 2 weeks) in most instancesif the right dose of medication is used. Continueddisease activity indicates inadequate treatment or acomplicating factor.

The initial treatment is identified by the extent andrate of progression of lesions.56 If they are few andprogressing slowly, individual lesions can be treated

topically with high-potency corticosteroid ointments orwith intralesional injections of corticosteroids. Newlesions that continue to appear in numbers that cannoteasily be managed topically should be controlled with alow dose of oral prednisone (2040 mg per day).Patients who do not respond, or those who initially haveextensive or rapidly progressive disease, are treated witha moderately high dose of prednisone (7090 mg daily).This dose is escalated every 12 weeks (depending ondisease activity and severity) in 50% increments untildisease activity is controlled. If only corticosteroids areused, this dose might have to be escalated in resistantpatients to 240 mg per day or more.

If patients do not respond to prednisone 120 mg dailyor more, other treatment options should be tried.Plasmapheresis62,63 can be used to physically removepathogenic intercellular antibodies. The procedure isnormally done three times a week, removing about 2 L ofplasma on every occasion. Plasmapheresis is mosteffective if coupled with the administration of a cytotoxicdrug, such as azathioprine or cyclophosphamide, toprevent the rebound in antibody concentrations thatotherwise occurs.64,65

Plasmapheresis can, however, be complicated bysevere infections, and is being increasingly replaced byadministration of intravenous immunoglobulin(IVIg).5154 IVIg is an interesting option, because it

seems to work in pemphigus by selectively and rapidlydecreasing circulating concentrations of pathogenicpemphigus antibodies.66 Serum concentrations of theantibodies have been reported66 to decrease by morethan half within 12 weeks of initiation of IVIg. Thedecrease is selective, because total concentrations ofIgG increase rather than decrease.66 This treatment is,therefore, different from all other treatments, whichnon-specifically suppress immune function. Webelieve IVIg works by rapidly increasing the catabolismof immunoglobulin molecules as a response to thepronounced increase in the serum concentrations thatfollow the procedure. This reaction results in theselective depletion of only pemphigus antibodies, sinceserum concentrations of other antibodies are replaced

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

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


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by those in the administered immunoglobulin. IVIg is

generally administered at a dose of 2 g per kgbodyweight over 35 days.67,68 Within 12 weeks, IVIgcan control disease activity unresponsive to high dosesof systemic corticosteroids in many patients.64

However, multiple cycles given every 24 weeks areusually needed.69 As with plasmapheresis, theeffectiveness of IVIg seems to be improved by theconcomitant administration of a cytotoxic drug, such ascyclophosphamide or azathioprine.70 With bothplasmapheresis and IVIg, serum intercellular antibodyconcentrations should be monitored, to ensure thepatient is responding. The procedure has not beenassessed in randomised trials.

Pulse therapy with intravenous methylprednisolone

1 g per day for 5 days71 is another option. No comparativestudies have been done to assess the relative effective-ness of these procedures. Patients who do not respond tothese approaches could have secondary bacterial, fungal,or viral (herpes simplex) contamination of skin lesions,which should be treated. This possibility can be excludedonly by appropriate culture of skin lesions, since theclinical appearance of infected lesions does not differfrom those that are not infected.

Consolidation phaseDuring 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 isalso measured in weeks, not months. If lesions areslow to heal, the intensity of therapy is inadequate andshould be increased. Treatment should not be tapereduntil most lesions (about 80%) have healed to reducethe chances of a subsequent flare in disease activity. Amajor unanswered question is whether flares indisease activity can be cut by more intensive or long-term therapy during the control or consolidation phaseof treatment, or both, or by use of adjuvant therapies.

Maintenance phaseThe maintenance phase begins once most lesions havehealed. The doses of medications are gradually tapered

to the lowest concentration needed to suppress theappearance of new lesions. The aim is to eventuallydiscontinue all systemic medication. This goal can beachieved over time in most patients.45 If the patient ison multiple drugs, these should be tapered one at atime. The rate of dose reduction is an essential part ofthe art of treating this diseasetapering too rapidlyincreases the chances of a flare, while tapering tooslowly leads to unnecessary exposure to the side-effectsof medication. One approach is to reduce prednisonedoses by about a quarter every one to two weeks, and togradually convert to an alternate day schedule once thedaily dose is at 8090 mg. The rate at whichmedications are tapered is based on the clinicalmanifestations of disease. Because there is a

correlation between serum intercellular antibody

concentrations and disease activity, tapering shouldproceed more slowly if the concentration of theseantibodies does not continue to fall. If a few (one tofive) new lesions appear while medications are beingtapered, these can be treated with intralesionalcorticosteroids or high potency topical corticosteroids,maintaining the patient on their current dose ofsystemic medications. If many new lesions appear,however, then we believe the dose of corticosteroidsshould be increased in 2550% increments untilcontrol is re-established.

