PEMPHIGUS

By
Demetris Ioannides1, MD
Associate Professor of Dermatology

Elizabeth Lazaridou1, MD
Lecturer in Dermatology

Dimitris Rigopoulos2, MD
Associate Professor of Dermatology

1. Aristotle University Medical School, Thessaloniki, Greece

2. National University Nedical School, Athens, Greece

Key words: pemphigus, bullous diseases, cadherins, treatment, corticosteroids,

plasmapheresis

Correspondence: Demetris Ioannides, MD, 3 P. P. Germanou Street, 54622,

Thessaloniki, Greece
Tel: +30-2310-272222, -992256, -250300, mobile: +30-6948109109
Fax. +30-2310-864800
e-mail: Dem@auth.gr
1
CME-CPD on line April 09

2
CME-CPD on line April 09

ABSTRACT

Pemphigus refers to a group of potentially life-threatening autoimmune

diseases of the skin and mucous membranes, characterized by the formation of
blisters and erosions of the skin. An autoimmune process, directed against
keratinocyte desmosomal cadherins, interferes with the adhesive function of these
molecules. This results in the separation of keratinocytes and clinical manifestation of
blistering. 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.
Diagnosis of pemphigus is based on three independent groups of criteria: clinical
features (flaccid blisters and erosions on skin and oral mucosa), histologic findings
(epidermal acantholysis) and immunological tests (circulating and skin-fixed
antibodies against keratinocyte surface antigens).
The principle aim of treatment is to reduce inflammatory response and
autoantibody production, thereby achieving disease remission. Systemic
corticosteroids are still the most useful drugs in the treatment of pemphigus and
continue to be the mainstay of therapy for this disease. Adjuvant drugs, such as
immunosupressants, are commonly used in combination, in order to increase efficacy
and have a steroid-sparing effect, thereby allowing reduced maintenance doses and
less side-effects of systemic corticosteroids. Other options include intravenous
immunoglobulin and plasmapheresis. However, more research is needed to develop
treatments with the least possible toxicity.

3
CME-CPD on line April 09

INTRODUCTION

The term pemphigus is derived from the Greek word pemphix meaning blister
or bubble.1 It has been recognized as a disease entity for more than two centuries and
was originally named by Wichman in 1791. The term pemphigus once included most
bullous eruptions of the skin, but diagnostic tests have improved and bullous diseases
have been reclassified. Today it refers to a group of potentially life-threatening
autoimmune diseases of the skin and mucous membranes, characterized by the
formation of blisters and erosions of the skin and mucousa and histologically by
acantholysis.
Clinically, pemphigus can be subclassified into several forms based on the
location of lesions within the epidermis. In the superficial forms of pemphigus
(foliaceous [PF], fogo selvagem [Brazilian PF] and erythematosus [PE]) the bullae
arise high in the epidermis just below the stratum corneum, whereas in the deep forms
of pemphigus (vulgaris [PV] and vegetans) the bullae arise in the deep layers of the
epidermis, above the basal cell layer.2 Other members of the pemphigus group include
paraneoplastic pemphigus,3 which generally is associated with lymphoma, and druginduced pemphigus, which usually develops after the administration of
penicillamine.4
An autoimmune process, directed against keratinocyte desmosomal cadherins,
interferes with the adhesive function of these molecules. This results in the separation
of keratinocytes and clinical manifestation of blistering. The antibodies in the various
forms of pemphigus appear to be directed to different target antigens by anatomical,
serologic and molecular analysis. The reasons that the lesions occur at different levels
of the epidermis in the different forms of pemphigus are still not completely clear,
4
CME-CPD on line April 09

although there are observations that suggest this is related to the stratification of the
different target antigens in different layers of the epidermis.5,6,19
Although pemphigus is relatively rare, its impact in the affected individual is
sometimes devastating. If left untreated, the disease may be lethal as the result of skin
loss, oropharyngeal ulcerations, debilitation and infection.7 Better understanding of
the disease would lead to earlier diagnosis and initiation of therapy, thereby allowing
the induction of earlier and possibly complete and durable remissions in disease
activity.

EPIDEMIOLOGY

Pemphigus has been reported to occur worldwide and affects 0.1-0.5 patients
per 100,000 population per year. Other authors estimate its incidence as high as 3.2
cases per 100,000.8 The disease affects all races but is found to be relatively common
in people of Ashkenazi Jewish, Greek and Indian descent.9
The sporadic form of PF affects all ethnic groups around the world, but an
endemic form (fogo selvagem = wild fire) is fairly common in the rural and tropical
regions of Brazil, where the ratio of cases of PF to cases of PV is nearly 20 to 1. It is
estimated that in this country there are approximately 15.000 patients with PF and that
there are regions, such is the Amerindian reservation of Limao Verde, in which the
prevalence of the disease is 3.4 percent of the population.10
The disease affects primarily middle-aged persons and the mean age of
onset is approximately 50-60 years of age.1 It can also occur in adolescence, or even
in childhood and in old age.7 Male-to-female ratio is approximately equal, but in
puberty, girls are more likely to be affected than boys.7
5
CME-CPD on line April 09

INHERITANCE AND GENETICS

It has been suggested that the various subsets of the pemphigus syndromes are
genetically predetermined.11 However, the occurrence of multiple family cases or
parent to child inheritance is very rare.12
It seems that the expression of different HLA alleles may play a role in the
epidemiology of pemphigus. There is a well-established HLA association with DR4,
DR14, DQ1 and DQ3 antigens. Several epidemiological studies in Jewish, in nonJewish and in Japanese population demonstrated that the HLA DR1*0402 and HLA
DR1*1401 alleles are highly prevalent in PV.8,9 It has been shown that the DR14
susceptibility was strongly associated with a rare DQ allele (DQ1*0503) in PV
patients.13 Furthermore, healthy relatives of PV patients who carried the PV
susceptibility haplotypes DR4/DQ8 and DR14/DQ5 appeared to produce low titers of
specific PV autoantibodies.11,12,14 The HLA class II alleles DR1*0402 and 1*1401
(in linkage disequilibrium with DQ1*0503) are also prevalent in drug-induced
pemphigus.15 The endemic variant of PF is characterized by a prevalence of two HLA
class II alleles DR1*04** and HLA DR1*0101.

PATHOPHYSIOLOGY OF PEMPHIGUS

Recent advances in molecular biological techniques have elucidated the

autoimmune nature of pemphigus. The basic abnormality in all forms of pemphigus is
acantholysis, which is the loss of adhesion between keratinocytes.16 It is now well
known that the most important structures for cell-cell adhesion in the epidermis are
6
CME-CPD on line April 09

the desmosomes. Ultrastructural studies of pemphigus lesions have suggested that

dissolution of desmosomes may result in the formation of blisters.17,18
During the process of acantholysis, circulating and skin-fixed auto-antibodies
are directed against intercellular adhesion structures of epidermal keratinocytes,
which act as antigens. Extensive studies have revealed that these antigens are
components of desmosomes, namely two groups of transmembrane glycoproteins
called desmoglein (Dsg) and desmocollin (Dsc). Both proteins consist of three
isoforms (Dsg 1-3 and Dsc 1-3), which belong to the cadherin gene family.19 Dsg-1 is
expressed primarily in the upper levels of the epidermis and weakly in the squamous
mucosae, whereas Dsg-3 is expressed strongly in mucosae and weakly in the
epidermis.
Autoantibodies in PV are predominantly directed against the extracellular
portion of dsg-3, the 130-kD PV antigen, while autoantibodies in PF are directed
against dsg-1, the 160-kD PF antigen(Tabla I).20 However, serological analysis and
immunoelectron microscopy studies demonstrated that PV autoantibodies bind not
only to the desmogleins, but also along to other desmosomal proteins, such as
desmocollins19, or along large portions of keratinocytes outside desmosomal
structures.21 Two potential new target antigens were recently identified which belong
to the group of cholinergic receptors.22 There is evidence that some forms of keratins
may also serve as pemphigus antigens.23
The appearance of clinical disease seems to depend on the subclass of the
antibody response. Autoantibody production in PV and PF is polyclonal and most
circulating autoantibodies against intercellular antigens are of the IgG4 subclass.
Patients in remission mainly have IgG1 antibodies, while healthy relatives of PV
patients and healthy carriers of PV-prevalent HLA class II alleles have low levels of
7
CME-CPD on line April 09

