Veterinary Dermatology 2004, 15, 90 98

Pemphigus: current therapy

Blackwell Publishing, Ltd.

WAYNE S. ROSENKRANTZ
Animal Dermatology Clinic, Tustin, CA 92780, USA
(Received 21 January 2003; accepted 6 June 2003)

Abstract Pemphigus is an autoimmune skin disease that can present in a variety of forms and can be a challenging disease to manage and treat. An overview of the different forms of pemphigus and diagnostics are discussed including pemphigus foliaceus (PF), pemphigus erythematosus (PE), panepidermal pustular pemphigus
(PPP), pemphigus vulgaris (PV) and paraneoplastic pemphigus (PNP). Emphasis on therapy is presented.
Included are the most current commonly used therapeutics (glucocorticoids, azathioprine, chlorambucil and tetracycline and niacinamide); current alternative therapeutics (cyclosporin and tacrolimus and mycophenolate
mofetil) and additional alternative therapeutics (cyclophosphamide, chrysotherapy, dapsone, sulfasalazine and
intravenous immunoglobulin (IVIG) therapy).
Keywords: azathioprine, chlorambucil, chrysotherapy, cyclosporin, dapsone, glucocorticoids, mycophenolate
mofetil, pemphigus, tacrolimus, tetracycline and niacinamide.

OVERVIEW OF DISEASE
Pemphigus is an autoimmune vesicobullous to pustular
skin disease that is characterized by acantholysis or loss
of adhesion between keratinocytes. In dogs and cats five
forms are recognized: pemphigus foliaceus (PF), pemphigus erythematosus (PE), panepidermal pustular
pemphigus (PPP), pemphigus vulgaris (PV) and paraneoplastic pemphigus (PNP).13 Pemphigus foliaceus (PF)
is the most common form in dogs and cats (Fig. 1). It
is seen at the authors practices at an incidence of 2% of
referral cases. Clinical lesions are variable and include
pustules, crusts, erosions, ulcers and alopecia. However,
clinical presentations may vary depending on the breed,
triggering factors and the cyclical nature of the disease
itself. Lesions include pustules, crusts, erosions, ulcers
and alopecia. Some cases may remain localized to the
head, face and pinnae, while others may generalize and
develop additional systemic symptoms. The foot pads
can become involved and in some situations lesions can
be limited to the footpads. An idiopathic form is most
commonly seen in chow chows, and akitas. It tends to
present with more generalized lesions often starting on
the face, nasal planum, pinnae and can spread to involve
the entire body. When generalized, limb oedema, fever
and lethargy are common. Pruritus is also more common in the generalized form. Some cases can be triggered by drug reactions or as a result of other chronic
diseases such as allergic dermatitis. The drug-induced
form is more common in the Doberman pinscher and

Correspondence: Wayne S. Rosenkrantz, 2965 Edinger Ave, Tustin,

CA 92780, USA. E-mail: AnDerm1@aol.com
Reprints will not be available from the author.
90

Figure 1. Pemphigus foliaceus in a Chow Chow with classic facial

erosions, ulcers and crusting.

Labrador retriever. Many cases of PF attributed to

chronic disease have often been treated with long-term
drugs and may in reality reflect drug-induced cases.4
Pemphigus erythematosus (PE) is considered to be a
variant of PF is limited to the face and does not generalize. PE can look similar to PF histologically but may
also show an interface dermatitis. This feature coupled
with a combination of immunopathology of both PF
and lupus erythematosus as well as a positive ANA
(antinuclear antibody) test in some cases, make this
form a possible cross over syndrome. However, this is
controversial and may simply represent a localized
form of PF. Collies and German shepherds may be predisposed. Photoaggravation may be a factor in PE.
Pemphigus vulgaris (PV) is a very rare form of pemphigus accounting for less than 0.1% of the referral
2004 European Society of Veterinary Dermatology