Systemic corticosteroids are the mainstay oftreatment for pemphigus, but the high and prolongeddoses needed can have side-effects that can be serious.

Alternative treatments are therefore continually beingsought. Because other drugs are generally usedtogether with, rather than instead of, steroids, they arenormally referred to as adjuvant therapies.44 Althoughwidely used, the role of adjuvant therapies in thetreatment of pemphigus remains uncertain, sinceobjective data on their effectiveness in the form ofrandomised clinical trials are mostly lacking. In thefew instances in which an adjuvant treatmentcyclophosphamide,59 cyclosporin60has been studied ina randomised trial, they were ineffective. The followingindications for their use are reasonable: presence ofrelative contraindications to the use of systemic

corticosteroids, development of serious side-effects tocorticosteroids, or inability to reduce corticosteroiddoses without repeated flares in disease activity.

Agents used as adjuvants include various immuno-suppressive drugssuch as cyclophosphamide,azathioprine, cyclosporin, methotrexate, and mycophe-nolic acidanti-inflammatory drugssuch as gold,dapsone, and antimalarialsand antibioticssuch astetracycline and minocycline.57 There is thought to be alag phase of 46 weeks before most of these agentsbecome effective. Because there is no hard data on theirrelative effectiveness, the choice of a particular agent isbased on the doctors experience with that drug and thepatients underlying medical condition(s), which might

make the side-effect profile of one agent more desirablethan that of another. As an example, the chronic use ofimmunosuppressive agents, such as cyclophos-phamide, is associated with loss of fertility and anincreased risk of cancer; thus, they should be avoidedin patients wanting to have children. In our experience,the two adjuvant treatments that have mostconsistently permitted systemic corticosteroids to betapered without a flare in disease activity have beenmycophenolate 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 isgiven orally every 12 h for three doses, once every week.Methotrexate should not be given to patients who areon 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 theirmethod of use in the treatment of pemphigus havebeen published.76 Based on the response of a fewpatients with pemphigus foliaceous treated withdapsone only,77 this drug is a preferred adjuvant for thetreatment of this form of pemphigus.

The mechanism of action of these drugs inpemphigus is not known. They do not necessarily workby suppressing the formation of autoantibodies, sincepatients can improve while intercellular autoantibodiesremain in the circulation. They might work locally atthe site of the lesion by blocking the processes thatcause acantholysis, by suppressing local inflammatoryresponse, or by increasing the adhesive properties of

keratinocytes.Topical treatment is used to reduce pain to a

minimum and to prevent and treat secondaryinfections, which can delay response to therapy. Painand the sticking of clothing to lesions can be reducedwith a light coating of an ointment such as vaseline.Lesions can be kept clean with compresses of normalsaline or diluted bacteriostatic solutions, such as silvernitrate or potassium permanganate. Recalcitrantindividual lesions can be treated with topical highpotency corticosteroids, such as clobetasol, or withintralesional corticosteroid injections. Intralesionalcorticosteroids are more effective when given in high

concentrationseg, 20

g/L triamcinolone acetonide.This dose can, however, cause local and temporaryatrophy of the skin. This complication is acceptablesince it might permit more rapid reduction of systemiccorticosteroids, whose potential side-effects are farmore serious. Individual lesions of pemphigus havebeen reported to also respond to topical tacrolimus, 7881

but in our opinion this agent is of limited use. Lesionsthat do not respond to therapy should be cultured toexclude secondary infections such as candidiasis orherpes simplex, which are often unsuspected.

Oral lesions are a challenge because they respond totherapy much more slowly than lesions on the skin.High-potency topical corticosteroids such as clobetasol,

steroids in an adherent base such as triamcinoloneacetonide in gelatin, letting tablets of corticosteroidsdissolve in the oral cavity rather than swallowing, andrinsing with dexamethesone solution can all be useful.Probably most effective is intralesional injection oftriamcinolone acetonide at a concentration of 20 g/L.Secondary infection with candida is a recurrentproblem that can be managed with clortimazoletroches or similar antifungal medications. Good oralhygiene and the treatment of periodontal disease isimportant, but should be weighed against the knownpropensity of dental trauma to exacerbate oral disease.Pain in the throat after swallowing should be assessedby laryngoscopy to ascertain whether it is due torecurrent pemphigus or secondary candidiasis.