IgG1 antibodies.14 Therefore, IgG1 antibodies against dsg-3 are present with equal
frequency in individuals with or without PV, but IgG4 antibodies are present almost
exclusively in patients with active disease. It seems that an as yet unknown triggering
factor, may lead to the production of non-pathogenic IgG1 antibodies against dsg-3,
whereas the appearance of clinical disease may be dependent on the presence of an
HLA susceptibility gene required for the production of a pathogenic IgG4 response.
In the case of endemic pemphigus this triggering factor could be an environmental
agent. It is not known whether the different pathogenic activity of these antibodies is
due to differences in effector function or to the fact that different subclasses may be
directed to different epitopes on the targeted antigens.24
Circulating intercellular antibodies are present in about 80% of patients with
active disease and are pathogenic. Evidence for the pathogenity of the autoantibodies
is provided by the following observations: i) their titer usually correlates with the
activity of PV;24 ii) they are able to induce acantholysis in organ cultures of human
skin;25 iii) when these antibodies are passively administrated to neonatal mice
pemphigus-like lesions are also induced;26,27 and, iv) newborn babies of mothers with
active disease temporarily exhibit lesions like pemphigus, due to the placental transfer
of autoantibodies.28
Little is known about the mechanisms by which intercellular antibodies arise.
In some patients, pemphigus is triggered by an external cause, such as a medication
containing sulfhydryl groups, or even food (garlic). Drugs implicated in pemphigus
are: a) thiols, like penicillamine, captopril, b) angiotensin-converting enzyme
inhibitors, like enalapril and fosinopril, and c) some other drugs like aspirin, NSAIDs,
rifampicin, interferon, nifedipine, propranolol, interleukin, levodopa and
phenobarbital.29,30 Most patients with drug-induced pemphigus have anti-cell surface
8
CME-CPD on line April 09

antibodies, but the autoantigens against which they are directed remain unclear.
While various causes have been implicated as triggering agents, HLA association is
probably the most important predisposing factor.
The exact process by which intercellular antibodies cause loss of cellular
adhesion is unclear. One hypothesis is that the binding of autoantibodies to their
antigens can disrupt adhesion of the bound antigens by steric hindrance.19 A second
theory is that the binding of antibodies to antigens acts as intracytoplasmic signal
transduction, and induces production of plasminogen activator. Thus, plasminogen is
activated leading to the production of active plasmin, which induces cell
dissociation.31 Another possibility is that the antigen-antibody complex can interfere
with adhesion and intracellular events via plakoglobin and other cytoplasmic
proteins.32 Finally, the autoantibodies may play an important role in reorganization of
the cytoskeleton of keratinocytes causing the affected cells to shrink and separate
from adjacent keratinocytes.24
The inflammatory infiltrate in pemphigus is poor, suggesting that cellular
immune responses are not directly involved in the pathogenensis of the disease.
However, there is evidence that Th1, Th2 and B-cells could enhance the process of
blister formation.33
The pathophysiology of paraneoplastic pemphigus (PNP)34 is strongly
associated with the underlying neoplasm. Somehow the tumor induces synthesis of
autoantibodies using an immune pathway which remains unclear. The autoantibodies
against Dsg-1 and Dsg-3 play a primary role in the pathogenesis of PNP. However,
there are intercellular antibodies directed also against other antigens, such as plakin
proteins (desmoplakin I and II, envoplakin, periplakin and plakoglobin), plectin, a
170KD protein, and the bullous pemphigoid antigen of 230KD.35
9
CME-CPD on line April 09

CLINICAL MANIFESTATIONS
Deep forms include pemphigus vulgaris and pemphigus vegetans, whereas
pemphigus foliaceous, fogo selvagem (Brazilian PF) and pemphigus erythematosus
are more superficial.
Differences in clinical picture between the two forms of pemphigus seem to
reflect regional variations in the expression of antigen targeted by autoantibodies in
the two forms of the disease, with lesions occurring in areas where antigen expression
is greatest.5 Oral lesions are common in PV but do not usually occur in PF, 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 disease. The mouth
expresses high concentrations of antigen related to PV, but low concentrations of
those associated with PF, and the expression of both types of antigens is high on the
face sclap and upper torso but low on the legs.5 In support of this conlusion is the fact
that in bullous pemphigoid and epidermolysis bullosa aquisita, two other autoantibody
mediated blistering diseases 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 these
diseases.6

Pemphigus vulgaris
In pemphigus vulgaris mucous membranes are most often affected first and
may precede skin lesions by months. As blisters rupture easily, the disease begins
typically with multiple, painful, superficial non-healing ulcerations most commonly in
10
CME-CPD on line April 09

the oral cavity36 (Figures 1,2). The most common sites involved are the buccal and
labial mucosa, the palate and the tongue. The erosions extend peripherally and may
spread to involve the pharynx and larynx with subsequent difficulty in eating and
drinking and hoarseness of the voice. Laryngeal and nasal lesions are more frequent
than usually believed.37 Involvement of other mucosal surfaces may occur including
the conjunctiva, oesophagus,38 vulva,39 cervix, urethra and rectal mucosa.
The primary lesion of the skin is a flaccid blister that is filled with a clear
fluid, arises on normal or erythematous skin and breaks easily leaving painful
erosions. Left untreated the erosions expand to form large denuded areas, which may
become crusted and may be complicated by infection or metabolic disturbances.
Blisters may arise anywhere, but the scalp, upper chest and back are most often
affected and the face and neck may also be involved. They have the tendency to
involve the medial surface of the trunk. Although relatively rare, periungual and nail
involvement must not be overlooked.40,41 A characteristic feature of the disease is the
Nikolskys sign, produced when lateral pressure is applied adjacent to an active lesion
with resultant separation of the epidermis.
With treatment the lesions of PV generally heal without scarring. However a
transient residual hyperpigmentation may be present. Mild forms of the disease can
even regress spontaneously.
It has been suggested that extrinsic factors, such as infection and exposure to
gardening materials, pesticides and metal vapor may interfere with the disease
process.42Our experience of managing many patients is in accordance with the
observations of Bystryn24 that exposure to the sun, dental work, cutaneous trauma and
stress are the most important factors that can trigger a flare of the disease and that
should be kept to a minimum.
11
CME-CPD on line April 09

Pemphigus vegetans
Pemphigus vegetans is actually a variant of PV in which erosions may develop
vegetation. Vegetating lesions tend to occur more frequently in intertriginous areas
(axillae, groin, inframammary area) and on the scalp (Figure 3). The lesions can be
secondarily infected and are usually more resistant to therapy.

Pemphigus foliaceous (PF)

In this variant of pemphigus, lesions manifest as recurrent crops of superficial
shallow crusted erosions on healthy looking skin of the upper trunk, face and scalp
(Figure 4). In its early form PF may mimic seborrhoeic dermatitis. The pathology of
PF is so superficial (subcorneal) that, intact blisters are very rarely seen. In advanced
cases severe exfoliation may occur and the clinical picture may resemble an
exfoliative erythroderma (Figure 5). Oral lesions are very uncommon.

Fogo selvagem (Brazilian PF, endemic pemphigus)

This form of pemphigus occurs endemically in Brazil and in certain rural areas
of the world. It is seen most commonly in young people and is clinically,
histologically and immunopathologically indistinguishable from PF.43

Pemphigus erythematosus (PE)

Also named the Senear-Usher syndrome,44 due to the authors who first
described this variant, PE is localized to the face and characterized by erythematous,
scaly, hyperkeratotic lesions, often in a butterfly distribution, thus resembling lupus
erythematosus. Moreover, apart from the intercellular deposits of antibodies there are
12
CME-CPD on line April 09

often granular deposits of immunoglobulin and/or complement at the dermoepidermal junction. These findings have raised the question whether PE is a crossover
syndrome between pemphigus and lupus erythematosus. However, granular deposits
are quite common on facial skin especially if it is sun-exposed.45 In contrast to that,
rare cases of concurrent PE and lupus have been documented.

Paraneoplastic pemphigus
This form of pemphigus involves the existence of painful mucosal erosions
alone or together with blisters and erosions on the skin, in the setting of a confirmed
or occult malignancy. Acantholysis, keratinocyte necrosis and interface dermatitis are
seen in histopathology. Direct immunofluorescence displays IgG and complement
intercellular deposits and indirect immunofluorescence reveals circulating antibodies
specific for stratified squamous or transitional epithelia. The most common
malignancy associated with paraneoplastic pemphigus is non-Hodgkin lymphoma,46
but it may coexist with chronic lymphocytic leukaemia, giant cell lymphoma,
Waldenstrm macroglobulinaemia, thymoma, Castleman tumor, poorly differentiated
sarcoma, bronchogenic squamous cell carcinoma and follicular dendritic cell sarcoma.
This form of pemphigus is often fatal.

Drug-induced pemphigus
In some cases pemphigus (either vulgaris or foliaceous) can be triggered by
certain drugs, the most common implicated one, being penicillamine. However, a
variety of drugs have been implicated in the onset of drug-induced pemphigus, that
may be categorized in thiol drugs (penicillamine, captopril, enalapril) and non thiol
drugs (penicillins, cephalosporins, piroxicam).47 The clinical, histological and
13
CME-CPD on line April 09

immunofluorescence findings are identical to idiopathic pemphigus. Treatment

includes the withdrawal of the responsible drug alone or together with appropriate
pemphigus therapy.

DIAGNOSIS OF PEMPHIGUS
Diagnosis of pemphigus is based on three independent groups of criteria:
clinical features, histologic findings and immunological tests. As none of the criteria
used to diagnose pemphigus is completely specific, basing a diagnosis on one or two
of these can lead to errors. Common errors include mistaking impetigo or apthous
stomatitis for pemphigus and vice versa.

HISTOLOGIC FINDINGS OF PEMPHIGUS

Histologically, pemphigus is characterized by defective adhesion of epidermal

cells, which lose their intercellular attachments, round up and float off into the
intraepidermal cavity thus formed (acantholysis). These isolated rounded-up cells are
called acantholytic cells. Widening of intercellular spaces precedes diminution of the
number of desmosomes, which eventually split permitting the separation of epidermal
cells from each other. Inflammatory cell infiltrates of the involved skin are generally
absent.
The form of the disease can be deduced by biopsy. PV shows intaepidermal
suprabasal cleft formation and acantholysis, whereas basal cells remain attached to the
basement membrane (Figure 6). In addition to suprabasal acantholysis, pemhigus
vegetans exhibits a downward proliferation of epidermal cells into the dermis,
epithelial hypertrophy abscesses formed by polymorphonuclear leukocytes and
14
CME-CPD on line April 09

granulation. In PF, PE and fogo selvagem, acantholysis and cleft formation are
confined to the granular layer and thus the blister is more superficial. Hyper- and
parakeratosis are common in these latter disorders.7
In all forms of pemphigus, cytologic smears obtained by scraping the base and
the roof of a blister reveal acantholytic epidermal cells (Tzanck preparation).