Pemphigus: current therapy

cases in a dermatology specialty practice.5 It is the
most severe form of pemphigus and is characterized
by vesicles or blisters that usually ulcerate. The most
common location of lesions is the oral cavity, axilla,
groin, flank, mucocutaneous junctions (lips, nostrils,
eyelids, nail beds, genitals and anus) and foot pads.
These cases may present with marked salivation and
halitosis and are often depressed and anorectic. This
form requires the most aggressive forms of combination
therapy.
Panepidermal pustular pemphigus (PPP) has been
described based on the presence of pustules found at all
levels within the epidermis and follicle epithelium. PPP
may simply represent a variant of PF, PE or pemphigus
vegetans (Hallopeau type) a variant of PV.6 Clinically
there is predominance for facial lesions but generalized
disease can occur. Lesions are short-lived pustules that
rupture and leave a thick adherent crust.
Paraneoplastic pemphigus (PNP) is a very rare form
of pemphigus that has been associated in a limited
numbers of dogs with lymphoma and in one case a
Sertoli cell tumour. Histopathologically, these lesions
appear to be a mixture of PV and erythema multiforme
(EM).7

AETIOLOGY PATHOGENESIS
The aetiology of pemphigus is not known in most
cases. The development of autoantibodies may result
from an abnormal immune regulation or abnormal
antigen stimulation. There is a strong genetic predisposition in both humans and dogs. In humans certain
HLA types and ethnic groups seem to be predisposed
to PF.8,9 Certainly the akita and the chow chow appear
to fall into this category, having PF more frequently
than other breeds. Infectious agents, such as viruses
have been suspected in certain regionalized outbreaks.
Of specific interest is the PF seen in humans in South
America (fogo selvagem) where an insect vector (black
flies), virus or local heat, humidity and tannin decomposition are suspected as predisposing factors.1012 It is
interesting to compare this form of PF in humans with
what is seen in the dog. There are many similarities
between the two when the clinical lesions are compared.4 Drug induced or association with chronic
skin disease has also been reported in humans and
dogs.8,10,13,14 The possibility of ultraviolet light irradiation exacerbating acantholysis also exists.14,15
The exact mechanism for the development of acantholysis is not completely understood. The patients
autoantibodies bind to one of two members of the
cadherin group (cell to cell adhesion molecules). In PF
the binding is to Dsg 1 and to Dsg 3 in PV.16 Calcium
has been shown to be very important for the adhesion
of cadherins.17 The binding of the autoantibody to
the cadherins results in activation of intracellular
pathways, which in turn leads to the disruption of intercellular adhesion. This results in the acantholysis.
There are many different possible causes for this

91

disruption. The release of the protease, urokinase

plasminogen activator (uPA) is thought to convert
plasminogen to plasmin which damages the intercellular adhesion.10,18,19 Complement may be involved
in some cases, but may just be an enhancing factor as
lesions can occur in its absence.20 One of the most current thoughts is a disruption in the regulation of the
assembly and disassembly of the desmosomes by the
binding of the autoantibodies.1

OVERVIEW OF DIAGNOSTIC METHODS

The hallmark of the pemphigus complex is the histological presence of acantholysis. In PF either intraepidermal or intrafollicular acantholytic pustules are
present. These pustules are most common in the corneal, granular or upper spinous cell layers. In PE subcorneal to intraspinous acantholytic pustules are also
present, but a lichenoid-interface dermatitis is usually
present. In PV the acantholysis is at the suprabasalar
level which can occur in the oral mucosa, epidermis or
follicular outer root sheath. In PPP intraepidermal
pustules can be seen at all levels of the epidermis and
follicular outer root sheath down to the level of the
suprabasal layer. Eosinophils may be more abundant
in this form. In PNP there are similar changes as seen
with PV, but in addition to the suprabasal cleft formation, apoptotic cells and vacuolar degeneration is
present.
Immunopathology, both direct and indirect immunofluorescence, has improved tremendously and has not
only aided in the diagnosis of pemphigus but the
pathogenesis of the disease. In many cases, antikeratinocyte autoantibodies can be demonstrated. However,
immunopathology should always be correlated with
the clinical and routine histopathology findings. In PF
the pattern of immunofluorescence is chicken-wire
involving all of the suprabasal layers.1 The autoantibodies are usually of the IgG type with some cases
having IgA and IgM. Complement may sometimes be
present. In the dog, desmoglein 1 (Dsg 1) 150 kDa is
the autoantigen that is targeted.1 In PE, the antikeratinocyte fluorescence is the same as in PF, however,
there is a linear deposition of immunoglobulins and/or
complement similar to what is seen in lupus erythematosus. A positive ANA can also be detected in 50% of
cases.21 In PV there is also membrane fluorescence of
the keratinocytes of all suprabasal epidermal layers,
which may extend to the basal cell membranes.21 The
major PV antigen in the dog is desmoglein 3 (Dsg 3)
130 kDa.19 The immunopathology of PPP is identical
to that of PF and PNP is the same as PV.
Other clinicopathology includes the presence of
acantholytic cells on routine cytology and variable
changes on complete blood counts and chemistry laboratory screens. Many pemphigus cases can have moderate to marked leukocytosis and neutrophilia, mild
nonregenerative anaemia, mild hypoalbuminemia and
mild elevations in globulins.