An important element of management is the regular

monitoring of patients for side-effects. Summaries ofthe side-effects of the drugs used to treat pemphigusare available.76,82 The side-effects of corticosteroid canbe reduced by prophylactic use of antacids, calcium,vitamin D, exercise, avoidance of smoking, and a lowsalt and low sugar diet. Guidelines for the prevention ofsteroid-induced osteoporosis should be followed.83

Patients should be closely followed-up, especiallywhile their disease is active and while medications arebeing tapered, because pemphigus is a dynamicdisease that responds rapidly to appropriate therapy. Inour opinion, doses of medication should be adjustedfrequently, increasing them if there is little or noresponse and decreasing them if the patient is

responding well.

Future treatmentsVarious treatment avenues are being explored,involving more potent, but non-specific, approaches tosuppress the production of pemphigus antibodies, andselective procedures that remove or prevent theproduction of only those antibodies that arepathogenic. Most of the approaches have been assessedin limited numbers of patients so their effectiveness,toxicity, and ultimate role in the management ofpemphigus remain uncertain. Complicating theassessment of these new approaches is the fact that

patients are often treated concurrently with othertherapies known to be effective in pemphigus.The most radical approach for non-specific

suppression of the formation of pemphigus antibodies isthe administration of immunoablative doses ofcyclophosphamide (50 mg per kg bodyweight daily for4 days) without stem-cell rescue. This option has beentried in three patients with pemphigus.84,85 Slow healingof skin lesions over several months was noted in twopatients, and no response in the third. All patients hadfebrile neutropenia. There was no evidence that thistreatment was safer or more efficacious than daily oralcyclophosphamide.84 A more selective but still non-specific approach is to attempt to suppress the formation

of pemphigus antibodies with rituximab. Rituximab is achimeric murine-human monoclonal antibody againstCD20, an antigen expressed on the surface of pre-B andmature B cells, but absent on plasma cells that actuallysynthesise antibodies. The drug reduces circulatingB cells and prevents their maturation into antibody-secreting plasma cells. It suppresses the production ofall plasma cells, not just those making pathogenicantibodies. Rituximab has been used at a dose of375 mg/m2 weekly for 4 weeks to treat a few patientswith pemphigus.8690 In most individuals, previouslyunresponsive skin lesions cleared in 14 months, andsome patients eventually entered complete remissionthat permitted withdrawal of all therapy. Not all patientsresponded. About half of those treated developed severe


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infections, one of which was fatal.86 Another selective but

still non-specific approach is to remove serumpemphigus antibodies with extracorporeal immuno-adsorption columns that bind IgG antibodies. Suchcolumns can be constructed from several absorbents.Those assessed in pemphigus include protein A91 andtryptophan-linked polyvinyl alcohol.92 Immuno-adsorption is similar to plasmapheresis in that itphysically and non-specifically removes IgG antibodies.By contrast with plasmapheresis, immunoadsorptiondoes not remove albumin and non-IgG serum proteins,and thus might have fewer side-effects. However, thecapacity of the available immunoadsorption columns toremove 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 cytotoxicagents non-specifically suppress all immuneresponsesgood and bad. The toxicity of the treatmentis therefore increased and its intensity limited. Futuretherapies need to be selective, and there is evidencethat this aim can be achievedIVIg is such anapproach. Another approach involves the intravenousadministration of high-dose desmoglein 3 peptides,which are recognised by immunomodulatory T cells, inan effort to induce high-dose tolerance. This procedureis safe and is being assessed in clinical trials. A thirdapproach is to selectively block the acantholytic activity

of pemphigus antibodies with cholinergic agonistssuch as pyridostigmine bromide. This approach is alsobeing assessed in clinical trials.

Finally, the formulation of acantholysis and blisters isan active process that depends on energy andenzymatic activity. Drugs that block these pathwayscould prove therapeutically helpful.

PreventionSeveral factors can exacerbate pemphigus, such asdental work, exposure to the sun, radiographs, stress,and trauma. All should be avoided. In our experience,flares in disease activity after dental work are sufficientlycommon to warrant prophylactic administration of

20 mg per day prednisone in addition to the patientsnormal requirement for 57 days, beginning with everydental procedure that is associated with trauma to thegums. Patients should be told to avoid exposure to thesun as much as possible and to use broad-spectrum sun-protective creams and clothing.

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