IMMUNOPATHOLOGICAL FINDINGS OF PEMPHIGUS

All forms of pemphigus are associated with the presence of skin-fixed and
circulating autoantibodies against keratinocyte cell-surface antigens (Figure 7).48
Tissue-fixed intercellular antibodies are present in lesions and adjacent healthy skin in
about 90% of patients with pemphigus and are detected by direct immunofluorescence
(Figue 8). These antibodies are very rare in other diseases and are more sensitive and
specific for the diagnosis of pemphigus than circulating antibodies. They are usually
IgG, but IgM and IgA with or without complement may also be deposited.
Circulating intercellular antibodies are detected by indirect
immunofluorescence assays of serum, using human skin, monkey esophagus or
guinea-pig esophagus as a substrate. If indirect immunofluorescence is negative in a
patient suspected of having pemphigus, the test should be repeated using another
substrate. Circulating antibodies are present in about 80% of patients with active
disease but can also be present in low titers in patients with antibodies to ABO blood
group antigens or with burns, fungal infections, drug reactions and myasthenia gravis.
It is generally agreed that there is a correlation between the titer of intercellular
antibodies and the activity of pemphigus. Serial determinations of intercellular
antibodies may be useful in guiding therapy, since a rise in their titer usually precedes
15
CME-CPD on line April 09

a recurrence in disease activity, while they usually decrease with successful treatment
and disappear in patients in remission.49
ELISA aassays 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 PV, whereas antibodies to
desmoglein 1 alone are associated with PF. ELISA is more specific and somewhat
more sensitive than indirect immunofluorescence, although its results are not
quantitative in high antibody concentrations, because the assay plates become
saturated.50

TREATMENT
The treatment of pemphigus was unsatisfactory until the introduction of
corticosteroids in the 1950s. The majority of patients died, usually from
overwhelming sepsis, within one year of the onset of their disease. Systemic
corticosteroids are still the most useful drugs in the treatment of pemphigus and
continue to be the mainstay of therapy for this disease. Their use has transformed an
almost invariably fatal disease51,52 into one whose mortality is less than 10% and
probably closer to 5%.53
The principle aim of treatment is to reduce inflammatory response and
autoantibody production, thereby achieving disease remission. A positive clinical
response is associated with a decrease in the circulating autoantibodies in the serum
and absence of bound autoantibodies in the skin. This is followed by a period of
maintenance treatment using the minimum drug doses required to achieve disease
control and minimize their side-effects. Nowadays, the ultimate aim of management
should be treatment withdrawal. In approximately 50% of patients, all therapy can be
discontinued and patients will remain lesion free for months to years.54 A recent study
reported remission rates of 38%, 50% and 75% achieved 3, 5 and 10 years from
diagnosis.55
16
CME-CPD on line April 09

Corticosteroids were first applied to patients with the disease by Thorn et al.56
and were later more widely used by Costello et al.57 and Lever and White.58 Since
then, various regimens regarding their administration have been introduced, dictated
by the age of the patient, the degree of involvement, the rate of disease progression
and the subtype of pemphigus. However, their prolonged administration and the need
for high doses may lead to serious side effects. Most patients, who die of pemphigus
at present, die of complications of therapy. This has led to a continued search for
additional treatments that might reduce the need for steroids. Those treatments, now
widely used, are given in combination with steroids and, for that reason, are referred
to as adjuvant therapies.
The major beneficial effect of corticosteroids in pemphigus relates to their
ability to decrease autoantibody levels.59 The oral route of administration is the one
most preferred and prednisone is the drug most frequently used. Clinical improvement
may be seen within days of starting treatment but new blisters stop to develop in 2-3
weeks60,61 and full healing may take 6-8 weeks.58 The optimum dosing schedule is not
known and dosing schedules are largely empirical. Previously it was routine to use
regimens with high doses of prednisone (100-200mg daily),58,62,63 which increased the
potential for life-threatening complications.62,64 Only one controlled trial has
compared dosing schedules and found that there was no significant difference in the
duration to achieve remission and in relapse rates at 5 years, between the group of
patients treated with high-dose (120-180mg daily) and those ones treated with lowdose prednisolone (45-60mg daily).61 Today there is a tendency that patients with mild
disease are treated with initial prednisolone doses of 40-60mg daily and in more
severe cases 60-100mg daily. Very mild disease may be treated with a trial of topical
corticosteroids, followed by low-dose (20mg/day) oral steroids.53 Topical and
intralesional corticosteroids have been used in the treatment of mild forms of the
disease, but they are rarely effective.65 A single morning dose is safer for long-term
use, but divided doses have more anti-inflammatory effect. Most patients can be
controlled with prednisone 1.0-2.0 mg/kg/day. If there is no response within 5-7 days
the dose is increased by 50% every 4-7 days, until there is disease control. Once
remission is achieved and maintained, with healing of most of the lesions, the dose
can be slowly tapered.66 The tapering may be relatively rapid at first (5-10mg/week),
but it should proceed more slowly as the dosage reaches 20mg/day. Steroid side
17
CME-CPD on line April 09

effects are numerous and may include infection, diabetes, osteoporosis, myopathy,
gastrointestinal bleeding, cataracts or central nervous system toxicity.
If prednisolone doses above 100mg daily are unresponsive, pulsed
intravenous therapy with 1gr of methylprednisolone or its equivalent in 150 ml of
dextrose and water, administered over a period of 90 minutes once daily, on 1-5
consecutive days, may be considered. The goal of this approach is to quickly achieve
disease control and allow a reduction in long term maintenance doses and side effects
and is usually applied to young, healthy patients. This method may result in serious
complications like electrolyte imbalance, hypertension, pancreatitis, seizures or
cardiac arrhythmias.67 One small retrospective study concluded that pulsed
intravenous therapy with methylprednisolone resulted in increased complete
remission rates and lower mean oral maintenance doses in nine patients with
recalcitrant pemphigus vulgaris compared with six controls.68 An other report showed
disease control in 7-10 days in five of nine patients given pulsed
methylprednisolone.69
Adjuvant drugs are commonly used in combination, in order to increase
efficacy and have a steroid-sparing effect, thereby allowing reduced maintenance
doses and less side-effects of systemic corticosteroids. However, a more recent study
demonstrated similar outcomes in PV patients treated with corticosteroids alone with
those of studies using adjuvants.70 Combination therapy is currently gaining
popularity even as the initial treatment of pemphigus, but in most cases the use of
adjuvants is recommended only if serious adverse effects of corticosteroids appear,
relative contraindications to their use exist, or they cannot be tapered because of
repeated exacerbations of disease activity.52 In contrast to that, other centers do use
adjuvant drugs as standard practice.66
Numerous problems make it difficult to evaluate and compare the
effectiveness of adjuvant therapies for pemphigus. The most principal ones are the
lack of controlled therapeutic studies, the variable severity and course of pemphigus,
the small number of patients included in most studies, the lack of criteria to define
response to treatment, the delay in action of some drugs and the concurrent
administration of corticosteroids. Although mortality and complete remission rates
have improved since the introduction of adjuvant drugs, this is in comparison with
historical controls. Moreover, this may be due to factors others than the introduction
18
CME-CPD on line April 09

of adjuvants, such as earlier initiation of therapy, milder forms of the disease and
better treatment of complications. Unfortunately, there are no prospective, controlled
studies to demonstrate the benefits of adjuvant drugs in PV.
The current treatment options for pemphigus are listed in table II. Adjuvant
therapy includes immunosuppressive and anti-inflammatory drugs or alternative
treatment modalities.
In general, adjuvant drugs are slower in onset than corticosteroids, their effect
may take 4-8 weeks to manifest and therefore are rarely used alone to induce
remission of the disease. Most often they are added to the treatment schedule after the
steroid tapering has begun, but alternatively, treatment may also be initiated with
adjuvant therapy concomitant with steroid therapy to decrease the total dose of
glucocorticoid needed.71
Adjuvant treatments fall into two categories. The first one includes treatment
modalities with an immediate effect that are used for a short period of time to control
disease activity in patients unresponsive to high doses of corticosteroids, like
plasmapheresis and pulsed intravenous corticosteroids. The second category includes
drugs that are intended to reduce the need for corticosteroids, like cytotoxic drugs,
gold or dapsone.
Immunosuppressive drugs are the most common form of adjuvant therapy
for pemphigus. The most commonly used are azathioprine72-77 and
cyclophosphamide.78-82 They are usually started when the prednisolone tapering has
begun and given in a dose of 1-2 or 3mg/kg/day. Both drugs seem to be effective
adjuvants in the treatment of severe and refractory pemphigus, but require close
monitoring. The complete remission rates of 28-45% and mortality rates of 1.4-7%,
regarding the co administration of corticosteroids and azathioprine, reported in
various studies,52,74 suggest, that combination therapy may be more efficacious than
corticosteroids alone. Moreover, several authors have reported the steroid-sparing
effects of cyclophosphamide at doses of 50-200mg daily.78-83 Azathioprine is
probably less effective than cyclophosphamide, but is more widely used due to the
fact that it is less toxic and therefore requires less monitoring. Cyclophosphamide
appears to be the most efficacious immunosuppressive drug for pemphigus, but may
be associated with various side effects, like bone marrow suppression, hemorrhagic
cystitis, infertility and bladder or other cancers.84 The use of pulse intravenous
19
CME-CPD on line April 09