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W. S. Rosenkrantz

CURRENT TREATMENTS
Therapy for all forms of pemphigus requires immunosuppressive or immunomodulating drugs. There are
variable responses to treatment with the different
forms of pemphigus recognized. As a result it is essential that a diagnosis be made.
Even with a specific diagnosis there appears to be
some controversy regarding the treatment success and
the ultimate long-term prognosis of canine pemphigus.
In general, PV tends to be a more aggressive disease
and more difficult to treat and manage. Despite treatment many cases may still die. PF tends to warrant a
better prognosis but in a recent report only 17/43 cases
(39.5%) were alive at the end of a 6-year study. Of the
dogs that had died, 92% were dead by 1 year into treatment. Of these cases, 87% were euthanized because of
drug side effects.22 These results are different from
what is seen at the authors practices. Currently, a largescale retrospective PF study is being conducted at the
authors practices. An initial review of 31 cases with
follow-up ranges from 1 to 5 years and a mean of
2.7 years, showed a survival rate of 22/31 (71%). Of the
9 cases (29%) that had died, 4/9 (44%) were euthanized
at the end of 1 year because of either poor response to
therapy (2/4) or discontinuation of medications and
subsequent relapse after the owners discontinued
drugs (2/4). The remaining 5/9 cases died because of
unrelated problems; heart disease (2), renal disease (1),
arthritis (1), old age (1). Many specialists and researchers consider PE, PEP and P vegetans benign variations
of pemphigus that usually respond well to treatment
and have less overall systemic manifestations.1,8
The author divides therapy into three categories:
common therapeutics, current alternative therapeutics
and additional alternative therapeutics.

COMMON THERAPEUTICS
Glucocorticoids
More localized forms of PF and PE can be treated with
topical glucocorticoids. Occasionally, the author uses
topical therapy in conjunction with systemic therapy
on more persistent focal areas that remain active
despite systemic treatment. When utilized a potent glucocorticoid is often needed initially and then if adequate response is seen switching to a less potent topical
glucocorticoid is recommended. The author likes 0.1%
amcinonide cream (Cyclocort, Lederle), fluocinonide
0.05% cream (Lidex, Dermik) or 0.015% triamcinolone acetonide solution (GENESIS, Virbac) used
daily for 7 days then EOD for 7 days and if an adequate response is seen switching to a 12% hydrocortisone cream or ointment (Hytone, Dermik and other
generics) on an as-needed basis is recommended. Some
1% hydrocortisone gels and sprays may also be helpful
in long-term management (Corticalm, Cortispray
DVM Pharmaceuticals, Resicort, Virbac). Persistent
use (daily for 14 days or longer) of more potent topical