cyclophosphamide may decrease adverse effects and risk of malignancy, while

maintaining or improving its efficacy.67,85 It is usually used with a concomitant pulse
of intravenous corticosteroids and consists of the intermittent administration of high
doses of intravenous corticosteroids and cyclophosphamide, usually three daily doses
of dexamethasone (100mg) or methylprednisolone (500-1000mg) and a single dose of
cyclophosphamide (500mg) given monthly.86 Low-dose oral cyclophosphamide
(50mg) is administered daily. Several studies report promising results with
dexamethasone-cyclophosphamide pulse (DCP) therapy.87-89 It is believed that
intermittent high-dose treatment with cyclophosphamide impairs immune surveillance
and gonadal function for short periods compared with daily administration, the
malignancy and infertility inducing potential of this regimen may be less than that of
standard oral protocols.90 A more recent study reported the successful use of
immunoablative, high-dose cyclophosphamide without stem cell rescue, i.e 50mg/kg
intravenous cyclophosphamide for 4 days, in one patient with severe and recalcitrant
pemphigus.91 The patient showed clinical and serological remission 4 months after
treatment. Other authors suggest that this method requires consultation of a
haematologist.92
Alternatively chlorambucil may be used especially in patients who develop
haemorrhagic cystitis in a dose of 4 mg daily, which may be increased to 10 mg. Shah
et al reported clinical improvement and remission in 6 out of 9 patients with PV or PF
who were treated with chlorambucil and prednisone.93
Cyclosporine was first used to treat pemphigus by Thivolet et al.94 The
response of PV to this drug is controversial. Initial small series reported that
cyclosporine was a useful adjuvant with steroid-sparing effects in PV,95,96 even as
monotherapy,97 in doses of 5 or 6-8 mg/kg/day. Mobini et al described six patients
with severe, unresponsive to high-dose systemic corticosteroids and azathioprine,
cyclophosphamide, dapsone, gold or methotrexate PV, who were treated with 1-3
mg/kg of cyclosporine daily. Existing lesions improved and no new lesions appeared
within 8-10 weeks.98 The total duration of treatment with cyclosporine lasted for 1320 months. There were no recurrences during the follow-up period. However, a single
randomized, prospective, controlled trial of 33 patients comparing the effectiveness of
glucocorticoids alone with that of a combination of glucocorticoids and cyclosporine
showed no benefit to the addition of cyclosporine to steroids in the treatment of PV.70
20
CME-CPD on line April 09

On the basis of current evidence cyclosporine may be of limited benefit as

monotherapy for PV and appears to be beneficial, when used in combination with
corticosteroids. More controlled studies are needed to clarify its potential as a steroid
sparing-agent.
In our department we do not use adjuvants from the beginning of treatment
because from the two studies we conducted,70,99 we concluded that combination
therapy with corticosteroids and cyclosporine or cyclophosphamide from the very
start of treatment offered no advantage over treatment with corticosteroids alone. In
mild cases of the disease, in terms of clinical picture and indirect immunofluorescence
results, we start treatment with 40mg of prednisolone equivalent. If there is no
response or in all other cases, we start with 0,75-2 mg/kg/day of prednisolone
equivalent until the resolution of lesions. At that point we begin to taper the
corticosteroid dosage until we reach the level of 20-30mg per day. It is then we add an
adjuvant, which usually is cyclophosphamide or cyclosporine. In more refractory
cases we prefer pulse therapy with steroids and plasmapheresis.
Mycophenolate mofetil (MMF) is a relatively new agent for the treatment of
PV. Enk and Knopp reported its use in PV in 1997 and 1999.100,101 The total daily
dose most often ranges from 2-2.5 g, divided in two, together with prednisolone. In a
series of 12 patients with PV who had failed treatment with prednisone and
azathioprine, 11 improved on mycophenolate mofetil, 2 g/day, and prednisone 2
mg/kg/day, without relapse during the 9- to 12-month follow-up period, even after
steroid tapering.101 Nousari and Anhalt required higher doses of MMF (2.5-3 g/day)
and longer periods of time (at least 8 weeks) to induce remission of PV in their
patients.102 In more recent reports the drug has shown to be effective in 31103 and 12
out of 17 cases of pemphigus with no treatment withdrawals because of safety
concerns.104 The effectiveness of MMF as monotherapy has been reported in two
cases.105,106 MMF could be considered as an adjuvant in recalcitrant cases of PV, but
in view of the fact that it has a more favourable side-effect profile and is not
associated with renal or hepatic toxicity, it may prove to be more useful in the future.
Methotrexate was first reported to be helpful by Lever and Goldberg107 but
there was a tendency to develop life-threatening infections in patients who were
treated with high doses (150 mg/week)108-110 and therefore it has not been a
commonly used adjuvant drug for PV. However, a recent study reports favourable
21
CME-CPD on line April 09

outcomes and few side effects with a dose of 12 mg of methotrexate weekly.111

Methotrexate could be considered as a useful adjunct to treatment of PV if more
established drugs can not be used. However, in a study of ours we concluded that the
administration of methotrexate from the initiation of treatment along with steroids
offered no advantage over treatment with steroids alone.
An other agent used as an adjuvant for the treatment of PV is parenteral gold
that was originally described by Penneys et al.112 A test dose of 5 or 10 mg is given,
followed by 25 mg one week later. After that, 50 mg is given biweekly or at 1 to 4week intervals. A therapeutic effect is usually expected after a total dosage of 500 mg
has been administered. When a clinical response is obtained, the interval between
doses is lengthened or the weekly dosage decreased. In 1984 Poulin et al reported a
series of 13 patients with PV who were treated with prednisone and gold.113 Seven of
the patients had complete remission and required no further therapy. The largest
reported case series is of 26 patients.114 Eighty-five percent of the patients had
responses, but only 15% were in complete remission at the end of the study.
Complications of therapy developed in 42% of the patients. PV patients with mild
disease may benefit from gold as monotherapy.115-117 Since 1985 gold can also be
administered orally in its oral form, auranofin, at a dose of 3 mg twice daily (up to 9
mg daily), which is easier to use and less toxic but has a slower onset of action.118
Although the efficacy of gold is inferior to that of immunosuppressive agents its use
is attractive for patients in their reproductive years, as it lacks the carcinogenic and
infertility side effects of immunosuppressive medications. However, side effects
reported with gold include gastrointestinal, renal and haematologic effects, which may
be severe.119
Dapsone may be useful in some patients with PV, although there is greater
support in the literature for its efficacy in pemphigus foliaceous and therefore it
appears to be a preferred adjuvant for the treatment of this form of pemphigus.120
There are only occasional reports that support its use in the treatment of PV.121-123
The efficacy of variable combinations of tetracyclines with or without
nicotinamide, together with corticosteroids or as the only oral agents, has been
evaluated in the treatment of pemphigus.12-128 They could be proposed as adjuvant
treatment, perhaps only in mild cases of the disease.
22
CME-CPD on line April 09

Plasmapheresis has been used in refractory cases in order to physically

remove pathogenic circulating antibodies.129,130 It is usually administered three times
weekly, removing about 2L of plasma. Its effectiveness, however, is controversial.
One controlled study in 1988 failed to demonstrate any additional clinical benefit of
plasmapheresis in patients treated with oral corticosteroids with or without additional
plasma eschange.131 Other studies have shown it effective at reducing serum levels of
autoantibodies and controlling disease activity.130,132-137 Although this procedure
temporarily lowers the level of circulating autoantibodies, a reactive burst of antibody
production from B cells results in a rebound effect. Therefore, it is necessary to
couple this method with the administration of both corticosteroids and
immunosuppressants.129,130,133,138 Plasmapheresis could be considered for the rapid
control of active disease in difficult cases or in patients with severe involvement, only
if it is immediately followed by immunosuppression.
In contrast to plasmapheresis, immunoadsorption (IA) specifically removes
distinct plasma components, including serum pemphigus antibodies, without the need
to substitute plasma proteins, such as albumin.139 IA uses extracorporeal columns
constructed from several absorbents. Those assessed in pemphigus include protein A
and tryptophan-linked polyvinyl alcohol. A recent case report showed that IA
combined with pulse corticosteroid therapy led to the remission of recalcitrant
pemphigus in a young girl.140 Staphylococcal protein A immunoadsorption (PA-IA)
specifically removes immunoglobulin from the circulation, allows treatment of larger
plasma volumes and does not require the substitution of plasma components.141
Schmidt et al treated five patients with severe pemphigus with PA-IA and
demonstrated a dramatic clinical improvement together with a rapid decrease in their
autoantibody levels.142 Lftl et al removed pathogenic autoantibodies in nine patients
with pemphigus by immunoadsorption with a tryptophan-linked polyvinylalcohol
adsorber. Clinically, mucosal and cutaneous lesions improved allowing for a
reduction of glucocorticoids.143 Very recently, Shimanovic et al reported an improved
protocol for treating PV with IA with a high initial dose of methylprednisolone (2
mg/kg) and a prolonged symptom-free interval.144 Azathioprine or mycophenolate
mofetil was administered as a steroid-sparing agent. Controlled studies are required to
compare side-effects and effectiveness with other treatment options for pemphigus.
23
CME-CPD on line April 09

Extracorporeal photopheresis (ECP), where peripheral blood leucocytes are

photoinactivated with methoxsalen and UVA in an extracorporeal system has been
used with success in the treatment of patients that failed drug therapy.145-148 In all
cases the patients were concurrently treated with corticosteroids and
immunosuppressive drugs. This modality however is preserved for patients in whom
conventional treatment has failed.
The administration of intravenous immunoglobulin (IVIg) is being
increasingly used instead of plasmapheresis in the treatment of recalcitrant
pemphigus. IVIg is an interesting approach, because it seems to work by selectively
and rapidly decreasing circulating levels of pathogenic pemphigus antibodies.149
Serum concentrations of the antibodies decrease by more than half within 1-2 weeks
of initiation of treatment. Moreover, the decrease seems to be selective, because total
concentrations of IgG increase rather than decrease.149 Several reports describe a total
of 48 patients with PV who have been treated with IVIg.149-159 IVIg is usually
administered at a dose of 1.2-2 g per kg bodyweight over 3-5 days every 2-4 weeks
for multiple cycles.160,161 It has a rapid onset of action and results in improvement
within days of its initiation. The benefit however appears to be transient unless
repeated courses are given.158,159 It is believed to work 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 by those in the administered immunoglobulin.24 The
effectiveness of IVIg seems to improve by the concomitant administration of a
cytotocic drug, such as cyclophosphamide or azathioprine.162 IVIg has a demonstrable
corticosteroid-sparing effect and, despite its high cost, it is a safe and effective
alternative treatment in pemphigus.163 Ahmed and Dahl published recently a
consensus statement on its use in the treatment of autoimmune mucocutaneous
blistering diseases.164
A novel approach to control pemphigus by suppressing the production of
pemphigus antibodies is by the use of rituximab. Rituximab, a chimeric murinehuman monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has
shown efficacy in patients with refractory antibody-mediated autoimmune
disorders.165 CD20 is an antigen expressed on the surface of pre-B and mature B cells,
24
CME-CPD on line April 09

but absent on plasma cells that actually synthesise antibodies. Rituximab, binds to
transmembrane CD20, reduces circulating B cells and prevents their maturation into
all antibody-secreting plasma cells, not just those making pathogenic antibodies. It
has been used at a dose of 375 mg/m2 weekly for 4 weeks.165-169 In most patients
resistant lesions cleared in 1-4 months. Response was associated with reduction in
serum antiepithelial antibodies.170 Not all patients responded and half of those treated
developed severe infections, one of which was fatal.167 Therefore patients should be
closely monitored for infectious complications. Infusion related symptoms like fever,
chills, nausea, pruritus, bronchospasm and dyspnea are usually controlled with
acetaminophen and diphenhydramine. Rituximab may be a valuable treatment for
refractory pemphigus but warrants further studies to evaluate the risk-benefit ratio of
its use. Both IVIg and rituximab are expensive treatment options and should be
applied to patients who are refractory to conventional treatment regimens or to those
who have contraindications for the administration of steroids.171
Novel approaches to the treatment of pemphigus that are currently under
investigation include the intravenous administration of high-dose desmoglein 3
peptides, which are recognized by immunomodulatory T cells, in an effort to induce
high-dose tolerance and the selective blockage of the acantholytic activity of
pemphigus antibodies with cholinergic agonists, such as pyridostigmine bromide.24,172
The need for selective therapies and common definitions for pemphigus is
now recognized to allow international large-scale, prospective multi-center trials,
which would help in the successful control of the disease with the least possible
toxicity.173

25
CME-CPD on line April 09

REFERENCES

1. Lever WF. Pemphigus. Medicine 1953;32:1-123.

2. Bystryn J-C, Abel E, Defeo C. Pemphigus foliaceous: subcorneal intercellular
antibodies of unique specificity. Arch Dermatol 1974;110:857-62.
3. Anhalt GJ, Kim S, Stanley JR. Paraneoplastic pemphigus; an autoimmune
mucocutaneous disease associated with neoplasia. N Engl J Med
1990;323:1729-35.
4. Brenner S, Bialy-Colan A, Anhaly GJ. Recognition of pemphigus antigens in
drug-induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad
Dermatol 1997;36:919-23.
5. Ioannides D, Hytiroglou P, Phelps RG, Bystryn J-C. Regional variation in the
expression of pemphigus foliaceus, pemphigus erythematosus and pemphigus
vulgaris antigens in human skin. J Invest Dermatol 1991;96:159-61.
6. Ioannides D, Hytiroglou P, Phelps RG, Bystryn J-C. Regional variation in the
expression of epidermolysis bullosa aquisita antigen. Eur J Dermatol 1992;2185-8.
7. Stanley JR. Pemphigus. In: Fitzpatrick TB, Eisen AZ, Wolff KI, et al (eds).
Dermatology in General Medicine. New York: McGraw-Hill, 1993;606-14.
8. Ahmed AR, Yunis EJ, Kharti K. Major histocompatibility complex haplotype
studies in Ashkenazi Jewish patients with pemphigus vulgaris. Proc Natl Acad
Sci USA 1990;87:7658-62.
9.

Ahmed AR, Wagner R, Kharti K. Major histocompatibility complex haplotypes

and class II genes in non-Jewish patients with pemphigus vulgaris. Proc Natl
Acad Sci USA 1991;88:5056-61.
26

CME-CPD on line April 09

10. Warren SJP, Lin MS, Giudice G, et al for the cooperative group of fogo
selvagem research. The prevalence of antibodies against desmoglein 1 in
endemic pemphigus foliaceous in Brazil. N Engl J Med 2000;343:23-30.
11. Ahmed AR, Mohimen A, Yunis AJ. Linkage of pemphigus vulgaris antibody to
the major histocompatibility complex in healthy relatives of patients. J Exp Med
1993;177:419-24.
12. Brandsen R, Frusic-Zlotkin M, Lyubimov H, et al. Circulating pemphigus IgG
in families of patients with pemphigus: comparison of indirect
immunofluorescence, direct immunofluorescence and immunoblottimg. J Am
Acad Dermatol 1997; 36:44-52.
13. Sinha AA, Brautbar C, Szafer F, et al. A newly characterized HLA-DQ allele
associated with pemphigus vulgaris. Science 1988; 239:1026-9.
14. Kricheli D, David M, Frusic-Zlotkin M. The distribution of pemphigus vulgaris
IgG subclasses and reactivity with desmoglein 3 and 1 in pemphigus patients
and first degree relatives. Br J Dermatol 2000;143:337-42.
15. Matzner Y, Erlich HA, Brautbar C, et al. Identical HLA class II alleles
predispose to drug-triggered and idiopathic pemphigus vulgaris. Acta Derm
Venereol 1995;75:12-4.
16. Koch PJ, Franke WW. Desmosomal cadherins: another growing multigene
family of adhesion molecules. Curr Opin Cell Biol 1994; 6: 682-7.
17. Hashimoto K, Lever WF. An electron microscopic study on pemphigus vulgaris
of the mouth and the skin with special reference to the intercellular cement. J
Invest Dermatol 1967; 48: 540.
18. Barnett ML. Effect of pemphigus antibodies on desmosomal structure in vitro. J
Invest Dermatol 1978; 70: 141.
27
CME-CPD on line April 09

19. Hashimoto T. Recent advances in the study of the pathophysiology of

pemphigus. Arch Dermatol Res 2003; 295: S2-S11.
20. Hashimoto T, Amagai M, Garrod DR, et al. Immunofluorescence and
immunoblot studies on the reactivity of pemhigus vulgaris and pemhigus
foliaceus sera wit desmoglein 3 and desmoglein 1. Epithelial Cell Biol 1995; 4:
63-9.
21. Nguyen VT, Ndoye A, Shultz LD, et al . Antibodies against keratinocyte
antigens other than desmoglein 1and 3 can induce pemphigus vulgaris-like
lesions. J Clin Invest 2000;106: 1467-79.
22. Nguyen VT, Lee TX, Ndoye A, et al. The pathophysiological significance of
non-desmoglein targets of pemphigus autoimmunity: pemphigus vulgaris and
foliaceus patients develop antibodies against keratinocyte cholinergic receptors.
Arch Dermatol 1998; 134:971-80.
23. Ioannides D, Bystryn JC. Pemphigus antibodies react to 85, 67 and 56 kD
epidermal antigens. Society for Investigative Dermatology Meeting, Seattle,
May 1991. J Invest Dermatol 1991;96(4):554(abstract).
24. Bystryn JC, Rudolf JL. Pemphigus. Lancet 2005;366: 61-73.
25. Hu CH, Michel B, Schiltz JR. Epidermal acantholysis induced in vitro by
pemphigus antibody: an ultrastructural study. Am. J Pathol. 1978; 90; 345.
26. Anhalt CL, Labib RS, Voorhees JJ et al. Induction of pemhigus in neonatal mice
by passive transfer of IgG from patients with the disease. N Engl J Med 1982;
306: 1189-96.
27. Amagai M, Hashimoto T, Green KJ, et al. Antigen-specific immunoabsorption
of pathogenic autoantibodies in pemphigus foliaceus. J Invest Dermatol 1995;
104: 895-901.
28
CME-CPD on line April 09