glucocorticoids can create atrophy, alopecia and localized pyoderma. Systemic absorption by percutaneous
absorption or ingestion via licking is also a major concern. Iatrogenic hyperadrenocorticism has been well
documented with potent glucocorticoids.23,24 The most
common form of therapy used in pemphigus management is systemic glucocorticoids. In the authors specialty referral practices, 35% of the PF cases are
adequately controlled with only glucocorticoid therapy. There are unlimited mechanisms as to why glucocorticoids are effective but it primarily relates to their
profound effects on the humoral and cell-mediated
immunity, phagocytic defences, and inhibition of
inflammatory mediators and suppression of autoantibody levels.25,26 Which form of oral glucocorticoid
therapy is selected depends on the individual case
response and the side effects seen in that particular
patient. Most commonly, prednisone or prednisolone
is utilized at immunosuppressive dosages. Initial
dosages at 2.24.4 mg kg1 every 24 h can be used. If a
response is seen within 1014 days this dosage is
reduced gradually on a daily basis over 3040 days and
then lowered to an alternate day basis with the ultimate
goal of dosing at 1 mg kg1 every 48 h or less. The
author prefers methylprednisolone (Medrol, Pfizer)
to prednisone or prednisolone due to the reduced
mineralcorticoid effects resulting in less polyuria and
polydipsia. In addition, there are some cases that will
respond more favourably to methylprednisolone than
prednisone or prednisolone. The dosing and tapering
regime is the same as for prednisone or prednisolone.
Oral triamcinolone (Vetalog, Fort Dodge) or oral dexamethasone (Azium, Schering-Plough and generics)
are alternative glucocorticoids that can be utilized in
more refractory cases or in cases that have profound
polyuria and polydypsia or other behavioural or personality changes. These glucocorticoids are considered
to be 610 times more potent than prednisone or
prednisolone. Starting immunosuppressive dosages for
these drugs range from 0.2 to 0.6 mg kg1 every 24 h
for triamcinolone and 0.20.4 mg kg1 every 24 h for
dexamethasone. As with prednisone therapy these
dosages need to be reduced gradually and eventually
tapered to an every 4872 h basis. As these glucocorticoids suppress the hypothalamicpituitaryadrenal
axis for 2448 h, it is optimal to give these drugs every
72 h for maintenance. However, the author has had
many cases do very well long-term on an every 48 h
basis as maintenance. Maintenance dosages range from
0.1 to 0.2 mg kg1 every 4872 h for triamcinolone and
0.050.1 mg kg1 every 4872 h for dexamethasone.
In severe cases of pemphigus foliaceus or vulgaris,
the author has, on occasion, given shock dosages of
prednisolone sodium succinate (10 mg kg1 IV) or dexamethasone (1 mg kg1 IV).4 This can be performed as
a one time treatment or given two days consecutively.
This can be followed with a modification of other oral
glucocorticoid therapy. This form of therapy has a
higher incidence of gastrointestinal ulceration, in particular gastric haemorrhage. Concurrent use of gastric

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 90 98

Pemphigus: current therapy

protectants is usually recommended when this form of
therapy is utilized.
Side effects are common with long-term oral glucocorticoid therapy. The most common seen include:
poor dull scaly hair coats, muscle atrophy, polyuria,
polydipsia, polyphagia, weight gain, behavioural
changes, panting and increased risk of infection. Secondary bacterial skin and bladder infections are common. Demodicosis and dermatophytosis are also more
frequent in dogs on chronic glucocorticoid therapy.
Ongoing cases that flare during their course of management should always be rechecked and screened for
these secondary opportunistic infections. Other skin
changes include atrophic skin, calcinosis cutis,
atrophic scars, comedones and milia follicular cysts.
Less common side effects include: gastrointestinal
ulcerations, diarrhoea, and pancreatitis. Steroid hepatopathy is a major concern and is one of the most
important organs to monitor in long-term cases. Other
endocrine concerns include the development of diabetes mellitus, adrenal gland suppression and reduced
thyroid hormone production.
Monitoring should include semi-annual complete
blood counts, chemistry profiles, urinalysis and urine
cultures. If cases are nonresponsive to glucocorticoids,
fail to control on safe alternative day to every 72 h dosing or have undesirable side effects, alternative or concurrent immunosuppressive drugs are indicated.
Azathioprine therapy
Azathioprine (Imuran, Glaxo Wellcome and generics)
is the authors favourite and first choice immunosuppressive to use in canine pemphigus cases. The author
has not seen any differences with brand name or
generic therapy. It can be used as a glucocorticoidsparing agent in cases when glucocorticoids cannot be
reduced to safe long-term levels, used in combination
with glucocorticoids or other immunosuppressives in
more refractory cases, or as a sole therapy (Figs 2, 3).
It is generally contraindicated in cats due to its more
profound myelosuppression and potential for fatal
reactions in cats. It is dosed at 1.52.5 mg kg1 every
2448 h. It is available is a 50 mg scored tablet. It is an
antimetabolite that interferes with the synthesis of
nucleic acids and is cytotoxic to T cells. It has its greatest effect on T-cell-dependent antibody synthesis. It
has a slow onset of action and usually takes 48 weeks
to see clinical effects. Adverse reactions primarily
include myelosuppression (lymphopenia, anaemia and
leukopenia) diarrhoea and increased susceptibility to
opportunistic infections when used long-term (pyoderma, demodicosis and dermatophytosis) (Fig. 4).
The diarrhoea that can be seen usually responds to
dosage reduction, although it can be severe (haemorrhagic) and require drug discontinuation. Less common complications include vomiting, hepatotoxicity
and possible pancreatitis. A rare azathioprine induced
hepatotoxicity can be seen that usually responds to
drug withdrawal.4 Dosage adjustments can be made
based on the results of lab monitoring and clinical

93

Figure 2. Poorly responsive case of generalized pemphigus foliaceus

to glucocorticoids.