28. Wasserstrum N, Lirus RK. Transplacental transmission of pemphigus. J Am

Acad Dermatol 1983; 249: 1480.
29. Wolf R, Tamir A, Brenner S. Drug-induced versus drug-triggered pemphigus.
Dermatologica 1991; 182: 207-10.
30. Ruocco E, Aurilia A, Ruocco V. Precautions and suggestions for pemhigus
patients. Dermatology 2001; 203:201-7.
31. Singer KH, Sawka NJ, Samowitz HR, et al. Proteinase activation: a mechanism
for cellular dyshesion in pemphigus. J Invest Dermatol 1980; 74: 363-7.
32. Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus
IgG, induces phosphorylation of desmoglein 3 and its dissociation from
plakoglobin in cultured keratinocytes. Eur J Immunol 1999; 29: 2233-40.
33. Veldman C, Stauber A, Wassmuth R, et al. Dichotomy of autoreactive Th1 and
Th2 cell responses to desmoglein 3 in patients with pemphigus vulgaris (PV)
and healthy carriers of PV-associated HLA class II alleles. J Immunol 2003;
170:635-42.
34. Anhalt GJ, Kim SC, Stanley JR et al. Paraneoplastic pemphigus. An
autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med
1990; 323: 1729-35.
35. Oursler JR, Labib RS, Ariss-Abdo L, et al. Human antibodies against
desmoplakins in paraneoplastic pemphigus. J Clin Invest 1992; 89: 1775-82.
36. Pisanti S, Sharav Y, Kaufman E, Posner LN. Pemphigus vulgaris: incidence in
Jews of different ethnic groups, according to age, sex and initial lesion. Oral
Surg 1974;38:382-7.
37. Hale EK, Bystryn JC. Laryngeal and nasal involvement in pemphigus vulgaris. J
Am Acad Dermatol 2001;44:609-11.
29
CME-CPD on line April 09

38. Amichai B, Gurnwald MH, Gasper N, et al. A case of pemphigus vulgaris with
esophageal involvement. J Dermatol 1996;23:214-5.
39. Batta K, Munday PE, Tatnall FM. Pemphigus vulgaris localized to the vagina
presenting as chronic vaginal discharge. Br J Dermatol 1999;140:945-7.
40. Engineer L, Norton LA, Ahmed AR. Nail involvement in pemphigus vulgaris. J
Am Acad Dermatol 2000;43:529-35.
41. Ahmed AR, Sami N. Uncommon manifestations of pemphigus vulgaris. J Eur
Acad Dermatol 2002;16:313-5.
42. Brenner S, Tur E, Shapiro J, et al. Pemphigus vulgaris: environmentalfactors.
Occupational, behavioral, medical and qualitative food frequency questionnaire.
Int J Dermatol 2001;40:562-9.
43. Diaz LA, Sampalo SA, Rivitti EA, et al. Endemic pemphigus foliacous (fogo
selvagem): clinical features and immunopathology. J Am Acad Dermatol
1989;20:647.
44. Senear FE, Usher B. An unusual type of pemphigus combining features of lupus
erythematosus. Arch Dermatol 1926;13:761-81.
45. Leibold AM, Bennion S, David-Bajar K, Schleve MJ. Occurrence of positive
immunofluorescence in the dermoepidermal junction of sun-exposed skin of
normal adults. J Cutan Pathol 1994;21:200-6.
46. Hertzberg MS, Schifter M, Sullivan J, Stapleton K. Paraneoplastic pemphigus in
two patients with B-cell non-Hodgkin's lymphoma: significant responses to
cyclophosphamide and prednisolone. Am J Hematol 2000;63:105-6.
47. Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol
1998;16:393-7.

30
CME-CPD on line April 09

48. Jablonska S, Chorzelski TP, Beutner H, et al. Utilization of immunofluorescence

in the diagnosis of bullous diseases, lupus erythematosus and certain other
dermatoses. Int J Dermatol 1975;14:83-9.
49. Bystryn JC. Interpretation of immunofluorescence tests in dermatology. Prog
Dermatol 1985;19:1-8.
50. Akman A, Jiao D, Bystryn JC. Limitations in ELISA assays for antibodies
against Dsg 1 and Dsg 2 in patients with pemphigus. Arch Dermatol
2002;138:1252-3.
51. Robinson JC, Nur FL, Frieden I. Oral pemphigus vulgaris. A review of the
literature and report on the management of 12 cases. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1997;84:349-55.
52. Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. An update.
Arch Dermatol 1996;132:203-12.
53. Bystryn J-C. Adjuvant therapy of pemphigus. Arch Dermatol 1984;120:941-51.
54. Bystryn J-C. Therapy of pemphigus. Seminars in Dermatology 1988;7:186-94.
55. Herbst A, Bystryn JC. Patterns of remission in pemphigus vulgaris. J Am Acad
Dermatol 2000;42:422-7.
56. Thorn GW, Forsham PH, Frawley TF, et al. Clinical usefulness of ACTH and
cortisone. N Engl Med 1950;242:865-72.
57. Costello MJ, Jaimovitch L, Dannenberg M. Treatment of Pemphigus with
corticosteroids. JAMA 1957;65:1249-55.
58. Lever WF, White H. Treatment of pemphigus with corticosteroids. Results
obtained in 46 patients over a period of 11 years. Arch Dermatol 1963;87:12-26.

31
CME-CPD on line April 09

59. Anhalt GJ, Patel HP, Labib RS, Diaz LA, Proud D. Dexamethasone inhibits
plasminogen activator activity in experimental pemphigus in vivo but does not
block acantholysis. J Immunol 1986;136:113-7.
60. Lever WF, Schaumburg-Lever G. Treatment of pemphigus vulgaris. Results
obtained in 84 patients between 1961 and 1982. Arch Dermatol 1984;120:44-7.
61. Ratnam KV, Phay KL, Tan CK. Pemphigus therapy with oral prednisolone
regimens. Int J Dermatol 1990;29:363-7.
62. Hirone T. Pemphigus. A survey of 85 patients between 1970 and 1974. J
Dermatol 1978;5:43-7.
63. Seidenbaum M, David M, Sandbank M. The course and prognosis of
pemphigus. A review of 115 patients. Int J Dermatol 1988;27:580-4.
64. Rosenberg FR, Sanders S, Nelson CT. Pemphigus. A 20-year review of 107
patients treated with corticosteroids. Arch Dermatol 1976;112:962-70.
65. Dumas V, Roujeau JC, Wolkenstein P, Revuz J, Cosnes A. The treatment of
mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid.
Br J Dermatol 1999;140:1127-9.
66. Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus
vulgaris. Br J Dermatol 2003;149:926-37.
67. Fellner MJ, Sapadin AN. Current therapy of pemphigus vulgaris. Mt Sinai J
Med 2001;68:268-78.
68. Werth VP. Treatment of pemphigus vulgaris with brief, high dose intravenous
glucocorticoids. Arch Dermatol 1996;132:1435-9.
69. Chrysomallis F, Dimitriades A, Chaidemenos GC, et al. Steroid-pulse therapy in
pemphigus vulgaris. Long term follow-up. Int J Dermatol 1995;34:438-42.
70. Ioannides D, Chrysomallis F, Bystryn JC. Ineffectiveness of cyclosporine as an
adjuvant to corticosteroids in the treatment of pemphigus. Arch Dermatol
2000;136:868-72.
71. Mutasim DF. Management of autoimmune bullous diseases: Pharmacology and
therapeutics. J Am Acad Dermatol 2004;51:859-77.
72. Wolff K, Schreiner E. Immunosuppressive Therapie bei Pemphigus vulgaris.
Arch Klin Exp Dermatol 1969;235:63-77.
32
CME-CPD on line April 09

73. Van Dijk TJA, van Velde JL. Treatment of pemphigus and pemphigoid with
azathioprine. Dermatologica 1973;147:179-85.
74. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the
treatment of pemphigus vulgaris. J Am Acad Dermatol 1987;16:527-33.
75. Krakowski A, Covo J, Rozanski Z. Pemhigus vulgaris. Arch Dermatol
1969;100:117.
76. Burton JL, Greaves MW, Marks J, Dawber RPR. Azathioprine in pemphigus
vulgaris. Br Med J 1970;3:84-6.
77. Roenigk HH, Deodhar S. Pemphigus treatment with azathioprine. Arch
Dermatol 1973;107:353-7.
78. Krain LS, Landau JW, Newcomer VD. Cyclophosphamide in the treatment of
pemphigus vulgaris and bullous pemphigoid. Arch Dermatol 1972;106:657-61.
79. Fellner MJ, Katz JM, McCabe JB. Successful treatment of cyclophosphamide
and prednisolone for initial treatment of pemphigus vulgaris. Arch Dermatol
1978;114:889-94.
80. Pasricha JS, Sood VD, Minocha Y. Treatment of pemphigus with
cyclophosphamide. Br J Dermatol 1975;93:573-6.
81. Piamphongsant T. Treatment of pemphigus with corticosteroids and
cyclophosphamide. J Dermatol 1979;6:359-63.
82. Ahmed AR, Hombal S. Use of cyclophosphamide in azathioprine failures in
pemphigus. J Am Acad Dermatol 1987;17:437-42.
83. Cummins DI et al. Oral cyclophosphamide for treatment of pemphigus vulgaris
and foliaceus. J AmAcad Dermatol 2003;49:276-80.
84. Ahmed AR, Hombol SM. Cyclophosphamide . J Am Acad Dermatol
1984;11:1115-26.
85. Boumpas DT, Austin HA, Fessler BJ, et al. Systemic lupus erythematosus:
Emerging concepts, 1: Renal, neuropsychiatric, cardiovascular, pulmonary and
hematologic disease. Ann Intern Med 1995;122:940-50.
86. Pasricha JS, Ramji G. Pulse therapy with dexamethasone-cyclophosphamide in
pemphigus. Indian J Dermatol Venereol Leprol 1984;50:199-203.
87. Pasricha JS, Khaitan BK, Raman RS, Chandra M. Dexamethasonecyclophosphamide pulse therapy for pemphigus. Int J Dermatol 1995;34:875-82.
33
CME-CPD on line April 09