Figure 3. Same case as Fig. 2 after 8 weeks of azathioprine and

glucocorticoid dose reduction.

Figure 4. Secondary demodicosis and dermatophytosis from immunosuppression associated with azathioprine therapy.

improvement. Starting at the lower end of the dosage

range is generally recommended. Increasing the dosage
after subsequent rechecks and lab monitoring can be
performed as the case progresses. Complete blood
counts with platelet counts are recommended every

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W. S. Rosenkrantz

23 weeks for the first 3 months of therapy. Initially

periodic (every 23 months) monitoring of chemistry
profiles is also recommended. Once cases are in remission monitoring can be reduced to every 6 months.
Chlorambucil
Chlorambucil (Leukeran, Glaxo Wellcome) is an
alkylating agent that functions by affecting the crosslinking of DNA. It is considered less toxic and slower
acting than other alkylating agents. It is dosed at 0.1
0.2 mg kg1 every 2448 h. It is available in a 2 mg nonscored coated tablet, making dosing in small dogs and
cats easier. Myelosuppression is a concern and similar
monitoring as listed with azathioprine should be performed. Other side effects include vomiting, diarrhoea
and anorexia.27 The author uses chlorambucil in the
canine as a glucocorticoid-sparing drug, as an alternative to azathioprine, in combination with glucocorticoids and azathioprine in more refractory cases or as a
sole therapy in cases not tolerating other therapies. It is
also the authors drug of choice in feline pemphigus
when glucocorticoids do not work or are not tolerated.
Tetracycline and niacinamide
The combination of tetracycline and niacinamide has
been used with variable success in dogs and humans
with pemphigus.28,29 The author commonly uses this
therapy but usually finds it an adjunctive therapy at
best for the pemphigus complex. It may be more successful in localized cases such as pemphigus foliaceus
limited to the face or pemphigus erythematosus. Tetracycline has anti-inflammatory properties affecting
complement activation, antibody production, chemotaxis, prostaglandin synthesis, lipases and collagenases.
Niacinamide inhibits mast-cell degranulation and
phosphodiesterase. Adverse reactions include vomiting, diarrhoea, anorexia and increased liver enzymes.
When gastrointestinal complications occur, discontinuing the niacinamide may reduce or eliminate these
problems. In rare cases the tetracycline may still produce beneficial results. The dosage recommendations
are 500 mg of each drug every 8 h for dogs weighing
> 10 kg and 250 mg every 8 h for dogs weighing
< 10 kg. Clinical response may take 12 months. If
clinical response is seen the frequency can be reduced
to twice or even once daily.

tacrolimus is much more potent and the oral formulations appear toxic in the canine. Currently, due to the much
greater potency and potential toxicity of tacrolimus and
lack of adequate dosing regimes, systemic administration is not recommended in canine clinical cases. Both
drugs become activated by binding to specific intracellular receptors, called immunophilins. Cyclosporine binds
to cyclophilin and tacrolimus binds to FK506-binding
proteins. Both drugs inhibit calcium-dependent pathways, particularly affecting the enzymatic actions of
calcineurin, a calmodulin-dependent protein phosphatase.
This results in blocking of regulatory proteins that
up-regulate activation genes of T-helper inducer and
cytotoxic cells. Of the cytokines affected interleukin-2
(IL-2) is most notably affected, although many other
cytokines are affected.32,33 The initial studies of cyclosporin in the treatment of pemphigus and other cutaneous autoimmune diseases has not been impressive
and only limited responses have been seen. 34 However, these early studies utilized older formulations of
cyclosporin. The author has seen some more recent
responses utilizing the microencapsulated formulation
(Atopica and Neoral, Novartis). It is dosed at 5
10 mg kg1 every 24 h with ketoconazole 5 mg kg1 every
24 h. It is also common to use cyclosporin in conjunction with oral glucocorticoids. However, it may be used
as a sole agent or as a glucocorticoid-sparing agent
(Figs 5, 6). Cyclosporine is also available as a topical
0.2% ointment (Optimmune, Schering-Plough). The
author and his associates have seen some adjunctive
effects utilizing this ointment for localized forms of
pemphigus. Even more impressive are the responses seen
from the topical administration of 0.1% tacrolimus.
In a recent study at the authors practice 10 cases of
discoid lupus erythematosus (DLE) and 2 cases of PE
were treated. Eight of the 10 dogs of DLE and both PE
cases improved with therapy. In 6/8 cases no other
medications were used except the topical tacrolimus.
No adverse reactions were noted in any of the cases.35