88. Kaur S, Kanwar AJ. Dexamethasone-cyclophosphamide pulse therapy in

pemphigus. Int J Dermatol 1990;29:371-4.
89. Fleischli ME, Valek RH, Pandya AG. Pulse intravenous cyclophosphamide
therapy in pemphigus. Arch Dermatol 1999;135:57-61.
90. Pandya Amit G, Sontheimer R. Treatment of pemphigus vulgaris with pulse
intravenous cyclophosphamide. Arch Dermatol 1992;128:1626-30.
91. 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;43:1065-9.
92. Nousari CH, Brodsky R, Anhalt GJ. Evaluating the role of immunoablative
high-dose cyclophosphamide therapy in pemphigus vulgaris. J Am Acad
Dermatol 2003;49;148-50.
93. Shah N, Green AR, Elgart GW, Kerdel F. The use of chlorambucil
withprednisone in the treatment of pemphigus. J Am Acad Dermatol
2000;42:85-8.
94. Thivolet J, Barthelemy H, Rigot Muller G, et al. Effects of cyclosporine on
bullous pemphigoid and pemphigus. Lancet 1985;1:334-5.
95. Lapidoth M, David M, Ben-Amitai D, et al. The efficacy of combined treatment
with prednisolone and cyclosporine in patients with pemphigus: preliminary
study. J Am Acad Dermatol 1994;30:752-7.
96. Barthelemy H, Frappaz, A, Cambazard F, Mauduit G, Rouchouse B, Kanitakis
J, et al. Treatment of nine cases of pemphigus vulgaris with cyclosporine. J Am
Acad Dermatol 1988;18:1262-6.
97. Alijotas J, Pedragosa R, Bosch J, Vilardell M. Prolonged remission after
cyclosporine therapy in pemphigus vulgaris: report of two young siblings. J Am
Acad Dermatol 1990;23:701-3.
98. Mobini N, Padilla T, Ahmed AR. Long-term remission in selected patients with
pemphigus vularis treated with cyclosporine. J Am Acad Dermatol
1997;36:264-6.
99. Chrysomallis F, Ioannides D, Teknetzis A, Panagiotidou D, Minas A.
Treatment of oral pemphigus vulgaris. Int J Dermatol 1994;33:803-7.
100. Enk AH, Knop J. Treatment of pemphigus vulgaris with mycophenolate
mofetil [letter]. Lancet 1997;349:541.
34
CME-CPD on line April 09

101. Enk AH, Knop J. Mycophenolate is effective in the treatment of pemphigus

vulgaris. Arch Dermatol 1999;135:54-6.
102. Nousari HC, Anhalt GJ. The role of mycophenolate mofetil in the
management of pemphigus. J Am Acad Dermatol 1999;135:853-4.
103. Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC.
Treatment of pemphigus vulgaris and pemphigus foliaceous with
mycophenolate mofetil. Arch Dermatol 2003;139:739-42.
104. Powell AM, Albert S, Al Fares S, et al. An evaluation of the usefulness of
mycophenolate mofetil in pemphigus. Br J Dermatol 2003;149:138-45.
105. Bredlich R-O, Grundmann-Kollman M, Behrens S, Kerscher M, Peter RU.
Mycophenolate mofetil monotherapy for pemphigus vulgaris. Br J Dermatol
1999;141:934.
106. Grundmann-Kollman M, Kaskel P, Leiter U, Krahn G, Behrens S, Peter RU,
et al. Treatment of pemphigus vulgaris and bullous pemphigoid with
mycophenolate mofetil monotherapy. Arch Dermatol 1999;135:724-5.
107. Lever WF, Goldberg HS. Treatment of pemphigus vulgaris with methotrexate.
Arch Dermatol 1969;100:70-8.
108. Jablonska S, Chorzelski T, Blaszcyk M. Immunosuppressants in the treatment
of pemphigus. Br J Dermatol 1970;83:315-32.
109. Ryan JG. Pemphigus. A 20-year survey of experience with 70 cases. Arch
Dermatol 1971;104:14-20.
110. Lever WF. Methotrexate and prednisone in pemphigus vulgaris. Therapeutic
results obtained in 36 patients between 1961 and 1970. Arch Dermatol
1972;106:491-7.
111. Smith TJ, Bystryn JC. Methotrexate as an adjuvant treatment for pemphigus
vulgaris. Arch Dermatol 1999;135:1275-6.
112. Penneys NS, Eaglstein WF, Frost F. Management of pemphigus with gold
compounds. A long term follow-up report. Arch Dermatol 1976;112:185-7.
113. Poulin Y, Perry HO, Muller SA. Pemphigus vulgaris: results of treatment with
gold as a steroid-sparing agent in a series of 13 patients. J Am Acad Dermatol
1984;11:851-7.
114. Pandya AG, Dyke C. Treatment of pemphigus with gold. Arch Dermatol
1998;134:1104-7.
35
CME-CPD on line April 09

115. Rotstein H. Gold therapy for pemphigus vulgaris. Australas J Dermatol

1977;18:119-22.
116. Penneys NS, Eaglstein WH, Indgin S, Frost P. Gold sodium thiomalate
treatment of pemphigus. Arch Dermatol 1973;108:56-60.
117. Sutej PG, Jorizzo JL, White W. Intramuscular gold therapy for young patients
with pemphigus vulgaris: a prospective, open clinical study utilizing a
dermatologist/rheumatologist team approach. J Eur Acad Dermatol Venereol
1995;5:222-8.
118. Salomon D, Saurat JH. Oral gold therapy (auranofin) in pemphigus vulgaris.
Dermatologica 1986;172:310-4.
119. Zvaifler NJ. Gold and antimalarial therapy. In: McCarty DJ, editor. Arthritis
and allied conditions: A textbook of rheumatology. 9th ed. Philadelphia (PA):
Lea & Febiger; 1979. pp. 355-64.
120. Basset N, Guillot B, Michel B, Meynadier J, Guilhou JJ. Dapsone as initial
treatment in superficial pemphigus. Arch Dermatol 1987;123:783-5.
121. Piamphongsant T. Pemphigus controlled by dapsone. Br J Dermatol
1976;94:681-6.
122. Haim S, Friedman-Birnbaum R. Dapsone in the treatment of pemphigus
vulgaris. Dermatologica 1978;156:120-3.
123. Bjarnason B, Skoglund C, Flosadottir E. Childhood pemphigus vulgaris
treated with dapsone: a case report. Pediatr Dermatol 1998;15:381-3.
124. Alpsoy E, Yilmaz E, Basaran E, et al. Is the combination of tetracycline and
nicotinamide therapy alone effective in pemphigus? Arch Dermatol
1995;131:1339-40.
125. Chaffins ML, Collison D, Fivenson DP. Treatment of pemphigus and linear
IgA dermatosis with nicotinamide and tetracycline: A review of 13 cases. J Am
Acad Dermatol 1993;28:998-1000.
126. Calebotta A, Saenz AM, Gonzalez F, Carvalho M, Castillo R. Pemphigus
vulgaris: Benefits of tetracycline as adjuvant therapy in a series of thirteen
patients. Int J Dermatol 1999;38:217-21.
127. Gaspar ZS, Walkden V, Wojnarowska F. Minocycline is a useful adjuvant
therapy for pemphigus. Australas J Dermatol 1996;37:93-5.
36
CME-CPD on line April 09

128. Ozog DM, Gogstetter DS, Scott G, Gaspari AA. Minocycline-induced

hyperpigmentation in patients with pemphigus and pemphigoid. Arch Dermatol
2000;136:1133-8.
129. Bystryn JC. Plasmapheresis therapy of pemphigus. Arch Dermatol
1988;124:1702-04.
130. Tan-Lim R, Bystryn JC. Effect of plasmapheresis therapy on circulating levels
of pemphigus antibodies. J Am Acad Dermatol 1990;22:35-9.
131. Guillaume JC, Roujeau JC, Morel P et al. Controlled study of plasma
exchange in pemphigus. Arch Dermatol 1988;124:1659-63.
132. Meurer M, Braun-Falco O. Plasma exchange in the treatment of pemphigus
vulgaris. Br J Dermatol 1979;11:231-2.
133. Auerbach R, Bystryn JC. Plasmapheresis and immunosuppressive therapy.
Effect on levels of intercellurar antibodies in pemphigus vulgaris. Arch
Dermatol 1979;115:728-30.
134. Roujeau JC, Kalis B, Lauret P et al. Plasma exchange in corticosteroidresistant pemphigus. Br J Dermatol 1982;106:103-4.
135. Ruocco V, Astarita C, Pisani M. Plasmapheresis as an alternative or adjunctive
therapy in problem cases of pemphigus. Dermatologica 1984;168:219-23.
136. Turner MS, Sutton D, Sauder DN. The use of plasmapheresis and
immunosuppression in the treatment of pemphigus vulgaris. J Am Acad
Dermatol 2000;43:1058-64.
137. Ljubojevi S, Lipozeni J, Brenner S, Budimi D. Pemphigus vulgaris: a
review of treatment over a 19-year period. J Eur Acad Dermatol Venereol
2002;16:599-603.
138. Ruocco V. Plasmapheresis and pulse cyclophosphamide therapy in pemphigus
vulgaris: a novelty or reappraisal? Arch Dermatol 1988;124:1716-8.
139. Ikonomov V, Samtleben W, Schmidt B et al. Adsorption profile of
commercially available adsorbents: an in vitro evaluation, Int J Artif Organs
1992;15:312-9.
140. Ogata K, Yasuda K, Matsushita M, Kodama H. Successful treatment of
adolescent pemphigus vulgaris by immunoadsorption method. J Dermatol
1999;26:236-9.
37
CME-CPD on line April 09

141. Braun N, Bosch T. Immunoadsorption, current status and future

developments. Expert Opin Investig Drugs 2000;9:2017-38.
142. Schmidt E, Klinker E, Opitz A et al. Protein A immunoadsorption: a novel and
effective adjuvant treatment of severe pemphigus. Br J Dermatol
2003;148:1222-9.
143. Lftl M, Stauber A, Mainka A, Klingel R, Schuler G, Hertl M. Successful
removal of pathogenic autoantibodies in pemphigus by immunoadsorption with
a tryptophan-linked polyvinylalcohol adsorber. Br J Dermatol 2003;149:598605.
144. Shimanovich I, Herzog S, Schmidt E, et al. Improved protocol for treatment of
pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol
2006;31:768-74.
145. Rook AH, Jegasothy BV, Heald P et al. Extracorporeal photochemotherapy
for drug-resistant pemphigus vulgaris. Ann Intern Med 1990;112:303-5.
146. Liang G, Nahass G, Kerdel A. Pemphigus vulgaris treated with photopheresis.
J Am Acad Dermatol 1992;26:779-80.
147. Gollnick HPM, Owsianowski M, Taube KM, Orfanos CE. Unresponsive
severe generalized pemphigus vulgaris successfully controlled by extracorporeal
photopheresis. J Am Acad Dermatol 1993;28:122-4.
148. Wollina U, Lange D, Looks A. Short-time extracorporeal photochemotherapy
in the treatment of drug-resistant autoimmune bullous disease. Dermatology
1999;198:140-4.
149. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with IVIg. J Am Acad
Dermatol 2002;47:358-63.
150. Tappeiner G, Steiner A. High-dosage intravenous gamma globulin: therapeutic
failure in pemphigus and pemphigoid. J Am Acad Dermatol 1989;20:684-5.
151. Humbert P, Derancourt C, Aubin F, Agache P. Effects of intravenous gammaglobulin in pemphigus. J Am Acad Dermatol 1990;22:326.
152. Messer G, Sizmann N, Feucht H, Meurer M. High-dose intravenous
immunoglobulins for immediate control of severe pemphigus vulgaris. Br J
Dermatol 1995;133:1010-8.

38
CME-CPD on line April 09

153. Beckers RCY, Brand A, Vermeer BJ, Boom BW. Adjuvant high-dose
intravenous gammaglobulin in the treatment of pemphigus and bullous
pemphigoid: experience in six patients. Br J Dermatol 1995;133:289-93.
154. Bewley AP, Keefe M. Successful treatment of pemphigus vulgaris by pulsed
intravenous immunoglobulin therapy. Br J Dermatol 1996;135:128-9.
155. Wever S, Zillikens D, Brocker EB. Successful treatment of refractory mucosal
lesions of pemphigus vulgaris using intravenous gammaglobulin as adjuvant
therapy. Br J Dermatol 1996;135:862-3.
156. Colonna L, Cianchini G, Frezzolini A. Intravenous immunoglobulins for
pemphigus vulgaris: adjuvant or first choice therapy. Br J Dermatol
1998;138:1102-3.
157. Jolles S, Hughes J, Rustin M. Therapeutic failure of high-dose intravenous
immunoglobulin in pemphigus vulgaris. J Am Acad Dermatol 1999;40:499-500.
158. Harman KE, Black MM. High-dose intravenous immune globulin for the
treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases.
Br J Dermatol 1999;140:865-74.
159. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients
with pemphigus vulgaris unresponsive to conventional immunosuppressive
treatment. J Am Acad Dermatol 2001;45:679-90.
160. Engineer L, Bohl KC, Ahmed AR. Analysis of current data on the use of
intravenous immunoglobulins in the management of pemphigus vulgaris. J Am
Acad Dermatol 2000;43:1049-57.
161. Rutter A, Luger TA. High-dose intravenous immunoglobulins: an approach to
treat severe immune-mediated and autoimmune diseases of the skin. J Am Acad
Dermatol 2001;44:1010-23.
162. Bystryn JC, Jiao D. Cytotoxic drugs improve the effectiveness of IVIg in
pemphigus. J Invest Dermatol 121:96C (abstr).
163. Sami N, Qureshi A, RuoccoE, Ahmed R. Corticosteroid-sparing effect of
intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch
Dermatol 2002;138:1158-62.
164. Ahmed AR, Dahl MV et al. Consensus statement on the use of intravenous
immunoglobulin therapy in the treatment of autoimmune mucocutaneous
blistering diseases. Arch Dermatol 2003;139:1051-9.
39
CME-CPD on line April 09

165. Dupuy A, Viguier M, Bedane C et al. Treatment of refractory pemphigus

vulgaris with rituximab (anti-CD20 monoclonal antibody). Arch Dermatol
2004;140:91-6.
166. Espana A, Fernandez-Galar M, Lloret P, Sanchez-IbarrolaA, Pnizo C. Longterm complete remission of severe pemphigus vulgaris with monoclonal antiCD20 antibody therapy and immunophenotype correlations. J Am Acad
Dermatol 2004;50:974-6.
167. Morrison LH. Therapy of refractory pemphigus vulgaris with monoclonal antiCD20 antibody (Rituximab). J Am Acad Dermatol 2004;51:817-9.
168. Herrmann G, Engert A, Hunzelmann N. Treatment of pemphigus vulgaris with
anti-CD20 monoclonal antibody (rituximab). Br J Dermatol 2003;148:602-3.
169. Cooper HL, Healy E, Theaker JM, Friedman PS. Treatment of resistant
pemphigus vulgaris with an anti-CD20 monoclonal antibody (Rituximab) Clin
Exp Dermatol 2003;28:366-8.
170. Goh MSY, McCormack C, Dinh HV, Welsh B, Foley P, Prince HM.
Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective openlabel pilot study in five patients. Br J Dermatol 2007;156:990-6.
171. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus
vulgaris with rituximab and intravenous immune globulin. N Engl J Med
2006;355:1772-9.
172. Grando SA. New approaches to the treatment of pemphigus. J Invest Dermatol
Symposium Proceedings 2004;9:84-91.
173. Samadi Z, Gorouhi F, Davari P, Firooz A. Think globally, act locally: Expert
opinions from Asia on the diagnosis and treatment of pemphigus vulgaris. Ind J
Med Sci 2007;61:144-51.

40
CME-CPD on line April 09

Table I. Antigens in pemphigus

Classification of Pemphigus19

Ig

Antigens

Pemphigus vulgaris
Mucosal dominant type

IgG

Dsg 3

Mucocutaneous type

IgG

Dsg 3 + Dsg 1

Pemphigus vegetans

IgG

Dsg 3 + Dsg 1

Pemphigus foliaceus

IgG

Dsg 1

Pemphigus erythematosus

IgG

Dsg 1

Drug-induced pemphigus

IgG

Heterogenous

Shift between pemphigus

Vegetans and foliaceus

IgG

Dsg 1 and/or Dsg 3

Paraneoplastic pemphigus

IgG

Plectin, desmoplakin,
BP230, envoplakin,
periplakin, p170, ,
Dsg 3, Dsg 1, (Dsc)

Endemic pemphigus
Brazilian

IgG

Dsg1 (Dsg3, Dsc 1-3?)

Tunisian

IgG

Dsg 1, Dsg 3

Colombian

IgG

Dsg 1+a

41
CME-CPD on line April 09

Table II. Treatment options for pemphigus

Corticosteroids:
Topical and intralesional, Oral, Pulse therapy
Adjuvants:
1. Immunosuppressive drugs: Azathioprine, Cyclophosphamide, Cyclosporine,
Mycophenolate mofetil, Chlorambucil, Methotrexate
2. Anti-inflammatory drugs: Gold, Dapsone, Nicotinamide and tetracycline
3. Immunomodulatory Procedures:
Plasmapheresis, Staphylococcal protein A immunoadsorption, Extracorporeal
photopheresis, Intravenous immunoglobulin
4. Rituximab

42
CME-CPD on line April 09

Figure legends

Figure 1. Pemphigus vulgaris, cutaneous lesions

Figure 2. Pemphigus vulgaris, oral Lesions
Figure 3. Pemphigus vegetans
Figure 4. Pemphigus foliaceus
Figure 5. Pemphigus foliaceus
Figure 6. Acantholysis within the epidermis (haematoxylin and eosin X200)
Figure 7. Indirect Immunoflurosence: intercellular staining with monkey esophagus
as substrate
Figure 8. Direct Immunofloresence of perilesional skin reveals a netlike intercellular
staining

43
CME-CPD on line April 09