CURRENT ALTER NATIVE

THERAPEUTICS
Cyclosporine and tacrolimus
Cyclosporine (Atopica and Neoral, Novartis) and
tacrolimus (Prograf oral formulation and 0.03 and 0.1%
Protopic topical preparation, Fujisawa USA, Inc.) are
immunosuppressant agents that have been used extensively in human medicine, primarily to prevent organ
transplant rejection.30,31 However, these drugs have
also been evaluated for the treatment of autoimmune
diseases. Both of these drugs work similarly, however,

Figure 5. Pre-cyclosporin therapy in a case of pemphigus

erythematosus.

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Pemphigus: current therapy

Side effects seen with cyclosporin most commonly
include anorexia, vomiting or diarrhoea. More serious
side effects are rarely seen. Other side effects reported in
limited cases include weight loss, nephrotoxicity, gingival
hyperplasia, papillomatosis, hirsutism and involuntary
shaking.34,36 Drugs which inhibit the hepatic microsomal isoenzyme P450 system, increase blood
cyclosporin levels thus ketoconazole is commonly used
concurrently with cyclosporin. It allows for a lower
cyclosporin dosage and thus cost, making cyclosporin
more cost effective. Severe side effects have been seen in
dogs with oral tacrolimus as a sole or combined therapy.
These side effects include anorexia, vomiting, diarrhoea,
weight loss, impaired glucose metabolism, marked hepatotoxicity and infections.37,38 Other side effects seen in
humans include nephrotoxicity, neurotoxicity and hypertension.37 The topical preparation appears very safe in
the cases treated the authors practice and no side
effects have been seen.35 Monitoring serum levels of
both cyclosporin and tacrolimus have been evaluated.
In the authors experience the serum levels of cyclosporin
generally do not correlate with clinical responses.
However, there may be some limited value to monitor
these levels when clinical responses are not seen. If levels are still in the low therapeutic range dosages could
be increased in an attempt to obtain a response. When
topical tacrolimus therapy was utilized in the authors
practice, there was no correlation with serum or whole
blood tacrolimus levels and clinical improvement or
adverse clinical effects or laboratory abnormalities.35
Mycophenolate mofetil
Mycophenolate mofetil (CellCept, Roche Pharmaceuticals) is a new drug that inhibits de novo purine (guanine) synthesis. B and T lymphocytes are dependent
upon guanosine synthesis because they are unable to
use the salvage guanosine synthesis pathway. This unique
aspect of lymphocytes allows mycophenolate mofetil

Figure 6. Twelve weeks post cyclosporin therapy in a case of

pemphigus erythematosus.

95

to inhibit the proliferation of lymphocytes and the production of antibodies relatively selectively with minimal effects on other tissues. In humans it has been used
in a variety of autoimmune skin diseases. The main
side effects include bone marrow suppression, nausea,
vomiting, diarrhoea and an increased incidence of
infections. It does not have significant renal or hepatic
toxicity. Canine studies show success rates of 50%
with some dogs weaned off prednisone completely,
whereas others have relapsed when the glucocorticoids
were dropped too low. Dosages ranged from 22 to
39 mg kg1 every 24 h divided every 8 h. Side effects
were minimal but the most common included pyoderma and malassezia, diarrhoea and leukocytosis.
Expense is a limiting factor as a 23 kg dog will require
therapy costing US$10 per day.39,40

ADDITIONAL ALTER NATIVE THERAPY

Cyclophosphamide
Cyclophosphamide (Cytoxan, Bristol Myers) is another
alkylating agent. It is considered very potent and can
be used individually or in conjunction with glucocorticoids and chlorambucil. It is available in 25 or 50 mg
tablets. The dosage is 1.5 mg kg1 every 48 h. The author
does not routinely use this drug due to the potential for
haemorrhagic cystitis and because of the effectiveness
of other therapies.
Chrysotherapy
Chrysotherapy is the use of gold as a sole or adjunctive therapy. It has immune-modulating and antiinflammatory effects but its exact mechanism of action
is not known.4,27 Gold is available in two forms, an oral
formulation auranofin (Ridaura, SmithKline Beecham)
and an injectable form. Only one of the injectable
forms is still commercially available sodium aurothiomalate (Myochrysine, Merck). The older form of
injectable gold, aurothioglucose (Solganal, Schering) is
no longer available. It is this form that most specialists
had experience with. The author found aurothioglucose to be quite effective in feline pemphigus as a sole
or combination therapy with glucocorticoids. The
author considered success in canine pemphigus poor.
When utilized it was dosed at 1 mg kg1 intramuscularly once a week. It had a long lag phase and some
cases would not respond for 1016 weeks. Once remission was obtained the dosage could be reduced to
monthly or in some cases of feline pemphigus, discontinued completely with remission maintained. The
author has not used the alternative injectable gold,
sodium aurothiomalate and no published reports exist
on its effectiveness in canine or feline pemphigus. The
author has limited experience using the oral formulation, auranofin, however, others have reported some
success using 0.050.2 mg kg1 every 12 h.41 The toxic
effects in humans are a concern with one-third of the
patients having some type of reaction, although the
majority are minor. The most common include skin

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W. S. Rosenkrantz

rashes, oral ulceration, proteinuria and bone marrow

depression. In dogs and cats reactions are limited but
can include bone marrow depression, oral ulcers,
glomerulonephropathy and one report of fatal toxic
epidermal necrolysis when two dogs were immediately switched from azathioprine to aurothioglucose.42
Eosinophilia may precede the development of the
cutaneous drug reactions. Monitoring should include
complete blood counts with platelet counts every 2
3 weeks for the first 4 months of therapy and then
quarterly to semi-annually thereafter. Periodic chemistry profiles and urinalysis should also be performed
initially every 46 weeks during the first 4 months of
therapy and then every 6 months thereafter.
Dapsone and sulfasalazine
Dapsone (Dapsone, Jacobus) and sulfasalazine (Azulfidine,
Pharmacia) have been used either as sole therapies or
in combination with glucocorticoids in cases of canine
pemphigus.27,43 Dapsone decreases complement activation, antibody production, lysosomal enzyme synthesis
and neutrophil chemotaxis. It is dosed at 1 mg kg1
every 8 h and should only be used in dogs. Cats have
increase sensitivity to dapsone with higher incidence of
haemolytic anaemia and neurotoxicity. Side effects
include anaemia, neutropenia, thrombocytopenia, hepatotoxicity, gastrointestinal signs, neuropathies and cutaneous drug eruptions. It has a lag phase of 48 weeks.
Monitoring complete blood and platelet counts, chemistry profiles and urinalyses every 23 weeks for the
first 4 months is recommended. After 4 months
monitoring can be reduced to every 34 months.
Sulfasalazine is converted in the colon to sulfapyridine
5-aminosalicylate which has anti-inflammatory properties. It is dosed at 1040 mg kg1 every 8 h. It may be
more effective in cases of pemphigus that are more neutrophilic. A severe side effect is the development of
keratoconjunctivitis sicca. Tear production should be
monitored every 2 4 weeks. Blood counts and chemistry
profiles should be checked initially every 2 weeks for
the first 6 weeks and then tapered to every 24 months.
Human Intravenous Immunoglobulin (IVIG) Therapy
High dose intravenous immunoglobulins (IVIgs) have
been used in human immune-mediated and autoimmune
diseases as an alternative or adjuvant therapy. They have
also been used in canine primary immune-mediated
haemolytic anaemia (IMHA). In a study of 10 dogs with
primary IMHA that had failed to respond to conventional
immunosuppressive therapy, 5 of the 10 dogs had clinically
significant responses. However long-term survival was
not improved compared with conventional therapy.44
More detailed reviews of IVIgs exist for human autoimmune diseases showing the treatment to generally
be safe and without many of the drug-related adverse
effects including immunosupression.45 One report showed
sustained remissions in 21 human patients with pemphigus vulagaris who previously had not responded to
prolonged oral prednisone and multiple other forms
of immunosuppressive therapy.46

IVIg is a sterile, high purified IgG preparation made

from pooled human plasma and typically contains
more than 95% unmodified IgG. It has a functionally
intact Fc-dependent effector function and only contains trace amounts of IgA and IgM. There are numerous immunomodulatory properties, most are mediated
by the Fc portion of the IgG. Some of the postulated
mechanisms include: functional blockade of Fc receptors, elimination of circulating immune complexes,
anti-idiotypic suppression of autoantibodies, inhibition of complement mediated damage, modulation
of cytokines, regulatory effects on cellular immune
response and blockade of cell surface death receptor
Fas and its specific ligand.45
IVIg should be given at 1 g/kg intravenously during
a 612 hour period once or can be given two days
consecutively. It is possible that this therapy could be
repeated monthly as it is used in humans but this has
not been fully evaluated in the canine. Since there is no
commercial canine immunoglobulin available human
products are used. There are many products commercially available but the author is only familiar with
Sandoglobulin (Sandoz, East Hanover, NJ, USA) a
6% solution. The safety of this form of therapy is not
completely evaluated in the canine but it appears to be
safe in the limited number of cases treated and is very
safe in humans. Mild side effects reported in humans
include: headache, myalgia, flushing, nausea, blood
pressure changes and tachycardia usually in the first
hour of administration. Severe anaphylactic reactions
may occur in patients with IgA deficiency. Sugar additives such as sucrose, maltose and glucose are often
added to stabilize the immunoglobulin preparations
and there are rare reports of acute renal failure related
to these sugars.45,46
Relapsing or Refractory Cases
A small number of cases will present as a therapeutic
challenge. Often these have been on traditional modes
of therapy, and have either failed to respond or have
had adverse reactions to these forms of therapy. When
dealing with such cases, switching the type of glucocorticoid therapy, may obtain a response. If this fails,
trying aggressive glucocorticoid shock intravenous
therapy can also be of value. This is often combined
with a different immunosuppressive or alternative
therapy as listed above. If these treatment options fail
trying some of the additional alternative therapies
should be discussed with the owner. Unfortunately
there will be a number of cases that will be euthanized
due to limited response, side effects from drugs or simply
financial restraints.

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Rsum Les pemphigus sont des dermatoses auto-immunes qui peuvent se prsenter sous des formes cliniques
multiples et reprsenter un challenge diagnostique et thrapeutique. Cet article prsente une revue des diffrentes
formes de pemphigus, notamment le pemphigus foliaceus (PF), le pemphigus erythematosus (PE), le pemphigus
panpidermique pustuleux (PPP), le pemphigus vulgaris (PV) et le pemphigus paranoplasique (PNP). Le traitement est dcrit en dtail en insistant sur les thrapeutiques les plus souvent utilises (glucocorticoides, azathioprine, chlorambucil et ttracycline et niacinamide); les alternatives actuelles (cyclosporine et tacrolimus et
mycophenolate mofetil) et dautres alternatives comme la cyclophosphamide, la cryothrapie, la dapsone et la
sulfasalazine.
Resumen El pnfigo es una enfermedad cutnea autoinmune que puede presentarse con una variedad de formas
y puede presentar dificultades de tratamiento. Se discuten los diferentes tipos y el diagnstico de pnfigo foliceo
(PF), pnfigo eritematoso (PE), pnfigo panepidrmico pustular (PPP), pnfigo vulgar (PV) y pnfigo
paraneoplsico (PNP). Se hace un especial hincapi en la terapia. Se incluyen las terapias ms frecuentemente
empleadas en la actualidad (glucocorticoides, azatioprina, clorambucil y tetraciclina y niacinamida); terapias
alternativas actuales (ciclosporina y tacrolimus y mofetil micofenolato) y terapias adicionales alternativas
(ciclofosfamida, crisoterapia, dapsona y sulfasalazina).
Zusammenfassung Pemphigus ist eine autoimmune Hauterkrankung, die in einer Vielzahl von Formen
vorhanden sein kann und schwierig zu handhaben und behandeln ist. Es wird ein berblick ber die verschiedenen Formen von Pemphigus, wie Pemphigus foliaceus (PF), Pemphigus erythematodes (PE), panepidermaler pustulrer Pemphigus (PPP) Pemphigus vulgaris (PV) und paraneoplastischer Pemphigus (PNP) und
deren Diagnose gegeben. Dabei wurde ein besonderer Schwerpunkt auf die Therapie gesetzt. Miteinbezogen
wurden die gebruchlichsten Therapeutika (Glukokortikoide, Azathioprine, Chlorambucil, und Tetrazyklin
und Niacinamid), gngige alternative Therapeutika (Cyclosporin, Tacrolimus and Mycophenolat mofetil) und
andere alternative Therapeutika (Cyclophosphamid, Chrysotherapy, Dapson und Sulfasalazin).

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 90 98